Clinical Bacteriology by DR Agwu Ezera

1
A Handbook of Medical Microbiology
Volume 1
Bacteriology and Mycology
Agwu Ezera, Ph.D, FSAFRI Senior Lecturer of Medical Microbiology & Parasitology Dean, School of Allied Health Sciences Kampala International University, Western Campus Box 71, Bushenyi, Uganda
A Handbook of Medical Microbiology by Dr Ezera Agwu
Table of contents 1. Infections of the Gastrointestinal Tract 2. Blood & Lymphatic System infections 3. Central Nervous System 4. Cardiovascular System infections 5. Soft Tissue and Skin infections 6. Respiratory System infections 7. Genital tract infections 8. Urinary tract infections
pages 3 30 40 51 56 74 102 112
1a. Bacteria infections of the Gastro-Intestinal Tract (GIT)

Overview of Bacterial GIT Infections Introduction The walls of the Gastro-Intestinal Tract GIT are lined with different epithelial cells good at transmembrane secretion, absorption and maintainance of intact mucosal surface and resident immune cells which protects the host from microbial pathogens and mutagens. The GIT is like a tube through which all of the liquid and solid material we ingest pass. The ingested material (food, water, drugs etc) may contain bacteria, which tend to colonize those parts of the tube (GIT) that offer a suitable environment for growth. After birth, normal flora come to reside in each part of the GIT. Each end of the tube is heavily colonized while the central part of the tube, are lightly colonized. Each portion of the GIT has special anatomic, physiological and biochemical barriers to infection by normal flora or pathogenic microorganisms. When microorganisms or their toxins breach these barriers they cause different diseases. Infection Barriers of the GIT a. Unbroken mucosal epithelium: This covers all parts of GIT. If the sloughing process of normal epithelial cells is interfered with (as is the case in radiation therapy or cancer chemotherapy), pathogens can form foci of infection and there may be mucosal ulceration resulting to nausea and vomiting. b. Glycocalyx: This is a glycoprotein and polysaccharide layer that covers the surface of the epithelial cells. This presents a thick physical barrier and a chemical trap that binds microorganisms c. Mucous: The mucous plays two roles in disease prevention; it acts as a physical barrier making it harder for the bacteria to access the epithelial cell surfaces and it coats the bacteria, making it easier to remove them via peristalsis. d. Acidity of the stomach: The normal pH of the stomach is less than 4. This acidity spills into the small intestine establishing a pH gradient that prevents most bacteria from colonizing the stomach, duodenum, jejunum and upper half of the ileum. Alteration of the acid barrier of the stomach by disease, surgery, drugs or antacids increases the survival rate of pathogens and can result in infections e. Bile: Bile solubilizes lipids. It can also inactivate organisms that have a lipid envelope. Many bacteria are prevented from growing in areas of high bile salts. f. Immunoglobulin A. Secretary IgA helps prevent microbial colonization of mucosal surfaces and so reduce their chance of disease establishment g. Gut motility (peristalsis): This has the following advantages: o Aid in the fluid absorption o Maintain appropriate dilution of indigenous enteric microflora. o Hinders microbial adherence to receptors on the epithelial cell surface
4 h. Peyer's patches: These are whitish unencapsulated patches of lymph follicles in the mucosa and sub-mucosa, which provide a homing site for lymphocytes. There is non-specific lymphocyte trafficking through the Peyer's patches; about 1-2% of the lymphocyte pool re-circulates each hr forming a ready source of WBC i. Normal flora: Of the normal microflora 99.9% are anaerobes. They are mainly members of the genera Bacteroides, Prevotella, Clostridium, and Peptostreptococcus. The remaining organisms are aerobes or facultative cells of the genera Escherichia, Proteus and Pseudomonas. The normal non-pathogenic flora competes with pathogens for nutrients and intestinal receptor sites Risk factors of GIT infection a. Ingestion of antacids neutralizes stomach and upper intestinal acidity and allows microorganisms to proliferate. b. Antibiotic therapy destroys the normal flora and reduces competition that pathogens are normally subjected to. c. Glucosteroid therapy reduces the immune reaction. d. Cancer chemotherapy reduces the normal flora and the cellular and humoral immunity as well as the intestinal epithelium integrity e. Radiation therapy f. Ingestion of pre-formed toxins with food and/or water or E. coli, Shigella, Salmonella etc that produce toxins/enzymes/ in situ h. Anatomic alterations. Intestinal obstructions to the flow of liquids, stones in the gallbladder, presence of large diverticula or the surgical formation of intestinal blind loops leading to bacterial overgrowth Epidemiology of GIT infection Nearly all persons have had dental caries sometime in their life. Most people have at least one case of diarrhea each year. Children have average 2-3 episodes of diarrhea in a year. Diarrhea is the most common cause of death in the developing world. Most of the time these diseases are self-limiting and people do not go to their physician unless their symptoms become severe or chronic. Pathogenesis of GIT infection Pathogenesis depends on the site infected or intoxicated. Two basic mechanisms used by infectious agents in causing disease includes: toxin production, when ingested will cause symptoms (Staphylococcus aureus-enterotoxin, and botulism toxins) called intoxication and actual infection of and/or destruction of the host cells. Some pathogens only attach to the surface of the epithelial cells and produce toxins that then cause cell damage and/or death (ETEC). This results in a watery diarrhea without inflammatory cells or blood in the stools. Others after attaching go into the cells and damage them (Campylobacter, Shigella, Salmonella). Depending on how deep the infection goes, the symptoms can vary from being a watery diarrhea-(Vibrio), bloody mucus covered stool (dysentery by Shigellosis), to invasion of the bloodstream (enteric fever; Salmonella typhi). Symptoms occur 24-72 hours following ingestion and generally resolve in 2-7 days (except enteric
5 fevers). Some gastrointestinal pathogens can cause chronic infections that remain with the host for months to years (Helicobacter pylori, Giardia lamblia) or a lifetime (Hepatitis B virus, Herpes Simplex virus). Manifestations of GIT infection: Mouth: Various lesions, dental cavities, tooth pain/sensitivity to hot and/or cold, bleeding gums, petechia, facial pain and/or swelling, abscesses, cellulitis. Salivary glands: jaw pain when swallowing, swelling under jaws. Esophagus: dysphagia (difficulty in swallowing), odynophagia (painful swallowing; unique to infectious causes of esophagitis), heartburn, atypical chest pain, regurgitation. Stomach: vomiting, epigastric pain that occurs 90 min to 3 hours after eating; eating relieves the pain; belching, indigestion, heartburn. Small intestines: large volume watery diarrhea, sometimes fatty stools, increased bowel sounds, cramps, diffuse abdominal pain, no guarding or rebound tenderness, rarely has white blood cells in stool. Large intestines: small volume bloody diarrhea with mucus in it (dysentery), cramps, diffuse abdominal pain, rarely any guarding or rebound tenderness, frequently has white blood cells in stool, fever. Liver: upper right quadrant pain of the abdomen, fever, icterus, clay-colored stools, dark urine Gallbladder (cholecystitis and cholangitis): Jaundice, right upper quadrant pain, high fever, chills. Peritoneum: sharp localized abdominal pain aggravated by motion, fever, chills, constipation, and abdominal distension; decreased bowel sounds, guarding, and rebound tenderness. Diagnosis of GIT infection This depends on the disease and where it is located in the systems. Laboratory examination A. Stool 1. Gross macroscopic examination (watery, mucoid or bloody) 2. Microscopic examination for conditions which may influence microbial infection and/or colonization of the gastrointestinal tract a. Fecal WBC detection by methylene blue staining- noninflammatory reaction-vs-inflammatory reaction. b. Sudan stain for fat globules (large fat globules indicates malabsorption). c. Eosin stain (stains undigested muscle fibers, indicating pancreatic insufficiency and maldigestion) d. pH (acidic pH indicates lactose intolerance in children) - normal pH is greater than 7. e. Copper sulfate reaction - presence of reducing sugars indicates carbohydrate malabsorption. f. Occult blood test. g. Culture for enteric pathogens B. Blood culture for septicemia C. Serological Tests (e.g., typhoid fever, amebiasis)
6 D. Toxin Assays Fibroblast cell assay for C. difficile toxin A and B E. ELISA Tests (Labile toxin of E. coli and cholera toxin of Vibrio cholerae) Prevention of GIT infection 1. All travelers to areas where diarrheal diseases are common should observe the following recommendations: 2. Drink only water that you have boiled or treated with chlorine or iodine. 3. Other safe beverages include tea and coffee made with boiled water and carbonated bottled beverages with no ice. 4. Eat only foods that have been thoroughly cooked and are still hot, or fruit that you have peeled yourself. 5. Avoid undercooked or raw fish or shellfish. 6. Make sure all vegetables are cooked avoid salads. 7. Avoid foods and beverages from street vendors. A simple rule of thumb is "Boil it, cook it, peel it, or forget it. Infections of the teeth jaw and mouth Dental caries is a lesion of the enamel and dentine of the teeth. Periodontal Diseases are disorders of the supporting structures of the teeth (gingiva, periodontal ligament and supporting alveolar bone). These are dental diseases. Poor dental hygiene can result in infections. Infections of the teeth and the gums can spread to contiguous structures (sinusitis, osteomyelitis of the jaw, aspiration pneumonia). Etiology Dental caries - Streptococcus mutans & Lactobacillus sp
Plaque-associated periodontal disease - gingivitis/periodontal disease - is a polymicrobial process caused by: Eubacterium sp.,
Peptostreptococcus, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Bacteroides forsythus, Fusobacterium nucleatum, Prevotella intermedia, Capnocytophaga sp., Selenomonas sp., Spirochaetes Epidemiology Dental caries is ubiquitous. However, with good dental hygiene and prevention practices the incidence in the Western world is falling. It is the leading cause of tooth loss in children under the age of 12. Gingivitis/periodontal disease are also very common and with good dental hygiene and prevention practices are decreasing in incidence in the Western world. It is the leading cause of tooth loss in adults and is present in 8-10% of the adult population. Pathogenesis and manifestations Dental caries: is a chronic infection of enamel or dentine due to bacteria normally found in the mouth. A biofilm (plague; high numbers of Streptococcus mutans) forms on the surface of the tooth. The bacteria in the plaque breakdown sugar in the saliva and produce acid that damages the enamel of the tooth eventually forming a cavity on the surface of the tooth. If the pulp is infected the tooth may die. Complications include pulpitis and dentoalveolar abscess. Manifest
7 as small little pits on the smooth surfaces and in the fissures of the teeth that can enlarge forming necrotic centers. Gingivitis: Gingivitis (plaque associated) - increased numbers of normal flora (Streptococcus, Capnocytophaga, Actinomyces, etc.) grow in the gingival crevice producing toxins that cause an inflammatory reaction in the gums. Plaque accumulates in the crevice resulting in an inflammatory reaction. Complications include development of periodontitis. Manifest as swollen, red, tender gums that bleed during brushing of the teeth. Periodontitis: This is an inflammation of the supporting structures of the teeth. It starts out as gingivitis that then spreads down to the root surface causing alveolar bone resorption and pocket formation. It can eventually lead to alveolar bone loss and damage to the periodontal ligament then can result in tooth loss. Other complications include periodontal abscess and osteomyelitis of the jaws. Manifest as periodontal pockets with gingivitis Diagnosis, therapy & prevention: Patients should be referred to a dentist and encouraged to practice good dental hygiene Infections of peri-apical tissue and jaw With the advent of good dental hygiene, most of these infections are uncommon. Ludwigs angina is the most commonly encountered neck space infection. These include infections around the end of the tooth roots, surrounding tissues, jawbone and the muscles in that area. Dentoalveolar abscess - forms at the end of the tooth root that extends to the base of the roots. It has a polymicrobial etiology and usually an endogenous infection, (obligate anaerobes, Streptococcus milleri). Periodontal abscess - forms deep in the gums along the tooth root following advanced periodontal disease. It has a polymicrbial etiology, including Gram-negative rods, S. viridans, anaerobic streptococci, and spirochaetes. Ludwigs angina - is a rapidly swelling cellulitis of the sublingual and submaxillary spaces, often arising from infection of the tooth roots that extend below the mylohyoid line of the mandible. Most abscesses in the spaces are caused by dental infections (90%). They can also occur following infections in the floor of the mouth, the base of the tongue, the lingual tonsils, and following salivary calculi or from intravenous injection of the internal jugular vein especially in drug abusers. There is a high incidence of associated systemic illnesses including diabetes mellitus, AIDS and HIV seropositivity Mostly caused by Streptococci, Bacteroides, Fusobacterium, S. aureus Osteomyelitis of the jaw This is an inflammation of the bone and the muscles around it. More commonly affects the mandible. Has a polymicrobial etiology which includes: Gram-negative rods, anaerobic streptococci, Actinomyces israelii.
8 Manifestations Dentoalveolar abscess - pain in and around the affected tooth, swelling of the face over the site of the abscess Periodontal abscess - as above for dentoalveolar abscess, the patient also has signs of periodontal diseases. Ludwigs angina - severely ill, severe dysphagia, trismus, cervical tenderness, swelling, limited range of motion, dysphonia. Patients may appear quite toxic, sitting upright, drooling, tachypneic, has edema (brawny) and erythema of the neck under the chin and of the floor of the mouth. The mouth is open and the tongue is lifted upwards and backwards, so that it is pushed against the roof of the mouth and the posterior pharyngeal wall, when this occurs, acute respiratory obstruction is likely to occur. Examination shows a brawny tense swelling of the submaxillary and submental regions with enlargement of the neighboring lymphatic gland. The patient has fever, considerable salivation and dehydration because the patient is unable to swallow (dysphagia). Osteomyelitis - Restricted jaw motion, pseudoparalysis; soft tissue around the inflamed bone, which is hyperemic, warm, edematous, and tender. Actinomycosis may also present with a localized swelling at the angle of the mandible Diagnosis Dentoalveolar Ludwigs angina - This disease can be diagnosed clinically. CT scans and blood cultures can be helpful. This disease can rapidly become life threatening. Dentoalveolar and periodontal abscesses - usually determined clinically, radiographs of the affected areas could be of help Osteomyelitis - Radiographs can take up to 3 weeks to be positive and yield a moth eaten appearance. CT scans are more sensitive. MRI can detect early changes. Bone scans with gallium to detect early disease. Tissue samples and culture may help in identifying the causative agents. In the case of actinomycosis needle aspiration of the abscess can be helpful. Look for the presence of sulfur granules in the aspirate following by Gram stains to show Gram-positive branching filamentous bacteria Therapy Dentoalveolar abscess - refer to dentist (tooth extraction or root canal. Antibiotic therapy may also be required). Periodontal abscess - refer to dentist (tooth extraction or drainage of the abscess followed by periodontal treatment, antibiotics). Ludwigs angina - there is four principal components in the treatment of Ludwigs angina. First, adequate airway management is essential Second, antibiotic therapy must be designed to cover both anaerobes and S. aureus. Penicillin with or without metronidazole is the first line therapy. Clindamycin or amoxicillin/clavulanic acid is considered highly effective.
9 Empiric antibiotic treatment in the immunocompetent host is considered safe; however, medical therapy must be guided by cultures and sensitivities in the immunocompromised host. Third, in the past, incision and drainage of abscesses was routine. Now, surgical therapy is usually reserved for cases of medical treatment failure. Finally, adequate nutrition and hydration can be a challenge in patients with significant oropharyngeal edema Prevention Dentoalveolar periodontal abscess - encourage good dental hygiene, regular visits to the dentist, & prompt treatment of oral/dental infections. Ludwigs angina - encourages good dental hygiene, regular visits to the dentist, and prompt treatment of oral/dental infections. Osteomyelitis of the jaw - encourages good dental hygiene, regular visits to the dentist, and prompt treatment of oral/dental infections. Infections of the tongue and mouth Neisseria gonorrhoeae can cause erythema, edema, vesicles, ulcers and pain in the mouth, usually following oral sex with an infected partner. These patients are more likely to develop systemic gonorrhea. Treponema pallidum infections can occur in the mouth resulting in chancre formation. Secondary syphilis can result in mucous patch formation on the tongue or in the mouth
Infections of the esophagus Esophagitis is an inflammation of the esophagus associated with dysphagia and odynophagia. Bacterial species (eg, normal flora, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, other) may cause disease but the main diseases are due to viruses and fungi. Infections of the stomach and upper duodenum Chronic Gastritis - is the inflammation or irritation of the stomach lining. Chronic gastritis is usually caused by Helicobacter pylori. Peptic ulcer disease (PUD) - refers to a group of ulcerative disorders of the upper gastrointestinal tract involving mainly the most proximal portion of the duodenum and the stomach. This term includes: duodenal ulcers, gastric ulcers, ulcers associated with Zollinger-Ellison syndrome, ulcers caused by gastrinomas, gastric or duodenal ulcers due to drug ingestion and stress. Duodenal ulcer disease - is a chronic and recurrent disease in which deep and sharply demarcated ulcers are produced. These are also called primary ulcers. Around 95% are found within the first portion of the duodenum. Around 90% occur within the 3 cm of the junction of the pyloric and duodenal mucosa. The ulcers are <1cm in diameter & penetrate via the mucosa & submucosa and often into the muscularis propria. The ulcer floor has no intact epithelium and
10 normally contains a zone of eosinophilic necrosis resting on a base of granulation tissue surrounded by variable amounts of fibrosis. Gastric ulcer disease - Secondary ulcers are usually gastric in location and occur more commonly in infants and young children. Helicobacter pylori is also the cause of most of these ulcers (60-70%). Etiology Many things cause gastritis (a variety of medications, medical and surgical conditions, physical stresses, social habits, chemicals, and infections). The most common cause of infectious chronic gastritis is H. pylori. Most ulcers (duodenal and gastric) are related to the inflammatory events associated with H. pylori infection and/or mucosal damage related to nonsteroidal anti-inflammatory drug (NSAID) use. It has been unequivocally demonstrated that treatment of H. pylorirelated ulcer dramatically alters the natural history of this disease process. Most cases of gastric cancer are also likely the consequence of lifelong H. pylori infection and the effect of this chronic infection on mucosal carcinogenesis. Eradication of the infection is as yet, unproved as a method of preventing H. pylori-related cancers Epidemiology Approximately two-thirds of the world's population is infected with H. pylori. In the United States, H. pylori are more prevalent among older adults (around 6070% people over 60 years of age), African Americans, Hispanics, and lower socioeconomic groups. Most ulcers are caused by an infection, not spicy food, acid or stress. Primary peptic ulcers characteristically occur in children older than 10 years, most commonly occur in the duodenum, are associated with H. pylori gastritis, and may result in chronic or recurrent symptoms Risk factors of Peptic Ulcer Disease (PUD) Colonization with H. pylori. Genetic factors Children with blood group O have a higher incidence of PUD. Emotional stress. Alcohol has been documented to produce inflammation, erosions, and hemorrhage in the gastric mucosa in animal and adult human studies. Caffeine intake also predisposes to PUD. Smoking may lead to ulceration, slow healing, and increased risk of recurrent disease. Male-to-female ratio is approximately 2:1 Duodenal ulcers usually occur in those aged 25-75 years. Gastric ulcer incidence peaks in those aged 55-65 years Pathogenesis The mechanisms of mucosal injury in gastritis and PUD are thought to be an imbalance between acid production or pepsin, and defensive factors, such as mucus production, bicarbonate, and blood flow. Infection with H. pylori, a short, spiral-shaped, microaerophilic gram-negative bacillus, is the leading cause of PUD and is associated with virtually all ulcers not
11 induced by NSAIDs. H. pylori colonize the deep layers of the mucosal gel that coats the gastric mucosa and disrupts its protective properties. The bacterium is motile and it uses its corkscrew motility to migrate within the gastric and duodenal mucosa. How the bacteria cause ulcers to form is not completely understood. However the ability of the bacteria to produce urease, a cytotoxic protein called vac A (vacuolating toxin) and to possess the cagA gene locus are important in pathogenesis of ulcer formation. The bacteria produce large amounts of urease allowing them to generate ammonium ions that buffer the gastric acid. The vac A protein causes vacuoles to form in certain cells and pore formation in human cells. Colonization of the stomach and duodenum is associated with an accumulation of inflammatory cells in the lamina propria. The inflammatory cells release cytokines that reduce somatostatin levels and cause an increase in gastrin levels. Damage to tissues results in gastritis. Eventually, an ulcer can form Manifestations Gastritis - oftentimes is asymptomatic however, if symptoms exists they include; pain located in the upper central portion of your abdomen (the "pit" of your stomach). Gastritis pain is in the left upper portion of the abdomen and back. o The terms burning, aching, gnawing, or sore may be used to describe the pain. o They feel a vague sense of discomfort, with sharp, stabbing, or cutting, pain o Feel the urge to belch, but belching either briefly or doesn't relieve the pain o Nausea and vomiting of clear, green yellow or bloody fluid depending on the severity of the stomach inflammation. o They may become pale and sweaty, with tachycardia. o People with gastritis may faint or feel as if they may faint, o Sometimes, they may have chest or severe stomach pain. o Internal bleeding may be shown by vomiting of blood, bloody bowel movements, or dark, sticky, foul-smelling bowel movements o Any or all of these symptoms can occur suddenly in the elderly. o The chronic phase of the pain may be dull and there may be loss of appetite with a feeling of fullness after several bites of food. If the pain is severe, there may be an ulcer as well as gastritis Primary peptic ulcer disease - The most common ulcer symptom is gnawing or burning pain in the epigastrium. This pain typically occurs when the stomach is empty (90 min to 3 hours after a meal), between meals and in the early morning hours, but it can also occur at other times. Less common ulcer symptoms: Nausea, vomiting, and loss of appetite, bleeding can also occur; prolonged bleeding may cause anemia leading to weakness and fatigue. If bleeding is heavy, hematemesis, hematochezia, or melena may occur. Diagnosis Establish a H. pylori infection of the stomach and/or duodenum. This can include serological test, a C13 labeled urea breath test, endoscopy with biopsy.
12 Endoscopy is quite useful in that it allows direct visualization of inflammation, ulcers and cancers. Biopsies can be performed and the material tested for the presence of urease and examined for inflammation and abnormal tissue growth. Treatment & Prevention Triple therapy is suggested for PUD which can also prevent development of cancer: A proton pump inhibitor (lansoprazole or omeprazole), amoxicillin, and clarithromycin. In Penicillin allergic patients metronidazole can be substituted for the amoxicillin. Some also include bismuth with the triple agent therapy.
Bacterial Infections of the Intestines Introduction There are many microoganisms that cause disease in the intestines ranging from bacteria, viruses, fungi, and parasites. Examples of bacteria agents includes E. coli, Salmonella, Shigella, Campylobacter, Clostridium. Infections of the intestines result in diarrhea or dysentery, nausea, vomiting, and abdominal cramping. If the infection is in the small intestine, symptoms include watery diarrhea and/or vomiting. Infections in the large intestine usually result in dysentery (small fecal volume, with mucus and many times blood). Some diseases follow certain predisposing conditions (antibiotic therapy: pseudomembranous colitis). Not all of these diseases follow infection but can occur following ingestion of preformed toxin (staphylococcal food poisoning). Usually symptoms (vomiting, diarrhea) of intoxication occur soon (1-8 hr) after ingestion of the toxin. This is called intoxication. Pathogens causing diarrhea can be transmitted to humans in three basic ways: in food, in water, and person to person. Many of these infections do not require treatment. Some can spread to other sites in the body and require treatment to prevent further damage.
Etiologies Intoxications: Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, Clostridium botulinum Infections: Escherichia coli (ETEC, EPEC, EHEC, EAEC, EIEC), Salmonella sp., Shigella sp., Campylobacter sp., Yersinia enterocolitica, Clostridium difficile, Vibrio cholerae, Vibrio parahemolyticus, Listeria monocytogenes, Aeromonas hydrophila, Clostridium botulinum (children under 1 year of age eating honey) Small Intestine: E. coli (ETEC, EPEC), Clost perfringens, Cholera sp., Large Intestine infections: E. coli (EHEC, EIEC, EAEC), Shigella sp., Salmonella sp., Campylobacter sp., Yersinia sp., Aeromonas sp., Plesiomonas sp., Clostridium difficile Gastroenteritis - Dysentery
13 This form is a large intestinal infection. Most of these organisms are invasive and cause the host to mount an inflammatory response. Frequently the stool volume is small, contains mucus and white blood cells, and if invasion is deep enough, can be heme-positive. The patient usually has fever, complains of abdominal pain, and of pain while attempting to defecate (tenesmus). Antimicrobial treatment of these infections can in most cases be beneficial. Treatment is not indicated when a person is infected with EHEC because treatment releases more shiga-like toxin and makes the patient more likely to develop HUS (hemolytic uremic syndrome). Treatment with antimotility drugs to stop the dysentery is NOT a good idea. The three most common causes of this form of gastroenteritis are: Salmonella, Shigella, and Campylobacter. Other important causes include: E. coli (EHEC, EIEC), Yersinia enterocolitica, and Entamoeba histolytica (a parasite). Campylobacteriosis Campylobacter jejuni is a gram-negative slender, curved, and motile rod. These organisms are comma shaped (seagull shape). It is a microaerophilic organism. It is relatively fragile, and sensitive to environmental stresses. Because of its microaerophilic characteristics the organism requires 3 to 5% oxygen and 2 to 10% carbon dioxide for optimal growth conditions. Surveys have shown that C. jejuni is the leading cause of bacterial diarrheal illness in the United States. It causes more disease than Shigella spp. and Salmonella spp. combined. C. jejuni is not carried by healthy individuals in the US or Europe. It is often isolated from healthy cattle, chickens, birds and even flies. It is sometimes present in nonchlorinated water sources such as streams and ponds. Three to five days after ingestion, overt disease occurs only if the organism penetrates the mucous coating the epithelial cells and invades the cell Etiology & Pathology Eight different species of Campylobacter cause gastrointestinal infections. C. jejuni is the most common cause of gastroenteritis worldwide. Campylobacter adheres to intestinal epithelial cells and M cells. Depending on the strain the bacteria can produce a heat-labile toxin or be ingested by the host cells. If the heat labile enterotoxin is produced a watery diarrhea occurs. Inflammatory colitis results when the organisms cause the host cells to ingest the bacteria. After adhering to the host cells the bacteria use a type III secretory system to inject bacterial proteins into the host cells. These bacteria proteins cause the host cells to ruffle and ingest the bacterial cells. Meanwhile, some strains of the bacteria produce a toxin called shiga toxin or verotoxin that gets into the host cells cytoplasm and stops protein synthesis by removing an adenine residue from the 28S rRNA in the 60S ribosomal unit. This toxic activity causes the host cells to die. Toxin activity produces superficial
14 ulcers in the bowel mucosa and induces an acute inflammatory response. Immunocompromised patients, patients with chronic illnesses and those at the extremes of ages are more likely to develop a self-limiting bacteremia. The syndrome produced by C. jejuni is similar to that produced by Shigella and enteroinvasive Escherichia coli (EIEC). Symptoms: Most cases are mild and subside within 7 days (60-70%). Some last for 2 weeks (20-30%) and a few persist longer (5-10%). In one third to one half of patients, initial symptoms include periumbilical cramping, intense abdominal pain that mimics appendicitis, malaise, myalgias, headache, and vomiting. Watery diarrhea is the most common manifestation. Inflammatory bowel disease symptoms include malaise, fever, abdominal cramps, tenesmus, bloody stools, and fecal leukocytes on light microscopy. The inflammation and pathology that results are indistinguishable from that due to Shigella sp., Salmonella sp., and E. coli. Clinical findings are not diagnostic. Along with the diarrhea there is sometimes pain, malaise and fever. Diagnosis Presumptive diagnosis is based on the finding of gull-shaped bacteria in watery, bloody, leukocyte-filled feces. They have a characteristic darting motility. Definitive diagnosis requires isolation of the organism from the stool or other sites of infection. This requires special media and isolation techniques. Campy-BAP or Skirrow media contain antibiotics that reduce the growth of other enteric microorganisms. These media should be incubated in 5% oxygen and 10% carbon dioxide at 42C. Treatment Most C jejuni infections are mild and self-limited. They do not usually require antibiotic therapy. Correction of electrolyte abnormalities and oral rehydration are usually sufficient. Treatment is reserved for compromised hosts or persons with fever, increasing bloody diarrhea, or symptoms that last longer than 1 week. C jejuni is usually sensitive to erythromycin, gentamicin, tetracycline, ciprofloxacin, and clindamycin. Shigellosis- Bacillary Dysentery Shigellosis is primarily transmitted by the fecal-oral route. Despite environmental hygiene shigellosis persists because 1. Shigella is present in the bases of toilets (can move from person to person) 2. They pass through toilet paper onto the fingers. 3. As few as 200 organisms can cause disease. 4. They can be spread by horseflies 5. Closed population groups often have substandard sanitation Etiological Agents Fifty Shigella species fall into one of four serological groups. Group B - S. flexneri is mostly isolated, group D - S. sonnei, is the most commonly isolated cause of shigellosis in the U.S. Shigella is nonmotile, nonlactose fermenting gram-negative rod whose natural habitat is the intestine of humans and other primates. Shigellae share antigens and toxin-producing capability with E coli.
15 Unlike Salmonella and Campylobacter Shigella are quite resistant to killing by stomach acid. The disease occurs when virulent Shigella organisms attach to, and penetrate, epithelial cells of the intestinal mucosa. After invasion, they multiply intracellularly, and spread to contiguous epithelial cells resulting in tissue destruction. Some strains produce enterotoxin and Shiga toxin (very much like the verotoxin of E. coli O157:H7). Shigellosis is mainly a disease of children between 1 and 4 years of age. It is transmitted by the 4-F's: food, fingers, feces and flies Pathology Shigella adheres to intestinal epithelial and M cells. After adhering to the host cells the bacteria use a type III secretory system to inject bacterial proteins into the host cells. These bacteria proteins cause the host cells to ruffle and ingest the bacterial cells. Once in the cells the bacteria use a surface hemolysin to lyse the phagosome membrane and escape into the cytoplasm. The bacteria then use the host cells actin to move around inside the cell (actin rocket tails). When the bacteria reach the periphery of the cell it pushes outward to form membrane projections that are then ingested by adjacent cells. Meanwhile, the bacteria are producing a toxin called shiga toxin or verotoxin that gets into the host cells cytoplasm and stops protein synthesis by removing an adenine residue from the 28S rRNA in the 60S ribosomal unit. This toxic activity causes the host cells to die. The cell-to-cell travel and toxin activity produces superficial ulcers in the bowel mucosa and induces an extensive acute inflammatory response. This inflammatory response usually prevents entry of the bacteria into the bloodstream. Symptoms After an incubation period of 36-72 hours, the initial non-specific symptoms of fever (39-39oC) and cramping abdominal pain are prominent. Watery diarrhea usually appears after 48 hours, with dysentery (bloody, mucous containing, small volume stools, pain is experienced when trying to defecate) supervening about 2 days later. Sigmoidoscopy reveals intense hyperemia, multiple small bleeding sites, loss of transverse mucosal folds and thick, purulent mucous secretions. Tenesmus is present and the feces are bloody, mucoid and small volume. Fluid and electrolyte loss may be quite significant, particularly in pediatric and geriatric populations. Escherichia coli septicemia may be initiated by shigellosis. Shigella only rarely gets into the bloodstream Treatment Shigellosis is a self-limited disease however to shorten the course of the illness and prevent person-to-person spread of the illness treatment with trimethoprimsulfamethoxazole or ciprofloxacin is usually recommended. Fluid and electrolyte replacement is necessary in severe cases. Antidiarrheal compounds which inhibit peristalsis, are contraindicated Salmonellosis Salmonella are gram-negative motile facultative anaerobes that do not ferment lactose. There is one species S. enterica with over 2460 unique serogroups (e.g.. S. enterica serovar typhimurium or S. enterica serovar enteritidis). There are exceptions to this rule. The Salmonella that cause enteric fevers will be called S. paratyphi and S. typhi. All of the strains of Salmonella, except S. paratyphi and S.
16 typhi, colonize virtually all animals. Salmonella are found in the intestines of chickens, reptiles, birds, and humans. Transmission from animals to humans and from animal food products to humans (raw meats, eggs, milk and dairy product, fish, shrimp, frog legs, yeast, coconut, sauces and salad dressing, cake mixes, cream-filled desserts and toppings, dried gelatin, peanut butter, cocoa, and chocolate) is common. S. paratyphi and S. typhi are only found in humans. A certain number of humans infected with these organisms become chronic carriers after the organisms colonize their gallbladder Etiologic Agents Salmonella enterica serovar (thousands of names; S. typhimurium, S. enteritidis, S. cholerasuis)- salmonellosis cause diarrhea, fever, and/or abdominal cramps. Salmonella typhi and Salmonella paratyphi- enteric fevers= paratyphoid fever and typhoid fever = 1st week gradually increasing fever, headache, myalgias, malaise, anorexia, constipation (sometimes diarrhea) followed in the 2nd week by diarrhea, splenomegaly, high fever, etc. Pathology Salmonella are sensitive to killing by gastric acid. Therefore, it requires large number of organisms to cause an infection. If for any number of reasons the acid in the stomach is reduced or neutralized fewer organisms are required. If they survive the stomachs acidity the bacteria will attach to the epithelial cell in the small intestine and colon. Once attached to the host cells the bacteria use a type III secretory system to inject bacterial proteins into the host cells. These bacteria proteins cause the host cells to ruffle and ingest the bacterial cells in large vacuoles. In the vacuoles the bacteria replicate and eventually cause the cells to lyse. They escape into the extracellular environment and gain entry into the mesenteric lymph nodes and some get into the bloodstream. Most infections result in fever, abdominal pain, and diarrhea. Some Salmonella are better at getting in the bloodstream than others. They cause little damage in the intestine and little if any diarrhea. S. typhi and S. paratyphi both cause enteric fever or typhoid fever (S. typhi) and paratyphoid fever (S. paratyphi). Some Salmonella (S. enterica serovar cholerasuis) are better at getting in the bloodstream and can cause nontyphoidal Salmonella bacteremias. Most infections are acquired by ingestion of heavily contaminated foods. Salmonellosis is more common in the summer where warmer temperatures allow for rapid growth of the organisms in the contaminated foods Symptoms: Enteritis- is the most common form of salmonellosis. Symptoms appear 6-48 hours after ingestion of the contaminated food or water. Initially the patient has nausea, abdominal cramps, vomiting and nonbloody diarrhea. They also have signs (fever, headache and myalgias) of systemic involvement. Symptoms last from 2 days to 1 week and usually spontaneously resolve. Septicemia- All Salmonella serovars can cause bacteremia. The following strains are most likely to cause bacteremia; S. typhi, S. paratyphi, and S. enterica serovar cholerasuis. The risk of bacteremia is higher in pediatric and geriatric patients and in immunocompromised patients (AIDS). The clinical presentation is just like any other gram-negative sepsis.
17 Enteric fever- S. typhi produces typhoid fever. S. paratyphi A, S. schottmuelleri, and S. hirschfeldii cause paratyphoid fever. These bacteria pass through the cells lining the intestines and are engulfed by macrophages. They replicate after being taken to the liver, spleen, and bone marrow. Ten to 14 days after ingestion the patients experience a gradually increasing fever with headache, myalgias, malaise, and anorexia. These symptoms persist for a week and then are followed by diarrhea. These disease manifestations correspond to an initial bacteremic phase, followed by colonization of the gallbladder and then reinfection of the intestines. S. typhi also causes skin lesions called rose spots and symptoms are more severe than those seen with the causes of paratyphoid fever. Asymptomatic colonization- Those Salmonella responsible for the enteric fevers can chronically colonize the gallbladder serving as a reservoir to infect other people. They can be colonized for up to a year following resolution of symptoms. This can occur in 1-5% of those infected Diagnosis Compared to shigellosis there is a less vigorous inflammatory response. Therefore there are fewer fecal leukocytes seen in the stools. Isolation of the organisms from the stool using S-S agar is necessary for a definitive diagnosis. Treatment: Enteritis is self-limiting in most people. Treatment appears to prolong carriage of the bacteria and does not appear to shorten the course of the illness. However, certain patient should be treated due to their greater likelihood of developing bacteremia, endocarditis, and/or osteomyelitis. These patients include: neonates, persons over 50 years of age, immunocompromised patients, patients with Sickle-cell disease, patients with prosthetic valves or vascular grafts. Patients with enteric fevers warrant immediate antibiotic therapy (ciprofloxacin or ceftriaxone). Fluid and electrolyte replacement is necessary in severe cases. Antidiarrheal compounds which inhibit peristalsis, are contraindicated Prevention People traveling to countries with high rates of typhoid fever should be vaccinated. Two typhoid vaccines are available for use in the United States: an oral, live, attenuated vaccine (Vivotif Berna vaccine, manufactured from the Ty21a strain of S. typhi by the Swiss Serum and Vaccine Institute) and a Vi capsular polysaccharide vaccine (ViCPS) (Typhim Vi, manufactured by Aventis Pasteur) for intramuscular use. Both vaccines have been shown to protect 50% 80% of recipients.
Escherichia coli
Intestinal E. coli strains have minimal or no invasive ability. The enteroinvasive E. coli (EIEC) has acquired certain genetic traits from Shigella sp. that allow it the same invasive capabilities. EHEC strains have acquired the genes to express Shiga-toxins. These toxins cause cell death, edema and hemorrhage in the lamina propria. Serotype O157:H7 commonly results in a hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). E. coli 0157:H7 is a facultative, Gramnegative, motile, rod-shaped bacterium that cannot ferment sorbitol.
18 Characteristics of E.coli substrains EHEC: The majority of the pathology occurs in the ascending and transverse colon lamina propria. Colonic biopsy specimens show focal necrosis and infiltration of neutrophils. Kidneys damage is due to the shiga toxin and results in swollen glomerular epithelial cells, fibrin deposition and infiltrates of inflammatory cells. EIEC- It is very similar to what has been described during Shigella infections. Most of the time in the case of EIEC only watery diarrhea is seen. However, a watery diarrhea followed by the onset of scanty dysenteric stools containing blood and mucus can occur. EPEC- Most strains are enteroadherant (EAEC) and cause alterations in the glycocalyx of the small bowel epithelial cells. They then intimately adhere to the host cells and inject (using type III secretory system) a bacterial factors into the host cells which cause alterations in the glycocalyx of the small bowel epithelial cells. EAEC - enteroadherant E.coli cause alterations in the glycocalyx of the small bowel epithelial cells ETEC- has multiple pathogenic mechanisms which include at least 2 distinct toxins; a heat-labile toxin (LT) and a heat stable toxin (ST). The ability to produce enterotoxin is mediated by a single plasmid. The E. coli LT is similar, but not identical to, the cholera toxin; because o It binds to the same site, o Has the same effect and o Serologically cross-reacts with cholera toxin. o Like cholera toxin it will bind to cells outside the intestine. The E. coli ST is quite different from the LT because: o It exhibits a rapid onset of action (immediate increase in the secretion of gut fluid), o does not bind to gangliosides of the mucosal cell membrane, o Low molecular weight, that is, less than 2000 daltons. o It is not antigenic but act by stimulating the guanylate cyclase with resultant cyclic GMP accumulation in mucosal cells. o It only affects cells of the small intestine. E. coli ST causes an almost immediate increase in the secretion of gut fluid. The increase in intracellular guanylate cyclase causes chloride secretion by gut mucosal epithelial cells in a manner similar to that seen with the cholera enterotoxin. E. coli ST differs from cholera enterotoxin by the following ways: o While the ST does NOT alter neutral sodium chloride absorption by the brush border co-transport route, cholera enterotoxin does. o ST binding is specific for small bowel mucosal cells and thus, affects only S/intestinal cells unlike cholera enterotoxin. EPEC and ETEC are similar in the production of colonization factors (fimbriae or pili) which allow them to adhere to mucosal cells. These strains alos produce little or no gross pathology.
19 Symptoms EHEC- shows severe crampy abdominal pain, watery diarrhea followed by grossly bloody diarrhea and little or no fever. The symptomology of HUS includes the triad of acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. EHEC usually precedes HUS. EIEC Produces watery diarrhea that can on occasion result in dysenteric stools Diagnosis & Treatment Isolation and identification of the etiologic agent is necessary for definitive diagnosis. To grow EHEC O157:H7 the carbohydrate sorbitol must be included in the medium. EHEC - Avoid antimotility drugs and use of antibiotics. Administration of antibiotics kills the bacteria releasing more toxins and increasing the chances that HUS will develop. EIEC - Usually is self-limiting however in severe cases treatment with trimethoprim-sulfoxazole or a fluoroquinolone or ciprofloxacin can be used. Again avoid antimotility drugs
Vibrio parahaemolyticus
Etiologic agent: Vibro parahaemolyticus- like V. cholerae also is a slightly curved halophilic rod which grows in estuaries marine environments attaching to plankton and shellfish. Hemolytic strains of V. parahaemolyticus are virulent. V. parahaemolyticusfollowing ingestion of inadequately cooked or uncooked (sushi) seafood, the organisms colonize the small intestine and produce an enterotoxin that causes some inflammation and a mild to moderately severe watery diarrhea. Pathology: Produces an enterotoxin which causes mild inflammation and diarrhea. Clinical symptoms: Causes watery diarrhea often with abdominal cramping, nausea, vomiting fever and chills. In about 25% of cases a bloody diarrhea can occur Diagnosis: not usually done. Culture the stool on TCBS medium. Treatment: Oral rehydration Prevention: Only eat cooked seafood. Gastroenteritis - Food Toxemia Food poisoning is a toxemia associated with the ingestion of preformed microbial toxins. It is NOT an infection. Since the toxins are ingested preformed and no microbial growth within the human is required, symptoms occur rapidly, usually within 2-12 hours. In all but botulism, symptoms occur relatively soon after ingestion of the toxin and does NOT include a fever. These toxins either affect the intestine (enterotoxin of C. perfringens) or the central nervous system (neurotoxin of C. botulinum) or both (S. aureus and B. cereus). Etiological Agents Staphylococcus aureus (gram+, aerobic, coccus), Bacillus cereus (gram+, aerobic, rod), Clostridium perfringens Type A (gram+, anaerobic, rod), Clostridium botulinum (gram+, anaerobic rod) Virulence factors and associated symptoms
20 The key difference between toxemia and infectious diarrhea are that in toxemia, there is rapidity of onset of symptoms following ingestion of contaminated food or drink, the lack of fever and the absence of fecal leukocytes. All of the toxemias result in symptoms occurring within 12 hours of toxin ingestion as compared to an incubation period of 24-72 hours for infections. i. S. aureus enterotoxins: Eight distinct antigenic types are labeled SEA, SEB, SEC, SEE, SEG, SEH, SEI, SEJ. They are water-soluble, low molecular weight proteins that are heat stable (resist boiling for 30 minutes). Their exact mode of action is unknown but they are thought to bind to the emetic reflex center causing nausea and vomiting, diarrhea occuring within 1-4 hours after ingestion of contaminated food. All are exotoxins produced by chromosomal genes ii. B. cereus enterotoxins: The spore germination process of B. cereus produces two enterotoxins which cause either vomiting (emetic form) or diarrhea (diarrheal form). The type of toxin produced is dependent on the type of food that the spore germinates in. o In a high carbohydrate food (rice, pasta), Type 1 disease, the emetic heat stable enterotoxin is produced causing nausea and vomiting, in less than 6 hrs (mean= 2 hours) after food ingestion with little diarrhea and no fever. How the heat stable enterotoxin causes vomiting is unknown. o The diarrheal form, Type 2 disease, resulting from the heat labile form of the enterotoxin is produced while the bacteria grow in a high protein food (meat). The enterotoxin stimulates the adenyl cyclase - cyclic AMP system in intestinal epithelial cells which then fills the intestine with fluids 10-14 hours after food ingestion with no fever. o Type 2 infections can also result when large numbers of the ingested bacteria produce the heat-labile toxin resulting in the same symptoms as indicated above iii. C. perfringens enterotoxin. This heat-labile protein binds to the brush border membrane in the small intestine. It disrupts ion transport in the ileum and jejunum altering membrane permeability. Excess amounts of ions go into the lumen with the water following them. This results in a watery diarrhea. The toxin is formed when the vegetative cells become spores. The alkaline conditions in the small intestine cause spore formation. Meat products contaminated with large numbers of organisms are needed to cause disease which shows in 8 to 24 hrs after ingestion of the toxin, with abdominal cramping and watery diarrhea with no fever. Refrigeration prevents growth of organisms in the meat and reheating the meat destroys the heat-labile enterotoxin. Thus the actual cause of poisoning by C. perfringens is temperature abuse of prepared foods. C. perfringens Type C beta-toxin producing strains can cause a rare disease called necrotizing enteritis or enteritis necroticans (pig-bel). Exposure to large numbers of organisms and malnutrition are risk factors for this disease iv. C. botulinum neurotoxin: Seven distinct antigenic neurotoxin types labeled A, B, C, D, E, F, G have been identified. Human disease is associated with toxin types A, B, E and F. Improperly canned foods are the most common source of this form of food poisoning. The spores of C. botulinum are not
21 destroyed and when cooled sufficiently will start growing and making an A-B type toxin. The length of the incubation period (1-2 days average) is a function of the amount and antigenic type of toxin ingested. The B portion protects the toxin from being inactivated by stomach acid and helps get the A portion inside the nerve cells. The A portion is a metalloproteinase that blocks neurotransmission of cholinergic synapses by preventing the release of acetylcholine at the neuromuscular junction. This causes a flaccid paralysis that will remain until the nerve endings regenerate. Bilateral descending weakness of the peripheral muscles develops in patients with flaccid paralysis and death is attributed to respiratory failure. The illness is characterized by symmetric impairment of cranial nerves, followed in a descending pattern by weakness or paralysis of the muscles of the extremities and trunk. Pathology There is no pathology associated with S. aureus or B. cereus toxemia. Epithelial cell lyses is a microscopic pathologic effect of C. perfringens toxemia; rarely, with heavily contaminated foods, there is diffuse, necrotizing enteritis of the jejunum, ileum and colon. The pathology associated with C. botulinum is minimum, inconsistent and non-diagnostic. Diagnosis: This may not be necessary for the food intoxications. They rarely cause significant long-term problems and are self-limiting. The only reason to determine the food source and cause would be in the case of food poisonings resulting at public institutions (restaurants, elderly care facilities, etc.). The contaminated food may be cultured or immunoassays performed to detect the enterotoxins in the food. The only fatal toxemia in this group is botulism (because of neurocomplications); the emphasis should be on ruling out botulism in the diagnosis. Presumptive diagnosis of botulism is made by detecting fast descending paralysis. A history of ingestion of home canned food or honey is helpful. Anaerobic culture of the organism from the food source and demonstration of toxin production using a mouse bioassay can be performed. Differential diagnosis should include Guillain-Barr syndrome - this is an ascending paralysis. Treatment In toxemia due to S. aureus, B. cereus, C. perfringens no treatment is usually given. If the patient becomes dehydrated intravenous replenishment of fluids and electrolytes is administered. Patients with signs or symptoms compatible with botulism, or patients who are known to have eaten food shown by laboratory testing to contain the toxin, should be given trivalent (A, B, E) botulinum antitoxin to neutralize unabsorbed toxin in the bloodstream and admitted to an intensive care unit if complication exist. Gastroenteritis-Diarrhoea In this group of infestation bacteria are introduced into the intestine where they attach to the intestinal epithelium and physicall weigh down the integrity of the involved mucosa. Some may disrupt the surface feutures of the epithelium
22 (effacing) while others may yet introduce entero-toxines that will alter the gut surface biochemistry ultimately leady to massive influx of fluid to the gut lumen (watery diarrhoea). Since there is not inflammation, caused by the bacteria or secreated toxins, there may be no observable pathological outcome. Escherichia coli: ETEC- Mainly responsible for infantile and travelers diarrhea EPEC- Mainly responsible for diarrhea in infants less than 6 months of age EAEC- The main cause of more persistent travelers diarrhea Pathology EPEC produces no demonstrable toxin. They cause an attaching-and-effacing in the small intestine. These E. coli strains are adherent to the epithelial cells and then disrupt the microvilli (effacement). They then intimately adhere to the host cells and inject (using type III secretory system) a bacterial factors into the host cells which cause alterations in the glycocalyx of the small bowel epithelial cells. EPEC expresses bundle-forming pili which create a network of plasmid mediated fibers that bind together the individual organisms and are used to bind the bacterial cells to the surface of the intestinal epithelial cells. The EPEC pili are homologous with toxin-coregulated pili of Vibrio cholerae. ETEC strains colonize the small intestine and produce a cholera-like (heat-labile; LT) toxin and a heat stable toxin (ST). Both toxins ultimately stimulate the secretion of chloride by the host cells resulting in a watery diarrhea. The LT toxin has a molecular weight of 86,000 daltons. It is an A-B toxin like the cholera toxin composed of one A subunit and 5 B subunits. The B subunits bind to GM1 ganglioside on the host cell. Following endocytosis of the bound toxin the A subunit is released into the cytoplasm and contains the enzymatic function in which ADP-ribosyltransferase transferes a ribose sugar from NAD to GTP-binding protein. The GTP-binding protein permanently activates adenylate cyclase resulting in increased intracellular levels of cAMP. The cAMP activates cAMP-dependent protein kinase (A kinase), which will cause supranormal phosphorylation of chloride channels. Stimulation of chloride ion secretion from secretory crypt cells and inhibition of NaCl absorption by villus tip cells causes an increase in luminal ion content drawing water passively through the paracellular pathway and an osmotic diarrhea The E. coli ST is quite different from the LT. This toxin is about 18-19 amino acids in length. ST binds to a membrane-spanning enzyme called guanylate cyclase. Guanylate cyclase is located in the apical membrane of intestinal epithelial cells and binding of the ST to the extracellular domains of the protein stimulates its intracellular enzymatic activity. This causes increases in intracellular cGMP, which ultimately stimulates chloride ion secretion and/or inhibition of NaCl adsorption. Once again an osmotic diarrhea occurs. EAEC- Invasiveness involves three stages that include: 1. Adherence to the mucosa, 2. Enhanced mucus production that encases the bacteria forming a biofilm, 3. Followed by elaboration of a cytotoxin, which damages the intestinal cells. They may have the ability to colonize both the small and large intestine.
23 Regardless of the symptoms, these infections are similar to most small intestinal infections. Symptoms Severe diarrheal disease caused by ETEC is generally characterized by the abrupt onset of watery diarrhea. In severe cases, the clinical picture is identical to that of cholera except that cramping abdominal pain is more commonly present with E. coli diarrheas and the duration is much less, seldom lasting more than 24 hours after initiation of fluid replacement therapy. The non-enterotoxin producing, noninvasive E. coli (EPEC) have thus far been incriminated only in mild diarrheal disease in infants less than 6 months of age primarily. EAEC is a common cause a more persistent diarrhea seen in adults and children Diagnosis: Diagnosis is made by isolating E. coli on MacConkey agar and then: 1. Inoculating them into a tissue culture of mouse adrenal cells or Chinese hamster ovary cells which respond morphologically to stimulation of their adenylate cyclase systems by the LT or 2. Performing an ELISA test on toxin bound to antibody or 3. Using a DNA probe to detect the LT gene. Treatment Intravenous or oral replacement of the fluid and electrolytes lost in feces. Oral therapy is almost always adequate. Tetracycline and trimethoprim - sulfamethoxazole are effective in shortening the duration of symptoms but are not essential. Bismuth subsalicylate may provide symptomatic relief (less severe abdominal cramps and less frequent stools). Vibrio cholerae This is a slightly curved gram-negative rod which has two major groups based on the O-antigen. These are identified by slide agglutination tests with specific antiserum. Classic epidemic cholera is caused by the 01 serotype; all other strains are designated the non-01 strains and they have the antigen designations 02-0139. These non-01 strains produce sporadic and milder forms of diarrhea Cholera is endemic in Sub-saharan Africa, India, West Bengal, Bangladesh and Louisiana in the U.S. The organism is ingested with water or food (especially shellfish and crabs) and causes an acute illness due to an enterotoxin elaborated by V. cholerae that have colonized the small bowel. In its most severe form, there is rapid loss of liquid and electrolytes from the gastrointestinal tract, resulting in hypovolemic shock, metabolic acidosis and, if untreated, death Pathology V. cholerae is acid sensitive and the majority of ingested organisms are killed by stomach acidity; it takes ingestion of 108-1010 cells to cause disease. Those organisms that survive attach to the microvilli of the glycocalyx of epithelial cells of the jejunum and ileum. There they multiply and liberate cholera enterotoxin, mucinase and endotoxin. They do not invade the mucosa. All signs, symptoms and metabolic derangements in cholera result from the rapid loss of liquid from the gut. The cholera enterotoxin (molecular mass of 84,000 daltons) consists of a
24 binding B-moiety (11,500 daltons X five subunits) and an activating A-moiety (about 26,500daltons). On exposure to small bowel epithelial cells, each B subunit rapidly binds to GM1 monosialoganglioside in the gut cell wall. Following binding, the A moiety migrates through the epithelial cell membrane. The A1 subunit contains ADP-ribosyltranferase activity and catalyzes the transfer of ADP-ribose from NAD to a guanosine triphosphate (GTP) - binding protein that regulates adenylate cyclase activity. The ADP-ribosylation of GTP binding protein inhibits the GTP turnoff reaction and causes a sustained increase in adenylate cyclase activity. The resultant increased intracellular cyclic AMP acts at 2 sites to cause net secretion of isotonic liquid within the small bowel lumen. The increased cyclic AMP inhibits neutral sodium chloride absorption across the glycocalyx via the cotransport mechanism; it also stimulates active chloride secretion into the gut lumen. There is no significant pathology because no inflammation. Clinical symptoms: Cholera- The onset is characterized by abrupt, watery diarrhea. Several liters of liquid may be lost within a few hours, rapidly leading to profound shock. Vomiting may ensue after diarrhea. The patient is cyanotic and has sunken eyes and cheeks, a scaphoid abdomen, poor skin turgor and thready or absent peripheral pulses. The voice is high pitched or inaudible; the vital signs include tachycardia, tachypnea and low or unobtainable blood pressure. The heart sounds are distant and often inaudible, and bowel sounds are hypoactive Diagnosis Cholera- In endemic or epidemic areas, the working diagnosis of cholera is made based on the clinical presentation, especially the presence of "rice water" stools. Confirmative diagnosis is made by plating a stool sample on TCBS (thiosulfatecitrate-bile salt-sucrose) agar, which is selective for Vibrio, and the adrenal cell assay Treatment & Prevention Cholera- Successful therapy requires only prompt replacement of fluids and electrolytes. Ringer's solution is most commonly used. It is given rapidly by IV injection - 50 to 100 ml per minute - until a strong radial pulse is restored. Tetracycline reduces the severity and length of disease. Chloramphenicol and furazolidone are slightly less effective. Cholera- Two vaccines for cholera are licensed and available in other countries not USA (Dukoral, Biotec AB and Mutacol, Berna). Both vaccines seem to provide a somewhat better immunity and fewer side-effects than the previously available vaccine. Infant Botulism C. botulinum can colonize the GIT of an infant less than 1 year of age. C. botulinum spores in honey used to sweeten infants milk or water, when ingested, geminate in the infants intestinal tract, colonize it and produce toxin in vivo. Constipation is the first sign of disease; the same neurological signs seen in the adult follow the constipation. Antibiotics are generally not effective and may
25 exacerbate the illness by elimination of normal flora. Therapy is the same as for adult botulism except that antitoxin is generally not used because the disease is milder in children. Invasive Gastroenteritis What happens when most of the enteric agent instead of being inflammatory and localized becomes invasive? Look at the following agents and review how they becomes invasive causing extra-intestinal infections: Typhoid fever Crohn's intestinal disease by Mycobacterium paratuberculosis Campylobacteriosis Shigellosis Escherichia coli Helicobacter pylori Prevention of diarrheal diseases A. Prevention is the best approach in dealing with these diseases. Avoid eating undercooked meat or seafood Avoid consuming unpasteurized milk or soft cheeses Avoid drinking untreated water Ensure the daycares your patients utilize practice proper hygiene and have the proper number of workers Warn travelers of the possible GI challenges they will encounter when traveling Offer the typhoid vaccine to travelers going to countries with a lot of typhoid fever B. If a patient comes in with diarrhea what do you do? Initiate rehydration (use oral rehydration therapy wh enever possible) Perform a thorough clinical and epidemiological evaluation for any significant diarrheal illness. C. Any other medical conditions Perform selective fecal studies Institute selective therapy for: o Travelers diarrhea- antibiotics o Shigellosis- antibiotics o Campylobacter infection- antibiotics Avoid administering antimotility agents with bloody diarrhea or proven infection with Shiga toxin-producing E. coli. Selectively administer available vaccines for travelers to (or residents of) areas where typhoid is endemic.
26
1b. Fungal Infections of the Gastrointestinal tract.

Background: Candida species belongs to the class Fungi Imperfecti, the order Moniliales, and the family Cryptococcaceae. The three major groups of fungi are moulds, yeasts and mushrooms. Candida are unicellular yeasts, somewhat larger than bacteria, that divide mostly asexually, can switch between a yeast- and a pseudohyphal or hyphal form and, flourish in habitats where there is an abundance of sugar. Candida species are amongst the most common causes of fungal opportunistic disease in humans. Candidiasis refers to acute or chronic and localized or systemic infections caused by Candida species. These yeasts causes a wide variety of diseases ranging from superficial (e.g. vaginal and oral thrush) to systemic (e.g. candidaemia) infections. Candida species are ubiquitous human fungal pathogens capable of initiating a variety of recurring superficial diseases especially in the oral and vaginal mucosa (Odds, 1998). While the genus Candida is comprised of more than 200 species only about 13 Candida species have caused infection in humans. Of these, the most important cause of disease is Candida albicans. Other Candida species that cause disease include C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis and others. Other diseases such as histoplasmosis, cryptococcosis, geotrichosis, and aspergillosis may also be seen less frequently in patients with HIV infection. Aspergillosis, cryptococcosis, zygomycosis and histoplasmosis are examples of common deep mycoses complicating HIV infection with orofacial manifestations. Virulence factors of oral Candidiasis Ever since it was discovered that Candida is an important pathogen, mainly in the immunocompromised host, there has been a huge body of invitro investigations evaluating its virulent attributes in an attempt to elucidate the pathogenesis of the disease. However, in vivo studies either in live humans or in animals are essential to elucidate and fully comprehend the mechanisms leading to candidal infection. Neither colonization with Candida species alone nor a significant increase in their salivary concentration is necessarily a precursor of the development of oral candidiasis. Therefore, other local or systemic factors must be present for the organisms to initiate infection and cause disease. An important cofactor associated with the pathogenesis of oral candidiasis appears to be the virulence of the infecting organism. The specific virulence features of the fungus that contribute to the development of oral candidiasis include: 1) its ability to adhere to and colonize the oral mucosa, 2) biofilm formation, 3) its ability to form cylindrical appendages termed germ tubes, 4) Its cell surface hydrophobicity. 5) phenotypic and genotypic switching, 6) extracellular aspartyl proteinase secretion and
27 7) Phospholipase production appears to play a subsidiary role in the pathogenicity. The hierarchical importance of these predisposing attributes is not well known. Epidemiology of human oral Candidiasis Isolation of Candida from the oral cavity may not imply disease, since its asymptomatic prevalence in healthy persons ranges from 3% to 48% and is even higher in healthy children, 45 to 65%. A median carriage rate of 38.1% of C. albicans alone has been observed while a higher carriage rate (up to 78%) has been observed in hospitalized elderly patients. Yeast carriage is higher in HIV seropositives and rises as the CD4+ T-cell count falls. Other pathogenic members of the genus Candida often isolated from the oral environment are (in descending order of virulence) C. glabrata, C. tropicalis, C. parapsilosis, C. pseudotropicalis, C. krusei and C. guilliermondi .C. dubliniensis is a recently discovered novel species, and its virulence potential is much like that of C. albicans due to their close genomic relatedness. Despite the existing diversity among the non-albicans species, it is the general belief that they are of low virulence and that disease manifestation is determined mainly by the health of the host. No significant difference in the carrier rate of Candida species between HIV infected subjects and controls (75% and 68% respectively) by culture could be demonstrated in South Africa. Candida albicans represented 95% of the species isolated from the HIV positive group; biotype 1 being most prevalent (API 20 C system). There are no significant associations between predominant Candida species biotypes and age, gender or malnutrition. It is unlikely that differences in Candida retrieval methodology will affect identification and prevalence reporet and culture methodology is more importance for definitive identification thank clinical. The prevalence of oral candidiasis in HIV-infected subjects reported from Africa varies between 1.5 and 94%. Unfortunately, many studies have not differentiated between the different clinical forms of the disease making direct comparisons difficult. Comparisons of Candida disease outcome in Africa are complicated by: 1) Absence of differentiation between the different clinical forms Candidiasis 2) differences in the study groups (dental outpatients, hospital in-patients), 3) HIV disease stage, 4) Ethnicity and racial diversity 5) socio-economic and demographic status, 6) Diet 7) Access to health care. 8) Rampant use of presumptive diagnosis to define the lesions 9) Unknown association of oral candidiasis with different HIV subtypes 10) Candidiasis prevalence is different in heterosexuals than homosexuals. The host oral defenses against Candida The host oral defenses against Candida essentially fall into two categories: nonspecific immune mechanisms (e.g., integrity of the mucosae, commensal bacteria, polymorphonuclear leukocytes, macrophages, and salivary factors) and specific immune mechanisms (e.g., serum antibodies, secretory antibodies, and
28 cell-mediated immunity). Six main ways in which the oral mucosa defends against Candida invasion are outlined: 1) The stratified squamous epithelium of the oral mucosa forms a continuous surface that protects the underlying tissues and functions as an impervious, mechanical barrier. The protection so provided is dependent on the degree of keratinization and the continuous shedding of epithelial cells. 2) The interaction between Candida species and the commensal microbial flora is the next vital mechanism modulating oral candidal colonization. The commensal flora regulates yeast numbers by inhibiting the adherence of yeasts to oral surfaces by competing for sites of adherence as well as for the available nutrients. A number of studies have also shown that candidal colonization of epithelia could be suppressed by Streptococci, which are the predominant resident commensals of oral mucosal surfaces. 3) Individuals with lowered levels of sIgA are more often afflicted with mucosal candidiasis, and functional sIgA appears to prevent the attachment of C. albicans to the mucosal epithelium. 4) Polymorphonuclear leukocytes and macrophages have the ability to phagocytose and kill Candida cells. However, the full expression of their activity is dependent on augmentation by cytokines synthesized or induced by T cells and the length of time they survive in the hostile oral environment bathed in saliva. 5) Mucocutaneous and systemic candidiasis are both typically associated with defects in the cell-mediated immune response. Multiplicity of defects in cell-mediated immunity in subjects with chronic mucocutaneous candidiasis has been examined and defined. 6) A quantitative reduction in salivary flow leads to a xerostomic state with a concomitant increase in oral candidal carriage and infection, indicating the importance of salivary defenses against invading fungi. Elements in saliva that inhibit the growth of Candida include nonspecific factors such as the histidine-rich proteins, the proline-rich proteins, the salivary peroxidase system, lactoferrin, and lysozyme. The antifungal activity of purified salivary histidine-rich polypeptides is known to be akin to that of imidazoles. Lysozyme and lactoferrin are two further nonimmunoglobulin salivary proteins that contribute to the regulation of oral Candida. A number of studies have documented the fungicidal effect of apolactoferrin against Candida. Clinical manifestations of oral candida infection This include: erythematous candidiasis, pseudomembranous candidiasis, angular cheilitis and linear gingival erythematous banding. Erythematous candidiasis (EC) This presents as a red, flat, subtle lesion either on the dorsal surface of the tongue and/or the hard/soft palates. EC tends to be symptomatic with patients complaining of oral burning, most frequently while eating salty or spicy foods or drinking acidic beverages. Clinical diagnosis is based on appearance, taking into
29 consideration the persons medical history and virologic status. The presence of fungal hyphae or blastospores can be confirmed by performing a potassium hydroxide preparation. Although EC has been identified as one of the more common oral manifestations seen in association with HIV disease, its presentation is frequently under-diagnosed. Treatment involves the use of topical antifungal therapies. Pseudomembranous candidiasis (PC) This appears as creamy white curd-like plaques on the buccal mucosa, tongue and other oral mucosal surfaces that may wipe away, leaving a red or bleeding underlying surface. The most common organism involved with the presentation of candidiasis is Candida albicans; however there are increasing reports of the increased incidence of non-albicans species. Like EC, diagnosis of PC is based on clinical appearance taking into consideration the persons medical history. Potassium hydroxide preparation, fungal culture or biopsy, may be useful in obtaining an accurate diagnosis. A review of the literature suggests that immune reconstruction alone does not account for PC reduction, but rather the added effect of protease inhibitors on candidal virulence factors such as aspartyl protease. Treatment should be based on the extent of the infection with topical therapies (nystatin, clotrimazole) utilized for mild to moderate cases and systemic therapies (fluconazole) used for moderate to severe presentations. Angular Cheilitis (AC) The clinical presentation of Angular cheilitis (AC) is erythema and/or fissuring of the corners of the mouth. Angular cheilitis is most often caused by an infection usually fungal, but it also can be viral or bacterial in origin. Studies have linked the initial onset with nutritional deficiencies, namely vitamin B (Riboflavin B2) and Cyanocobalamin B12) and iron deficiency anemia, which in turn may be evidence of poor diets or malnutrition (e.g. celiac disease). Physical causes include the overclosure of the mouth by someone without teeth, thumb-sucking, lip biting, and continual licking of the lips. Less severe cases occur when it is quite cold (such as in the winter time). Angular cheilitis can exist for an extensive period of time if left untreated. Treatment involves the use of a topical antifungal cream directly applied to the affected areas four times a day for the two-week treatment period. Linear Gingival Erythematous Banding (LGEB) This is a periodontal disease which presents as a red band along the gingival margin, which may or may not be accompanied by occasional bleeding and discomfort. LGEB is seen most frequently in association with anterior teeth, but commonly extends to the posterior teeth. LGEB can also present on attached and non-attached gingiva as petechia-like patches. It is typically associated with no symptoms or only mild gingival bleeding and mild pain. Histological examination fails to reveal any significant inflammatory response, suggesting that the lesions represent an incomplete (aborted) inflammatory response, principally with only hyperemia present. Research has indicated there may be a relationship between sub-gingival colonization of Candida species and HIV-related periodontal
30 conditions including LGE. The most recent classification of periodontal diseases by the American Academy of Periodontology grouped LGE under gin gival disease of fungal origin. Treatment for this condition would include debridement by a dental professional followed by twice daily rinses with a 0.12% chlorhexidine gluconate suspension for two weeks and improved oral hygiene home care.
2a. Bacterial Infection Of The Blood & Lymphatic System

Bacteraemia
Introduction Bacteria may enter the bloodstream, giving rise to Bacteraemia, from an existing focus of infection, from site with commensal flora or by direct inoculation into the vascular system. If the bacteria persist in the blood resulting in signs & symptoms, its called Septicaemia. Bacteraemia refers to the transitory presence of bacteria in the blood of patients without symptoms. Septicaemia is the presence of bacteria in the blood with signs and symptoms of infection. Bacterial origin is from forcus of infection from which they enter the circulation. The method by which bacteraemia is acquired can be grouped into two: Community Acquired Bacteraemia (CAB) and Hospital Acquired Bacteraemia (HAB) Community Acquired Bacteraemia (CAB) It occurs in previously healthy people. CAB is usually caused by organisms sensitive to many antibiotics. It can occur in association with infection at a local site from where organisms enter the blood stream. Organisms responsible for CAB most often comes from patients own commensal flora. Examples of etiologic agents of CAB include: S. aureus, E. coli, & S. pneumoniae. i. E. coli It is the commonest with 26.1-72.7% in prevalence. About 60% of UTI study focus is on women than on men. Bacteraemic UTI has a variety of clinical presentations such as: pyelonephritis; non-specific illness (asymptomatic) in the elderly, diabetics and in females. It is encouraged by urinary retention or other obstructive pathology. Biliary tract study focus is associated with cholelithiasis and local malignancy. Other foci include GIT and vertebral osteomyelitis. It originates from colonic flora whatever the focus of infection. The predominant serotype of E. coli in order of frequency is O6, O2, O4, O1, O18 and O75 but many other serotypes may be found. Its is uncertain whether the predominance of certain serotype in the urinary tract or colonic flora determines the uropathogenicity. E. coli O15 serotype caused a community based epidemic in SE London in 1986. This epidemic manifested as UTI and bacteraemia. The strains of E. coli isolated were found to be resistant to antibiotics e.g. amoxicillin, ampicillin, trimethoprim, tetracycline and chloramphenicol.
31 ii. S. pneumoniae This is 2nd to E. coli in causing CAB. Most cases are associated with RTI & meningeal infection. No focus of infection is found in most patients with pneumoccocaemia. Most cases may be traced to: Splenectomy Trauma Asplenic patients due to Sickle cell disease Occult pneumococcaemia a condition seen in young children less than 2 yrs of age. Pneumococaemia may be mistaken to be viral respiratory infection with febrile convulsion. Pneumococaemia was first described in 1967 by Belsey and is better referred to as occult bacteraemia. It is more common in United States & Finland (69%) than UK. The most common serotype is serotype 14, followed by serotypes 3, 8 and 1. It is common in those with underlying infections such as broncheopulmonary disorders, alcoholism and HIV. iii. S. aureus Here most cases may arise due to local tissue infections and other cases may be unclear, but may be traced to skin lesions. Common places of localization include bone, joint and heart valves. Less common sites are RT and preinephric abscess. Acute osteomyelitis of the long bone usually common in young boy children is now much less common while incidence of hematogeneous vertebral osteomyelitis has increased being most common in the elderly. In Staphylococcal vertebrate osteomyelitis, isolation of S aureus from blood cultures is the 1st indication that the patients backache or neck-ache has an infective aeteology. Staphylococcal septic arthritis is less common than Staphylococcal osteomyelytis. It can occur in previously healthy people but is even more likely in patients with pre-existing joint pathology (rheumatoid arthritis). In such patients, more than 1 joint may be affected and diagnosis may be difficult b/c symptoms are arttributed to underlying disease. Other organism Mycobacterium species Streptococcus pyogenes Listeria monocytogenes Haemophylus spp Coliform (Not E coli) Salmonella spp Neisseria menigitidis Hospital Acquired Bacteraemia (HAB) HAB is most common in tertiary Hospitals which have all kinds of patients. Technological advancement and invasive procedures increases the incidence. The coagulase ve Staph and enterococci has contributed to the increase. Coagulase -negative Staphylococcus The most common is S. epidemidis which accounts for about 75% cases followed by S. haemolyticus (12%). They frequently colonize RT of babies leading seldom
32 to RTI and bacteraemia. Their clinical relevance is difficult to determine in adults except immunosuppressed persons.
Staphylococcus aureus
This is also involved in HAB accounting 17.5%. Source of infection include haemodialysis and surgical wounds (including sternal wound abscess, abdominal wound infection and hysterectomy)
Enterococcus spp
It accounts for 7.7% in the 90s. They are mostly associated with intravascular line. E. faecium and E faecalis are most common. They are vanco, amp, and amox, & gent resistant
E. coli
Focus of infection include intravenous line and other devices where urethra are manipulated such as change of catheter, use of instruments such as cytoscope or bladder dilatation devices. The incidence of infection is from 46 to 52%. Sensitivity pattern is similar to that due to CAB Other Gram-ve bacilli P. aeruginosa (9%) Klebsiella spp (6%) Enterobacter spp (4.8)% Proteus spp (3.7)% Other enterobacteria causing HAB (not E. coli accounts for about 20%) Other organisms Anaerobic bacteria have decreased in incidence from 7.2-3.6% in the last 2 decades. This decrease may be due to use of antimicrobial agents. Increases yeast bacteraemia results from infected intravascular line. The concluding remark The conclusion of bacteraemic infection depends on both virulence of the pathogen and the underlying condition of the patient at the onset of bacteraemia. Bacteraemia hardly kills but if it does it is more likely to be CAB. Mortality rate for patients with: good prognosis is 23%, intermediate prognosis is 62% and poor prognosis is 88%. Innate virulence of pathogens of CAB enhances their mortality rate more than that of HAB Septic Shock or Bacteriogenic Shock This is characterized by sepsis syndrome and hypotension not explained by hypovolaemia or cardiac cause. About 30-60% of Septic shock patients have negative blood cultures. Septic shock may refer to a subset of patients with the sepsis syndrome who also have hypotension not explained by hypovolaemia or cardiac cause. Systemic inflammatory response syndrome is non-infective conditions such as pancreatitis and burns mimicking bacterial sepsis. There is high mortality with shock and organ failure patients Pathogenesis This involves both microbial virulence and host factors. It may be polymicrobial in origin. In Gram negative bacterial shock, LPS binds to different carrier molecules forming a complex which then interacts via cell surface molecules with
33 host monocytes and endothelial cells. Superantigenic bacterial toxins such as Staphylococcal toxic shock toxin 1, (STST-1 or TSST-1) and Strptococcal pyrogenic exotoxin A (SPEA) causes profound hypotension, inflammation and organ failure in animal mordel. Staphylococcus sp and Streptococcus sp which express this toxin causes syndrome in man. These toxins trigger T-lymphocyte activation & proliferation with release of cytokines. The host immune system is stimulated by infection and in an attempt to combat this produces numerous proinflammatory mediators which assist target cell to eradicate the pathogen Modulating and anti-inflammatory mediators are released simultaneously and if the balance is inappropriate the host may suffer harmful consequences. Thus host factors produced in response to infection can produce deleterious effect and contribute to pathogenesis of septic shock. Treatment with TNF & Monoclonal AB may not be very beneficial. Septicemia Introduction When bacteria overcome the defenses of the body and reproduce within the CVS and lymphatic system, then can produce septicaemia or blood poisoning. Gram negative and positive bacteria are involved. S. aureus and S. pyogenes are prominent in Gm+ve group. Pseudomonas aeruginosa, E. coli, Enterobacter aerogens, Serratia marcescens, Proteus mirabilis, Salmonella spp etc are involved. They release LPS (endotoxins) from their cell walls when they lyse in the circulatory system. Endotoxins in circulation damage blood vessels and cause inflammation of CVS & lymphatic systems. Presentation of Septicemia Red streaks may appear under the skin along the arms and legs due to inflammation of the lymph vessels. This may be followed by fever, BP and shock. Treatment includes use of necessary antibiotics to eliminate the infecting bacteria. Typhoid fever This is a systemic infection caused by Gram negative bacterium S typhi. Outbreaks are associated with contaminated water supply and handling of food products by infected individual. (Typhoid Mary) Portal of entry There is enough evidence to confirm the fact that the etiologic agent enters the circulation through the feco-oral route. It is transmitted through food, milk, water and the ulcerated ileal payers patches. It penetrates the cells of the small bowel to the lamina propria. They move to mesenteric lymph nodes and by way of the lymphatic system & thoracic duct to blood stream giving rise to 1o infection. The bacteria can settle in the bone marrow, spleen and liver from where they multiply and cause secondary infection. The stomach and normal flora of jejunum act as barriers to bacterial invasion. Intact O antigen and a complex of genes is needed to invade the stomach epithelium. In the lamina propria, bacteria are engulfed by macrophages/neutrophiles where they survive and are taken to regional lymph
34 nodes, blood stream and RES. Localized infection is in the lymphatic tissues like payers patches of the intestine, liver, kidney, spleen and lungs Clinical manifestation In the classical case, incubation is about 10-14 days and it starts with fever malaise and headache. During the first week the fever becomes steadily high being higher in the evening (0.5oC) than morning. There is abdominal discomfort rather than pain, constipation, relative bradycardia and mild splenomegaly. In the 2nd week, the fever may be steady or swing, patients becomes weaker, mentally confused and rose spot appears on the abdomen & lower chest. In the 3rd week, if untreated patient becomes uncomprehending, muttering and disoriented. Carriage There is high carriage rate because it can remain and multiply within infected cells. It can also grow in the gallbladder providing a source of bacteria that enter the intestine and are shed in feces. This helps in continual spread of the bacterium from carriers. Mortality rate is 10% in untreated cases. Chloramphenicol is effective despite its side effect. The quinolones are also effective Puerperal Fever Puerperal fever is a systemic bacterial infection characterized by high fever and if not treated has a high mortality rate. Most frequent etiologic agent is betahemolytic group A & B Streptococcus sp. It can also be caused by Staph, Pseudo, Bacteroides, Peptostreptococcus, Clostridium, etc. Sources of infection are from obstetrician, obstetrical instrument, normal flora and beddings. Plague: This is caused by Yersinia pestis, a Gram negative, non-motile pleomorphic rod that shows bipolar staining. Animal reservoir is wild rodent, mice, rats, rabbits & dogs while the insect vector is flea. The introduction of Y. pestis into humans through flea bites initiates a progressive plague infection. By phagocytosis some are killed but it soon develops capsule which resist phagocytosis. Bubonic (enlarged lymph nodes) plaque In this infection Y. pestis is localized and cause inflammation in the regional lymph node e.g. ampits, neck, groin and upper legs. Symptoms include malaise fever and sever pain in the infected regional Lymph Nodes (LN). Exotoxin causes tissue death while subcutanous hemorrhage leads to blackening of the skin. Pulmonary plaque occurring via droplets may establish pneumonic plague. In the lung it manifest through sever prostration, respiratory difficulties and death within few hours of onset. Drug of choice is Streptomycin Gas Gangrene This is an infection that may result from the growth of Clostridium sp. Tissue damage interrupt circulation to certain area creating anaerobic environment that will make strict anaerobe to grow. Since gas is not formed till later path of infection, this infection is better called Clostridium myonecrosis. Gas gangrene is due to a mixed infection of organisms capable of producing large number of enzymes that enhance their invasive capacity Pathogenesis
35 Development of disease depends on deposition of Clostridium endospores in wound tissue and development of anaerobic conditions due to necrosis of local tisues permiting germination and growth of bacteria. The exotoxins produced by Clostridium are tissue necrosins and hemolysins that may spread from infected to uninfected tissue killing them. This allows the infection to spread rapidly to adjacent areas as they lose circulation and become anaerobic. Co2, H2, Low Molecular Weight metabolic products are produced by growing clostridium. The build up of gas pockets in the tissue cause crackling or rattling called crepitation. Onset is within 72 hr of wound occurrence. Debridement and antibiotics can help block bacterial spread. Prevention depends on securing the wound (aedquate drainag) to prevent anaerobic bacteria from entering & foregn material and dead tissues. An oxygen chamber kills the Clostridium spp Relapsing fever This is caused by Borrelia recurrentis, Gram negative spirochetes that are helically coiled around a central filament attached to the end of the cell. It is transmitted to human by rodent through tick bites of the soft tick ornithodorus. Pathogenesis In the tick the bacteria are transmitted by trans-ovarian passage, through the ovaries to the eggs so that it is passed congenitally from generation to generation.Under crowded condition epidemic outbreak may occur with human to human body louse transmission. Clinical manifestation and treatment It presents with sudden but intermittent fever approaching 105oF for 3 to 6 days. The fever then falls & becomes normal for 5-10 days. Infecting bacteria alters their surface antigens to evade the immune system permitting a relapse of the fever. There are two relapses in the epidemic form and three to four in the endemic form of the disease. Anatomical abnormalities and lesions may develop in the spleen and other body organs. Antibody mediated response may remove Borrelia naturally from the body. Penicillin, Tetracycline, and Chloramphenicol are effective againt Borrelia and are used in treating the disease. With proper treatment, over 95% of patients with relapsing fever recover. Rickettsial Diseases Rickettsia species are obligate intracellular parasites which can not generate enough ATP. They are cultured using tissue culture techniques. They are vector borne disease. Different species cause different disease as outlined A. Rocky mountain spotted fever This is caused by Rickettsia rickettsii transmitted through tick bites. When injected into the human host, it multiplies within the endothelial cell of the blood vessel. Skin rash is due to vascular lesions. Rash most prevalent at the extremities and lesions may occur at the meninges causing sever headache and mental confusion. Prevention involves avoiding tick bites. Tetracycline & chloramphenicol are used for treatment. B. Typhus fever (epidemic)
36 All types are caused by rickettsia transmitted to human by infected arthropod vector. Epidemic typhus is caused by Rickettsia prowazekki, (via body louse), transmitted from person to person. It multiplies within the midgut of the louse. When infected body louse bites, it defecates at the same time depositing faeces containing R. prowazekii which then enters through the wound created by the bite. The onset involves headache and rash. The heart and the kidney are the site of vascular lesion. Fatality rate is 50% in persons 10-30 years of age. Chloramphenicol, tetracycline and doxycycline are effective. C. Murine typhus or endemic typhus fever This is caused by Rickettsia typhi, transmitted to humans by rat fleas. Transmission and symptoms are similar to epidemic typhus but milder. Chloramphenicol, tetracycline and doxycycline are effective D. Scrub typhus This is caused by R tsutsugamushi transmitted via mite bites and reservoir is rat. The infection becomes localized in the lymph node. Symptoms include fever, severe headache and rash.Chloramphenicol, tetracycline and doxycycline are effective E. Rickettsialpox This is caused by R akari transmitted to humans by the mouse mite. Systemic spread of the disease is followed by onset of the illness manifested by fever, headache, and secondary lesions. The rash may develop on any part of the body but not palms and soles Tularemia This is caused by Francisella tularensis, a gm-ve fastidious coccobacillus. This is transmitted by biting ticks & deer-flies, inhalation of contaminated aerosols and ingestion of contaminated food and water. It may enter the body directly through hair follicles and the fingernails. Transmission to humans can occur through ingestion of contaminated meat and handling of infected animal e.g. rabbits. It is localized within the regional lymph node. Finger and skin ulcers, elevated fever and enlargement of lymph nodes are common. Streptomycine, tetracycline and chloramphenicol are effective Brucellosis This is caused by Brucella spp, a Gram negative small, nonmortile, aerobic rods. This is an infectious disease of nonhuman animals. B. arbortus (cattle), B. suis (swine), B. melitensis (goats) and B. canis (dogs). It is transmitted to humans through infected animals and milk. In the body, it spreads via the mononuclear phagocytes and are localized in the regional lymph nodes. Symptoms include liver and spleen enlargement, weakness, chills, malaise, headache, backache and fever (undulant fever). Because they are intracellular, combination of tetracycline and streptomycine are effective. Prevention involves elimination in animal reservoirs like sheep, cattle & goats using vaccines Lyme disease
37 This is an inflammatory disease caused by the spirochete Borrelia burgdorferi and transmitted to humans by Ixodes ticks. White tailed mouse and white tailed deer are the reservoirs of Borrelia burgdorferi. It begins with circularly expanding indurated skin painless lesions with wide boarders and central clearing. Accompanying symptom may resemble mild flu, mild meningitis or encephalistis, hepatitis, musculoskeletal pain, enlarged spleen and cough. Week to months later arthritic joint pain and some neurological disorders is a second stage of the disease. Crippling arthritic and sever neurologic symptoms mimicking multiple sclerosis appears years later as 3rd stage of disease Bartonellosis It is an infection caused by the obligately intracellular gm-ve bacterium, Bartonella bacilliformis. It is transmitted to people through the bite of infected sandfly and occurs only in the valleys of Andes Mountains of Peru, Ecaudor and Colombia. B. bacilliformis proliferate within the endothelial cells of the blood vessels after inoculation by the bites of sandfly vector. The bacteria reenter the circulatory system and infect erythrocytes causing severe anemia, fever, headache, delirium. Chloramphenicol is effective
2b. Fungal disease of the blood and lymphatic system

Introduction The prevalence of invasive fungal infections is increasing in very low birth weight (VLBW) (<1500 g) infants. Factors that predispose these low birth weight and immunocompromised infants to fungal infection include: invasive procedures with central vascular catheters and endotracheal tubes, exposure to broadspectrum antibiotics, parenteral nutrition and exposure to postnatal steroids. Most fungal infections in preterm neonates are due to Candida species; a much smaller number of infections may be attributed Malassezia, Zygomycetes, or Aspergillus pathogens. Candida species are commensal organisms that colonize the skin and mucosal surfaces and adhere to catheter surfaces. Candida can invade the bloodstream and disseminate in these infants because of their immature immune systems. These infants are at the highest risk of acquiring invasive fungal infections during the first weeks of life, when the most invasive therapies are performed. Infection control, prophylaxis, and aggressive treatment (antifungal therapy and central catheter removal) during this period have the greatest potential to improve the infection outcome of this population. Pathogenesis The pathogenesis of fungal infections in preterm infants involves adherence, colonization, and dissemination. Adherence and the slow-growing nature of Candida facilitate its ability to colonize and disseminate into the bloodstream and body tissues before clinical signs and symptoms of infection become apparent. Surface glycoproteins (INT1p) play a role in fungal adherence. Antibiotic use leads to Candida colonization of mucosal surfaces but when dexamethasone is introduced (to amplify the inherent immunoincompetence), both colonization and dissemination may increase futher.
38 C albicans is dimorphic, having both yeast and filamentous forms (eg, hyphae, pseudohyphae, germ tubes), and is assumed to have increased virulence in immunocompromised patients because of the filamentous forms. Filamentous forms may contribute to colonization and infection, although species that do not form filaments, such as Candida glabrata, also colonize and cause invasive disease in VLBW infants. In preterm infants, vertical and horizontal transmission leads to colonization of the skin, mucosal membranes (GI and respiratory tracts), and central vascular catheters. After exposure, patient factors, such as degree of prematurity, skin condition, endotracheal intubation, central vascular access diseases (eg, necrotizing enterocolitis, focal bowel perforation and abdominal surgery) can contribute to fungal infection. Fungal factors that contribute to neonatal infection include the size of the inoculum and factors that favor colonization and proliferation (eg, use of broad-spectrum antibiotics, postnatal steroids, histamine type-2 [H2] antagonists, parenteral nutrition, or lipid emulsions [ Malassezia species]). Invasive infection of the blood, urine, cerebrospinal fluid (CSF), or peritoneal fluid can lead to disseminated infection, which most commonly involves the heart, kidneys, CNS, eyes, and/or liver. Risk factors In the VLBW infant, colonization of the skin, mucosal membranes, and/or vascular catheters commonly precedes infection. Biofilm formation on catheters inhibits the host's defense mechanisms and the penetration of antifungal agents. Infusates may also become contaminated and directly seed the bloodstream. Risk factors for Candida colonization and sepsis are similar. Central vascular catheters, vaginal delivery, use of third-generation cephalosporins, and high acuity are risk factors for C albicans infection. H2 antagonists, third-generation cephalosporins, central vascular catheters, parental nutrition and lipid emulsions, and high acuity are risk factors for Candida parapsilosis infection. GI disease (eg, NEC, FBP), exposure to fluconazole or antibiotics, prolonged hospitalization, and infection with other fungi increase the risk of sepsis due to C glabrata. GI mucosal injury, antibiotic suppression of bacterial flora, neutropenia, and parenteral nutrition are risk factors of sepsis due to Candida tropicalis. Disseminated infection Patients with disseminated infection may present with several complications. Endocarditis: Endocarditis has been reported in 5-15% of candidemia cases. Renal abscess: Renal abscess is detected in 5% of patients with candidemia. It may occur in 36.6% of VLBW infants with fungal urinary tract infections. CNS abscess/ventriculitis: CNS abscess occurs in 4% of patients with candidemia. This may be a complication in infants with fungal meningitis. Endophthalmitis: This occurs in 3-6% of patients with candidemia as multiple or single, yellow-white, raised lesions with indistinct (fluffy) or circular edges located in the posterior fundus or vitreous. It may affect one or both eyes. Liver abscess: Liver abscess occurs in 3% of patients with candidemia. Liver ultrasonography is recommended in patients with persistent Candidemia but is particularly indicated if hepatomegaly results.
39 Splenic abscess: Splenic ultrasonography is recommended in Candidemia patients with over 5 days splenomegaly. Cutaneous abscess: Skin abscesses should be cultured and drained, Osteomyelitis: Evaluation should be considered in infants with infection who are not moving, have limited range of motion, or have swelling of an extremity. Septic arthritis: Septic arthritis manifests with joint swelling. It may also occur several months after antifungal treatment. Peritonitis: Peritonitis may occur with any bowel perforation, FBP, and NEC. It can be a complication of any abdominal surgery Malassezia infections Presentation of infection with Malassezia organisms is similar to that seen with invasive candidiasis. Causes localized infection therefore end-organ surveillance is needed only if species are persistently isolated from several cultures. Malassezia furfur is a lipid-dependent fungus that may colonize central venous catheters when lipid emulsions are infused. It can also colonize the skin and GIT. Horizontal transmission is common. These fungi readily grow in Sabouraud medium coated with sterile olive oil. Treatment can include stopping lipid infusions for 48-72 hours, administering amphotericin B for 7 days and removing the central venous catheter. Malassezia pachydermatis is not an obligate lipophilic organism. It has been reported to cause sepsis, urinary tract infection, and meningitis in VLBW infants but not in other neonates. Horizontal transmission occurs and can be prevented with hand washing. Aspergillosis Aspergillus infections are rare in neonates but are associated with a high morbidity and mortality rate. Aspergillus species are ubiquitous filamentous fungi (eg, molds) that form spores in the air, soil, decaying vegetation, and dust. For the neonate, transmission usually involves airborne spores. The site of entry may be the respiratory tract, skin, or central vascular catheter. Infection is due to exposure to contaminated dust. Invasive aspergillosis in infants can be cutaneous, pulmonary, or systemic infections, with occasional dissemination to the CNS. Diagnosis is difficult, and a high index of suspicion is needed. Any culture that is positive for Aspergillus must be considered serious in preterm infants. Any skin or oral rashes or lesions should be cultured. Pulmonary presentation should be considered if infection is suspected with negative culture results and persistent signs despite antibacterial treatment. When involved in injured skin areas, it rapidly progress to necrotic eschars. Diagnosis is made by demonstrating septate hyphae with 45 angles characteristic of Aspergillus species. Spores do not readily grow in blood cultures. The organism can be isolated from Bronchoalveolar lavage fluid, lung or skin samples when they are cultured on Sabouraud dextrose agar. Responds to treatment with amphotericin B and does even beter with newer antifungals, including voriconazole and echinocandins (eg, caspofungin or micafungin). Prevention involves filtration of Neonatal Intensive Care Unit (NICU) ventilation systems and containment of dust and ceilings, during hospital renovation
40 Zygomycosis Zygomycotic infections initially present as a black eschar at a site of local trauma or intravenous catheter insertion or infiltrate and progress to a necrotizing soft tissue infection. Early diagnosis, treatment with amphotericin B, and surgical debridement are needed to prevent ulceration, necrosis, and rapidly fatal dissemination. A high degree of suspicion is needed, and tissue biopsy must be performed to identify the nonseptate hyphae with right-angled branches. The mortality rate associated with these infections is reported to be 61%.
3a. Bacterial Disease of the Central Nervous System (CNS)

Introduction The brain and the spinal cord make up the CNS which lies on an environment well protected from infectious agents. Three membranes (dura, arachnoid and pia) called the meninges cover the surface of the brain and the spinal cord. Inflamation of arachnoid and pia leads to menigities. Etiology The commonest cause of bacterial meningitis is Neisseria meningitides. In unimmunized population, the capsulated strains of Haemophylus influenza type b (Hib) is the second most prevalent bacterium, followed by Streptococcus pneuminiae, Mycobacterium tuberculosis, clostridia, and Listeria monocytogen. In neonatal menigitis, group B Streptococcus and E. coli predominates while Listeriosis is common in neonates, during pregnancy and at old age. Bacteria like Staph spp, P. aeruginosa and Acinetobacter spp may cause meningitis associated with in-patient hospital care, severe immunosuppression, neurosurgery or CSF infection shunt. Mortality rate is about 10% in developed countries and over 30% in developing countries. Epidemiology of disease has changed with vaccination against Hib, group A & B meningococcal minigitis and Pneumococcus Pathophysiology of Bacterial Meningities This follows a sequence of exposure to the pathogen, acquisition and then invasion. Invasion is devided into 3 processes: mucosal penetration, blood stream and meninges invasion. The human nasopharynx is the natural habitat of meningococcus, Hib and pneumococcus among others. Invasion and colonization depends on the frequency and intimacy of interaction between colonized and susceptible individuals and the capacity of colonized individuals to diseminate bacteria from the nasopharynx. Dissemination may be influenced by colonization intensity, intercurrent viral infection, ambient temperature and humidity. Carriage rate reflect acquisition and duration of carriage. With age nasopharynx becomes less susceptible to colonization by Hib, Pneumococcus and meningococcus Sources of CNS infection The blood is the chief source of CNS infection followed by the nerves and direct extension from bones. Some pathogeens enter the CNS by way of the nerve bundles probably within the nerve fibers themselves e.g. tetanus toxin, rabies and HSV infection can extend via bone to the CNS from the: sinuses, mastoids, skull
41 fractures, face above the level of the mouth involving veins that communicate directly with veins on the brain surface or the middle ear. Bacteria invasion of CNS The three major bacterial meningitis pathogen; Hib, pneumococcus and meningococcus can invade the CNS by the following mechamisms: i. Produce an IgA1 protease closely associated to invasion potential. ii. Has capsular strains which are more virulent than non-capsular strains iii. Influenza A may increases the risk/severity of meningococcal diseases. iv. Bacteria is bound by cerebral capillary endothelium of the choroid plexus, undergos fimbrial phase variation and cross the blood brain barrier (BBB). v. Bacteria may also gain access to the subarachnoid space within host phagocytic cells where they are transiently sheltered from the defense of the host. From here they can release substances which can alter the BBB vi. Most of the bacteria has pilli and are coated with surface polysaccharide that interferes with phagocytosis. They survive passing through the circulatory system, reach the CNS and enter the cerebral fluid. They survive in the CSF because there are few phagocytes, low concentration of Ig & complements, and presence of nutrients like sugar that support bacterial growth in CSF. In CSF, Hib LPS induces the production of inflamtory cytokines e.g. TNF and ILN-1. Pneumococcal cell wall which contains peptidoglycan and teichoic acid are more potent than capsular polysaccharides in inducing subarachnoid inflamation. When BBB is destroyed, larger molecules flow in from circulation and phagocytic cells flow into the CSF Clinical features This is determined by age, causative organisms and route of entry. Early signs and symptoms are non-specific but include: fever, weariness or lassitude, malaise, muscular aches and pains, nausea, vomiting, headache, inconsolable crying, a fit, and evidence of decreased consciousness in febrile children. Diagnosis of meningitis Though CSF examination is central in the diagnosis of meningitis, raised intracranial pressure is followed by herniation of the brain stem through the foramen magnum. A CT scan is very helpful since the old papilloedema is an insensitive indicator or intracranial pressure. CSF examination is still the best way of isolating and identifying causative organism. Even when bacteria can not be recovered from culture, gram staining may confirm diagnosis and indicate likely causative organism. A portion of CSF is examined for leukocytes types present. Bacterial meningitis is indicated by high neutrophil count. About 5% showed positive culture but no leukocytes in CSF. Patients on antibiotics, with viral meningitis, cerebral hemorrhage or have had a fit may show mixed cell population of lymphocytes & polymorphs. CSF glucose and protein estimation are also helpful. CSF blood glucose level is reduced in bacterial meningitis while protein is raised indicating leakage of blood protein into CSF and may later reflect local antibody production. Microscopy may reveal an organism that may be missed by culture if the patient has been on antibiotic. By gram staining the 3 major agents may be identified. Culture of CSF on BA in 5% Co2 is confirmatory while PCR of DNA of agents is specific and sensitive. Less sensitive blood
42 sample may also be used in the absence of CSF. Nasopharyngeal swabs provides evidence of etiology. Meningoccoccal Disease Epidemiology This remains a global problem occurring intermittently as clusters of cases and as epidemics. Lapeyson (1963) was the first to describe Meningitis belt as an area in Africa, south of the Sahara and extending from coast to coast where epidemics of the meningitis disease occur every 5-10 years. The boundaries of the meningitis belt may be defined by climatic factors. The disease is seasonal in the meningitis belt with an upsurge during harmattan (dry season) and cessation at the start of rainy season. Epidemics are reported to be due to the spread of new clones of sero-type A. The highest attack rate is in the age group 5-15 years. Carriage They are not carried by animals and not recovered from the environment. Humans may be selectively colonized because meningococci are only able to acquire iron from human transferin and lactoferin. Fimbriae facilitate binding to human epithelial cells but capsulation reduces adherence. Expression of capsule may be downregulated during prolonged carriage. Carriage rates are low in infants and young children, rises with age to peak in late teenage and early adult life, decline in the next 20-30 years and are very rare above 65years. (The graph is like a cup). Most nasopharyngeal meningococci belong to serogroup of low virulence (x or y), and exposure to these strains only boost levels of antibody against non-capsular surface antigen. Carriage appears to remain high and unaffected by season, intercurrent viral infection or vaccination with purified capsular polysaccharide. Smoking has a strong dose-related effect but contact with meningococcal disease is the most important risk factor for carriage. Cross reacting bactericidal IgG acquired by exposure to N. lactermica at infancy may confer immunity to Meningococcal group A and C disease. Serogroup C is associated with outbreaks in play-groups, schools and barracks Immunology Secretary or circulating IgA antibodies may block meningococcal surface antigen. Meningococcal surface antigen interacts with host IgM and IgG to activate complement which may finally cause complement-dependent immune lyses. Therefore the blocking action of IgA is important in meningococcal disease in older children and adults. Risk factors and presentations This includes many congenital diseases, AIDS, lack of factors P (properdin), C5 and C9. Meningococcal disease presents 75% as meningitis and 20% as septicaemia. The characteristic feuture is the presence of petechiae or purpura in the skin. Though hemorrhagic skin rash may occur in Hib, it is most frequent in meningococcal meningitis and all cases of meningococcal septicaemia. Pathology Meningitis resembles a localized shwartzman reaction (organisms endotoxin increases the bodies sensitivity to repeated endotoxin exposure). In older patients it presents with malaise, muscular aches & pains (evidenced by stiff neck &
43 back), diarrhea and sometimes vomiting, fever and headache progressing to confusion, coma, shock and circulatory collapse, if unrecognized. In the later stage a hemorrhagic skin rash is almost inevitable. Septicaemia is a far more serous condition with a mortality rate > 20-25%. It can occur with or without evidence of meningitis. Fever, shock and hemorrhagic skin rash is the hallmark of this condition. Onset is abrupt and multisystem failure is common. In addition to antibiotics, inotropes, mechanical ventilation and hemodialysis may be required for considerable period. Survivors of sever septicaemia may need amputation of necrotic fingers, toes or limbs. Antibiotic susceptibility Benzylpenicillin is the drug of choice in meningococcal disease. Cefotaxime, ceftriazone and chloramphenicol are suitable alternatives. Beta-lactamase production and penicillin-resistant meningococci which may have resulted from acquisition of genetic material from the related oropharyngeal commensal, Neisseria flavescens have been globally reported. Rifampicin, Ciproflox, dexamethasone and Ceftriazone can eliminate nasopharyngeal colonization. Novel therapies under consideration for treatment of sever meningococcal disease are anti-endotoxin, anti-cytokines response agents, leukocyte activation antagonists, cardiovascular support agents and many others. Vaccines Prospects for serogroup B vaccine are more distant because it is a weak antigen in humans. Much effort is being invested in search for stable surface-expressed serogroup B antigens that will provoke the development of human bactericidal antibodies. Lack of correlation between the immune response to candidate antigens in lab animals and in man is another problem in the search for serogroup B vaccine. Class 1 outer membrane protein, iron binding and iron regulated proteins are being investigated. Pneumococcal meningitis (PM) Pneumococci are the second most common cause of meningitis in countries that have introduces Hib conjugate vaccine. Mortality rate of 25% and is higher that this in the elderly. Rate of 40-50% has been reported in tropical Africa. Morbidity is also higher than in Hib and meningococcal meningitis. High morbidity may be because of the high number of bacteria found in the subarachnoid space, and their capacity to induce a viscid gelatinous exudate into which antibiotic penetration is poor. Antibiotic resistance to penicillin, third generation cephalosporin and chloramphenicol has been reported and is becoming a global therapeutic problem. Epidemiology S. pneumonia causes bacteraemia and meningitis in all ages but attack rate is higher in infants falling to low level in children and young adult. Bacteraemic level is high in the elderly and meningitis is not. About 1/6th of all pneumococcal infection leads to meningitis. Highest prevalence is in the first week of life when the agent is acquired from the maternal birth canal. Males are affected more than females and infection is more in dry season (winter). Age is the most important risk factor followed by host conditions (splenectomy, thalassaemia, sickle cell disease, alcoholism, myeloma, hypogamma-globulinaemia & complement
44 deficiency). They gain access to the CNS by blood-borne dissemination, infected middle ear, infected mastoid cavity and meningeal tear after craneal trauma. A distant focus of 1o infection like pneumonia, mastoiditis or sinusitis is more common in pneumococcal meningitis than others. Patients with pneumococcal menigitis (PM) often have underlying medical condition. Out of about 84 serotypes of pneumococci, only 15 (1-9, 12, 14, 18, 19, 22, 23) are able to establish invasive pneumococcal disease. A particular serotype may be associated with CNS infection Clinical presentation This depends on age and is similar to other types of pyogenic meningitis. The presentation is abrupt but sumptoms develop over several days. Patients tend to more ill than Hib and meningococcal meningitis. Fits are commoner and there may be focal neurological signs especially cranial nerve palsies. Comatose or semicomatose patients are more likely to have pneumococcal than meningococcal meningitis (MM). Petechial rashes (less common compared to MM) may occur especially in asplenic patients. Clinical presentations in neonates are similar to that of other bacteria meningitis. Death may occur in elderly patients, those with decreased consciousness and convulsion. Treatment Antibiotic treatment can be achieved using penicillin, cephalosporins, vancomycin and rifampicin. There are reports of penicilin, quinolone and cephalosporin resistance globally. Detection of resistance to beta-lactam antibiotics is associated with treatment failure. Steroids like dexamethasone may reduce mortality and morbidity. A contact with a case of PM does not confer increased risk of disease. Neither antibiotic prophylaxis nor vaccination can confer protection from contacts. The occurrence of a second episode of PM should raise suspision of dural tear and cranial trauma. This should be a neurological case. Pneumococcal capsular polysaccharides (CP) are the major virulence determinants and are immunogenic. Prevention Multivalent vaccines are used because they are more than 80 serotypes, and protection is serotype specific. Purified pneumococcal polysaccharides do no make ideal vaccine. They stimulate B lymphocytes directly without stimulating T cells. T-cell independent antigens are defective as vaccine candidate because no memory is induced, there is no affinity maturation, T cell not required, late ontogeny of response, and antibody response restricted to isotypes. In older children and adults the antibody produced does not persist leading to waning of protection over time. The capacity of the commonly used 23-polyvalent vaccine to induce immune response decreases after 60-65 years. Immunogenicity is poor but recommended in patients with: increased risk of invasive deases, asplenia, hyposplenism, HIV/AIDS, sickle cell disease, metabolic disorders (diabetes) chronic respiratory, liver and renal disease. Vaccination does not protect against recurrent PM due to dura tears but repair of the defect is the only effective treatment. Candidate pneumococcal vaccine being tested for future use include conjugated pneumococcal polysaccharide vaccine, pneumolysin, neuraminidase pneumococcal surface protein A a 37kDa outer membrane proteins.
45
Haemophylus influenza type B (Hib) meningitis Epidemiology: Haemophylus influenza type b is the commonest cause of bacteria meningitis in children under the age of 5yrs in almost all countries. While it accounts for about 48% of the reported bacterial meningitis, it has the lowest (6%) mortality rate. It is especially prevalent in about 6months of age and the antibody acquired from the mother confers immunity for only 2 months. The carrier state in the throat of children is high. The degree of increased risk depends on intimacy of contacts. Household contacts are at greater risk than day-care and pre-school play group contacts. Rifampicin prophylaxis and a cause of Hib vaccine should be given to unimmunized children population. In the US, higher or disease rate may be due to socioeconomic rather racial factors. Social changes and accurate diagnosis may have contributed to decreased incidence of Hib invasive disease in UK and US in the 1980s. Non capsulated strains of Hib are of low pathogenicity and rarely invade, but causes mainly localized infection of the respiratory tract in patients with existing disease. Capsulated minority posses polysaccharide which defines 6 serotypes designated a-f. Before vaccination was introduced the b serotype was responsible for more than 95% invasive disease Clinical manifestation Menigitis was the commonest clinical manifestation followed by epiglotistis, bacteraemia without localizing features, cellulitis, septic arthritis and pneumonia. The overall carriage rate in unimmunized populations is 1% in children under 6 years. The peak carriage occurs in children aged 24-36 months. In 1993, Fothergill and Wright showed that blood samples of children aged 3 months to 3 years lack bactericidal activity compared to that from neonates, older children and adults probably due to a shift in maternaly conferred and acquired (from exposure) bactericidal activity. It was further shown that administration of Hib antiserum caused an increase in the phagocytosis of Hib bacteria in the subarachnoid space suggesting the importance of opsonizing type specific antibodies Immunological aspect Protective antibodies to children carrying Hib strains may result from exposure to heterologous bacteria that produce polysaccharides with antigenic determinants similar to those on Hib polysaccharides (polyribosephosphate PRP). E coli K100 expresses almost identical polysaccharide, and if fed to volunteers or experimental animals induces antibodies that show bactericidal and opsonic activity against Hib Clinical features Hib meningitis may develop insidiously over 24-48hrs. The child begins to snuffle, followed by fever, vomiting, failure to feed, pallor, instability and persistent crying. Low consciousness, shock and seizure are later signs. In older children, headache, neck stiffness, and photo-phobia are more common. Treatment But for nephrotoxicity and irreversible bone marrow suppression, Chloramphenicol is an alternative to resistant ampicillin. Cefotaxime and
46 ceftriazone are better than cefuroxime because the later takes time to sterilize the CSF and is associated with higher incidence of hearing loss. Administration of dexamethazone during antibiotic therapy reduces the incidence of neurological sequalae (deafness). Steroids given after the first dose of antibiotic therapy are ineffective because they probably act by blocking the inflammatory cascade induced by the release of endotoxin into the subarachnoid compartment Vaccination The first Hib vaccine consisted of polyribosephosphate and suffered all the setbacks of T-cell independent vaccine. Conjugated polysaccharides are Tdependent antigens and their introduction as vaccine is more promising since they are immunogenic, even in infants under 3 months. Conjugated polysaccharides induce IgG and long term immunity that can be boosted with the vaccine. The impact of Hib vaccine is immediate because they occur in children and infants Neonatal Bacterial meningitis This is rare but serous with mortality rate up to 30-40% and permanent sequale in up to 30% of survivors. The causative organism result from ascending infection in utero or from the birth canal during delivery. Hib, pneumococcus, other Srteptococci, meningococcus, Listeria monocytogen, Staphylococcus aureus are examples. Prematurity, low birth weight, Prolonged rupture of membranes, and prolonged labour febrile pregnant mothers all are at risk. Neonates show little specific evidence of meningeal irritation Clinical manifestation Non Specific symptoms like (listleness, pallor, crying, failure to eat, jaundice, unstable control of respiration, temperature & heart rate, and vomiting), may lead to more specific depression of consciousness and raised intra-cranial pressure. High suspicion of meningitis should lead to CSF or blood culture after ruling out infection at other sites such as UTI. Choice of antibiotics depends on the agent. Combination of benzylpenecillin and gentamycin should be used to commence treatment while the result of culture is being awaited. If gm-ve bacilli is isolated combination of cephalosporin and amynoglycosides may be appropriate treatment being guided by antibiotic sensitivity pattern of isolate Clostridial disease Though it does not grow in the CNS, it produces its meningitis by its potent neurotoxin (exotoxins) that dirupts nerve cell transmission. In some cases, the toxins are ingested in contaminated food while in other cases, toxin production is at the site of action of clostridia infection in tissues and toxins spread to CNS. Tetanus C. tetani produces a neurotoxin that inhibits relaxation of neurons which produce several muscle spasms (spastic or convulsive paralysis). Transmission occurs by puncture of wounds that inoculates the body with spores of C. tetani. C. tetani is non invasive while the neurotoxin spreads systematically to cause the signs of the diseasae. Attempts should be made to prevent oxygen depletion in wounds that may favour growth of C. tetani. Botulism
47 This is caused by neurotoxin produced by C botulinum. The toxins are absorbed from the intestinal tract and transported in the circulatory system to motor nerve synapses where their action blocks normal neural transmision. The botulinum neurotoxins inhibits motor signals which results in flaccid (limp or loose) paralysis. These toxins are produced during food poisoning. They cant grow at pH <4.5 Tuberculosis Meningitis This may arise due to dissemination of tubercle bacilli from a distant focus of infection e.g. lungs. The disease is caused by liberation of tubercle bacilli from subpial tuberculomata into the subarachnoid space. Postmortem examination confirms the gelatinous nature of the exudate which is consistent with high incidence of cranial nerve palsiers seen in Tb meningitis. Clinical outcome There is persistent headache and fever for weeks or months. The disease is never acute. CSF cellular exudates are lymphocytic but may be mixed with high protein and reduced sugar. Direct microscopy may not reveal Tb but culture will. PCR is most accurate and fast. Chest and stomach radiograph, computed tomography and nuclear magnetic resonance imaging of the cranium are helpful. Tb is always considered meningitis in the differential diagnosis of patients with aseptic meningitis or chronic meningitis syndromes. Involvement of the CNS with tuberculous meningitis is usually caused by rupture of a tubercle into the subarachnoid space. The presentation may be acute, but the classic presentation is subacute and spans weeks. Patients generally have a prodrome of fever of varying degrees, malaise, and intermittent headaches. Patients often develop central nerve palsies (III, IV, V, VI, and VII), suggesting basilar meningeal involvement. Clinical staging of meningeal tuberculosis is based on neurologic status. Stage 1 shows no change in mental function with no deficits and no hydrocephalus Stage 2 refers to a patient with confusion and evidence of neurologic deficit. Stage 3 refers to an individual with stupor and lethargy. Rifampicin, isoniazid, and pyrazinamid are useful empirical treatment strategy if the picture is strongly surgestive, since direct microscopy may not give a positive result
Listeria monocytogenes
It is a small gram-positive bacillus that causes 8% of bacterial meningitis cases and is associated with one of the highest mortality rates (22%). It is widespread in nature and has been isolated in the human stool of 5% of healthy adults. Most human cases appear food-borne. It is a common food contaminant, with a recovery rate of up to 70% from raw meat and vegetables. Outbreaks have been associated with consumption of contaminated coleslaw, milk, cheese, and alfalfa tablets. Persons at risk include pregnant women, infants and children, elderly individuals (>60 y), patients with alcoholism, adults who are immunosuppressed, individuals with: chronic liver and renal disease, diabetics and iron overload (eg, hemochromatosis or transfusion-induced iron overload).
S. agalactiae
48 S. agalactiae (group B streptococci) is a gram-positive coccus that is isolated from the lower gastrointestinal tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common (70%) agent of neonatal meningitis. It has also been reported in adults, primarily affecting individuals older than 60 years. The overall case-fatality rate in adults is 34%. Predisposing risks in adults include diabetes mellitus, pregnancy, alcoholism, hepatic failure, renal failure, and corticosteroid treatment. In 43% of adult cases, no underlying disease is present. Aerobic gram-negative bacilli This includes E coli, Klebsiella pneumoniae, Serratia marcescens, P aeruginosa, and Salmonella species. As a group, they can cause meningitis in certain groups of patients. E coli is a common agent of meningitis among neonates. Other predisposing risk factors include: age (neonates and old age), neurosurgical procedures or intracranial manipulation, immunosuppression, high-grade gramnegative bacillary bacteremia; and disseminated strongyloidiasis, which has been reported as a classic cause of gram-negative bacillary bacteremia (as a result of the translocation of gut microflora with the Strongyloides stercoralis larva during hyperinfection syndrome).
Staphylococcus species (S aureus and coagulase-negative Staphylococci),

Staphylococci species are gram-positive cocci that are part of the normal skin flora. Meningitis caused by Staphylococci is associated with the following risk factors: status of postneurosurgery and posttrauma, presence of CSF shunts infective endocarditis and paraspinal infection. Staph epidermidis is the most common cause of meningitis in patients with CNS (ventriculoperitoneal) shunts Spirochetal Meningitis (T Pallidum) T pallidum is a slender tightly coiled spirochete that is usually acquired by sexual contact. Other modes of transmission include direct contact with an active lesion, passage through the placenta, and blood transfusion (rare). Three stages of disease are described, and involvement of the CNS can occur during any of these stages. Syphilitic meningitis usually occurs during the 10 or 20 stage, complicating 0.32.4% of 10 infections during the first 2 years. It presents with headache, nausea, vomiting, and meningismus. Other CNS syphilitic syndromes include meningovascular syphilis, parenchymatous neurosyphilis, and gummatous neurosyphilis, all of which are manifestations of late symptomatic neurosyphilis. Meningovascular syphilis occurs later in the course of untreated syphilis, and the symptoms are dominated by focal syphilitic arteritis (ie, focal neurologic symptoms associated with signs of meningeal irritation) that spans weeks to months and results in stroke and irreversible damage if left untreated. Patients with HIV have an increased risk of accelerated progression. Borrelia Burgdorferi
49 It is the agent of vector-borne Lyme disease. It is a tick-borne spirochete that occurs in the temperate regions of North America, Europe, and Asia. Lyme disease is characterized by 3 stages. Although rare during stage I, CNS involvement (with meningitis) may occur and is characterized by the concurrent appearance of erythema migrans at the site of tick bite Aseptic meningitis syndrome Aseptic meningitis is the most common infectious syndrome. Most episodes are caused by viruses, but they can also be caused by bacteria, fungi, or parasites. Partial treatment of bacterial meningitis accounts for many meningitis cases with a negative microbiologic workup. It occurs 2-10 weeks following the erythema migrans rash. This represents stage 2 of Lyme disease, or the borrelial hematogenous dissemination stage. Chronic neuroborreliosis is a hallmark of the third stage of Lyme disease and is characterized by subacute encephalopathy manifested by disturbance in mood, memory, language, or sleep. Symptoms Headache is the most common symptom, with photophobia, nausea, and neck stiffness occurring less frequently. Symptoms of somnolence, emotional lability, and impaired memory and concentration may occur. Facial nerve palsy is the most common cranial nerve deficit. These symptoms of meningitis usually fluctuate and may last for months if left untreated.
3b. Fungal disease of the centran nevous system- Meningitis

Cryptococcosis Introduction Cryptococcosis is an infection caused by inhaling the fungus Cryptococcus neoformans. It is one of the diseases affecting AIDS patients. Cryptococcosis may be limited to the lungs, but frequently spreads throughout the body. Although almost any organ can be infected, the fungus is often fatal if it infects the nervous system where it causes an inflammation of the meninges and spinal cord. C. neoformans is found worldwide in soil contaminated with pigeon or other bird droppings. It has also been found on unwashed raw fruit. Cryptococcosis is a rare disease in healthy individuals, but is the most common fungal infection affecting person with AIDS. People with Hodgkin's disease or who are taking large doses corticosteroids, chemotherapy drugs are also more susceptible. Cryptococcosis is also called cryptococcal meningitis (when the brain is infected), Busse-Buschke disease, European blastomycosis, torular meningitis, or torulosis. Disease outcome Most patients are not diagnosed as having cryptococcosis until they show signs of cryptococcal meningitis. Symptoms appear gradually over a period of two to four weeks. Fever and headache are the most common symptoms, occurring in about
50 85% of patients. Nausea, vomiting, unwanted weight loss, and fatigue are also common. Other symptoms seen in 25-30% of patients are blurred vision, stiff neck, aversion to light, and seizures. Since the symptoms of classic meningitis, such as stiff neck and aversion to light, do not occur in many patients, diagnosis is often delayed. In addition to meningitis, inflammation of the brain (encephalitis) and brain lesions called cryptococcomas or tortulomas can also develop. In addition to the brain, the cryptococcal infection can spread to the kidneys, bone marrow, heart, adrenal glands, lymph nodes, urinary tract, blood, and skin. Painless rashes and lesions that mimic other skin diseases, such as molluscum contagiosum, may develop in association to cryptococcal meningitis. Diagnosis The preferred methods of diagnosis are to use blood and cerebrospinal fluid (CSF) tests that detect the presence of an antigen produced by the fungus. The cerebrospinal fluid test is generally more sensitive to detecting the meningitis form of the infection. A small amount of ink (called India ink) is added to a sample of CSF or a sample prepared from skin lesions. If the fungus is present, it will become visible when the ink binds to the capsule or covering that surrounds the fungus. Antigen tests are routinely recommended for non-symptomatic patients with advanced AIDS. Another way to diagnose cryptococcosis is to culture a sample of sputum, tissue from a lung biopsy, or CSF in the laboratory to isolate the fungus. Cultures are also done to assess the effectiveness of treatment. Treatment Treatment begins with amphotericin B (Fungizone), sometimes in combination with oral 5-flucytosine (Ancobon) followed by oral fluconazole (Diflucan). Amphotericin B is a powerful fungistatic drug with potentially toxic side effects, such as kidney toxicity and lower concentrations of hemoglobin. Prevention The best way to prevent cryptococcosis is to stay free of HIV infection. People with suppressed immune systems should try to stay away from areas contaminated with pigeon or other bird droppings, such as the attics of old buildings, barns, and areas under bridges where pigeons roost. Coccidioidomycosis Coccidioides immitis and Coccidioides posadasii are dimorphic fungi endemic to the Western Hemisphere, to certain arid regions in the southwestern United States, and to Mexico, Central America, and South America. The 2 species are morphologically identical but genetically and epidemiologically distinct. C immitis is geographically limited to California's San Joaquin valley region, whereas C. posadasii is found in the desert of the southwest United States, Mexico, and South America. The manifestations of exposure to either organism are assumed to be identical (a hypothesis not yet tested) Pathogenesis: Inhaled airborne arthroconidia are deposited into the terminal bronchiole and transform into spherules, causing an inflammatory reaction. Spherules react with complement and promote chemotaxis of neutrophils and eosinophils. The spherules reproduce by a process known as endosporulation, rupture, and liberate
51 viable endospores. Some of the endospores are engulfed by macrophages, initiating the acute inflammation phase. If the infection is not cleared during this process, a new set of lymphocytes and histiocytes descend on the infection site, leading to granuloma formation with the presence of giant cells. This is the chronic inflammation phase. Coccidioidal meningitis can be part of disseminated disease but can also occur without involvement of other sites. Meningitis manifests as a persistent headache, which should be evaluated thoroughly upon worsening, unusual severity, associated nausea and vomiting, blurry vision, or a change in mental status (eg, drowsiness and confusion). Other common manifestations include nuchal rigidity and photophobia. Symptoms related to increased intracranial pressure (eg, nausea, vomiting, altered mental status) are relatively common. Less-common presentations include focal neurologic deficits, cranial nerve palsies, tremulousness, intention tremor, papilledema, gait abnormalities, seizure, and coma. CSF usually contains increased protein levels and decreased levels of glucose and lymphocytic pleocytosis. Eosinophils in the CSF in the appropriate clinical situation support the diagnosis. MRI shows ventricular enlargement and hydrocephalus. Nonspecific laboratory abnormalities may include hyponatremia in association with syndrome of inappropriate antidiuretic hormone (SIADH).
4a. Cardiovascular system infections

Carditis, or inflammation of the heart, may be divided into three categories: Pericarditis - Inflammation of the pericardium; Myocarditis - Inflammation of the heart muscle; Endocarditis - Inflammation of the endocardium Pericarditis Introduction Pericarditis, inflammation of the fibroserous sac enclosing the heart, has multiple infectious and noninfectious causes. Infectious pericarditis exists in three forms: a. Acute pericarditis (Purulent) usually due to hematogenous spread of bacteria- Staphylococcus aureus, Streptococcus pneumoniae, and other streptococci. b. Chronic pericarditis (Tb pericarditis) - the result of infection by M. Tb or fungi. c. Idiopathic pericarditi- presumed to be do to viral pathogens In most cases the infecting microorganism reaches the pericardium through: the circulatory system during primary disease, lymphatic drainage from the respiratory tract, or via direct spread from the lungs or pleura and rarely by direct inoculation during surgery, invasive medical procedures or trauma. The organism colonizes the pericardium and stimulates an inflammatory reaction, which can result in destruction of heart tissue or/and in the accumulation of serous/purulent exudate, which may cause cardiac tamponade (exertion of pressure on the heart) and circulatory failure. Pathology
52 Infection foci include: pneumonitis (pneumococci and 1o pulmonary pathogens), bacteremia (Staph, Meningococci & H. influenza), post operative infections (S. aureus & Gram-ve aerobic rods) and pre-existing, noninfectious pericarditis Acute-Purulent pericarditis: Bacteria produce an effusion containing many PMN WBC, manifesting as fever, dyspnea and chest pain. Tissue damage is the result of: bacterial toxin & enzymes. Myocardial damage, cardiac tamponade and healing is associated with broad fibrosis that may form chronic constrictive pericarditis. Mortality exceeds 50%. Chronic pericarditis Tb pericarditis may manifest as vague, dull chest pain, weight loss, night sweats, cough and dyspnea. About 5% of patients with Pulmonary Tb will have pericarditis. The early granulomatous stages are associated with sero-sanguineous pericardial effusions containing mainly mononuclear cells. The inflammatory process gradually becomes chronic leading to constrictive pericarditis and circulatory failure due to the fusion of the parietal and visceral pericardium Idiopathic pericarditi- is presumed to be do to viral pathogens Diagnosis Pericardiocentesis can be used in some cases (purulent pericarditis, with cardiac tamponade) to culture for the infecting agent. Echocardiography- detects pericardial thickening and fluid accumulation Treatment Purulent pericarditis- emergency surgical drainage (pericardiocentesis) and systemic antibiotics after culture of drianage (mortality still up to 30%) Tuberculous pericarditis- Use four drug anti-tuberculous regimens, Prednisone to prevent constriction. If calcifications form, pericardectomy is required Myocarditis Introduction: The disease is an infection of the myocardium or muscle of the heart. The bacteria/virus is ingested in contaminated water and/or food and eventually, either directly or indirectly, reaches the heart. There may be a prior skin infection before heart effects are seen. The bacteria/virus invades the heart muscle cells and causes necrosis of the cells and clinical effects. Most cases are self-limited and are followed by full recovery. Fulminant myocarditis can be fatal or lead to chronic congestive heart failure. The true incidence of this disease is unknown. About 15% of cases of viral illnesses have myocardial involvement. Bacterial causes include Legionella, Chlamydia, & Borrelia burgdorferi Pathology Bacteria/Viruses may directly invade the myocytes and cause damage to the infected cells. Forced exercise, pregnancy, use of steroids or nonsteroidal antiinflammatory agents, use of ethanol and nutritional deficiencies are factors that predispose a patient to symptomatic myocarditis Clinical manifestations Many are asymptomatic. If symptoms are present, it may include; non specific flu-like illness with chest pain when the pericardium is involved, arrhythmias, Left ventricular dilatation can lead to expansion of the mitral valve ring and a mitral regurgitant murmur. If the pericardium is also involved then a friction rub
53 may be present. Only in a minority of patient are cardiac enzymes (CK-MB & troponin) elevated Treatment Bacterial, fungal and protozoan myocarditis can be treated with the appropriate antibiotics. Immunosuppressive drugs are contraindicated. In fulminant disease the patient may die or can be saved by cardiac transplantation. Infective Endocarditis Background: Infective endocarditis (IE) is an infection of the endocardial surface of the heart. The intracardiac effects of this infection include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE produces a wide variety of systemic signs and symptoms through several mechanisms and various immunological phenomena. The incidence is around 2/100,000. Risk factors of IE 1. It is more common in elderly males. 2. Normal flora cause most cases of I.E. They gain access to the blood via minor trauma to the mucosa of the oropharynx, GIT or genitourinary tract. 3. Underlying cardiovascular lesion or suppressed immune system. 4. Hospital or nosocomial IE (NIE), 5. Intravenous drug abuse (IVDA) IE, 6. Prosthetic valve endocarditis (PVE). 7. Intravascular devices and procedures. 8. Congenital abnormalities such as: Congenital heart disease (bicuspid aortic valve is the most common example), calcific aortic stenosis, ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot, atrial septal defect , mitral valve prolapse and native valve endocarditis 9. Rheumatic heart disease 10. Presentation and clinical course of IE may be described as either acute (involving normal valves in healthy or debilitated patients) or subacute (involveing only abnormal valves). Etiology This depends on the condition of the heart valve, if the person: is an IV drug abuser, has a prosthetic heart valve and how long the prosthetic heart valve has been in place before an infection results in symptoms Native heart valve: Staphylococcus aureus (20-35%) Rare causes: Gram-negative bacilli and HACEK group (Haemophilus sp. (H. aprophilus and H. paraaphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, slowgrowing (longer than 7 days) and require CO2 Very rare: Anaerobic bacteria, Coxiella burnetii (Q fever), Chlamydia sp Intravenous drug abusers: Staphylococcus aureus (50%), Gram negative bacilli (15%; mostly Pseudomonas aeruginosa). Streptococcus (15%)
54 particularly viridans group and enterococci. Fungi (5%), mostly Candida albicans Polymicrobial infections are also frequent Prosthetic valve infections: Early (within first 2 months) - nosocomial pathogens= Staphylococcal sp (50%), gram-negative aerobic bacilli (20%), fungi (5%). Late (more than 2 months post surgery) - organisms from mouth and skin flora; Viridans Strept sp. (35%), coagulase negative staph (20%), and S. aureus (10%) are most common. Gram-negative bacilli and fungi are less common but still important There are about 5% cases of culture-negative IE. These may have noninfectious causes (eg, vasculitis) or may be caused by nutritionally variant streptococci. Overall, the most common cause of culture-negative IE is the prior use of antibiotics followed by Coxiella burnetii and Bartonella species. S aureus may burrow deep within the thrombus, becoming sequestered from the vascular space. IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate use of antimicrobial agents or by underlying conditions in individuals who are frail, elderly or immunosuppressed. Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis has probably had little effect in decreasing the incidence of IE Pathology IE is preceded by the formation of a sterile cardiac lesion which serves as bacterial attachment site. The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis (NBTE). Damage to the endothelial cells of the heart and the heart valve can lead to the accumulation of platelets and fibrin producing (NBTE). The development of subacute IE depends on a sufficient inoculum of bacteria to allow invasion of the preexistent thrombus. Thrombus is the result of bacterial clumping produced by agglutinating antibodies. In acute IE, the thrombus may be produced by the invading organism (S aureus) or by valvular trauma from intravenous catheters. S aureus can invade the endothelial cells and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. NIE or health careassociated IE (HCIE) is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of the beginning of clinical disease Two types of NIE The right-sided variety affects a valve that has been injured by placement of an intravascular line. The valve is then infected by a nosocomial bacteremia. The left sided NIE occurs in a previously damaged valve and is more likely to occur on the left side. Bacteria and platelets tend to accumulate on the downstream or low-pressure side of a valvular lesion (Venturi effect). When bacteria colonize the NBTE they form vegetations. NBTE may result from stress, renal failure, malnutrition. Propensity to develop vegetations after trauma is from mitral>aortic>tricuspid>pulmonary valve. With the exception of intravenous drug abusers, right-sided endocarditis is uncommon. When right-sided endocarditis does occur it is usually on the tricuspid
55 valve. Surface adherence factors are essential for the bacteria to colonize the NBTE (Strept sanguis binds to platelet receptors. S aureus binds to fibronectin.). These vegetations vary in size from tiny bodies to masses large enough to occlude valve orifices (arterial emboli). There is no correlation between size of vegetation and severity of endocarditis. The bulk of the vegetation is an amorphous mass of fibrin and platelets containing colonies of microorganisms. There may be inflammatory cells attached to the vegetation. There are four consequences to the formation of this vegetation: 1. Organisms within the vegetation are protected from antibodies, complement and leukocytes. 2. Organisms within the vegetation are metabolically inactive, replicating at an unusually slow rate, rendering them relatively resistant to the action of many antibiotics 3. Healing is slow because macrophages and fibroblasts must spread through the vegetation and endothelial cells must grow over the surface. Emboli are generated when vegetations break off causing infarcts (an area of tissue that undergoes necrosis due to obstruction of local blood supply, as by a thrombus or embolus). 4. Abscesses may develop by direct invasion of the valve rings of the heart near the vegetations. These are common with pyogenic cocci but rare with other organisms
Clinical symptoms Subacute endocarditis takes more time for nonspecific symptoms to develop while acute endocarditis progresses very rapidly with more severe symptoms, more common in IV drug abusers and in staphylococcal infections of the heart. Subacute endocarditis - The interval between the colonization of the endocardium and the onset of symptoms is usually less than two weeks. Lowgrade fever (range of 38oC) is the most common symptom. Only in acute endocarditis does the temperature go above 40oC. Fever is usually accompanied by chills and sometimes by night sweats. Fatigue, anorexia, weakness, myalgias, arthralgias and malaise are common. Debilitating low back pain is a prominent complaint in a smaller percentage of patients. Acute endocarditis There is rapid onset (hours to days) of signs and symptoms. Most commonly associated with Staphylococcus aureus or enterococcus. Fever is high (40oC) and accompanied by rigors. Patients are very ill and the likelihood of extravascular complications is higher. Lab findings are nonspecific in nature o Anemia of chronic disease- normocytic, normochromic, low serum iron and low iron binding capacity. o Peripheral leukocyte count usually normal except if myocardial abscess formation, if an extravascular site of infection exists or in acute endocarditis o Erythrocyte sedimentation rate and C-reactive protein is elevated o About 50% of patients positive for rheumatoid factor
56 o o o Diagnosis o Elevated serum globulins (20-30% of patients) Cryoglobulins, depressed complement levels, false positive syphilis serology Urinalysis is usually abnormal (proteinuria and hematuria)
Acute endocarditis- rapid diagnosis and treatment are mandatory to reduce valvular destruction and embolic complications. o After a very careful history and physical exam is performed then a number of tests will help in confirming your diagnosis of endocarditis. o Chest radiographs may demonstrate distinct round cannonball-like pulmonary emboli in right-sided endocarditis. o Pulmonary edema may be present in those with acute mitral regurgitation or decompensated left-sided heart failure due to aortic valve regurgitation. o Blood cultures- are critical for making the diagnosis. Infective endocarditis is associated with a constant low-level bacteremia. Obtain 3 blood samples (at least 10 mls of blood) at least 15 minutes between each blood letting over a 24-hour period. If the patient is acutely ill do this over a 45 minute period of time. No antibiotics until the blood cultures confirms positive for bacteremia. Treatment o Antibiotic therapy must persist for 4 to 6 weeks, even if symptoms disappear prior to that time. One exception is subacute bacterial endocarditis caused by viridans Streptococcus sp. in which the combination of penicillin G and gentamicin for two weeks works as well as treatment for 4 weeks. A combination of antibiotics, rather than a single antibiotic, is always used. o If no organism has been isolated after repeated attempts the recommended therapy for subacute bacterial endocarditis is: Ampicillin, given IV every 4 hours + Gentamicin, given every 8 hours. o Empiric therapy for acute bacterial endocarditis: Vancomycin, ampicillin, and gentamicin o If an organism has been isolated, then the antibiotic regimen is based on the species of the etiologic agent, the age of the patient and the extent of the disease. The regimens are complex and are listed in various reference books. o If antibiotic therapy is not successful surgical removal of infected endocardium may be necessary. This is especially true with fungal infections and when the patient has an infected prosthetic valve.
5a. Bacteria Soft tissue and skin infection

Classification Soft tissue infections may be classified as follows: superficial or deep, as nonnecrotizing or necrotizing, as primary (idiopathic) or secondary, and as monomicrobial or poly-microbial. Superficial infections involve the epidermis, dermis, superficial fascia, or subcutaneous tissue. Superficial soft tissue infections may be caused by o A single aerobe, (S. pyogenes or S. aureus). o Infections associated with skin damaged by animal or human bites,
57 o Cellulitis associated with decubitus or other non healing ulcers, o Infections in immunocompromised patients. These infections are usually poly-microbial, involving aerobic or facultative gram-negative organisms and anaerobes and aerobic gram-positive bacteria. Deep infections involve the deep fascia or muscle. Deep necrotizing soft tissue infections are poly-microbial 70% to 75% of the time and caused by the synergistic activity of facultative aerobes and anaerobes such as: o Gram-positive aerobes- (S. aureus, S. pyogenes, & enterococci) o Gram-negative enteric organism (Escherichia coli) o Common anaerobes (Bacteroides species and Peptostreptococci) The remaining 25% to 30% of deep necrotizing infections are monomicrobial. Most primary necrotizing soft tissue infections are monomicrobial. These infections are more fulminant and are notable for their acute onset, rapid progression, and systemic toxicity. Their characteristic clinical manifestations are related to exo-toxin production by the pathogen involved and S. pyogenes is the pathogen in more than half of monomicrobial infections; S. aureus, C. perfringens, Vibrio vulnificus, and P. aeruginosa are less common. Necrotizing soft tissue infections are distinguished by the presence of extensive, rapidly progressing necrosis and high mortality. Such infections are termed necrotizing cellulitis, necrotizing fasciitis, or myonecrosis according to whether the deepest tissue layer affected by necrosis is subcutaneous tissue, deep fascia, or muscle, respectively. Primary (idiopathic) soft tissue infections occur in the absence of a known causative factor or portal of entry for bacteria. Such infections are uncommon and are believed to result from hematogenous spread or bacterial invasion through small unrecognized breaks in the epidermis. Only 10% to 15% of all necrotizing soft tissue infections are idiopathic; the remaining 85% to 90% are secondary infections, developing as a consequence of some insult to the skin that predisposes to infection. Secondary soft tissue infections may be further categorized as posttraumatic, postoperative, or complications of preexisting skin conditions. Mono-microbial soft tissue infections - caused by a single organism Polymicrobial soft tissue infections - caused by multiple organisms Risk factors of bacterial soft tissue infection: Soft tissue infection commonly results from: 1. Inoculation of bacteria through a defect in the epidermal layer of the skin, e.g injury, preexisting skin disease, or vascular compromise. 2. Extension from a subjacent site of infection (osteomyelitis) or of 3. Hematogenous spread from a distant site (diverticulitis or Clostridium. septicum infection in patients with colonic carcinoma). 4. De novo in healthy patients with normal-appearing skin, often as a result of virulent pathogenic organisms.
58 5. Clinically occult infection or poor treatment of other conditions (as seen in patients with diverticulitis; perirectal, pilonidal, or Bartholin's cyst abscesses; strangulated hernias; or panniculitis). 6. Delayed or inadequate treatment of superficial infections (e.g., folliculitis, furuncles, carbuncles, cellulitis, and surgical site infections). 7. Chronic illnesses can contribute to a diminished immunologic response. 8. Peripheral vascular disease impairs the local blood and oxygen supply. 9. Diabetes mellitus inhibits white blood cell function. 10. Chronic pulmonary disease can result in systemic hypoxemia. 11. Patients with congestive heart failure or significant coronary artery disease may not increase their cardiac output in response to infection. 12. Malnutrition can result in a lack of nutrients and critical enzymatic cofactors involved in the normal cellular response to infection. Pathogenesis of Soft Tissue Infections Soft tissue infections generally induce localized inflammatory changes in the involved tissues, regardless of the species of bacteria involved. As the infection progresses, tissue necrosis occur as a result of: o Direct cellular injury from bacterial toxins, o Major inflammatory edema within a closed tissue compartment, o Thrombosis of nutrient blood vessels, and o Tissue ischemia. The exotoxins produced by gram-positive cocci and some gram-negative bacteria are powerful proteolytic enzymes. o S. pyogenes produces hemolysins, fibrinolysins, hyaluronidases, and streptolysins. S. aureus and P. aeruginosa produce coagulases that result in local tissue damage and necrosis. o C. perfringens produces numerous exotoxins. The -toxin, a lecithinase enzyme, is highly lethal: it destroys cell membranes, causes hemolysis, and alters capillary permeability. Other clostridial toxins lyse red blood cells and have direct cardiotoxic effects. These toxins also cause platelet aggregation and fibrin deposition, with resultant vascular thrombosis and necrosis. Production of the -toxin leads to intravascular leukostasis and inhibits diapedesis of white blood cells into infected tissue. This unique collection of bacterial toxins accounts for the rapid progression of C. perfringens infection in a setting of minimal inflammatory changes. That most necrotizing soft tissue infections involve multiple bacterial species strongly suggests that bacterial synergy plays an important role in their pathogenesis. Toxin-induced cellular necrosis establishes an anaerobic environment that facilitates the growth of both facultative and anaerobic bacteria. These anaerobes elaborate additional enzymes and other by-products that facilitate tissue invasion and destruction. Pre-existing local tissue damage frequently serves as a nidus for soft tissue infection. The reduced oxygen tension of this abnormal environment allows pathogens to proliferate. Bacterial Skin Infections
59 Bacterial Skin Infections are caused by the presence and growth of microorganisms that damage host tissue. The extent of infection is generally determined by how many organisms are present and the toxins they release. Staph aureus infections 1. Impetigo This is a common superficial skin infection which is very contagious and is seen mostly in children. It can be either blistering or non-blistering. It is caused by Staph sp followed by S. pyogenes. It is spread by direct contact, more common in warm climates with high humidity and is associated with mild skin trauma. Bullous impetigo is caused by Staph aureus, usually Phage II Type 71 and presents with blistering in young febrile children. The non-blistering or nonbullous type usually occurs at sites of minor trauma to the skin such as insect bites, reactions, abrasions, cuts, and hand burns. It starts as a small blister particularly on the face, trunk or buttocks; slowly enlarge to rupture leaving shiny skin which then becomes eroded. There is often a surrounding scale. Non-bullous impetigo which makes up the majority of infections usually starts with small reddish patches measuring about 2-4mm. They evolve to form tiny crusted blisters. It spreads by direct extension. It is most commonly seen on the face around the nose, mouth and also the extremities. May be self limiting Ecthyma: This is a deeper form of impetigo. It occurs in the epidermis and the dermis, producing a superficial ulcer that becomes secondarily crusted. It usually occurs after trauma and in associarion with poor hygiene. The lesions will often last for many weeks becoming essentially ulcerated and may even scar the skin. Secondary cellulitis and osteomyelitis are very uncommon developments. Treatment: The application of topical antibiotics such as mupirocin cream or ointment (Bactroban) and Fusidic acid (Fucidin) is very effective. More extensive infections are treated with oral cloxacillin, erythromycin or cephalexin and cloxacillin or Keflex are often required for ecthyma. 2. Folliculitis This is an infection in the hair follicles. It is inclined to be on surface of the opening of the pore or deeper in the tissue. This is most commonly caused by staphylococcus aureus. It is seen on the face, upper trunk, arms and on buttocks. Deeper involvement can produce large red papules and sometimes pustules. Treatment: Topical antibiotics such as Bacitracin or mupirocin cream or ointment (Bactroban) or fusidic acid (Fucidin) can be used. 3. Abscess, Furuncles & Carbuncles These are collections of pus. They can occur anywhere on the skin. They are more commonly seen in teenagers and young adults. This most commonly occurs at the edge of minor trauma or friction and underneath belts or tight clothing. Treatment: Compression of the deeper lesions, drainage or oral antibiotics 4. Staphylococcal Scalded Skin Syndrome
60 This is also known as Ritters disease. This condition is caused by a toxin produced by Staphylococcus sp and is similar to that producing bullous impetigo or the toxic shock syndrome. It is seen in young children, rarely seen in immunosppresed adults with renal failure. Fatigue, fever, irritability, tender skin, runny nose and conjunctivitis are common. This starts on the head, spreads to other parts of the body. The skin develops redness and a wrinkling appearance over soft blisters which later loosen to leave moist open areas followed by scaling and peeling off and skin swabs are negative for Staph aureus. Treatment: Antitoxin and systemic antibiotics recommended 5. Toxic Shock Syndrome This is caused by a toxin produced by Staphylococcus sp. It was commonly seen: in menstruating young women, after surgical procedures, on infusion sites for insulin pumps and with deep skin infections. This starts with high fevers, diarrhea, headaches, sore throats, aches and pains, progressing to shock. Initially there is diffuse redness that starts on the trunk and spreads outwards with swelling and peeling of the palms and soles and the mouth, tongue and eyes become red. Treatment: Isolation and intensive care including oral antibiotics will assist the organs and blood pressure.
Streptococcus pyogenes 1. Cellulitis This is an infection of the deeper dermis and the subcutaneous tissues, commonly caused by Streptococcus, Staph aureus and Hemophylus Influenza. Skin breaks are needed to establish infection in the healthy population. Alcoholism, diabetes, poor circulation and fungal infections are risk factors. It may present with: fever, chills, red swollen and tender skin, blisters, pustules, swelling of the lymph nodes and rarely acute glomeruli nephritis. Treatment: Oral and systemic antibiotic required 2. Erysipelas This is an infection of the deeper dermis (face and lower legs) and lymph drainage system caused by Streptococcus pyogenes, seen in the young, aged and the sick (chronic limb swelling and chronic ulcers). It is more common in the summer with an abrupt onset of fever and malaise. There is well defined redness on the cheeks. The skin feels hot, tender, tense and swollen (local lymph glands). Diagnosis is by skin examination. Treatment: Penicillin and Erythromycin recommended. 3. Scarlet Fever This is a childhood disease (less than ten years), caused by a Group A beta hemolytic Strept (GABS), mostly in the fall and winter season. GABS toxin
61 causes the skin effects. The disease starts with a sore throat, headaches, fatigue, chills, high fever, abdominal pain and vomiting. The rash begins with redness in the neck; chest and armpits, small red papules (sunburn) develop. It is commonly seen: in menstruating young women, post-operative sites, insulin pump infusion sites and with deep skin infections. It starts with high fever, diarrhea, headaches, sore throats, aches, pains and progresses to shock. Diffuse redness starts on the trunk and spreads outwards, peeling of the palms and soles with red mouth, tongue and eyes are seen. There are streaks of bruises in the body folds. Treatment: Oral erythromycin recommended. 4. Necrotizing Fasciitis This is a fatal infection of the fat and muscles similar to that seen in cellulitis. Treatment: Oral antibiotics and surgical intervention are necessary 5. Streptococcal Peri-anal Disease This is a Strep pyogenes disease showing bright well defined redness in the perianal area, seen in children under four. There is peri-anal itching and discomfort, sore throat and bowel movements. Treatment: Oral antibiotics recommended 6. Streptococcal Toxic Shock Syndrome Streptococcal toxic-shock syndrome (STSS) is syndrome characterized by the isolation of group A Streptococci from a sterile body site together with hypotension and either renal impairment, acute respiratory distress syndrome, abnormal hepatic function, coagulopathy, extensive tissue necrosis, or an erythematous rash. More than 60% of patients with STSS have bacteremia. The M proteins (M1 and M3) are associated with most of Streptococcal necrotizing soft tissue infections. Streptococcal pyrogenic exotoxins (SPEs) are the cause of the fever, shock, and tissue injury associated with this syndrome. SPE-A and SPE-B induce the synthesis of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6. Peptidoglycan and lipoteichoic acid can also induce TNF- production. Clinical manifestation It produces fever, shock and organ failure followed by swelling, tenderness, redness pain at the extremities and blistering occurring mostly in the healthy people and young adults. The skin protective mechanism is disrupted allowing for the introduction of Streptococcus. Treatment: Intensice care, general support for the internal organs and oral Clindamycin are recommended. 7. Erythrasma This is a superficial chronic infection caused by Corynebacterium minutissimus. It is mostly seen in the groin, armpits and folds. There are well defined large brown scalling patches. Initially light red in colour but becomes brownish over time with the defined symptoms. Definitive diagnosis is with woodlight skin examination. Treatment: Anti- bacterial soaps and topical antibiotics are okay.
62 8. Pitted Keratolysis This common and well defined erosion is mostly seen on the undersurface of the feet where bacteria eat away the keratin surface of the skin producing small craters and erosions with no inflammation and no symptoms. Treatment: Anti-perspirants and topical antibiotics are recommended 9. Trichomycosis axillaris This is a superficial bacterial infection of the armpits and the pubic area hairs. There are easily seen small red, brown or yellowish nodules or thickened cylinders attached to the hair causing some discolouration on underwears clothing. It is produced by a Corynebacterium sp. Treatment: Antibacterial soaps and oral erythromycin are recommended. 10. Reactive Arthritis (Reiter's syndrome) This is a type of joint inflammation or arthritis mounted by the body in response to infection elsewhere in the body. It is also associated with conjunctivitis and urethritis. Reactive arthritis may also be called Reiter's syndrome, seronegative spondyloarthropathy, urogenital or gastro-intestinal reactive arthritis (triggered by veneral disease or eating contaminated food). The seronegative spondyloarthropathies are a group of disorders (psoriatic arthritis, ankylosing spondylitis, and arthritis accompaning inflammatory bowel disease) which can cause whole body and spine inflammation. Reactive arthritis begins about 1-3 weeks after infection by Chlamydia trachomatis, Chlamydia pneumonia, Salmonella, Shigella, Yersinia, and Campylobacter. Men (20-40 years) are more likely to get urogenital acquired rective arthritis while men and women are equally likely to get gstro-intestinal reactive arthritis. Symptoms of Reactive Arthritis Reactive arthritis mostly results in inflammation of the urogenital tract, the joints, eyes, mouth ulcers and skin rashes. Diagnoses: Detection of HLA-B27 gene in about 80% of the population is considered relatively diagnostic for reactive arthritis but not confirmatory. Treatment Reactive arthritis presently has no cure, but symptoms of the disorder may be relieved by the following treatments: o Use of Nonsteroidal anti-inflammatory drugs (NSAIDs)aspirin, ibuprofen, indomethacin and tolmetin, o Corticosteroid injections If NSAID did not work o Topical corticosteroids--to reduce inflammation and promote o Immunosuppressive medicines(sulfasalazine or methotrexate), o TNF inhibitors-- etanercept and infliximab. o Exercise-- when introduced gradually may help improve joint function. Other Bacterial Infection of Skin and Muscle 1. Mycobacterial skin infections
63 Mycobacterial infections provide a slowly developing chronic infection. 1a. Leprosy: This is a chronic skin infection caused by Mycobacterium leprae. It does not grow in artificial culture media but grows on the footpad of immunosuppressed mice (nine-banded armadillo sp). This mice (nine-banded armadillo) species is a mamal with the lowest body temperature that suits the growth of Mycobacterium leprae and explains why lesions affect only superficial tissues. It is acquired after prolonged close contact with an infected individual in an overcrowded area characterized with poverty and poor poor hygiene. Mycobacterium leprae causes many diseases depending on the strength of the cellular and humoral immune system. A population with strong cellular response suffer from distinct depigmentation of the infected skin and loss of sensation due to damaged nerves in the underlying tissue (tuberculous leprosy) while those with stronger humoral response develop extensive tissue damage and destroyed nasal septum, producing a collapsed nose with face looking like the face of a lion (lepromatous leprosy). Mycobacterium leprae damages the nerves and produce an anaesthetic effect which looks like sun burn outwardly. Laboratory diagnosis is based on demonstration of acid alcohol-fast bacilli in biopsy material or skin scrapings. 1b. Scrofuloderma Scrofuloderma is formed when the skin overlying a tuberculous focus, at a lymph node and the skin over infected bones or joints. There is a fistula and scarring and lesions manifest as: firm, painless, subcutaneous, supporative and ulcerative nodules with sinus tracts in overlying skin. Characteristic ulcers have undermined edges and a floor of granulation tissue. Mycobacterium tuberculosis can be identified in the nodes/draining material. Anti-tuberculous therapy and surgical removal required. 1c. Warty tuberculosis It is the most common form of cutaneous TB in developing countries where it causes a warty plaque, on the hands, knees or buttocks. 1d. Environmental Mycobacterial Diseases Atypical mycobacterium is more common in HIV infection, elderly, leukaemia or immunosuppressive therapy. They cause swimming pool (or fish tank) granuloma (M. marinum) and Buruli ulcer (M. ulcerans).
2. Buruli Ulcer Buruli ulcer caused by M. ulcerans is also known as Bairnsdale ulcer or Searles' ulcer, (Australia), and Kakerifu ulcer or Toro ulcer (Congo). Its a re-emerging infection and is now the third most prevalent mycobacterial disease worldwide, behind tuberculosis and leprosy. Its acquired from vegetation or water after trauma. Its initially a painless erythematous nodule, usually on the leg or forearm, becomes necrotic and ulcerates.
64 Treatment is by wide surgical excision. Antimicrobial therapy with rifampicin and clarithromycin is recommended before and after surgery. BCG gives short term prevention. 3. Fish tank granuloma (or swimming pool granuloma) It is caused by M. marinum infection, Causes a reddish, slightly scaly plaque on the hand. M. marinum is sensitive to minocycline, clarithromycin, amikacin, rifampicin, ethambutol and doxycycline. 4. Lymphadenitis Mainly affects single cervical lymph nodes of healthy children under 5 years old. M scrofulaceum and M avium are causative agents. Treat by Surgical excision of infected lymph nodes 5. Other environmental Mycobacteria M kansasii localized primary cutaneous infection is associated with immunocompetence whereas disseminated or pulmonary infections are associated with immunocompromised state. It may resemble cellulitis or sporotrichosis by presenting with tenosynovitis; cutaneous lymphadenitis and clinical presentation are similar to lupus profundus and ulcerative perineal lesions. M malmoense This shows as cervical lymphadenitis in preschool-aged children associated with cutaneous nodules on the hands. M szulgai presents with cellulitis, nodules and plaques. M gordonae This is a granulomatous synovitis/bursitis, also called tap water scotochromogen which can cause granulomatous nodules on the back of the hand. M haemophilum This causes multiple, , ulcerative tender, cutaneous nodules on the limb joints with muscle wasting, tenosynovitis, and joint effusions . Investigations Tissue culture, DNA fingerprinting technology, pulsed-field gel electrophoresis, and Polymerase chain reaction are recommended.including doing the purified protein derivative test (antigen skin test used to aid the diagnosis of tuberculosis) which is usually negative with atypical mycobacteria infections Treatment Surgical drainage, debridement, and use of combined antimicrobial agents,
5b. Fungal Infections of the skin and skin structures

1. Phaeohyphomycosis: Used for skin and eye infections due to melanin-like pigment producing, or dematiaceous, species of moulds. Melanin is a black pigment or fungal structures in tissue or clinical specimens, and fungi that produce melanin-like pigment are visibly black or brown. Fungal tissue melanin (combination of hyphae, pseudohyphae, or yeast cells) detection is simplified by staining with Fontana
65 masson dye. The hyphae may be short, elongated, distorted, swollen (toruloid hyphae), regularly shaped, or combinations of the above. The yeast is variable in size and differes from sclerotic medler cells seen with chromoblastomycosis in subcutaneous tissue. Wangiella (Exophiala) dermatitidis and Exophiala jeanselmei produce a combination of hyphae, yeast, and sclerotic cells from deep infections that are not chromoblastomycosis. Laboratory diagnosis The dematiaceous nature of the hyphal elements in 10% KOH preparation of clinical specimen is diagnostic of phaehyphomycosis. Fontana masson stains may help in the detection of regular or variable shapped hyphae. Inhibitory Mould Agar, Saboraud Dextrose Agar or a Medium containing cycloheximide are media of choice for hyphal isolation. 2. Hyalohyphomycosis: This term is used for a mycotic infection of man or animals caused by hyaline (non-dematiaceous) hyphomycetes with mycelia tissue morphology, different from phaeohyphomycosis caused by brown-pigmented fungi. It is a general term used to characterize infections caused by unusual hyaline fungal pathogens. Penicillium, Paecilomyces, Acremonium, Beauveria, Fusarium and Scopulariopsis are common etiologic agents. Clinical manifestations range from safe saprophytic colonization to acute invasive disease. Risk factors include prolonged neutropenia (leukemia or bone marrow transplant) corticosteroid therapy, cytotoxic chemotherapy and AIDS. 3. Dermatophytes: This refers to three fungal genera Epidermophyton, Trichophyton, and Microsporum associated wih skin, hair and nail infections. These three fungal genera control the manifestation of the following disease states: a. Dermatophytosis b. Dermatomycosis c. Onychomycosis d. Piedra e. Mycetoma f. Lobomycosis g. Miscellaneous/other Syndromes: sporotrichosis and Candidiasis a. Dermatophytosis Epidermophyton, Trichophyton, and Microsporum are the main fungal agents causing dematophytosis characterized by being keratinophylic on living host compared to Chrysosporium indicum or C. keratinophilum which are also keratinophylic only on biopsy material. Substrates for the keratinophilic fungi include: feathers, animal hooves, hair, and animal skin. They are associated with series of Latin-named disease called the "tineas" e.g. Tinea: capitis; favosa; corporis; pedis; manuum; imbricata; cruris; barbae; nigra and ungium i. Tinea capitis (Ringworm of the scalp and hair)
66 Description Tinea capitis is the fungal infection of the scalp due to dermatophytes. The hair of head, eyebrows, and eyelashes may also be involved. Trichophyton rubrum affects only the skin. Hair infection may be devided into three: o Endothrix, where the infecting organism penetrats the hair and grows up the interior main axis and fragments into arthroconidia (Trychophyton tonsurans) o Favus, an endothrix-like growth showing characteristic empty channels formed within the hair shaft and clinically manifesting as scutulum- waxy mass of hyphal elements found at the base of a hair follicle (Trichophyton schoenleinii). o Ectothrix where infecting organism penetrates the hair, but extends back and out through the hair outer wall of the hair to form a mass of arthroconidia around the hair shaft (Microsporum canis) Epidemiology: Trichophyton tonsurans is the most (90%) prevalent yeast affecting school aged children (5-14 years) in the developed world. Risk factors include overcrowding, poor hygiene and protein malnutrition. Clinical manifestations: Differential diagnosis includes seborrheic dermatitis, atopic dermatitis, psoriasis, alopecia areata, trichotillomania, bacterial folliculitis, abscesses and neoplasias. Three clinical manifestations of Tinea capitis include: NonInflammatory- which manifests as luster and grayish hair covered with arthrospores, due to scaly alopecia seen around broken hair and caused by erythematous papules on the hair shaft. Inflammatory Manifest as diffuse pustular- kerion (scattered painful pruritic pustular folliculitis) associated with regional lymphadenopathy and fever with scarring alopecia and nodules filled with broken hair appearing later. Black dot: This is a condition where fragile hair on the scalp breaks due to endothrix infection making the rest of the infected hair look like a black dot. Other dematotophytes implicated in various forms of Tc include: Microsporum audouinii, Microsporum canis, Microsporum distortum, Microsporum gypseum, Trichophyton megninii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton tonsurans, Trichophyton verrucosum Treatment of Tc: Oral agents- Griseofulvin and ketoconazole are effective and terbinafine, itraconazole, selenium sulphide, and povidone iodine shampoos and fluconazole are also recommended. ii. Tinea favosa or T. favus Tinea favosa mainly caused by Microsporum gypseum, Trichophyton schoenleinii may be considered a type of Tinea capitis because of its incolvement with the scalp though it can also involve the glabrous skin and nails. Risk factors are poor hygiene and malnutrition and transmission is by intimate contact. It manifests as scutula- dense masses of mycelium and epithelial debris forming yellowish cupshaped crusts which on removal may show an oozing, moist, red base.
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iii. Tinea corporis (Ringworm of the body) Definition: This infection involves the glabrous (hairless) skin limited to the stratum corneum of the epidermis. It can infect the fine hair present on hairless skin (vellus hair) using the hair follicle as reservoir. Tinea pedis, manuum, and cruris are Tinea corporis found on the foot, hand, and groin. Epidemiology: Transmission is through contact with infected animals (especially cats and dogs), infected humans, or contaminated fomites such as furniture and clothing. Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes are the most common etiologic agent. It is most common in the tropics because warmth and humidity favor its establishment. Tinea imbricata is an unusual form of Tinea corporis caused by Trychosporium concentricum with an autosomal dominant genetic predisposition and restrited to Far East, South Pacific, and South and Central America. Clinical manifestations Zoophilic organisms affect exposed body surfaces (the face, neck and arms) while anthropophilic organisms affect occluded body surfacesareas. Sub-types of tinea corporis are outline bellow: o Tinea circinata or ring worm of the smooth skin is a type of tinea corporis showing annular lesions with active, erythematous, spreading borders and central clearing. o Bullous tinea corporis presets as spongiotic, herpetiform or subcorneal vesicles o Tinea fasciale is a type of tinea corporis in 3-4% subpopulation who shows an erythematous, scaly rash on the face with or without telangiectasia, atrophy, and photoexacerbation o Tinea incognito is a side effect of treating other tinea corporis with corticosteroids in which skin lesions atypically lose the characteristic scaling of tinea corporis and presents with patches, papules, or small nodules o Tinea profunda showa as subcutaneous abscesses, associated with T mentagrophytes. o Tinea axillaris involves the armpit region. Treatment: griseofulvin, terbinafine, ketoconazole, itraconazole or fluconazole are recommended. Laboratory diagnosis Detection of septate, branching hyphae with or without arthrospores in a 10% KOH preparation is diagnostic and may be confirmed by isolation on Sabouraud dextrose agar. iv. Tinea cruris (Jock itch, ringworm of the groin)
68 This is fungal infection of the groin, perineum, and perianal region caused by Epidermophyton floccosum, Microsporum canis, Trichophyton mentagrophytes and Trichophyton rubrum. It is more common in men because the temperature, humidity, and occlusion of the scrotum and groin area by clothing aid fungal development. Transmission is by direct contact with infected individuals and indirect contact with nonliving contaminated materials like towels, clothing, bed linens, urinals, and bed pans. Clinical manifestations: Tinea cruris presentation is characterized by sharply demarcated papulovesicular lesions, raised erythematous margin and thin dry epidermal scaling involving the genitocrural area and medial upper thigh. The scrotum is rarely affected as opposed to Candida intertrigo which affects the scrotum. When Trichophyton rubrum is involved, it can extend to pubic area, lower abdomen, buttock, and perianal areas. Topical therapy in powder form is recommended. v. Tinea pedis (Athlete's foot, ringworm of the foot) This is a fungal infection of the feet, (toe webs and soles) closely associated with footware. Risk factors include use of more occlusive shoes, contact with bath or pool floors, summer and tropical climates. Epidermophyton floccosum, Trichophyton mentagrophytes. Trichophyton rubrum, Trichophyton tonsurans are common etiologic agents of tinea pedis. Clinical manifestations: Tinea pedis may present as four general clinical forms distinguished distinguished as follows: Intertriginous tinea pedis: this form is characterized by chronic scaling; fissuring and maceration affecting the third to fifth interdigital areas and pathogenesis enhanced by interact with mixed toe-skin flora. Tinea pedis with a papulosquamous pattern ("moccasinlike"): this form affects the soles and lateral part of the feet. Characteristic high scaling and minimal inflammation with bilateral infection called "one hand, two feet" is evident. Vesicular or vesiculobullous tinea pedis: this form affects the regular and mid-anterior aspect of the sole manifesting as small, confluent vesicles surrounded by scales. Ulcerative tinea pedis: this type is characterized by maceration and ulceration of large areas of the soles with white hyperkeratosis and strong heady odor. Bacterial superinfection, with gram-negative organisms is common Laboratory diagnosis; Detection of septate, branching hyphae with or without arthrospores in a 10% KOH preparation is diagnostic and may be confirmed by isolation on Sabouraud dextrose agar. Therapy: Terbinafine, itraconazole, fluconazole are recommended
69 vi. Tinea barbae (Ringworm of the beard, tinea sycosis, "barber's itch") Tinea barbae is when fungi (T mentagrophytes, T verrucosum, Microsporum canis, Microsporum gypseum, Trichophyton megninii, Trichophyton rubrum, Trichophyton schoenleinii, Microsporum nanum) colonize the bearded areas of the face and neck. Contact with cattle, dogs and other animals and barbing in a barbershop without antiseptic can help spread the fungus. Clinical manifestations: Lesions are of three types: mild superficial; inflammatory, deep, pustular, kerion-like, and the circinate, spreading formas. The superficial form causes diffuse erythema and perifollicular papules and pustules, resembling bacterial folliculitis with endothrix affected hair. The inflammatory type involves the chin, neck or maxillary area and presents with nodular lesions covered with crusts and seropurulent material which looks like an abscess. Brittle hair permanent alopecia and scarring may be present. The circinate type has a spreading vesiculopustular border with central scaling, like tinea circinata. Treatment: Griseofulvin, ketoconazole, fluconazole, itraconazole, and terbinafine are recommended. vii. Tinea Nigra (Pityriasis Nigra, Tinea Nigra Palmaris) Tinea nigra is a superficial fungal (Hortaea werneckii) infection of the stratum corneum common in tropical climates of Central and South America, Africa, Asia, and North America. Contact with decaying vegetation, wood, or soil is the form of acquisition and incubation periods may be up to 20 years. Clinical manifestations: show as brown to black nonscaly macular lesions with well-defined borders on the palmar surfaces\- Tinea nigra palmaris", and on the soles- "Tinea nigra plantaris". Differential diagnoses include Addison's disease, pinta, stains, and syphilis. Laboratory diagnosis; Detection of septate, branching hyphae with or without arthrospores in a 10% KOH preparation is diagnostic and may be confirmed by isolation on Sabouraud dextrose agar. Therapy: Combination of keratolytic preparations with topical antifungals is recommended. b. Onychomycosis Onychomycosis is a term used to describe the invasion of the nail plate by a fungus. Ringworm of the nail and Tinea unguium may mean the same thing if their etiology are dematophytes. Trichophyton rubrum is the main agent followed by: Trichophyton mentagrophytes, Epidermophyton floccosum, Acremonium species, Aspergillus species, Fusarium oxysporum, Scopulariopsis brevicaulis, Onychocola Canadensis and Scytalidium dimidiatum (which are all moulds) and Candida species (which is yeast).
70 Epidemiology: Rates depends on population studied but 2 to 3% and 13% has been repoted in USA and Finland respectively with men being twice more vulnerable than women. Age-related increase in disease outcome depends on host factors such as reduced peripheral circulation, diabetes, inactivity, HIV/AIDS, increased nail trauma, and poor nail hygiene. Infection is lower in children because they have smaller nail surfaces and faster nail growth. Clinical Manifestations: Onychomycosis is classified into three main categories as follows: Distal subungual onychomycosis (DSO): This is the most frequent form and is caused by Trichophyton rubrum. Infection begins with hyonychium invasion and may result to onycholysis and thickening of subungueal area if bacteria superinfection takes place making the nail plate to turn yellowish brown. Toe nails are affected more than fingernails. Proximal subungual onychomycosis (PSO): This is common among HIV/AIDS patients and rare among the general population. It begins with Trichophyton rubrum invasion of the proximal nail fold and penetration into a newly forming nail plate below but allowing the distal nail to remain normal until late in the disease process. Common disease presentations include the following: subungual hyperkeratosis, leukonychia, proximal onycholysis, and nail unit destruction. Again toe nails are affected more than fingernails. White superficial onychomycosis (WSO): This depicts about 10% in disease prevalence and is caused by: Trichophyton mentagrophytes; Aspergillus terreus; Acremonium roseogriseum and Fusarium oxysporum. The superficial layer of the nail plate is first invaded before involving deeper layers. It shows white patches on the external nail plates which then coalesce to cover the entire nail plate. Total dystrophic onychomycosis is the final stage of any of the above three forms of onychomycosis. Unsual blastomycosis which shows nodular and papular lesions extending from foot to legs (Calf) may be seen Laboratory diagnosis; Detection of septate, branching hyphae with or without arthrospores in a 10% KOH preparation is diagnostic and may be confirmed by isolation on Sabouraud dextrose agar. Treatment: Griseofulvin, terbinafine and itraconazole, are recommended c. Dermatomycosis This is a fungal infection which looks clinically like the dematophytosis described above but whose etiology may be anyother fungal that is NOT any of the dematophyte species. They are therefore mainly described as tinea-like infections of the skin. Example there is Tinear-pedis-like infection due to Scytalidium dimidiatum and a Tinea barbae-like infection due to Geotrichum candidum. Few exemptions to this guideline in disease normenclature include pityriasis versicolor, a distinctive syndrome in which yellow-to-brown lesions appear on the chest, trunk, or abdomen and are caused by Malassezia furfur. Look for other examples!!
71 d. Piedra When the hair shaft is colonized by a fungus which results in firm, irregular nodules it is called piedra. Piedraia hortae produces a dark nodule (Black Piedra infection) while Trichosporon beigelii produces a white nodule (White Piedra infection). The black nodule (ascostroma) firmly adhere to the hair shaft and is ha brd to detached while thw white nodule (a loose aggregate of hyphae and arthroconidia) are not firm in their adherence to the hair shaft and are easily detached from the hair shaft. e. Mycetoma Mycetoma and chromoblastomycosis together invades the sub-cutaneous tisues alike but may differ from other described skin infection because of the dept of tissue invasion involved. Mycetoma manifests as tissue swelling and draining sinuses which release sclerotia/granules/grains. Melanin or hyaline loving fungi may cause this infection which results into different colors of the sclerotia, an observation which is diagnostic of the etiologic agents. The following represents the etiologic agents of mycetoma and the corresponding color of associated diagnostic granules: Eumycotic mycetoma (granule color); Acremonium falciforme (white); Acremonium recifei (white); Aspergillus nidulans (white); Exophiala jeanselmei (black); Leptosphaeria senegalensis (black); Madurella grisea (black); Madurella mycetomatis(black); Neotestudina rosatii (white) Pseudallesheria boydii (white to yellow); Pyrenochaeta romeroi (black). Laboratory diagnosis; Detection of Actinomycete granules, fungal hyphal elements and isolation from IMA, SDA are recommended. Treatment: Ketoconazole, surgical debridement and amputation (where necessary) are recommended f. Chromoblastomycosis (Chromomycosis) This is an infection of the cutaneous and subcutaneous tissue by Fonsecaea pedrosoi (and other melanin producing fungi) to produce muriform cells which has both horizontal and vertical dividing walls. The observation of a muriform cell distinguishes chromomycosis which is always by demaciacuous fungi from phaeohyphomycosis, mycetoma or related infection. Traumatic implantation of Fonsecaea pedrosoi and Phialophora verrucosa in the cutanouse and subcutanouse tisuea initiates the disease lesions which are verrucoid, ulcerated, and crusted, with satellite lesions developing following autoinoculation and by lymphatic spread to adjacent areas. It is a localized mycotic infection with extensive keloid formation. Secondary infections may lead to Elephantiasis and lymphatic stasis. The following represents the etiologic agents of chromomycosis: Cladophialophora carrionii; Fonsecaea compacta; Fonsecaea pedrosoi and Phialophora verrucosa Laboratory diagnosis; Examination of crusts mounted in 10% KOH contain dematiaceous, septate branching hyphae, dematiaceous round, thickwalled, muriform bodies are diagnostic and may be confirmed by isolation on BHI agar or on Sabouraud dextrose agar.
72 Treatment: Surgical excision, electrodesiccation, cryosurgery or topical antifungals such as Thiabendazole, 5-fluorocytosine, and amphotericin B are recommended for early infection while Itraconazole, luconazole, voriconazole and terbinafine are recommended for advanced infection g. Lobomycosis (Keloidal blastomycosis or Lobo's disease) Lobomycosis is a rare, cutaneous and subcutaneous infection caused by an ascomycete- Lacazia loboi or Loboa loboi manifecting as keloids, verrucoid to nodular lesions, crusty plaques, and tumors. Laboratory: Detection in 10% KOH recommended and confirmed by PCR. h. Sporotrichosis Sporotrichosis is a tropical localized subcutaneous infection caused by the dimorphic fungus Sporothrix schenckii and acquired through direct inoculation into the skin. The smooth or verrucose painless, ulcerative draining skin lesions follow the lymphatic drainage and do not involve the lymph nodes. Common forms of the diseases include: o Lymphocutaneous form affects the skin, subcutaneous tissues & regional lymphatics o Fixed form is a localized skin lesion that does not spread o Osteoarticular forms are arthritis and tenosynovitis that may affect joints of the hands, elbows, ankles or knees sparing the spine, hips and shoulders. o Pulmonary form produces enlarging cavitary lesions with pulmonary infiltrates, pleural effusion and hilar lymphadenopathy and associated with alcoholism, diabetes, corticosteroid use, sarcoidosis and tuberculosis. o Meningitis form produce meningitis better detected by serology than CSF culture. o Disseminated form is multifocal tenosynovitis and arthritis mimicing gonococcal infection or seronegative spondyloarthropathy. Common feutures include widespread visceral involvement associated with fungemia and involving the central nervous system (meninges or parenchyma), liver, spleen, bone marrow, and colon Treatment: Local application of hyperthermia for cutaneous lesions, systemic therapy with oral itraconazole, iodide (given as a saturated solution of potassium iodide, or SSKI), Amphotericin B (reserved to treat relapse and for serious infections presenting during pregnancy), and antibacterial antibiotics (for secondary bacterial infections) are recommended Laboratory diagnosis: Fluorescent antibody staining techniques, Diastase digestion prior to staining with H & E or PAS and isolation from IMA, SDA or BHI with entamycin, chloramphenicol, and cyclohexidine. i. Cutaneous Candidiasis Syndromes
73 Cutaneous candidiasis is possibly the most common form of candidiasis involving the outer-most layers of the skin. They are itching (pruritic), irritating noninvasive disease with common forms manifesting as: 1. Intertrigo- well demarcated areas of erythema and maceration with satellite papules and pustules on the axillae, groin and skin folds (beneath breasts, or rolls of abdominal fat). 2. Erosio interdigitalis blastomycetica- eroded erythematous area surrounded with macerated skin on the finger or toe webspace. 3. Diaper rash- eroded areas surrounded with distinct scaling and rare pustules on the perianal and genitalia area 4. Candidal balanitis - multiple distinct pustules and diffuse erythema on the glans penis and inner aspect of the foreskin 5. Perianal candidiasis - progressively worsening erythema and maceration on the anal region 6. Candidal folliculitis - small pustules at the base of the hair follicles found on any hairy areas of the body that is frequently covered by clothing 7. Generalized cutaneous candidiasis- characterized by a spreading rash with vesicles which affects the genitocrural, anal, trunk and extremities. It can occur both in children and adults. 8. Candidal granulomas - large, dry, wart-like hyperkeratotic processes associated with chronic mucocutaneous candidiasis. 9. Disseminated candidiasis is due to hematogenous spread of the infection from the blood to the skin. Epidemiology The key epidemiologic factor is prolonged exposure of dry skin to moisture. Risk factors include: occupations requiring frequent immersion of hands in water, Obesity, Diabetes and the use of systemic or topical corticosteroids. Neonatal cutaneous candidiasis can be invasive and therefore may form disseminated disease. Mucocutaneous candidiasis is not pathognomonic or required condition for systemic disease. Two unique varieties of neonatal candidal skin diseases are: Cutaneous Congenital Candidiasis (showing extensive skin rash, macular,pustular popular or vesicular erythema that may lead to extensive desquamation, paronychia and dystrophy of the nail plates. Lesions may resolve spontaneously or after oral nystatin). Invasive Fungal Dermatitis characterized by ulcerative and erosive lesions with crusting. Treatment: Topical antifungal agents, patient education, powdered miconazole, oral nystatin are recommended
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6a. Bacteria-Respiratory System infections

Introduction Only few microorganisms can colonize the air ways and cause disease out of all microorganisms inhaled with air. For each microorganisms inhaled there could be at least 1 of 4 possible outcomes. The microorganism may be quickly cleared from the system They may lodge in the upper respiratory tract and cause asymptomatic colonization in that very site. They may persist in regions that are normally sterile such as below the larynx as is observed in chronic obstructive pulmonary disease They may penetrate the epithelium and initiate parenchymal disease as in pneumonia or they may invade the blood stream and cause systemic disease. Pulmonary defence mechanisms This is of 2 types, Residence defence and Recruited defenses Resident defence include: Airway architecture, epithelial barrier, mucociliary clearance, soluble factors in airway secretions (plasma proteins, lysozymes, surfactants etc) complements, immunoglobulins and Alveolar macrophages Recruited Include: Phagocytic cells and Bronchoalveolar lavage fluid Pathogenesis of bacterial respiratory infections Disease results when the equilibrium between the organism that enter the respiratory tract and the resident host defence is disturbed. Microbial load and host defense must be balanced and disease results when local defense are overcome. This may be due to defect in host defence, an overwhelming microbial challenge or a combination of the two. Host defence defects Failure of the epithelial barriers and reflexes Failure of the mucociliary clearance ( intrinsic abnormalities- defective radial spoke etc ) Immunoglobulin deficiencies Reduced Phagocytic activities (immunosuppression) Disturbed cellular immunity (Leukemia, HIV infection or drug therapy ) Environmental influence on the host (smoking, pollution etc) Respiratory bacterial virulence mechanisms Infections are promoted by virulence mechanisms that include: Increased adherence to mucosal epithelial cells Avoidance of mucociliary clearance Increased nutrition acquisition and Avoidance of complement deposition and phagocytosis S. pneumoniae Virulence factors Protein adhesin that binds to RT glycopeptids (Immglobin A protease that inactivates respiratory mucosal IgA) Pneumolysin, a 52.8 kDa protein is a thiol-activated cytotoxin
75 Antiphgocytic capsule which permit evasion of recruited nutrophil Lipoteichoic acid is pro inflammatory Hydrogen peroxide
Hemophiles influenza Fimbriae for adhesion Capacity to bind to GalNAc1-4Gal sequence of human lung glycolipid Secretion of soluble toxin that reduce ciliary beating Production of human toxic Lipo-olygosaccharide Bordetella pertussis It produces several adhesin including filamentous agglutinins, fimbrae and array of toxins that can bind to respiratory tract ciliated cells and macrophages. Pertussis toxin cause epithelial cell cytotoxicity by increasing cAMP level B. pertussis can survive in human phagocytes by inhibiting phagosomlysosome fusion but does not inhibit respiratory burst. Pseudomonas aeruginosa Fimbrial/non fimbrial adhesin helps bind to epithelial cell gangliosides. Exotoxin A which damages respiratory epithelial tissue and inhibit phagocytosis Elastase - damage epithelial cells & blood vessels Rhamnolipid, pyocyanine and 1-hydroxyphenazine reduce ciliary beating mucociliary clearance Alginate (adhesin), forms a viscous gel around bacteria & prevents phagocytosis Legionella pneumophila It has a 24 kDa outer membrane, macrophage invasion protein Produce several bacterial enzymes - acid phosphatase, phopholipase C, protein kinase and superoxide dismutase which enhance intracellular survival Produce a protease that cause lung damage Produce metalo-protein similar to P aeruginosa elastase. Respiratory tract commensals Anterior nares: Staphylococci, Micrococci and Corynebacterium spp Paranasal sinuses & LRT below the larynx: Sterile Oropharynx: Strept, Neisseria & Bacteriodes spp, Coliforms, Fusobacteria, Actenomycetes, yeasts, -hemolytic Strept, S pneumoniae, N meningitidis, H inluenza, M catarrhalis Bacterial Infections of the upper respiratory tract (URT) Sinusitis
76 Sinusitis is an acute inflammation of the paranasal sinuses due to infections of the upper respiratory tract. Acute sinusitis may follow common cold, vasomotor and allergic rhinitis, and obstruction of the sinusal ostia due to deviation of the nasal septum, presence of foreign bodies, polyps and tumors. Dental extractions or an extension of infection from the roots of the upper teeth may lead to the infection of maxillary sinus. Etiology: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are most common with Staphylococcus aureus, Streptococcus pyogenes, gram-negative organisms and anaerobes rarely involved. Chronic sinusitis is a polymicrobial infection involving aerobic and anaerobic organisms. Pathogenesis and clinical manifestation Sinusitis leads to the impairment of the ciliary activity of the epithelial lining of the sinuses and increase mucous secretions. This leads to obstruction of the paranasal sinusal ostia which impede drainage. Bacterial multiplication in the sinus cavities converts the mucus to mucopurulent exudates. Irritation of the mucosal lining by pus causes more edema, epithelial destruction and ostial obstruction. Mucosal thickening, development of mucoceles and polyps results from chronic sinusitis. Sinusitis involves mainly hhe maxillary and ethmoid sinuses and rarely the frontal and the sphenoid sinuses. Clinical manifestations include: pain, sensation of pressure and tenderness over the affected sinus, malaise, low grade fever, purulent nasal discharge and sinus mucosa thickening Laboratory diagnosis A bacterial culture of the nasal discharge on differential media to eliminate contaminants is needed for acute infections while dental examination an antral puncture to obtain sinusal specimens for bacterial culture is needed to confirm diagnosis for chronic infection. Treatment Symptomatic treatment with analgesics and moist heat over the affected sinus pain, a decongestant to promote sinus drainage, a beta-lactamase resistant antibiotic such as amoxicillin-clavulanate or a cephalosporin, irrigation of the affected sinus, are recommended Otitis Otitis externa is an infection of ears while otitis media denotes inflammation of the middle ear Etiology Staph epidermidis, S. aureus, Diphtheroids, Propionibacterium acnes, acute and Pseudomonas aeruginosa are common agents of otitis externa while Streptococcus pneumoniae, Hemophilus influenzae and beta-lactamase producing Moraxella catarrhalis and common agents of otitis media followed by Respiratory viruses, Mycoplasma pneumoniae are common. Pathogenesis Risk factors for otiti externa are factors that may disrupt the natural protective mechanisms of the epithelial surface of the external auditory canal such as high temperature and humidity, trauma, allergy, tissue maceration, removal of cerumen
77 and an alkaline pH environment, prolonged immersion in a swimming pool coupled with frequent ear cleansing. On the other hand, risk factors for acute otitis media follow an upper respiratory infection from the nasopharynx through the eustachian tube to the middle ear. Such factors include: vigorous nose blowing during a common cold, sudden changes of air pressure, and perforation of the tympanic membrane. Clinical Manifestations Otitis externa: It manifests as furuncles causing severe pain and a sense of fullness and when it drains may present with purulent otorrhea, itching, pain, tenderness of the ear lobe on traction, and loss of hearing due to obstruction of the ear canal by swelling and purulent debris. However malignant otitis is common in the elderly diabetic patients and is characterized by severe persistent earache, foul smelling purulent discharge and the presence of granulation tissue in the auditory canal. Disseminated infection may cause osteomyelitis of the temporal bone or osteochondritis Otitis media: Acute otitis media presents mostly in young children with persistent severe earache (crying in the infant), fever, vomiting and bulging, erythematous tympanic membrane with loss of light reflex and landmarks. When perforated the tympanic membrane exude serosanguinous or purulent discharge and If obstructed, the eustachian accumulates gives off a sterile effusion resulting in serous otitis media. Treatment Adequate otoscopy, history, clinical symptomatology, culture, arre recommended. A combination of topical neomycin sulfate, polymyxin B sulfate, corticosteroids eardrops, acidification of the ear canal by applying a 2% solution of topical acetic acid, tympanocentesis and allowing spntanous drainage of furuncle is present are recommended. Amoxicillin for acute otitis media, Amoxicillin-clavulanate for lactamase producing H influenzae and M catarrhalis, oral preparations of trimethoprim-sulfamethoxazole, 2nd and 3rd generation cephalosporins, tetracyclines and macrolides are also recommended. Chronic otitis media and frequent recurrences of middle ear infections may be treated with oral amoxicillin or trimethoprim-sulfamethoxazole during the winter and spring and those with persistent effusion of the middle ear may be treated by surgical interventions with myringotomy, adenoidectomy and the placement of tympanotomy tubes. Pharyngitis This is an inflammation of the pharynx involving lymphoid tissues of the posterior pharynx and lateral pharyngeal bands. The etiology is mostly viral followed by bacterial, fungal or noninfectious (smoking). Epstein-Barr virus, cytomegalovirus infections, common cold or influenza are frequently associated with most pharyngitis. S pyogenes is the most important bacteria followed by C. diphtheriae, mixed anaerobic infections (Vincent's angina), Corynebacterium haemolyticum, N. gonorrhoeae, and C trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis and C albicans have been associated with acute pharyngitis and tonsillitis.
78 Pathogenesis Bacteria invade the mucosa of the upper respiratory tract and the many clinical manifestations of infection may be due to the immune reaction to products of the bacterial cell. Streptococcus pyogenes There is person to person spread with the bacterial cell, aided by cellular and extracellular products, attaching to the mucosal epithelial cells using F and M proteins and subsequent invasion of the mucosa to produce the relevant clinical outcome. There may direct extension to other sites and nonsuppurative lesions resulting in rheumatic fever and glomerulonephritis may occur Corynebacterium diphtheria- This causes localized UTI mucosal infections and it is only the C. diphtheriae lysogenic for the bacteriophage carrying the toxin gene which can causes diphtheria infection. Disease is spread by droplets during cold wathersear. Source of infection may include healthy carriers, convalescent patients, and patients incubating the disease. It is a global health challenge. The disease is established when pharynx and heart and nerves are damaged of death due to ADP-ribosylating elongation Factor II generated nby diphtheria toxin. Chlamydia pneumoniae- causes about 5% of the infections, 10% of community acquire pneumonia in the USA and usually presents a biphasic pattern with pharyngitis resolving before bronchitis or pneumonia develops. Clinical Manifestations Presents with red, sore, or "scratchy" throat, tonsils and tonsillar pillars covered by inflammatory exudates, non-specific beefy-red-swollen uvula; petechiae palate; excoriated nares, a scalatiniform rash, ulcerative pharyngeal walls, fever, malaise, myalgia, or headache, nausea, vomiting, abdominal pain, anterior cervical lymphadenopathy and difficulty in swallowing. Diphtheria Pharyngitis presents with pharyngeal pain, formation of a pseudomembrane seen on the tonsils, regional lymphadenopathy, edema of the surrounding tissues, foul breath, low-grade fever, cough, neurologic abnormalities, myocarditis, airway obstruction and exotoxin induced cell necrosis and local inflammation. Laboratory Diagnosis This is focused on identification of phryngitis due to group A beta-hemolytic streptococci. Clinical diagnosis can not distinguish the various forms of the disease highlighting the relevance of routine throat cultures for bacteria inoculated onto sheep blood and chocolate agar plates. Thayer-Martin media are used for N gonorrhoeae isolation, serologic studies are used to confirm the diagnosis of viral, mycoplasmal or chlamydial pharyngitis, Rapid diagnostic tests with fluorescent antibody or latex agglutination are used to identify group A streptococci from pharyngeal swabs, Gene probe and PCR can be used to detect unusual organisms such as M pneumoniae, chlamydia or viruses. Treatment Laboratory result should determine the drug of choice but penicillin G is the therapy of choice for Streptococcal pharyngitis, Mycoplasma and chlamydial infections respond well to erythromycin, tetracyclines and the new macrolides,
79 diphtheria pharyngitis is better treated with antiserum to the elaborated diphtheria toxin and Erythromycin is used for penicillin allergic patients. Prevention No vaccine is available for Group A streptococcal pharyngitis and rheumatic fever. Quarantine of infected patients and prophylaxis of treated persons with penicillin, through the patient's childhood years, or life long prophylaxis is permanent heart damage occurred and active immunization with toxoid will prevent diphtheria. Epiglottitis, Laryngitis and Laryngotracheitis These are acute inflammatory diseases of the upper airway often collectively called croup disease and whose ultimate goal is to kill the victim by obstructing the airway, a condition which the youg can hardly cope with. Etiology: Haemophilus influenzae type b is the most common cause of epiglottitis, among children aged 2 to 5 years. Adult epiglottitis and laryngotracheitis are rare and mostly of viral etiology. Other agents of severe bacteria infections are H influenzae type b, group A beta-hemolytic streptococcus, Mycoplasma pneumonia, and C diphtheriae. Pathogenesis: Hib infection, assisted by viral upper respiratory infection presents with erythema, swelling of the epiglottis, and bacteremia. Inflammation and edema involving the epithelium, mucosa and submucosa of the subglottis leads to airway obstruction Clinical Manifestations: Epiglottitis begins with the acute onset of fever, sore throat, hoarseness, drooling, dysphagia and progresses to severe respiratory distress and prostration. The diagnostic finding of inflamed pharynx is a "cherry-red" epiglottis. A history of earlier cold-like symptoms indicates laryngotracheitis, usually accompanied with rhinorrhea, fever, sore throat and cough. Tachypnea, (deep barking cough and inspiratory stridor) finally develop. Blood, Sputum/pharyngeal, culture and ELISA, DNA probe and PCR procedures are recommended for isolation and identification of isolates. Prevention and Treatment: Intubation of children to maintain an open airway, antibacterial therapy, supportive care, such as fluid, humidified air, and racemic epinephrine and conjugated vaccine, is recommended for prevention of Hib associated infections. Bacterial infections of the lower respiratory tract (LRT) Infections of the lower respiratory tract include bronchitis, bronchiolitis, tuberculosis and pneumonia. Although viruses, mycoplasma, rickettsiae and fungi can all cause LRT infections, bacteria are the dominant pathogens; accounting for a higher percentage of lower than of upper respiratory tract infections. Bronchitis and Bronchiolitis
80 These diseases refer to inflammatory processes of the bronchial tree that do not involve the pulmonary alveoli. Usually, bronchitis and bronchiolitis are due to infectious agents. Acute bronchitis is seen at all. Chronic bronchitis is seen in adulthood. Bronchiolitis is a disease of the infants. Bronchitis is preceded by an upper respiratory tract infection. Bronchitis Chronic bronchitis with a persistent cough and sputum production are caused by a combination of environmental factors (smoking), and bacterial infection with the following pathogens such as H influenzae and S pneumonia, Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Salmonella typhi, and Streptococcus pyogenes. Bronchitis occurs after when previous URT infections extends to the bronchial tree. The disease is most common in the winter when there is increased tendency to generate aerosols which assist transmission of respiratory pathogens. Predisposing factors for the bronchitis development in children include poor nutrition, air pollution allergy, deficiencies in IgG subclasses and rickets while emphysema or chronic respiratory diseases such as tuberculosis are common on adults. Bronchiolitis Bronchiolitis is an acute viral respiratory self-limiting disease of infants caused by respiratory syncytial virus. M pneumoniae may also cause bronchiolitis. The incidence of this disease parallels respiratory infections in older children and adults. No predisposing factors influence this infection and it is is maybe an extension of infection from the upper respiratory tract to the bronchioles. Pathogenesis Infection of the bronchial tree results in hyperemic and edematous mucosa with production of abundant bronchial secretions. The impact of this infection on the mucosa include: loss of mucociliary function, disruption of the respiratory epithelium, inflammation, increased number of mucosa producing cells, bronchial and bronchiolar walls are thickened. Necrotic material, respiratory secretions and the narrowing of the bronchial lumen lead to airway obstruction. Respiratory failure will be as a result of development of areas of trapping and atelectasis Clinical Manifestations Initially there is cough, followed by mucopurulent sputum, moderate temperature elevations, severe respiratory distress, coryza, fever, restlessness, retractions of the chest wall, nasal flaring, grunting, wheezing or an actual lack of breath sounds may be seen. These may lead to respiratory failure and death. There may also be malaise, headache, coryza, and sore throat. A non productive cough first develops before giving way to mucopurulent cough. Laboratoey Diagnosis Laboratory examination, culture of purulent respiratory secretions, sputum is the sample of choice for chronic bronchitis patients. Nasopharyngeal Swabs for viral assessment in infants with bronchiolitis, Serologic tests for bacteria/viruses antigen/antibodies can be done, Rapid diagnostic tests, ELISA or DNA probe procedures are used for detection of pathogens.
81 Whooping Cough (Pertussis) etiology and epidemiology This is a global health challenge caused by Bordetella pertussis - a Gram-negative small bacillus. The disease (tissue damage) is caused by the pertussis toxin. ADPribosylates guanine nucleotide-binding proteins affect regulatory mechanisms in the cells. Other important products in the disease process are the tracheal cytotoxin, a hemolysin, and a filamentous hemagglutinin. The only natural hosts for organism are humans and the disease is transmitted from person to person by droplets. A primary infection does not ensure protection from a second infection with Bordetella pertussis. There is no human carrier state but people in close contact with symptomatic patients may briefly harbor the organism. A significant number of children with pertussis have no obvious source, over half can be traced to adults with chronic cough and a minority of cases may be traced to children transmitting the disease. Children less than 1 year old suffer most sever cases. Pathogenesis and Pathology The inhaled invading organism attaches to the ciliated epithelium of the respiratory tract and ultimately produce cough through increased mucuos production induced by extracellular bacterial products. The disease process is complicated by coinfection with nosocomial Gram-negative organisms, Staph aureus, Strept pneumoniae and a neurological effect of the infection is associated with hypoxia, lymphocyte plugging, and intracerebral hemorrhage. Clinical Manifestations: This begins after 7-10 days incubation period of bacteria agents, followed by the catarrhal phase, similar to an upper respiratory tract infection but persist for about 2 weeks. The 2-4 weeks paroxysmal coughing phase follows the most infectious catarrhal phase. The intensity of the cough produces sleeplessness, loss of appetite, vomiting and most importantly a respiratory stridor clinically diagnosed as whoop. Diagnosis: Whoop is diagnostic of pertussis and the Bode. pertussis may be isolated from nasopharyngeal aspirates using Regan-Lowe medium, or BordetGengou medium. Immunofluorescent staining of secretions and serologic test (ELISA) with acute and convalescent sera is quite accurate are also recommended Treatment: Antibiotics are only useful at the paroxysmal stage to stop superinfection, supportive care is essential to prevent complications and Erythromycin is the drug of choice if antibiotics are required. Prevention: This is best achieved using the acellular DTaP-vaccine, containing toxoids of diphtheria-D, tetanus-T, & an acellular pertussis vaccine-aT. Pneumonia Pneumonia may be defined as an inflammation of the lung parenchyma, involving the entire lobe of the lungs (lobar pneumonia) or occurring in an inconsistent distribution without involving the entire lob (bronchial pneumonia). Bronchial and lobar pneumonia are mostly caused by Strept pneumonia. Bronchial pneumonia affects the alveoli adjacent to the larger bronchioles of the bronchial tree while lobar pneumonia involves all of a single lobe of the lungs where it turns the involved area into a consolidated mass, an observation different from the spongy texture of normal lung tissue. Pneumonias occurring in healthy persons
82 not confined to the hospital are known as community-acquired pneumonias while pneumonia arising while a patient is hospitalized is called hospital-acquired or nosocomial. All pneumonia types will produce the following gross pathology characteristics: 1. Engorgement stage in which the lung when cut is wet edematous and congested; 2. High fever, cough and rusty sputum stage, during which the lung is dry, red friable and solid and 3. Softening stage during which the cut lung softens with exudation of yellow purulent fluid. Community acquired pneumonia This is more common in the winter and affects more males than females. It is commoner among old persons with symptoms including cough, sputum, dyspnoea and pleuritic pain while extrapulmonary symptoms may include headache, confusion and myalgia Epidemiology: This is a nasopharyngeal bacterial flora of asymptomatic individuals. In Papua New Guinea with a record highest global rate of pneumococcal disease, serotypes 2,3,5,8 and 14 rarely colonize the oropharynx. Serotypes (6, 19f, & 23f) are carried frequently by the general population and cause more disease in children than adult. High incidence of pneumococcal bacteraemia occurs in children under 2 years of age, low in teenage and young adults but increases again in 70s and above. Most vulnerable groups are AIDS young adult, South African gold miners and military recruits Pathogeneses: Streptococcus pneumoniae is a normal flora of the human URT which can cause lobar pneumonia type, paranasal sinusitis, otitis media or meningitis with pneumonia and otitis media being the most common form of infection. Strept pneumoniae is now the most important cause of invasive bacterial disease in children and the elderly and can also cause disease in monkeys, rabbits, horses, mice and guinea pigs. Nasopharyngeal colonization of Strept pneumoniae occurs in about 40% of the general population. During colonization, pneumococci either adheres tightly to the nasopharyngeal epithelium resulting in an immune response which generates type-specific immunity, or moves to the lungs, sinuses or middle ears depending on individuals involved and the invading serotype. If the pneumococci decide to move up the eustachian tube, it has to induce changes in the surface receptors of the epithelial cell, using neuraminidase, or cause inflammation in the middle ear using its cell wall components or use its pneumolysin to inflict major cytotoxicity on ciliated cells of the cochlea. If it decides to go to the lungs, it is assisted by aerosols, and can easily by-pass the ciliated upper respiratory epithelial cells unless there is damage to the epithelium before it will again uleash most of the pathogenic principles shown on its way to the Eustachian tube to deal with the challenge. They move to the alveolus and associate with specific alveolar cells which produce a choline-containing surfactant. In healthy tissues, about 100,000cell/ml is needed to trigger an inflammatory response but if a
83 proinflammatory signal (cytokines or intercurrent viral infection) is supplied, inflammation ensues with as few as 10 bacteria cell. Invasion: After colonization, pneumococci are able to proceed with invassion because: they can resist the host phagocytic response and multiple inflammatory cascades are activated by the bacterial cell wall. Such activated cascades include: the alternative complement pathway, the coagulation cascade, the cytokine cascade (induction IL-1, IL-6 and TNF from macrophages and other cells). Lysis of bacterial cells in response to host defensins and antimicrobial agents, leads to the release of cell wall components and pneumolysin that lead to intense inflammation and cytotoxic effects. Pneumolysin & hydrogen peroxide produced by the bacteria kills host cells and induce production of nitric oxide which may play a key role in septic shock of the host. During invasion, bacterial cell wall choline interacts with the receptor-G-proteins of host platelets activating factor (PAF) to produce a state of altered vascular permeability in the lung, leading to the arrival of an inflammatory exudate. A serous exudates is formed in the first instance followed a switch from a serous to a purulent exudate orchestrated by the arrival of leukocytes. Pneumococci are able to openly invade human endothelial cells with choline (located on the cell wall teichoic acid which serves as a direct ligand to the PAF receptor) and the cholinebinding protein CbpA, (which binds to a specified carbohydrate on the alveolar cell surface). A receptor-mediated endocytic process assist the PAF-receptorbound-bacteria to ento a vauole which move it accros the cell wall into the ablumenal surface of the host cell. The risk of meningitis increases if bacteremia occurs and the bacteria Pneumococci can adhere to cerebral capillaries using the same interaction of bacteria choline to PAF receptor and CbpA to carbohydrate receptor. Thus, the bacteria challenge the endocytosis-recycling pathway of the PAF receptor for cellular transmigration. Once in the CSF a variety of pneumococcal cell wall components, provoke the inflammatory response Bacterial Determinants of Virulence 1. Capsule: The bacterial capsule interferes with phagocytosis by leukocytes 2. The pneumococcal cell wall is a collection of potent inflammatory stimuli which can activate the alternative complement pathway to generate leukocyte chemotaxins and the coagulation cascade to promote a "procoagulant state" favoring thrombosis. 3. The phosphorylcholine found on the teichoic acid and the lipoteichoic acid acts both as an adhesin and as a docking site for the choline-binding proteins (CBPs). Haemophilus, Pseudomonas, Neisseria and Mycoplasma have 4. Phosphorylcholine found on LPS, proteins or fimbriae of Haemophilus, Pseudomonas, Neisseria and Mycoplasma suggest a shared mechanism for respiratory tract invassion. 5. PAF receptor and C-reactive proteins recorgnizes and binds to bacteria choline
84 6. C-reactive protein response is a part of the constitutive defenses which may be shared by invasive respiratory pathogens to subvert the signaling cascade of endogenous PAF. 7. Pneumococcal Peptidoglycan/teichoic acid complex is highly inflammatory. 8. Cytokine cascade which produces IL-1, IL-6 and TNF are stimulated by endotoxin induced inflammation 9. (PspA) slow down pneumococcal complement-mediated opsonization, 10. Autolysin LytA is associated with pneumococcal lysis 11. Autolysin LytB is involved in cell separation, 12. Autolysin LytC shows lysozyme-like activity. 13. CBPA is a potent Pneumococcal adhesin which binds to carbohydrates, nasopharynx, secretory IgA and complement- C3 and the pulmonary epithelial surface, 14. Peumolysin (a hemolysin and exotoxin) binds to cholesterol found on all cell surfaces including receptors, mediate cell lysis, stimulate the production of inflammatory cytokines, inhibit beating of the epithelial cell cilia, inhibit lymphocyte proliferation, decrease the bactericidal activity of neutrophils, and activate complement. 15. Hydrogen peroxide, Neuraminidase & IgA protease are pneumococci products Epidemiology S. pneumoniae is a temporary member of the normal flora, colonizing the nasopharynx of 40% of healthy adults and children. Asymptomatic nasopharyngeal carriage in children is about 4-6 weeks. New serotypes are acquired every 2 months. Serotypes 6, 14, 18, 19, and 23 are the most prevalent accounting for 60-80% of infections depending on the area of the world. This includes children between 6 months and 4 years of age, adults over 60 years of age, chronic care facilities, military camps and day care centers. Clinical signs Cough, sputum production, chronic obstructive pulmonary disease, viral respiratory infection and fever are common and non specific symptom in children includes abdominal pain, vomiting, and irritability. Diagnosis Streptococcus pneumoniae are Gram-positive, lancet-shaped cocci (elongated cocci with a slightly pointed outer curvature), seen as pairs of cocci (diplococci), or singly and in short chains, alpha hemolytic on BA, non sporing, non mortile, catalase negative, ferment glucose to lactic acid, have no M protein, hydrolyze inulin, and their cell wall composition of their peptidoglycan and their teichoic acid). Cultivation Streptococcus pneumoniae is fastidious bacterium, growing best in 5% carbon dioxide. Nearly 20% of fresh clinical isolates require fully anaerobic conditions. Macroscopically, on culture media, it is glistening colonies, about 1 mm in
85 diameter. Serotypes 3 and 37, are mucoid. Pneumococci undergo a phase variation from opaque to transparent colonies. The transparent colony type can colonize the the nasopharynx, while the opaque type can live in blood. Special tests such as inulin fermentation, bile solubility, and optochin (an antibiotic) sensitivity are used to differentiate the pneumococcus from Strept viridians. S pneumoniae is a very fragile bacterium and contains within itself the autolysin with ability to disrupt and to disintegrate the cells. Identification This includes bile solubility, optochin sensitivity, Gram-positive staining, alpha hemolytic activity and in anaerobic conditions they switch to beta hemolysis caused by an oxygen-labile hemolysin. Serotyping The quellung reaction (swelling reaction) forms the basis of serotyping and depends on the swelling of the capsule when bound to homologous antibody. Observation of capsule swelling in anigen-anibody reaction is the basis for this test. There is cross reaction between capsular strains: 2 & 5; 3 & 8; 7 & 18; 13 & 30, and with E coli, Klebsiella, H influenzaeType b, and certain viridans streptococci Antimicrobial Chemotherapy Drug-resistant S pneumoniae strains (DRSP) have become increasingly prevalent worldwide and rates of decreased penicillin susceptibility have been reported. The mechanism of resistance to beta-lactams involves modifications of penicillinbinding proteins. There is resistance to tetracycline, macrolides, trimethoprim-and sulfamethoxazole, but it is sensitive to doxycycline, clindamycin, and fluoroquinolones (moxifloxacin, gatifloxacin, and vancomycin). All firstgeneration cephalosporins are equally effective against pneumococci. Levofloxacin and sparfloxacin have good activity against penicillin-susceptible and penicillin-resistant strains. Moxifloxacin is the most active quinolone against pneumococci. Among the new agents are trovafloxacin and grepafloxacin Vancomycin is the only glycopeptide class that is useful in the treatment of severe pneumococcal infections. Clindamycin also may be used to treat nonmeningeal penicillin-resistant S pneumoniae. Imipenem also is useful to treat penicillinresistant S pneumoniae. Prevention/Vaccines Since there is 90 different capsular pneumococci which can cause infection independently, a comprehensive vaccine based on polysaccharide alone may not be feasible at least for now. Presently, vaccines based on a subgroup of highly prevalent types have been formulated. The composition of pneumococcal serotypes in the vaccine was 4 in 1945, 14 in the 1970s and currently 23-valent formulation (25 mg of each of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). These serotypes represent 85-90% of those that cause invasive disease. Underutilization of the vaccine has made pneumococcus to remain the most common infectious agent leading to hospitalization in all age groups. This problem is complicated by the fact that polysaccharides are not immunogenic in children under the age of 2 years where a significant amount of disease occurs.
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Nosocomial Pneumonia This may be defined as a pulmonary infiltrate one week after hospitalization. Early Hospital-Acquired Pneumonia (EHAP) or incubating community-acquired pneumonia (ICAP) is when hospitalized patients develop pneumonia in less than 5 days. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, are the main etiologic agents of both CAP and HAP. Other rare agents include aerobic gram-negative bacilli (not H influenzae), P aeruginosa, S aureus (Methicillin-susceptible S aureus- MSSA, methicillin-resistant S aureusMRSA. Pathogenesis Bacteria reach the lungs by inhalation, aspiration, and hematogenous spread. Primary inhalation pneumonia is pneumonia due inhalationa of aerobic GNB from respiratory support equipments or from upper respiratory tract. The underlying principles of bacteria pneumonia establishment are of two types namely necrotizing (P aeruginosa) or none-necrotizing (Gram negative bacteria GNB and Gram positive cocci). Necrotizing pneumonia is followed by rapid cavitation, microabscess formation, blood vessel invasion, and hemorrhage while nonenecrotizing pneumonia causes histologically indistinguishable none necrotizing pneumonia. HAP occurs when a large number of organisms enter the lower respiratory tract, overwhelm and impair the host defenses. Tthe most important factor influencing the development of HAP is microaspiration of contaminated oropharyngeal secretions. With four days of hospitalization, 35% of the oropharynx is colonized by GNB of moderately ill people while colonization is up to 73% in critically ill patients. This shift in oro-pharyngeal microbial population makes the previously benign event of microaspiration to become a mechanism by which virulent organisms are introduced into the lower respiratory tract to cause pneumonia. NP is most common in the elderly alther affects all ages. It has high mortality and morbidity with no racial differences or sexual predilection. Clinical manifestations include tract symptoms, which may include an increase in respiratory rate, shortness of breath, and a productive cough, Laboratory Diagnosis Obtain blood for culture to retrospectively diagnose hematogenous pathogens. Respiratory secretions are obtained and sent to the laboratory for semiquantitative bacterial cell counts and results are compared with normal respiratory secretions which contain Citrobacter, Flavobacterium, Enterobacter, Stenotrophomonas maltophilia, Burkholderia cepacia, S aureus, Enterococcus, and Candida species. Treatment Treatment regimens should cover core organisms including aerobic gram negative bacilli (Enterobacter spp, Escherichia coli, Klebsiella spp, Proteus spp, Serratia marcescens, and Hemophilus influenzae) and gram-positive organisms like Streptococcus pneumoniae and Staphylococcus aureus. o Monotherapy with a second-generation cephalosporin (cefuroxime); a non-pseudomonal third-generation cephalosporin (ceftriaxone); or a betalactamase inhibitor (ampicillin/sulbactam, ticarcillin/clavulanate, or
87 piperacillin/tazobactam) are recommended for patients with mild infections and no risk factors for resistant or unusual pathogens, o Use a fluoroquinolone for patients with penicillin allergies, clindamycin, and beta-lactam for patients with witnessed aspiration or who had stomach surgery; vancomycin for Staph aureus in patients on coma, with: head trauma; influenza virus infections; diabetes, chronic renal failure, or who are injection drug users. o Give macrolides to patients who have received long courses of steroids because they are at increased risk for Legionella species. Patients on antibiotics before developing pneumonia, with structural lung disease, on steroids and patients with a prolonged ICU stay are recommended for a combination of antibiotics (aminoglycoside, quinolones and antipseudomonal beta-lactam) for core pathogens and Acinetobacter spp or Pseudomonas aeruginosa infections Prevention Prevention supplements appropriate diagnostic and therapeutic procedures to reduce mortality rate of HAP. Prevention strategies are directed towards general measures: for infection control; directed at specific patient risk factors and to limit the use of antibiotics in the reduction prevalence of resistant organisms. To reduce HAP, implement interventions like reduced immunosuppression, sedation and transportation of patients out of the ICU, and to provision of sufficient nutrition. Body positioning may also impact on the development of HAP, because it has the protective effects against aspiration of refluxed gastric contents by being in the semi recumbent position than in supine. Aspiration Pneumonitis Aspiration pneumonitis may be defined as acute lung injury sustained after the inhalation of regurgitated gastric contents. This syndrome is common in patients with serious disturbance of their consciousness due to drug overdose, seizures, a cerebrovascular accident, or the use of anesthesia. Aspiration of gastric contents results in a chemical burn of the tracheobronchial tree and pulmonary parenchyma, causing an intense parenchymal inflammation. The outcome is a biphasic pattern of lung injury after acid aspiration: o Phase one starts, one to two hours after aspiration and results from the direct, caustic effect of the low pH of the aspirate on the cells lining the alveolarcapillary interface, o Phase two starts four to six hours later, and is associated with infiltration of neutrophils into the alveoli and lung interstitium. After gastric aspiration, the lungs are injured by a spectrum of inflammatory mediators, inflammatory cells, adhesion molecules, and enzymes, including tumor necrosis factor, interleukin-8, cyclooxygenase and lipoxygenase products and reactive oxygen species. Neutrophils and complement plays a major role in the development of lung injury. The early stage of aspiration pneumonitis is a sterile disease state established by the gastric content which bars bacterial participation. Bacterial infection may occur at a later stage of lung injury when colonization of the gastric contents is encouraged by the use of: antacids to increase the pH;
88 histamine H2receptor antagonists, or proton-pump inhibitors. It may manifest as wheezing, coughing, shortness of breath, cyanosis, pulmonary edema, hypotension, hypoxemia, severe acute respiratory distress syndrome and death. Aspiration Pneumonia Aspiration pneumonia may be defined as lung injury sustained after the inhalation of colonized oropharyngeal content. Hemophylus influenzae and Streptococcus pneumoniae colonize the nasopharynx or oropharynx before they are aspirated. Aspiration pneumonia may also refer to the development of a radiographically evident infiltrate in patients who are at increased risk for oropharyngeal aspiration. About half of healthy adults aspirate some amounts of oropharyngeal secretions during sleep. Increased volume or bacterial burden of oropharyngeal secretions in immunocompromised person may lead to aspiration pneumonia. Prevalence of aspiration pneumonia is lesser in teethless patients. The episode of aspiration pneumonia is hardly seen but diagnosis may be inferred when a patient at risk for aspiration has radiographic evidence of an infiltrate in a characteristic bronchopulmonary segment. Risk Factors for Oropharyngeal Aspiration This includes patients with: neurologic dysphagia, disruption of the gastroesophageal junction, anatomical abnormalities of the upper aerodigestive tract, patients with stroke, elderly persons because of the increased incidence of dysphagia and gastroesophageal reflux, oropharyngeal colonization by Enterobacteriaceae, Pseudo aeruginosa, and Staph aureus because they receive poor oral care. Treatment of Aspiration pneumonia/Pneumonitis Suction of the upper airway mainly after a witnessed aspiration of gastric contents, endotracheal intubation, for coma patients is recommended. Empirical antibiotic therapy is right for patients who aspirate gastric contents and who have small-intestine obstruction. Antibiotic therapy is recommended for patients with aspiration pneumonitis which fails to resolve within 48 hours after aspiration. Treatment of Aspiration Pneumonia Antibiotic therapy (Penicillin, clindamycin, third-generation cephalosporins, fluoroquinolones, and piperacillin) recommended for patients with aspiration pneumonia. Complications of Pneumonia Pleural effusion is an effussuin which accumulates abnormally in the the pleural space. Excess fluid results from the disruption of the equilibrium existing across pleural membranes. Empyema is inflammatory fluid and debris within the pleural space. It results from an untreated pleural-space infection which progresses from free-flowing pleural fluid to a complex collection in the pleural space. HIV/AIDS predisposes patients to bacterial pneumonia infections, particularly with encapsulated organisms such as Strept pneumoniae and H influenzae. There is increased rate of bacterial pneumonia in HIV/AIDS patients with less than 200
89 CD4 lymphocytes/mm3and immune dysfunction occurs even with a minimal reduction in the CD4 lymphocyte count Cystic fibrosis (CF) This is an inherited disease in which there is pancreatic dysfunction and airway associated abnormal secretion where thick tenacious sputum causes obstruction and recurrent infection. In CF among children, S aureus produce - and -toxin and induce bronchial wall injury and abscess formation followed by Pseudo aeruginosa colonization. H influenza and Xanthomonas maltophylia can lasi colonize CF. Combined antibiotic therapy, oral quinolones and aerosolized tobramycin given by nebulizers are recommended. Pulmonary tuberculosis Mycobacterium tuberculosis (MTB) causes tuberculosis (Tb) in humans while Mycobacterium bovis is responsible for Tb in cows and rarely in man. Humans can get the infection through consuming unpasteurized milk. Mycobacterium avium cause a Tb-like disease in AIDS patients, while Mycobacterium leprae causes leprosy in man. The Mycobacterium tuberculosis complex includes M tuberculosis, M bovis, M africanum, M. microti; M canetti and all closely related species or subspecies of Mycobacteria that may cause the disease tuberculosis (TB) in humans. Tuberculosis is an infectious disease which may involve many organs like the lung, liver, spleen, kidney, brain, and bone. The normal host immune response may be enough to control the infection and prevent clinical manifestation in endemic regions. Cell Wall Structure Mycolic acids contributes to MTb virulence by: providing a strong hydrophobic impermeable surface due to formation of lipid shell around the organism, preventing attack of the mycobacteria by cationic proteins, lysozyme and oxygen radicals in the phagocytic granule and by protecting extracellular mycobacteria from complement deposition in serum. Cord Factor (trehalose 6,6-dimycolate (TDM) is a surface glycolipid which enables Mycobacterium tuberculosis to form cords in vitro, stops IFN- from activating macrophage, provokes secretion of TNF and is an inhibitor of PMN migration. Wide Angle X-ray diffraction (Wax-D) in the cell envelope is the major component of Freund's complete adjuvant (CFA). Antigen 85 complex: This complex is made of fibronectin binding proteins which assist in walling off the bacteria from the immune system and may enhance the formation of tubercle Slow generation time. This prevents the immune system from: recognizing the bacteria and from being sufficiently triggered to eliminate them from the system. High lipid concentration in cell wall, accounts for impermeability and resistance to antimicrobial agents, resistance to killing by acidic and alkaline compounds in both the intracellular and extracellular environment, and resistance to osmotic lysis via complement deposition and attack by lysozyme.
90 Pathophysiology After inhalation of Mycobacterium tuberculosis, it travels to the pulmonary parenchyma and straight to the lower lobes. From the pulmonary parynchyma, it is ingested by alveolar macrophages and it stays dormant and untouched inside the macrophage resisting all efforts by the macrophage to digest it with its potent virulence mechanisms. Later, the bacilli may travel through the pulmonary lymphatics or enter the vascular system and are seeded in distant sites including the liver, spleen, or bone marrow. Macrophages will succeed in controlling the bacilli in apparently healthy immunocompetent individuals and this stage is called primary, self-limiting or sub-clinical tuberculosis. Primary tuberculosis is common in children in endemic regions but HIV may force adults to present with primary tuberculosis. Progresive primary tuberculosis is formed when pulmonary macrophages are overwhelmed by the bacilli ultimately resulting in clinically apparent infection-miliary tuberculosis, systemic or disseminated disease. Postprimary - reactivation tuberculosis is found in patients whose initial infection was contained successfully by the pulmonary macrophages, some bacilli remaining viable within the macrophages are activated and they attack the host cells when the host's immune status (T cells) is compromised. Mycobacterium tuberculosis disease progression may be grouped into 5 stages depending on the Tb strain, host prior exposure, immune status and vaccination, and infectious dose of the bacilli. It is only a small percentage of MTb infection produce disease or progreses till the final stage five outline below Stage one: Droplet nuclei containing about 3 tubecle bacilli are inhaled from aerosols generated by talking, singing and coughing. It is estimated that coughing generates about 3000 droplet nuclei at once, talking for 5 minutes generates 3000 droplet nuclei, singing generates 3000 droplet nuclei in one minute while sneezing generates the most droplet nuclei which can spread to individuals up to 10 feet away. On getting to the pulmonary alveoli, the bacteria are taken up by unactivated alveolar macrophages which are unable to destroy the intracellular organisms. Thus, tuberculosis begins the moment droplet nuclei reach the alveoli. Stage two This is taken to start when M.Tb multiplies unrestricted within unactivated macrophages until the macrophages burst and release their contents. The presence of young tubercles released from the bursting macarophages then spontenously induce the migration of other unactivated macrophages from the surrounding vessels to the lung parenchyma where they also starts the to phargocytose the tubercles. The unactivated macrophages can not harm the tubercle bacilli because they are unactivated Stage three The presence of young tubercles released from the bursting macarophages leads to leukocyte (T-cells) migration to the lungs but unlike the unactivated macrophages, the T-cells specifically recorgnizes the M-Tb surface antigens, process the antigens and presents them to antigen presenting cells (APC type 1). Afterwards the T-cells are activated and cytokins (IFN) are released which finally
91 activates the macrophages which are now capable of destroying MTb. Consequently, individuals become tuberculin-positive at this stage because the host has developed a strong cell mediated immune (CMI) response to the bacilli. An antibody mediated immune (AMI) is ineffective in Tb control because MTb is intracellular and is resistant to complement killing due to the high lipid concentration in its cell wall. A CMI response is necessary for Tb control and also responsible for most Tb associated pathologies. Immune pathology develops due to release of lytic enzymes, reactive intermidiates and cytokins. This also marks the begening of tubercle formation whose center is semi-solid or cheesy and also called caseation necrosis. MTb cannot multiply within these tubercles but can persist for some time because of the low pH and anoxic environment. Stage four Persistent MTb which cannot multiply in the semi-solid tubercle are picked by unactivated macarophages sorounding the tubercle. Inside this unactivated macrophage MTb multiples without resistance until macrophage burst to lease young tubercle bacilli into the tubercle (lung lesions). Thus the influx of unactivated macrophages repeats stages two and three above (multiplication of tubercle bacilli and ultimate formation tubercle lesion) making the formed tubercle lesion to grow or expand. The growing tubercle may invade a bronchus to cause infection of other parts of the lungs, artery or other blood vessels. A hematogenous spread of metastasizing tubercle bacilli (about the size of a millet seed) may result in extrapulmonary tuberculosis (milliary tuberculosis), which can occur at any part of the body including the genitourinary system, bones, joints, lymph nodes, and peritoneum. These secondary lesions of milliary tuberculosis are either exudative; in which a soft tubercle is formed due to unrestricted multiplication of Mycobacterium tuberculosis in the midst of accumulated PMN leukocytes; or productive/granulomatous in which a hard tubercle is formed due to the hypersensitivity of host to tuberculoproteins. Stage five When the caseous centers of the tubercles suddenly liquefy for unknon reasons, it forms a liquid which supports the rapid extracellular growth of tubercle bacilli. Bronchial necrotic cavities are formed with activities of the fast multiply tubercle bacilli giving way for other parts of the lungs and airways to be infected. When the primary lesion heals in an effort by the host to control the diseae, it becomes fibrous and calcifies forming the popular Ghon complex easily seen in chest Xrays. If a small metastatic foci containing low numbers of MTb calcify (with viable organisms), it is Simon foci also visible with chest X-ray are often the site of disease reactivation. Identification of Mycobacterium tuberculosis Cultural methods: Mycobacterium tuberculosis is a large non motile rodshaped bacterium distantly related to the Actinomycetes. Many non pathogenic mycobacteria are components of the normal flora of humans, found mostly in dry and oily locations. Mycobacterium tuberculosis is an obligate aerobe measuring measures 2m to 4m by 0.2m to 0.5m and must therefore be found in the well aerated upper sections of the lungs lobe during classical pulmonary tuberculosis.
92 It is also a facultative intracellular (macrophages) bacterium with a slow generation time of 15-20 hours, a characteristic considered significant in its virulence. Middlebrook's medium and Lowenstein-Jensen medium are commonly used to isolate the bacterium and they show small & buff colored colonies when grown on either medium. Middlebrook's medium and Lowenstein-Jensen media contain inhibitors to suppress the growth of contaminants during the 6-8 weeks it takes to get visual colonies on either type of media. It is seen microscopically as serpentine cords (first seen by Robert Koch) in chains of cells in smears made from in vitro-grown colonies. Staining methods: Although the bacteria contain peptidoglycan (murein) in their cell wall, it does not have the required chemical characteristics of Grampositive or Gram-negative bacteria cell wall and can therefore not be classified as such. Mycobacterium species and Nocardia species are classified as acid-fast bacteria due to their cell wall impermeability by certain dyes and stains. But once stained, acid-fast bacteria will retain dyes when heated and treated with acidified organic compounds. Ziehl-Neelsen staining is the method of choice for acid and alcohol-fast organism and Acidand alcohol-fast organisms appear pink in a contrasting blue background using this method. The Ziehl-Neelsen carbolfuchsin or Kinyoun carbolfuchsin staining techniques are cheap, fast and depending on the bacterial load, a single sputum smear may have sensitivity between 22% and 80%, but a multiple sputum smear would have a better yield. With Fluorochrome staining techniques, mycobacteria fluoresce with a bright orange color and can be easily seen on low-power microscopy. Skin Testing The tuberulin or Mantoux test uses purified protein derivative (PPD) as the test antigen. Tuberculin units are injected in the sub-cutaneous layer of the forearm and test is read within 48-72 hours. The test is positive if the diameter of the resulting erythematous, indurated lesion is 10-15 mm or more showing current infection or previous exposure. False possitive tests manifest as lesser reactions for this test indicating prior exposure, infection with other Mycobacteria or vaccination with BCG while false negative result are due to defective CMI common in AIDS. There is no known sensitive and specific serologic assay for M tuberculosis Gene probes Gene probe is based on transcription-mediated amplification which identifies Mycobacterium tuberculosis by targeting the mycobacterial ribosomal RNA. It is best used with ZN positive samples. Tuberculosis Treatment Effective regimens for the treatment of Tb must contain multiple drugs to which the organisms are susceptible including rifampin (RIF) isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) or streptomycin (SM). Prevention A vaccine against M.TB is called BCG (Bacillus of Calmette and Guerin, after the two Frenchmen that developed it). It has a live attenuated strain derived from the
93 microflora Mycobacterium bovis. However, BCG cannot stop disease reactivation in previously exposed individuals.
6b. Fungal Infections of the Respiratory Tracts

Histoplasmosis Histoplasmosis is an infectious non-contagious disease caused by Histoplasma capsulatum, a fungal genus with two varieties: Histoplasma capsulatum var. capsulatum (North America) and Histoplasma capsulatum var. duboisii African strain. It has a teleomorph called Ajellomyces capsulatus. North American Histoplasma capsulatum: This is a dimorphic fungus, existing as mycelia at room temperatures and grows as yeast at human body temperature. The fungus is found in temperate climates throughout the world especially in river valleys between latitudes 45 north and 30 south including Ohio, Missouri, and Mississippi river valleys in the United States. Mycelia grows better on acidic damp environment with high organic content, common in most endemic areas inhabited by bats and birds. The soil contaminated by birds droppings encourages mycelia growth and becomes potentially infectious for many years. Birds cannot be infected by the fungus and therefore do not transmit the disease. However, bats can become infected, and they transmit the fungus through droppings. Histoplasmosis is mostly asymptomatic in many patients but may show as full disease in endemic areas where infectious dose is very high. It can also cause opportunistic infections in HIV/AIDS patients. Cell-mediated immunity impairment results from recurring latent Histoplasma species from healed granulomas. Pathophysiology H capsulatum may exist as mycelia growing as free saprophyte in the environment but macroconidia and microconidia produced by the hyphae of mycelium are converted to pathogenic yeast form intracellularly at body temperature. Inhaled aerosolized conidia and mycelial fragments from contaminated soil are deposited in the results in alveolar deposition via inhalation. Mounted non-specific host defense against the fungus includes the fungistatic properties of neutrophils and macrophages. Host susceptibility to fungal dissemination is high with impaired cellular immunity. After phagocytosis by macrophages, the yeast replicates within the phagosome in about 15-18 hours probably due to production of inhibitory proteins against lysosomal protease. Yeast growth ceases within two weeks of exposure to increasing host immune response. Cytokines activates the fungistatic activity of macrophages against intracellular yeasts and delayed-type hypersensitivity to histoplasmal antigens occurs is established with six weeks after exposure. Almost every healthy exposed person (85-90%) will produce a positive response to skin antigen test for Histoplasma species. Later the inflammatory response to Histoplasma species produce calcified fibrinous granulomas with areas of caseous necrosis.
94 Clinical Details Continued exposure to large inocula produces a clinical picture of either localized or extra-pulmonary infection. Hematogenous spread of Histoplasma species to regional lymph nodes may occur through the lymphatics or the liver and spleen. Impaired vision and blindness develop in some people because of "presumed ocular histoplasmosis" probably associated with hypersensitivity to H. capsulatum instead of direct exposure of the eyes to the microorganism. The clinical manifestation of this disease depends on the extent of exposure, age, presence of underlying lung disease, general immune status, and specific immunity to H capsulatum. Infections can either be localized pulmonary or disemminated extrapulmonary histoplasmosis. North American pulmonary histoplasmosis Acute asymptomatic pulmonary histoplasmosis: This type commonly (>90%) occur in immunocompetent individuals living in endemic areas presenting with positive skin-test and negative serology-test results. Acute symptomatic pulmonary histoplasmosis: This is a benign, self-limiting illness characterized by: fever, chills, headache, cough, retrosternal or pleuritic chest pain, malaise, weakness, fatigue, and myalgia. Acute reinfection pulmonary histoplasmosis: This may be found in those living in endemic areas and subjected to constant re-exposure with the duration of illness shorter than in primary infection. Chronic pulmonary histoplasmosis: This is most common in patients with underlying chronic obstructive pulmonary disease (COPD), who develop productive cough, dyspnea, chest pain, fatigue, fever, and sweats and has fibrotic apical lesions with cavitation on chest radiographs or CT. Progressive disseminated histoplasmosis (PDH): It occurs in immunodeficient patients with defective T-cell immunity, geriatric patients. Most cases of PDH are believed to arise from endogenous reactivation, because the diseases are common among dwellers of remote endemic areas. Most common presentations are fever and malaise followed by weight loss, cough, diarrhea hepatosplenomegaly, lytic bone lesions, skin lesions, peripheral, prostatitis, lymphadenopathy or epididymitis. Miliary pulmonary histoplasmosis: This follows a more intense exposure where patients develop reticulonodular or miliary pulmonary infiltrates and may progress to respiratory failure or extrapulmonary PDH. Cinical manifestations of Extra-pulmonary histoplasmosis Pericarditis: Immunologic reaction to histoplasmosis in the adjacent mediastinal lymph nodes leads to pericarditis in 5-10% of symptomatic patients. Rheumatologic syndromes, (arthralgias, erythema nodosum, and erythema multiforme), are present in 6% of patients, (mostly women) and there is no Frank arthritis. Differential diagnosis of histoplasmosis should be considered in patients presenting with mediastinal or hilar lymphadenopathy and live or recently lived in endemic region,
95
African histoplasmosis H capsulatum var duboisii is a variant primarily seen in Africa, with few cases being reported in the United States and Chile. The yeast form of H capsulatum var duboisii is larger, with a thick wall and a diameter of 15 m. The clinical picture of H capsulatum var duboisii is different from that of H capsulatum var capsulatum. Most often, the skin and skeleton are affected andthere is skin ulcers, nodules, and psoriasis-like lesions. Osteolytic bone lesions of skull, ribs and the vertebrae are noted in 50% of patients. The organism produces granulomatous inflammation within bone and rarely involves the pulmonary system Clinical manifestation of African histoplasmosis Mediastinal granuloma: Mediastinal granuloma, characterized by enlargement of the mediastinal lymph nodes, is a rare outcome of mediastinal adenitis. Enlarged nodes will creat sinuses or fistulas between the airways and the pericardium or air-ways and esophagus. Enlarged nodes do not cause fibrotic reaction but compression of the trachea from the outside can cause respiratory distress common in young children, and prolonged obstruction can cause bronchiectasis or bronchial stenosis. Fibrosing mediastinitis: This is an excessive fibrotic response to a prior episode of histoplasmosis in which almost all mediastinal structures (superior vena cava (SVC), pulmonary arteries or veins, the bronchi, and the esophagus) are involved. The fibrosis is assumed to occur due to leakage of antigen from caseous nodes into the mediastinum, which stimulates an abnormal immunologic/inflammatory response leading finaly to fibrosis. Children are most vulnerable to this infection which is mostly astmptomatic. Obstruction of the mediastenal structure gradually develops the symptoms which may include cough, dyspnea, SVC syndrome, dysphagia, hemoptysis, and hoarseness. Broncholithiasis: Calsified lymph nodes and pulmonary granulomas may eat into into the adjacent bronchi, causing hemoptysis and/or obstruction and tracheoesophageal fistula. Cavitary pulmonary histoplasmosis: This is a possibility although the lungs are not the target of African histoplasmosis. It is characterized by progressive upper lobe infiltrates with cavitation. Gariatric patiets with preexisting chronic lung disease (usually emphysema) are most vulnerable. Diagnosis Histoplasmosis can be detected by identifying H. capsulatum in clinical samples in tissues or secretions, testing the patient's blood serum for antibodies to the microorganism, and testing urine, serum, or other body fluids for H. capsulatum antigen and testing of transbronchial biopsy. It may be culturerd in mice, sacrificing the mice after 4 weeks, and streaking agar plates with portions of each mouse's liver and spleen. The plates are watched for week, for the growth of H capsulatum. Polymerase chain reaction (PCR) technology allows direct identification of pathogenic fungi in clinical samples without culture. The
96 immunodiffusion test measures precipitating antibodies (H and M precipitin lines or bands) to concentrated histoplasmin. The H band of incicate acute infection the immunodiffusion test is usually present for only 4 to 6 weeks after exposure, it indicates active infection. The M band appears soon after infection, and may persist up to patients recovery. Complement-fixation test measures antibodies to the intact yeast form and mycelial (histoplasmin) antigen. A rapid radioimmunoassay method can be used to measure H. capsulatum polysaccharide antigen (HPA) levels in body fluids. Histoplasmin skin test, similar to a tuberculin skin test, becomes positive 2 to 4 weeks after infection by H. capsulatum, and repeated tests will give positive results for the rest of the person's life. False-negative skin test can be reported early in an infection or HIV/AIDS patients. A false-positive skin test can result from crossreactions with antigens of certain other pathogenic fungi. Occupational risk factors Acquired immunodeficiency syndrome (AIDS) or cancer, persons receiving cancer chemotherapy; high-dose, long-term steroid therapy; or other immunosuppressive drugs. Occupation at risk include: Bridge inspector or painter, Chimney cleaner, Construction worker, Demolition worker, Farmer, Gardener, Heating and air-conditioning system installer or service person, Microbiology laboratory worker, Pest control worker, Restorer of historic or abandoned buildings Roofer and Spelunker (cave explorer). Severerity of infection is a function of the dose of microorganisms inhaled Treatment: Amphotericin B and Itraconazole are recommended Coccidioidomycosis Coccidioidomycosis is adisease caused by Coccidioides immitis and C posadasii. These are thermally dimorphic fungi which are phenotypically identical but genetically different. They can be found in the soil of warm, dry areas with low rain fall, high temperatures and low altitude. Because of their phenotypic similarities, they will be refered to the pair of species as C immitis/posadasii. C immitis/posadasii inhabits alkaline soil. It is isolated arid environment where rodents live. Coccidioides immitis/posadasii has no teleomorph and is a pathogenic fungus causing true systemic (endemic) mycoses. It is widespread at southwest United States, Northern Mexico, Central and South America and may be if endemic areas are visited. Pathogenicity and Clinical manifestation Coccidioides immitis/posadasii is the causative agent of coccidioidomycosis, true systemic (endemic) mycoses, acquired by of the dry arthroconidia of Coccidioides immitis/posadasii, which are carried by dust storms. Hematogenous spread of the organism leads to infection of distant sites such as the skin, bones, joints, lymph nodes, adrenal glands, and central nervous system. The infection may show as acute and self-limited respiratory infection or progresses to a chronic disease depending of the underlying medical condition, sociodemographic and geographical factors. Spontaneous healing may be seen in 95% of the apparently
97 healthy host and dissemination may occur in careers and pregnancy. Coccidioidomycosis is mainly a disease of the immunocompetent and may also affect the immunocompromised patients with AIDS and organ transplant recipients. Occupational risk includes activities related to tillage of the soil, such as agricultural work, telephone post digging, archeology, or playing with soil. Laboratory diagnosis At 25 or 37C and on Sabouraud dextrose agar, the colonies are moist, glabrous, membranous, and grayish initially, later producing white and cottony aerial mycelium and ilder conolonies are tan to brown in color. At 25C: Clasical raquet-like (in young cultures), hyaline, septate and thin hyphae produced. Arthroconidia produced are thick-walled, barrel-shaped, and are 2-4 x 3-6 m in size. At 37C: Large, round, thick-walled spherules (10-80 m in diameter) filled with endospores (2-5 m in diameter) are seen. Invitro production of spherules will need inoculation into a converse liquid medium; an incubation temperature of 37-40C and presence of CO2 at a concentration of 20% or else Coccidioides immitis/posadasii will continue to grow as a mould and will not produce spherules in vitro. Thus, spherule formation is regulated by temperature and other variables. The definitive identification of an isolated Coccidioides immitis/posadasii strain requires demonstration of spherule production in vitro, use of DNA probes, Molecular typing studies, application of exoantigen tests, or demonstration of spherule production in vivo by animal experiments. The arthroconidia and the disjunctor cells of the the two genera Malbranchea and Coccidioides are similar. However, Malbranchea differs from Coccidioides immitis/posadasii because they do not produce spherules containing endospores, do not reacting with Coccidiodies immitis/posadasii specific reagents during the exoantigen test or the DNA test probe. Again the fertile hyphae of Malbranchea are curved whereas those of Coccidioides are straight. Treatment and prevention: Amphotericin B, itraconazole, fluconazole, ketoconazole, capsofungin, sordarins, nikkomycins and voriconazole are recommended. Vaccine research is in progress for this disease Blastomycosis This is a fungal disease caused by a soil saprophytic, thermally dimorphic fungus named Blastomyces which produces ascospores as sexual spores. It specifically inhabits decaying wood material and Isolation from the environment is best when the sample contains soil and is rich in animal feces, plant fragments, insect remains, and dust. It prefers a substrate that is moist, not directly exposed to direct sunlight, contains organic debris, and has a pH of less than (6). African type strains (pH of < 6.0), are different from the North American strains. These two groups are serotypes of Blastomyces dermatitidis showing geographical diversity, common/varying antigens. The sexual state (teleomorph) of Blastomyces dermatitidis belongs to the family Onygenaceae and is called Ajellomyces dermatitidis. Pathogenicity and Clinical manifestations Blastomyces dermatitidis causes blastomycosis; true systemic mycoses which manifest as cutaneous and systemic (disseminated) blastomycosis. Blastomycosis
98 is acquired by inhalation of spores and it affects maily the immunocompetent host. Primary cutaneous infection is due to direct inoculation of the fungus into the skin while hematogenous spread may results in infection of distant sites including skin, bones, kidneys, male urogenital system, CNS, eyes, larynx, paranasal sinuses, tongue, adrenal glands, uterus, ovaries, gastrointestinal tract, liver and spleen. Otitis media, resulting in cranial osteomyelitis may also develop. Reactivation blastomycosis and subclinical, self-limited infections are possible. The pathogenesis of Canine (dog) and human blastomycosis are similar. Although there is no correlation between canine blastomycosis and human disease canine disease can serve to predict the danger of possible outbreak from the environment Laboratory diagnosis This is a thermally dimorphic fungus, existing as mould-like at 25C and yeastlike at 37C. Species identification is based on a proof of fungal dimorphism, use of exoantigen test, direct flourescent antibody test and nucleic acid probes. At 25C; the growth rate is slow, colony diameter is 0.5 to 3 cm after 7 days incubation on potato glucose agar and microscopically athere is septate hyaline hyphae and unbranched short conidiophores. At 37C: It is converted to a yeast form when grown on an enriched medium (BHI); the growth rate is slow; colony diameter is 0.5 to 3 cm after 7 days incubation. The usual way to isolate Blastomyces dermatitidis from environmental sources is by animal inoculation. In vitro method of isolation involves placing the soil on a neutral aqueous solution containing allantoin, tween 80, potassium phosphate, magnesium sulphate, penicillin and streptomycin and is incubated at 37C for 22 days. Then, a small amount of the solution (100 l) is plated onto yeast-extract phosphate agar and incubated at 20 to produce moulds. Yeast form may be obtained by culturing on yeast-extract phosphate agar and later on to brain-heart infusion agar. Treatment Amphotericin B, ketoconazole, itraconazole fluconazole, voriconazole, posaconazole, VER-002, and caspofungin appear active against Blastomyces. Paracoccidioidomycosis This is caused by a mitosporic thermally dimorphic fungus Paracoccidioides brasiliensis obtained from soil and digestive tract of some animals, and whose natural habitat is still unidentified. It is abundant in humid soil, rich in proteins. Randomly amplified polymorphic DNA analysis has been used to determine the geographical distribution of Paracoccidioides brasiliensis although the epidemiology of its disease outcome is not fully understood. The fungus is common in Central and South American countries like Brazil, Venezuela, and Colombia. The genus Paracoccidioides is made of one species, Paracoccidioides brasiliensis and has no teleomorph. Pathogenicity and Clinical manifestation The range of the fungal disease paracoccidioidomycosis varies from an asymptomatic infection to a subclinical, symptomatic or chronic infection. The infection is most likely acquired by inhalation of the fungal conidia, followed by primary colonization of the lungs before it becomes obvious years after the first
99 exposure to the etiologic agent-Paracoccidioides brasiliensis. Virulence factor for tissue invasion is the exocellular serine-thiol proteinase enzyme. It manifests as primary pulmonary, acute pulmonary, chronic pulmonary and disseminated Laboratory infestigation: Paracoccidioides brasiliensis grows either as mould form at 25C and in its yeast form at 37C. At 25C, colonies are filamentous, slow growing, leathery, flat to wrinkled, woolly or cottony. Microscopically, it produces hyaline, septate sterile hyphae and aleuriconidia which do not sporulate. AT 37C, colonies are transformed from mould to yeastlike, white, or wrinkled form if grown on Brain Heart Infussion (BHI) agar and incubated for 10 to 20 days. Microscopically it produces multiple buds sounding the mother yeast. Treatment: Aamphotericin B, ketoconazole, itraconazole, fluconazole, and voriconazole may be recommended although standard MIC for this organism is not yet in place Cryptococcus infection Background This is a fungal disease caused by an encapsulated yeast Cryptococcus neoformans. Defective cell-mediated immunity among HIV/AIDS patients is a significant risk factor of disease establishment than fungal virulence. Other defective CMI patients include patients: undergoing organ transplant, with reticuloendothelial malignancy, undergoing corticosteroid treatment (excluding those with immunoglobulin deficiency), and patients with sarcoidosis. Mycology: Characteristics of C neoformans var (neoformans and gattii) a. C neoformans has 2 varieties (neoformans and gattii) and 4 serotypes serotypes A and D (C neoformans var neoformans) and serotypes B and C (C neoformans var gattii). b. The C neoformans var neoformans is common with temperate zones and in aged pigeon droppings while C neoformans var gattii develops in tropical and subtropical climates and grows in the waste around Eucalyptus camaldulensis, and Eucalyptus tereticornis trees c. C neoformans var neoformans serotype A infects immunocompromised patients while C neoformans var gattii infects immunocompetent patients. d. C neoformans var gattii contains genotypes VGI and the more commonly identified VGIIa and VDIIb. e. The mating of serotypes A and D produced F neoformans var neoformans f. C neoformans var gattii exist in the perfect state of Filobasidiella bacillisporus a results of the mating of serotypes B and C. g. Mating can occur between some strains of A and D and strains of B and C. Growth Characteristics: 1. C neoformans reproduces by budding, forming round yeas-tlike cells, 3-6 m in diameter.
100 2. It may form a large polysaccharide capsule around each cell within the host and in certain culture media. 3. C neoformans forms smooth, convex, and yellow or tan colonies on solid media at 20-37C. This fungus is differentiated from non-pathogenic strains based on its microscopic appearance, biochemical test results, and ability to grow at 37C 4. C neoformans does not metabolize lactose and nitrates or produce pseudomycelia on cornmeal or rice-Tween agar. 5. C neoformans can use creatinine as a nitrogen source, explaining why it grows well in creatinine-rich avian feces. 6. C neoformans, produce melanin when the fungal enzyme phenol oxidase acts on certain substrates dihydroxyphenylalanine, caffeic acid. Epidemiology Most cases of cryptococcosis involve C neoformans serotypes A and D. Serotypes B and C are commonly found in tropical and sub-tropical areas from around some species of eucalyptus trees and the air under them. C neoformans var neoformans, recovered from aged pigeon feces, bird nests, and guano, is from serotype A or D. Birds do not transmit the disease or carry the fungus but bats do. In moist pigeon excreta, C neoformans may remain viable for two or more years in moist pigeon excreta. In the environments, C neoformans grows unencapsulated in the environment. It is not a zoonotic disease and is not transmited by droplets although the fungus occurs naturally in animals and humans. Infection is acquired by inhalation of air-borne spores- propagules which infect the lungs and CNS. Risk group include preexposure to pigeons or bird feces and laboratory workers exposed to an aerosol of the organism. Pathophysiology Human disease is associated with only C neoformans of 19 known species. Following inhalation, the yeast goes to the pulmonary alveoli, and is assisted by Glucosylceramide synthase the cellse (GCS) in extra-cellular survival. A cryptococcal polysaccharide capsule is antiphagocytic and immunosuppressive. The antiphagocytic properties of the capsule prevent leukocyte migration by avoiding being recognized by by phagocytes. Humoral responses define cryptococcal host response to infection. The host would successfully response to cryptococcal infection if it increases helper T-cell activity, skin test conversion, and a reduction in the number of tissue-viable cells. Antibodies to a cryptococcal antigen and its complement are important in enhancing the macrophage- and lymphocyte-mediated immune response to the organism. Lack of identifiable endotoxins or exotoxins partly causes the absence of extensive necrosis early in cryptococcal infections. C neoformans can cause an asymptomatic pulmonary infection and then meningitis, which is the first sign of the disease. Patients with disease confined to the lungs are immunocompetent. Pulmonary cryptococcosis Cryptococcal pulmonary disease may present: with asymptomatic saprophytic airway colonization, an acute respiratory distress syndrome common in
101 immunocompromised hosts (AIDS and organ transplant patients) or as a slowly progressive mass which may compress thoracic structures (vena cava). Moreover, there may be fever, malaise, cough with limited sputum, pleuritic pain, hemoptysis (rare), pleural rub and pleural effusions (rare). There may be pulmonary disease without extra pulmonary involvement and conversely there may extra pulmonary disease (meningitis) without particular pulmonary disease. CNS cryptococcosis It shows as subacute or chronic meningitis and meningoencephalitis. Depending on the underlying medical conditions (diabetes, sarcoidosis, glucocorticoid use, and the immune status of the host), the following are evident: headache, altered mental status, nausea, vomiting, fever, stiff neck, hearing defects, seizures, ataxia, aphasia, and choreoathetoid movements. If arachnoiditis, papilledema, optic nerve neuritis, and chorioretinitis occur, it comes with blurred vision, photophobia, and diplopia. Late complications may include dementia which indicates the presence of hydrocephalus. Cryptococcosis in other sites Cryptococcosis may also involve the skin, prostate, and medullary cavity of the bones. Cutaneous form occuring in 10-15% of cases presents with papules, pustules, nodules, ulcers, draining sinuses cellulitis with necrotizing vasculitis organ transplant patients. It may also manifest as Myocarditis; Chorioretinitis; Hepatitis; Peritonitis; Renal abscess; Prostatitis; Myositis; Adrenal involvement. Laboratory Diagnosis CSF analysis for Cryptococcus remains the gold standard for disease diagnosis and culture of CSF for the Cryptococcus is recommended even when hematological parameters appear normal. Presumptive diagnosis disease from CSF with India ink is common. Presumptive diagnosis must be confirmed with culture of CSF, urine, sputum, bronchoalveolar lavage washings and blood for the fungus on Sabouraud dextrose agar, with or without antibiotics for bacterial growth suppression. C neoformans species would be seen growing at 37oC assimilates inositol, produces urease, and does not produce mycelia on cornmeal agar. It is also a melanine producing fungus. A latex agglutination test can be used to detect cryptococcal polysaccharide in serum or CSF but result must be confirmed by culture. Treatment Amphotericin B, flucytosine, fluconazole in the correct combinationa are recommended
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8. Bacteria infections of the genital tract

Introduction The sexually transmited infections (STI) are the main public health concern among bacteria infectious agents of the Genital Tract (GT). STI's are among the most common infectious diseases in the world, most prevalent among teenagers and adults younger than 25 years of age due to high sexual activity among this group. Disease epidemic has social, demographiuc and cultural implications. The most reliable way to avoid transmission of STIs is either to abstain from sexual intercourse (i.e., oral, vaginal, or anal sex) or to be in a long-term, monogamous relationship with an uninfected faithful partner. Abstinence is recommended for infected persons receiving treatment. STI prevention Methods include the use of male or female condom, vaginal spermicides, sponges, and diaphragms Five concepts of STI prevention 1. Education and counseling of persons at risk on ways to adopt safe sex 2. Effective diagnosis and treatment of infected persons; 3. Evaluation, treatment, and counseling of sex partners of infected persons 4. Pre-exposure vaccination of persons at risk for vaccine-preventable STIs 5. Changing the sexual behaviors that place persons at risk for infection. Five groups of STI 1. Diseases Characterized by Genital Ulcers 2. Diseases Characterized by Urethritis and Cervicitis 3. Other STI's includes Pelvic inflammatory Disease (PID), Epididymitis, Proctitis, Proctocolitis, and Enteritis 4. Diseases Characterized by Vaginal Discharge 1. Diseases Characterized by Genital Ulcers Four main disease conditions characterized by genital ulcers to be analyzed include: Syphilis Chancroid Granuloma Inguinale Lymphgranuloma Venereum Syphilis Treponema pallidum is the causative agent for Syphilis. The spiral shaped morphology and characteristic motility pattern are important for diagnosis via darkfield microscopy. T. pallidum does not grow in laboratory media. Transmission is by direct contact with infectious lesions mainly through sexual contact and man is the only known host. The organisms enter the body through minute abrasions, penetration of mucous membranes or through hair follicles followed by fast systemic spread through the blood and lymphatics. Primary Syphilis
103 After the incubation phase of about 10-90 days, it produces a highly infectious hard chancre, characterized by the following: 1. They may occur anywhere on the body 2. They are painless 3. Healing of chancre may take in 3-6 weeks. 4. Regional lymphadenopathy may develop during primary syphilis. 5. The nodes are firm, non-suppurative 6. It may persist for months, after the chancre has healed. Secondary syphilis This starts 6-8 weeks after the appearance of the initial chancre and when the bacteria are in the circulation. It manifests as skin and mucous membrane lesions, or as systemic disease accompanied by high bacteremia. Skin lesions appear as macular, papular, pustular or nodular type rashes. It is commonly seen on the palms and the soles of patients and last about 2-6 weeks before the patient enters the latent phase. Non-specific manifestation of systemic disease of 2 syphilis include: malaise; anorexia; headache; sore throat; arthralgia; low grade fever and generalized lymphadenopathy. Latent syphilis Latent syphilis is the stage which lacks clear disease symptoms but shows positive when samples are analyzed using serological tests. It is a highly variable phase and what happens next is unpredictable. It has been reported that in about 25% of patients the bacteria may come from latency to repeat the secondary bacteremic phase while in about 35% of patients, the bacteria may establish tertiary syphilis. Tertiary or late syphilis Tertiary or late syphilis is a non-communicable but very critical phase of syphilis which may manifest itself in several forms: Late benign or gummatous syphilis: Late benign or gummatous (nodular granulomatous inflammatory lesions found in any organ) syphilis is the most common form of 3 syphilis occurring in 15% of untreated cases which has lasted 1-10 years after infection. Cardiovascular syphilis: This develops in 10% of untreated syphilis and within 10-40 years after initial infection. It is characterized by aortitis, aortic regurgitation (due to altered aortic valve function), aneurysm and obstruction of the coronary ostia Neurosyphilis: This develops in 8% of untreated cases and within 5-35 years after the primary infection. Bacteria invades the CNS occurs during generalized dissemination in the secondary phase of sypjilitic infection. There are four forms of neuro-syphilis as outline below: 1. Asymptomatic neurosyphilis: This is characterized by lack of evidence to illustrate CNS involvement but laboratory investigation shows abnormal CSF result with elevated lymphocytes and protein and also a positive CSF VDRL tests. 2. Acute meningitis: This is the classical meningitis affecting the third cranial nerve, seen within 2 years of infection and characterized with the conventional headache, vertigo nausea, vomiting, generalized convulsions and cervical rigidity.
104 3. Chronic meningovascular neurosuphylis: This is another form of classical meningitis affecting mostly the middle and posterior arteries and, 3rd, 4th, 6th cranial nerves. It is seen within 2-5 years of infection. There is blood verssel blockage and nerve tissue nicrosis due to proliferative endarteritis and perivascular infiltration with lymphocytes. Gradual erosion of intellectual and emotional capacity also sets in. 4. General paresis: About 5% of patients experience general paresis, seen 20 or more years after untreated infection and may manifest as personality changes and hyperactive reflexes. The eyes, senses, intellect, speech are all affected and the patients may finally become paralyzed. Congenital syphilis Congenital syphilis is transmission from mother fetus around the 4th month of pregnancy. It may lead to still birth if the mother is heavily infected. Manifestations within the first two years of life of survivors include Rhinitis, snuffles, skin and mucocutaneous lesions, Osteochondritis (inflamed bone & cartilage) & osteitis (inflammation of bone), Hepatosplenomegaly and lymphadenopathy and Immune complex-induced glomerulonephritis. Pulmonary hemorrhage, 2 bacterial infection and hepatitis may combine to kill the pstient within the first two years. Infection is subclinical in 60% of 2-year survivors while the remaining 40% may show deafness, bone, teeth and joint abnormalities. Diagnosis This entails evaluation of signs and symptoms and contact history. Laboratory investigation involves darkfield examination of exudative material in syphilitic lesions and direct fluorescent Ab test for T. pallidum (DFAT-Tp). Serology This may either using non-treponema or treponema antigens. A Nontreponemal tests evaluates anti-treponemal antibody with a cross reactive cardiolipin lecithin as an antigen rather than the actual bacterial antigens. The test in this category include: VDRL slide test, USR - (Unheated Serum Reagin), RPR, TRUST (Toluidine Red Unheated Serum Test) and RST (Reagin Screen Test). Treponemal antigen tests rely upon antigen derived from T. pallidum. Examples include: Fluorescent treponemal antibody-absorption test (single and double staining) and hemagglutination test T. pallidum. False +ve serological reactions in non-treponemal antigen tests are common in patients with: hepatitis, infectious mononucleosis; pregnancy; connective tissue disease like SLE; disease with Ig abnormalities in some healthy people. False positives in direct treponemal tests are but associated with: diseases with Ig abnormalities, multiple myeloma and SLE Treatment Benzathine penicillin G remains the treatment of choice. Chancroid or soft chancre disease
105 Chancroid is an acute sexually transmitted infection (STI) caused by Haemophilus ducreyi (a Gram negetive rod in chains) and characterized by genital ulceration and suppuration. Transmision of infection is by contact and so how contagious infection can be is determined by level of hygiene. Most outstanding risk factor is prostitution and T. pallidum or HSV frequently co-infect with Haemophilus ducreyi in chancroid disease. Clinical manifestations Soft chancre develops after about 14 days of incubation and it deffersfrom the syphilitic chancre by being extremely painful, lacks induration and soft and hence the name soft chancre. In the beginning of the infection process, characteristic lesions (acute, painful inflammatory inguinal lymphadenopathy) are single and separated before spreading by autoinoculation. Haemophilus ducreyi enters the body through skin abrasions and induces ulcerative papule or vesicle which shows thick inflammatory exudate with PMNs but not mononuclear cells. Diagnosis: It can be diagnosed by lesion evaluation and taking sexual history and definitive diagnosis will depend on culture and isolation of H. ducreyi. Treatment Azithromycin, Ceftriaxone, Ciprofloxacin, Erythromycin are drugs of choice. Granuloma inguinale Granuloma inguinale (ulceration granuloma of the pudenda and granuloma contagiosa) is a chronic, sluggish, ulcerative, granulomatous disease of the skin and lymphatics caused by Gram negative bacilli (with characteristic bipolar staining) called Calymmatobacterium granulomatis. It has a characteristic safetypin like appearance is stained tissues called Donovan bodies. This is a venereal, contagious, slowly ulcerative, sexually transmitted, tropical disease which manifest with localized genital lesions and subcutaneous granulomas in the inguinal regions. The lesions may be called pseudo-buboes because they do not involve the lymph nodes. The known route of entry is by direct inoculation through skin abrasions or mucous membranes. Indurated papules are first formed before they progress to typical ulceration. Donovan bodies (mononuclear cells with intra cytoplasmic vacuoles packed with the bacteria) are highly diagnostic for granula inguinale Treatment: Trimethoprim-sulfamethoxazole, Erythromycin, Doxycycline and Ciprofloxacin are receommended Lymphogranuloma Venereum (LVG) Lymphogranuloma Venereum, (LVG) or Durand-Nicolas-Faver disease or tropical/climate bubo or por-adenitis, or lymphopathia venereum or lymphogranuloma inguinale is a sexually transmitted infection caused by Chlamydia trachomatis and is characterized by acute inguinal lymphadenitis and genital ulceration. L1 - L3 are three separate immunotypes of Chlamydia trachomatis which cause LGV. Epidemiology & Manifestations
106 This is another STI common in tropical and subtropical climates. A primary genital herpetiform and transitory lesion is seen after 3 to 30 days of incubation. Lymphadenitis & genito anorectal syndrome is seen after the initial lesion heals. Primary inguinal syndrome starts 2-6 weeks after exposure to the bacterium as a painful inguinal lymphadenopathy. The acute stage may be followed by systemic manifestations such as fever, chills headache, anorexia, myalgias arthralgias, hypergammaglobulinemia and splenomegaly including genito-anorectal syndrome occuring after rectal intercourse or through spread from genital infection sites in women. Common manifestations include rectal strictures, genital elephantiasis and a chronic induration of the penis or vulva due to lymphatics obstruction. Late complications include abscesses, urethra destruction and draining fistulas. Pathology and pathogenesis Chlamydia trachomatis enters the body through minute skin abrasions from where it induces local genital lesion which progresses to involve the regional lymph node and disseminated systemic effects because unactivated macrophages phagocytize them and carry them around as intracellular parasites. Diagnosis Diagnosis is based on clinical manifestations (. Inguinal lymphadenopathy with pathopneumonic groove sign for LGV) and agglutination reactions with complement fixtion test. Isolation of the organism using tissue culture (McCoy cells) is conclusive although not a routine practice.
2. Diseases Characterized by Urethritis and Cervicitis These are disease characterized by urethral discharge of mucopurulent or purulent material and may be accompanied by dysuria or urethral pruritis. Most common pathogens in men are N. gonorrhoeae and C. trachomatis. Gram stain of urethral secretions shows greater than 5 WBCs/HPF. Leukocyte esterase test on first-void urine is positive Gonorrhea Gonorrhea is an infection of the columnar and transitional epithelium of the genital tracts caused by Neisseria gonorrhoeae, a Gram positive intracellular diplococcic. Neisseria gonorrhoeae are very fragile and fastidious organisms not transmitted by formites and have low tendency of developing resistance to antimicrobial agents except plasmid-directed penicillinase-producing N. gonorrhoeae (PPNG). The main virulence mechanisms are possession of pili, production of an IgAase and ability to scavenge iron. Human are the only known host and infection is by sexual contact. The risk of contracting gonorrhea through conventional sexual intercourse is more for women than in men. Manifestations of gonorrhoeae
107 o Signs in males include copious purulent urethral discharge and dysuria characterized by inflammation and erythema around the opening of the urethra, purulent urethral discharge & painful urination. o Generally it may manifest as: inguinal lymphadenitis; urethral stricture; local abscess formation and inflammation of epididymitis, prostatitis and disseminated gonococcemia which show as skin lesions. o In homosexual men, infection may involve the urethra, anal canal, pharynx, anorectal infection characterized by rectal pain and mucopurulent rectal discharge o Cervical infection (asymptomatic in 30% of females) leads to contiguous spread to the urethral and anal areas resulting in anorectal infection (pain, purulent discharges, and rectal bleeding) and urethral infection (purulent exudates, dysuria and increased frequency bartholinitis). o Manifestations in about 10-20% of cervical infections leads to gonococcal PID due to upward spread of the bacteria resulting in endometritis, salpingitis, tubovarian abscesses and pelvic peritonitis o There may also be Fitz-Hugh-Curtis syndrome, a form of perihepatitis resulting from direct inoculation of gonococci on the surface of the liver. o About 1-3% of asymptomatic disseminated gonococcal infection (ADGI) of urogenital and/or pharyngeal infection may manifest as low grade fever; migratory polyarthralgias involving the large joints; septic arthritis; increased pain and swelling; purulent synovial fluids and joint destruction including tenosynovitis (Skin rashes). o Gonococci infect the conjunctivitis, pharynx, respiratory tract and geastriintestinal tract during delivery (child birth). Constant use1% silver nitrate or 0.5% erythromycin or 1% tetracycline following birth prevents ophthalmia neonatorum. Diagnosis Diagnosis can be made by evaluation of symptoms, taking of sexual history; Gram stain of urethral exudates and culturing for N. gonorrhoeae. Gonococci are isolated from calcium alginate swabs plated on Thayer Martin medium (chocolate agar with added Vancomycin, Colistin and Nystatin) or New York City medium. Nucleic acid amplification and other DNA technologies are employed for speciation at the molecular level. Treatment: Cefixime, Ceftriaxone, Ciprofloxacin, Ofloxacin, Levofloxacin, Azithromycin, Doxycycline recommended for uncomplicated cases of cervicitis, pharyngitis, urethritis, and proctitis. Disseminated infections require parenteral Ceftriaxone and pharyngeal infections need ceftriaxone & Ciprofloxacin Prevention: Since gonococcal pili vaccines, were not protective, control now depends on better education, proper reporting, follow-up of patients and their contacts, use of condoms, and chemoprophylaxis to prevent neonatal gonoccocal conjunctivitis Nongonococcal urethritis (NGU) NGU tends to cause urethritis in heterosexual men and is diagnosed if Gramnegative intracellular diplococci are absent from urethral smears. Complications
108 of NGU among men infected with C. trachomatis include epididymitis and Reiter's syndrome. Other agents of NGU include: Ureaplasma urealyticum, Mycoplasma genitalium, and Trichomonas vaginalis. C. trachomatis types D to K, U. urealyticum and Mycoplasma genitalium, lacks cell wall requires tissue culture to grow. G. vaginalis is a rod shaped gram variable bacteria which more commonly causes vaginitis but can on occasion cause NGU in males. Epidemiology Sexually active men (aged of 15 to 30) with many sex partners are most at risk. No eteiologic agents will be found in up to 50% of the cases of NGU because the organisms needs tissue culture for isolation and identification, a method not commonly used. Gonococcal urethritis is common among city dwellers and among homo-sexuals and heterosexuals (80-90% of the urethritis). Symptoms and Signs There is visible abnormal urethral discharge, positive LE test from males less than 60 years of age and without history of kidney disease or bladder infection, prostate enlargement, urogenital anatomic anomaly, or recent urinary tract instrumentation. Microscopic evidence of urethritis on a Gram stain of a urethral smear is diagnostic. Diagnosis and treatment NGU diagnosis is made when there is no laboratory evidence of N. gonorrhoeae infection. Diagnosis requires demonstration of a PMN response and exclusion of N. gonorrhoeae. The whole genital region should be examined for lesions and rashes and an endo-urethral swab specimen or first voided urine is collected for analysis. Culture of the various organisms is okay except NGU caused by U. urealyticum and C trachomatis which requires tissue culture. Azithromycin & Doxycycline and examination of all sex partners Chlamydial infections This occurs among sexually active adults although in most cases disease is asymptomatic and it rarely causes epididymitis. Females with symptoms may have mucopurulent cervicitis. Disease outcome may include pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. PID is more common in adolescent and young women. Sensitive and specific methods used to diagnose chlamydial infections include tissue culture, immuno-serology and and Nucleic acid amplification tests. Prenatal screening of pregnant women can prevent Chlamydia trachomatis infection among neonates which results from perinatal exposure to the mother's infected cervix. Pregnant women less than 25years are at high risk for infection and neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant. Manifestations: Initial C. trachomatis perinatal infection involves mucous membranes of the eye, oropharynx, urogenital tract, and rectum. Neonatal C. trachomatis infection mainly manifest as conjunctivitis, 5--12 days after birth. Chlamydia is the most frequent identifiable infectious cause of ophthalmia neonatorum and also a common cause of subacute, afebrile pneumonia with onset
109 from 1--3 months of age. Asymptomatic infections also can occur in the oropharynx, genital tract, and rectum of neonates. Diagnosis: Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests. Specimens must contain conjunctival cells, not exudate alone. Specimens for culture isolation and nonculture tests are obtained from the everted eyelid using a dacron-tipped swab or the swab specified by the manufacturer's test kit. Therapy: If treatment is needed, oral Erythromycin or ethylsuccinate 50 mg/kg/day are recommended. Treating infected patients, pregnant women and sex partners with Azithromycin, Doxycycline are encouraged 3. Other Sexually transmitted infections of the genital tract Pelvic Inflammatory Disease (PID) PID is the clinical syndrome (in women) resulting from the ascending spread of microorganisms from the high-vagina and endocervix to the endometrium, the fallopian tubes and/or to neighboring structures including the oraries. PID is polymicrobial infection and the disease outcome may include endometritis, salpingitis, tuba-ovarian abscess, and pelvic peritonitis. N. gonorrhoeae and C. trachomatis are the most common bacteria agents followed by anaerobicBacteroides, E. coli, Mycoplasma hominis and Actinomyces israelii. If there were earlier infections of the fallopian tubes with N. gonorrhoeae or C. trachomatis, resulting in the damage of the ciliary cells lining the fallopian tubes, then it will encourage other organisms to ascend the fallopian tubes and to cause infections in neighboring structures. Risk factors include multiple sex partners, history of previous PID, menstruation, use of IUD, marital status. Risk factors of PID include: moderate fever, lower abdominal pain greatest in the fallopian tubes region, increased vaginal and purulent endocervical discharge, irregular bleeding, tenderness on cervical motion, nausea and vomiting, infertility, perihepatitis leading to Fitz-Hugh-Curtis syndrome; ovarian abscesses which may lead to death if it ruptures, tubal occlusion, scarring, and adhesions. Definitive diagnosis rests on the cultural confirmation of the etiologies of PID. Starting with parenteral therapy: Cefotetan, Cefoxitin, Ofloxacin, Levofloxacin Ofloxacin, Levofloxacin, Metronidazole, Doxycycline and switching to oral therapy are recommended Epididymitis This disease is common among the sexually active age bracket of 15 to 35 years in hetero-sexual men and in the insertive partner during anal intercourse. Sexually transmited epidimytis is accompanied by asymptomatic urethritis and commonly caused by C. trachomatis or N. gonorrhoeae. Nonsexually transmitted epididymitis, associated with UTI are caused by Gram-negative enteric organisms occurs more frequently among men aged more than 35 years and men who have recently undergone urinary-tract instrumentation.
110 General signs may be testicular pain and tenderness; hydrocele and palpable swelling of the epididymis. The evaluation of men for epididymitis should include: a presumptive diagnosis of a Gram-stained smear of urethral exudate or intraurethral swab specimen showing greater than or equal to five polymorphonuclear leukocytes per oil immersion field and a definitive (confirmatory) diagnosis comprising of a culture of intraurethral exudate (for isolation) or a nucleic acid amplification test (either on intraurethral swab or first-void urine) for identification of N. gonorrhoeae, C. trachomatis and other agent of epidimitis. Rulling out syphilis by serology and HIV by counseling and testing are recommended. Treatment: Ceftriaxone, Doxycycline, Ofloxacin and Levofloxacin are recommended. Proctitis, Proctocolitis, and Enteritis o Proctitis is the inflammation of the anus and rectum and is commonly caused by: sexually-transmitted disease; non-sexually transmitted infection; autoimmune disease; noxious agents. Proctitis inflammation is limited to the distal (10-12 cm) rectum which may be associated with anorectal pain, tenesmus, or rectal discharge. o Proctocolitis is when the inflammation of the anus and rectum (proctitis) is accompanied by diarrhea or abdominal cramps and inflammation of the colonic mucosa extending to 12 cm above the anus. Proctitis and proctocolitis are common outcome of anal intercourse. o Enteritis is when a patient has diarrhea and abdominal cramping without proctitis or proctocolitis and it is common among persons who practices oral-fecal sex. Etiologic agents of proctitis may include N. gonorrhoeae, HSV, T. pallidum, Chlamydia trachomatis and the lymphogranuloma venereum serotypes of Chlamydia trachomatis (L1-L3), Entamoeba histolytica, Streptococcus pyogenes (non STI), Autoimmune proctitis is linked with ulcerative colitis (Crohn's disease) and radiation proctitis (association with radiotherapy). Inserssion of chemicals into the rectum, and medications can also cause proctitis. Etiologic agents of proctocolitis may include Campylobacter sp., Shigella sp., Entamoeba histolytica, and, rarely, LGV serovars of C. trachomatis. Giardia lamblia is mostly involved in enteritis among the healthy individuals. Diagnosis of proctitis, proctocolitis, and enteritis include appropriate diagnostic procedures such as Stool examination, culture and anoscopy or sigmoidoscopy. Treatment is based on specific outcome of diagnosis Prostatitis Prostatitis is an inflammation of the prostate gland accompanied by an acute bacterial infection and chronic pain syndromes. Most of prostatitis cases are due to an infection by Gram negative bacteria (Escherichia coli). Common etiologic agents of acute bacteria prostatitis includes: Klebsiella sp, Proteus sp. Pseudomonas aeruginosa, Enterococcus spp, Chlamydia spp., Staphylcocccus aureus, or anaerobic Bacteriodes spp. Despite its widespread prevalence,
111 prostatitis remains a poorly studied and little understood condition with about 15% genitor-urinary foci of infection. Pathogenesis & Pathology The pathogenesis of Acute Bacterial Prostatitis (ABP) is still largely unknown but proposals from two schools of thought may guide our understanding the the disease process. The first school believes that ABP is due to reflux of infected urine into the glandular prostatic tissue through the ejaculatory and prostatic ducts followed by ascension of a urethral infection from the meatus during sexual intercourse. The second school of thought believes that ABP is due to inflammation of the prostate occasioned by many PMN's found in and around the acini, associated with intraductal desquamation, cellular debris, tissue invasion by lymphocytes, plasma cells and macrophages. This generates microabscesses which may lead to large abscesses formation. Chronic prostatitis is characterized by less inflammation of the prostate and infiltration of the acini by plasma cells and macrophages. Manifestations Acute Bacterial Prostatitis may be characterized by fever, shaking chills, perineal pain, low back pain, dysuria, urinary frequency, urinary urgency, decreased libido (impotence), painful ejaculation and bladder outflow obstruction. Patients with ABP may also have symptoms of cystitis or pyelonephritis. Chronic Nonbacterial Prostatitis or Chronic Pelvic Pain Syndrome (CNP/CPPS): This may be inflammatoey of non-inflammatory. Over 90% of main with urologic syndroms are typical cases of CNP/CPPS, characterized with obstructive urinary symptoms, decreased libido, painful ejaculation, pain in the penis, testicles, or scrotum, low back pain, rectal or perineal pain, or pain along the inner thighs. CNP/CPPS do not have recurrent urinary tract infections. Diagnosis The Stamey-Meares four glass localization method or the pre- and post-massage test (PPMT) is used if necessary to express prostatic secretions so as to isolate the microbial etiology. If there is no test, empirical antibiotic therapy is recommended Therapy Acute Bacterial Prostatitis: Tetracycline, trimethoprim-sulfamethoxazole, or quinolone are recommended Chronic Bacterial Prostatitis: Trimethoprim-sulfamethoxazole and norfloxacin are recommended. Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome- (CNP/CPPS): Hot sitz baths, nonsteroidal anti-inflammatory drugs (NSAIDs), avoiding intake of alcohol or spicy foods, anticholinergic drugs or alpha-blocking agents and counseling are recommended. Asymptomatic Prostatitis: A 14 day course of antibiotics may return Prostate Surface Antigen (PSA) levels to normal. Treatment with antibiotics is only recommended in chronic asymptomatic prostatitis patients known to elevate Prostate Surface Antigen (PSA). 4. Diseases Characterized by Vaginal Discharge
112
Bacterial Vaginosis and Vaginitis Bacterial vaginosis is a situation where there is a raised level overgrowth of bacteria in an environment while bacteria vaginities is a situation where there is both raised level of bacteria in an environment and inflammation of sorounding cells. Bacterial vaginosis can be transmitted by sexual contact and by overgrowth of certain bacteria in the vagina. It is the most common cause of vaginitis symptoms among women of childbearing age. Bacterial vaginosis may be due to Gardnerella vaginalis, Mycoplasma hominis anaerobic Mobiluncus species, and anaerobic Bacteroides species, Candida albicans and Trichomonas vaginalis. Vaginitis is characterized by discharge, irritation, and/or itching of the vagina. Microscopic analysis of vaginal fluid for Trichomonas vaginalis and culture for bacteria and fungal isolation and characterization are required for a correct diagnosis. Bacteria vaginosis is characterized by an unpleasant vaginal odor and an excessive white or gray vaginal discharge with a milk-like consistency. Stronger odor is perceived when the acidity of the vaginal secretions is mixed with semen or during menstruation. In women with bacterial vaginosis, other microorganisms out-grow the Lactobacillus which secretes hydrogen peroxide to maintain a normal balance of microorganismsin the vagina. Increased douching, an increased number of sexual partners and use of intrauterine devices have been correlated with bacteria vaginosis. Diagnosis is based on identifying: thin homogeneous discharge with pH greater than 4.5, Clue cells in saline wet mount, Gram stain of vaginal discharge and mixture of vaginal discharge and 10% KOH to generate an "amine-like" or "fishy" odor. Specimen culture to isolate and identify the organisms is a definitive diagnosis. Treatment, Metronidazole, clindamycin, suspension from douching and suspension from use feminine hygiene spray during treatmen are recommended.
8. Bacteria infection of the Urinary Tract

Background The urinary system is made of the kidneys, ureters, bladder, and urethra with kidney as the key factor. The kidney is responsible for: excretion of waste (in urine), osmoregulation and produce a hormone that aids the formation of red blood cells. Ureters carry urine from the kidneys to the bladder from where they are emptied through the urethra. The presence of multiplying bacteria in the urinary tract is called bacteurea and Urinary tract infection (UTI) may be defined as a significant bacteriuria in the presence of symptoms. UTI is one of the most common infections of childhoodresulting in the recognition of underlying structural or neurogenic abnormality of the urinary tract. The site of UTI is often unclear when a child with pyuria and clinically significant bacteriuria has another potential source of fever (otitis media, pharyngitis).
113 Etiology/Causes An infection occurs when bacteria from the digestive tract, attach to the opening of the urethra and begin to multiply. Most infections are caused by Escherichia coli, Chlamydia and Mycoplasma, Mycoplasma. A urethra infection is called urethritis and a bladder infection is called cystitis. Bacteria infection of the kidneys is called pyelonephritis. Prostatic secreations is bacteriostatic. The presence of 100000 (105) bacteria cell per mill in carefully collected midstream urine distinguishes bacteriurea from contamination. Enterobacteria are the most common cause of UTI especially in females. More than 90% of acute UTIs in apparently healthy patuemts are caused by E. coli strains. About 10-20% is caused by coagulase-negative Staphy saprophyticus and about 5% are caused by other enterobacteriaceae or enterococci. E. coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus sp., Pseudomonas aeruginosa are the most common cause of complicated UTI resulting from anatomic obstructions or catheterization. Candida albicans can rarely cause UTI, preferable among diabetic patients. S. saprophyticus is the second most common cause in young sexually active women. In 2004, Agwu and co-researchers suggested restrictive impact of HIV on indiscriminate sex, fecal contaminants, and poor personal hygiene as being responsible for the observed changing pattern of bacterial UTI (higher Staph species instead of E coli) in a population of apparently healthy sexually active Nigerian women. Pathophysiology Majority of UTIs are ascending in origin and disturbance of the normal periurethral bacterial flora, which is part of the host defense against colonization by pathogenic bacteria, predisposes a person to a UTI. Turbulent urine flow causes infection by encouraging uropathogens to gain access to the urinary bladder and proliferate. Successful urinary bladder colonization only takes place when bladder defense mechanisms (normal voiding) are impaired. After birth, the peri- and distal- urethra area are colonized by aerobic and anaerobic bacteria. Enterobacteria and enterococci becomes part of the normal periurethral flora in early childhood. E. coli dominates in young girls, whereas E coli and Proteus species predominate in boys. The 5 years old are predisposed to UTIs, partly because of periurethral colonization by E coli, enterococci, and Proteus species. Epidemiology The UTI's is only second to respiratory infections in their incidence in the U.S. with male/female ratio reported to be 1:30. While about 40% of all sexually active women may experience at least one episode of a UTI in life, males experience more episodes when they are above 40 years old probably induced by prostate gland hypertrophy. Occurrences of a first-time symptomatic UTI are highest for both sexes during the first year of life with average incidence in the first 2 years of life being 2% in both sexes. Pyelonephritis is characterized by: fever, abdominal pain, vomiting, dehydration, bacteremia, clinical sepsis, cystitis, hypertension, impaired kidney function, end-stage renal disease (ESRD), UTI, pregnancy-related hypertension and low-birth-weight neonates. Long-term complications of UTI are caused by renal damage secondary to pyelonephritis. Cystitis may cause voiding symptoms and require antibiotics.
114 Risk factors for UTI Any factor which tends to obstruct or slow down urine flow will lead to UTI. These factors include: enlarged prostate gland, insertion of catheters, diabetics, Immunosuppressed, infant congenital abnormalities, sexual intercourse or genital manipulations (in women), use of diaphragm and/or spermicides, patients with a neurogenic bladder or bladder diverticulum, postmenopausal women with bladder or uterine prolapse and pregnancy. Female urethral anatomy vis--vis the anus may also increase UTI incidence. Bacteria virulence factors (adhesions, hemolysins, endotoxins etc) Kidney infection This may arise due to microbial ascent from the lower urinary tract. Therefore any factor leading to retrograde flow of the urine to the kidney will predispose the host to pyelonephritis. Example of such factors includes: 1. Incomplete development of ureterovesical valves, 2. Physiological malfunctions (poor emptying of the bladder), 3. Pregnancy (which dilatates and decrease peristalsis of the ureters), 4. Urethral catheters, 5. Urinary tract stones (Proteus species- produce urease which split urea to ammonia and carbon dioxide), Clinical Manifestations/Trtmnt/Prevention It may manifest as urethritis, cystitis, hemorrhagic cystitis or pyelonephritis Urethritis Urethritis is an inflammation of the urethra caused by infections or posttrauma. It may be gonococcal urethritis (GU) or nongonococcal urethritis (NGU) although other several clinical conditions may cause urethral irritation. Neisseria gonorrhoeae causes gonococcal urethritis while Chlamydia trachomatis, Ureaplasma urealyticum, or Trichomonas vaginalis are the common causes of NGU urethritis. Urethritis is common in men and women who complain of discomfort during voiding. Infections are mainly caused by sexual intercourse which (apart from GU and NGU) may also involve lymphogranuloma venereum, herpes genitalis, syphilis, mycobacteria, and some Gram-negative rods associated with cystitis with urethral stricture. Other rare causes may include viral, Streptococcus, anaerobic bacteria, meningococcus, epididymitis, orchitis, prostatitis, proctitis, Reiter syndrome, iritis, pneumonia, otitis media, or urinary tract infection. Post-traumatic urethritis is possible 2-20% of patients practicing intermittent catheterization or foreign body insertion. PID causes about 40% of the morbidity in women. Children born to mothers infected with Chlamydia species may develop conjunctivitis, iritis, otitis media, or pneumonia if exposed to the organism during delivery (Birth). Cesarean delivery use of antichlamydial eyedrops has decreased disease incidence. Morbidity occurs in about 2% of male patients with urethritis due to urethral stricture or stenosis induced by postinflammatory scar. Other possible complications include prostatitis, acute epididymitis, abscess formation, proctitis, infertility, abnormal semen, Diseminated gonococcal infection (DGI) and Reiter syndrome, arthritis, meningitis, and endocarditis.
115 Urethral syndrome or frequency-dysuria syndrome This is characterized by urinary frequency, dysuria and suprapubic discomfort without urological abnormalities. There is also sterile urine confirmed by culture results including urinary frequency during the day more than during the night. Patients (women aged 30-50 years) may complain of difficulty in starting urination, slow stream, and a feeling of incomplete emptying of the bladder. Although etiology is unknown, hormonal imbalances, inflammation of the female prostate (Skene glands and the paraurethral glands), a reaction to certain foods, environmental chemicals (eg, douches, bubble bath, soaps, contraceptive gels, condoms), hypersensitivity following UTI, and traumatic sexual intercourse are thought to play a part. Cystitis This is a non-invasive infection or irritation of the bladder. Bactria or yeast from the lower GIT (rectum) enters the urinary tract through the urethra to cause urethritis or travel direct to the bladder to start an infection. Cystitis may manifest as: frequent and urgent need to urinate, passing only small amounts of urine, abdominal or pelvic pain, burning sensation during urination, leaking urine, cloudy-bad-smelling urine, blood in urine and pyuria. Risk factors of cystitis This include: being a female, sexual activity, use of diaphragm for birth control, use of women condom, menopause, vesicoureteral reflux or polycystic kidneys, paraplegia, sickle cell disease, kidney transplant, diabetes, kidney stones, enlarged prostate, Weak immune system, week immune system, tight underwear and clothing, chemicals in soaps, douches and lubricants, Diagnosis Good medical history, physical examination and urine sample collection and testing for blood, pus, bacteria and other indicators of cystitis. The definitive diagnosis is based on quantitative cultures of midstream urine, urethral catheter urine or suprapubic urine in children or patients who can not pas urine. Positive leukocyte esterase tests (with 75% to 90% sensitivity) in detecting pyuria associated with a UTI are now commonly used. Pyuria indicates inflammation which not be of infectious in origin. False negative results may be seen in patients taking Vitamin C and phenazopyridine. Treatment Trimethoprim/sulfamethoxazole, nitrofurantoin, fluroquinolones are ecommended Prevention Reduction of the chances of bacteria entering the urinary tract by: drink lots of liquids; urinate when there is urging; emptying the blader and drinking some glas of water after sexual intercourse; washing genitals daily; taking showers instead of baths; encouraging women to wipe from the front to the back after having a bowel movement or passing out stool, avoiding the ise of douches and feminine hygiene spray and avoid wearing tight underwear or clothing, Hemorrhagic cystitis
116 This is characterized by large quantities of blood in the urine probably caused by an infection (bacterial or adenovirus types 1-47) or as a result of radiation, cancer chemotherapy, or select immunosuppressive medication. All causes result in irritative voiding symptoms. Adenovirus is a common cause and is self-limiting in nature. Hemorrhagic cystitis is often confused with glomerulonephritis, but hypertension and abnormal renal function are absent in hemorrhagic cystitis. Pyelonephritis This infection results from ascension of the bacteria to the kidney from the lower urinary tract, but also can arise by hematogenous spread. Pyelonephritis is an invasive disease unlike cystitis which seams to be a localized infection. Blood cultures are positive in up to 20 % of women. Symptoms of pyelonephritis include: suprapubic tenderness, urinary urgency and frequency, fever, pain, Costovertebral angle tenderness (CVA tenderness), nausea and vomiting, peripheral leukocytosis, Treatment Parenteral treatment with a third-generation cephalosporin, such as ceftriaxone or cefotaxime, use of ampicillin, gentamicin, cephalosporins, are recommended.

Clinical Bacteriology by DR Agwu Ezera

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1

A Handbook of Medical Microbiology

Bacteriology and Mycology

A Handbook of Medical Microbiology by Dr Ezera Agwu

pages 3 30 40 51 56 74 102 112

A Handbook of Medical Microbiology by Dr Ezera Agwu

1a. Bacteria infections of the Gastro-Intestinal Tract (GIT)

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

1b. Fungal Infections of the Gastrointestinal tract.

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

2a. Bacterial Infection Of The Blood & Lymphatic System

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

2b. Fungal disease of the blood and lymphatic system

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

3a. Bacterial Disease of the Central Nervous System (CNS)

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

Staphylococcus species (S aureus and coagulase-negative Staphylococci),

A Handbook of Medical Microbiology by Dr Ezera Agwu

3b. Fungal disease of the centran nevous system- Meningitis

A Handbook of Medical Microbiology by Dr Ezera Agwu

4a. Cardiovascular system infections

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

5a. Bacteria Soft tissue and skin infection

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

5b. Fungal Infections of the skin and skin structures

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu

A Handbook of Medical Microbiology by Dr Ezera Agwu