Diarrhea TBL

4/11/13
Readings: ICM Acute Diarrhea PDF Pharm K&T pp 389-396 (macrolides/tetracyclines); K&T pp 403-409 (fluroquinolones and trimethoprim-sulfamethoxazole); PPT from anti-protozoal drugs (from 4/10/11) Treatment of Diarrhea PDF Micro Acute Diarrhea PDF

ICM
1. Compare and contrast acute diarrhea, dysentery and chronic diarrhea Acute 3+ loose, watery stools within 24 hours Chronic/Persistent Episodes of diarrhea lasting more than 14 days Dysentery Blood diarrhea, with visible blood and mucus present in the diarrhea 2. Describe common causes of bloody diarrhea Bloody stools most often correlate to invasive or cytotoxin releasing pathogens o if the stool is bloody but there are NO fecal leukocytes, suspect EHEC (enterohemorrhagic E. coli) o do not occur with viral agents or the enterotoxin releasing pathogens Examples: o EIEC enteroinvasive E. coli also associated with fever o EHEC also associated with hemolytic uremic syndrome o Campylobacter does not always produce bloody diarrhea, but does occasionally most frequent in infants and children (<2yoa) in developing countries o Shigella dysenteriae type 1 produces same Shigella toxin as EHEC and is associated with epidemics o Salmonella induced diarrhea can be with or without blood o Bloody diarrhea also seen with Yersenia and C. difficile induced diarrheas 3. Describe what clinical elements are needed to assess the level of dehydration in a patient with diarrhea Things you need to know about to assess dehydration: general appearance, alertness, BP and pulse, postural hypotension, mucous membranes, sunken eyes, skin turgor, capillary refill, JVD, and sunken fontanelle Children: No dehydration: normal alertness, no sunken eyes, normal drinking patterns, immediate skin pinch test Mild dehydration (2 signs): restless or irritable, sunken eyes, drinking eagerly, slow skin pinch test (<2 seconds) Severe dehydration (2 signs): abnormally sleepy or lethargic (these are not the same thing!), sunken eyes, drinking poorly or not at all, very slow skin pinch test (>2 seconds) Adults: signs for dehydration include: o pulse rate >90

o postural hypotension o supine hypotension and lack of palpable pulse o dry tongue o sunken eyeballs o slow skin pinch test Note that irritability and doughy feeling of the skin are typical of hypernatremic dehydration which requires a specific treatment, so look for those! 4. Describe the components and clinical utility of Oral Rehydration Solutions ORS likely has a greater impact on the rate of mortality with diarrhea and less impact on the incidence of diarrhea as ORS use increased, the rates of mortality from diarrhea decreased (since 1980s) oral rehydration therapy consists of rehydration with water and electrolytes, as well as maintenance fluid therapy Contains the following (totaling up to a 245 mmol/L solution): o 75 mmol/L sodium o 65 mmol/L chloride o 75 mmol/L anhydrous glucose o 20 mmol/L potassium o 10 mmol/L citrate Rice based ORS is superior in cholera treatment but is NOT superior to standard ORS in noncholera diarrhea oral rehydration solutions for global use have been developed that are more effective and lower-osmolarity: reduced sodium and glucose concentrations, associated with less vomiting and stool output, and reduced need for IV fluids compared with standard ORS for uncomplicated cases of diarrhea, ORS treatments can be administered at home o Homemade recipe: 1 level tsp salt 8 level tsp sugar 1L clean drinking or boiled water, cooled makes 5-200mL cupfuls For No Dehydration: no rehydration therapy needed if pt is <10kg body weight, give 60-120mL ORS for each diarrheal stool or vomiting episode continue breast-feeding or age appropriate diet For Mild to Moderate Dehydration: ORS: 50-100mL/kg body weight over a 3-4 hour period if pt is <10kg body weight, give 60-120mL ORS for each diarrheal stool or vomiting episode after initial hydration, continue breast-feeding or normal diet if vomiting is persistent, IV fluids may be necessary For Severe Dehydration: Rehydrate with lactated ringers (100mg/kg body wt) IV for 4-6 hours, then administer ORS until patient recovers if pt is <10kg body weight, give 60-120mL ORS for each diarrheal stool or vomiting episode after initial hydration, continue breast-feeding or normal diet

treating with 5% dextrose with normal saline is unsafe because it does not balance sodium and can cause severe hyponatremia, convulsions, and loss of consciousness if lactated ringers are unavailable, use 5% dextrose with standard normal saline 5. Describe the types of diarrhea based on the clinical history, in particular the type of diarrhea and the incubation period The images from the document are really helpful here: o Incubation periods with likely causes of diarrhea:

History details with causes of acute diarrhea:

Clinical features with select pathogens:

Non-objective stuff that looked important: incidence and risk for mortality from diarrheal diseases is greatest in children less than 1 yoa Bacteria and parasites are more common in developing countries and occur mostly in the summer months Viral causes are predominant in industrialized countries and occur mostly in winter months Among viral agents, rotavirus is mostly kids between 4-23 months of age, while norovirus/calicivirus is in all age groups vomiting is associated with viral illnesses and toxemia (i.e. Staph aureus toxin ingestion)

Microbiologic investigation is indicated only in patients who are dehydrated or febrile or have blood or pus in their stools. in a child, the identification of a pathogenic bacterium, virus, or parasite in a stool specimen does not necessarily indicate that it is the actual cause of the illness For all children with diarrhea, supplementary treatment with 20mg zinc for at least 14 days o treating with zinc sulfate for 10-14 days can reduce the incidence of diarrhea for 2-3 months in kids suffering persistent diarrhea Food should be started 4 hours after starting ORT or IV fluids, should be frequent small meals throughout the day, and should avoid canned fruit juices that can aggrevate diarrhea antimicrobial therapy is not usually indicated in children unless they have bloody diarrhea, cholera, or a non-intestinal infection For adults, Doxycycline is DOC for cholera, ciprofloxacin for Shigella, Metronidazole for amoebas and Giordiosis, and Azithromycin for Campylobacter if treating at home, consider taking the patient to hospital if: signs of dehydration, changed mental status, <6 months old, fever, visible blood in stool, high output diarrhea, persistent vomiting, lack of response to ORT, no improvement in 48 hours A fecal specimen should be obtained in cases of severe bloody, inflammatory, or persistent diarrhea, or if an outbreak is expected.

MICRO
1. Diagnose gastrointestinal infections based on clinical presentation and lab results. some of the info from this paper is covered in the ICM objectives the incubation period chart is probably relevant here In addition to assessing dehydration, its important to get a history of the onset, frequency, and quantity or diarrhea; the character (bile/blood/mucus); if theres also vomiting; past medical history; underlying medical conditions; and any epidemiological clues they may give For possible community acquired or travelers diarrhea o culture or test for Salmonella, Shigella, or Campylobacter o if theres a hx of bloody diarrhea or HUS, test for E.coli O157:H7 or shigella toxin o if theres hx of recent antibiotics, chemotherapy, or hospitalization, test for C. difficile toxins A & B For possible nosocomial diarrhea (onset >3 days after hospitalization) o test for C. difficile A & B toxins o if theres bloody diarrhea, test for shiga-toxin-producing E. coli (EHEC) o if there is a current outbreak going on or the pt is >65 yoa with coexisting conditions, immunocompromised, or neutropenic or you suspect systemic infection, test for Salmonells, Shigella, and Campylobacter For persistant diarrhea >14 days o test for EPEC (enteropathogenic E. coli) o consider protozoas such as Giardia, Cryptosporidium, Cyclospora, and Isosproa belli o screen for inflammation If the patient is immunocompromised, especially HIV+ add a test for Microsporidia, Mycobacterium avium complex, Cytomegalovirus, and Strongyloides

2. Describe pathogenic mechanisms of bacterial GI infections and intoxications E. coli o ETEC travelers diarrhea and in infants/children in developing countries o EPEC children <2; chronic diarrhea o EIEC bloody, mucoid diarrhea often with fever o EHEC bloody diarrhea that can lead to HUS o EAEC watery diarrhea in young kids; persistent diarrhea in children/adults with HIV Campylobacter is prevalent in adults and is one of the most frequently isolated bacteria from the feces of infants and children in developing countries. Asymptomatic infection is very common, associated with the presence of cattle close to dwellings. o Infection is associated with watery diarrhea and on occasion dysentery o Peak isolation rates are found in children 2 years of age and younger. o GuillainBarr syndrome is a rare complication. o Poultry is an important source of Campylobacter infections in developed countries Shigella species primarily in children; It is more common in toddlers and older children than in infants o S. sonnei mildest illness; seen most commonly in developed countries. o S. flexneri dysenteric symptoms and persistent illness; most common in developing countries. o S. dysenteriae type 1 (Sd1) produces Shiga toxin with bloody diarrhea with casefatality rates approaching 10% in Asia, Africa, and Central America. Vibrio cholera serogroups O1 and O139 cause rapid and severe depletion of volume, hypovolemic shock and death which can occur within 1218 h after the onset of the first symptom. o Stools are watery, colorless, and flecked with mucus; Vomiting is common; fever is rare. o In children, hypoglycemia can lead to convulsions and death. o There is a potential for epidemic spread; any infection should be reported Salmonella o Infants and the elderly appear to be at the greatest risk. o There is an acute onset of nausea, vomiting, and diarrhea that may be watery or dysenteric, and fever develops in 70% of affected children. o Bacteremia occurs in 15%, mostly in infants. o Enteric fever Salmonella typhi or paratyphi A, B, or C (typhoid fever). o Diarrhea (with or without blood) develops, and fever lasting 3 weeks or more

PHARM
1. Describe the mechanisms of action and resistance for macrolides, tetracyclines, fluoroquinolones, and trimethoprim-sulfamethoxazole Protein Synthesis Inhibitors Tetracyclines o MOA: bind 30S binding site on ribosome to prevent binding of amino acid-charged tRNA o RESISTANCE: widespread; development of efflux pumps; formation of ribosomal protection protein that prevent tetracycline binding o INTERACTIONS: can be inactivated by divalent metals so watch milk, antacids, etc; bind UV light and cause PHOTOSENSITIVITY + GI super-infections; can damage BONES AND TEETH o DOC for Rickettsiae, Chlamydiae, Borrelia (Lyme disease), and mycoplasma pneumonia; also useful for H. pylori, propionic bacterium, treponema pallidum Macrolides o MOA : reversibly bind 50S ribosomal subunit near the MLSb site o RESISTANCE: efflux pumps; methylase that adds methyl group to ribosomal binding site to block macrolide binding o Clarithromycin o Azithromycin (z-pack) usually a 5 day treatment used as single dose for Chlamydia o most effective for aerobic g(+) cocci and bacilli including: Strep. pneumonia, pyogenes, and viridans group Clostridium perfringens and tetani Corynebacterium diphtheria o also effective for g(-) bacilli such as: hemophilus influenza and decreyi Legionella pneumophilia (DOC) and Bordetella Pertussis (DOC) o adverse effects include GI motilin agonist cholestatic jaundice prolonged QTc interval Folic Acid Synthesis Inhibitors Sulfonamides o MOA: bacteriostatic inhibitors of folic acid synthesis by competitively inhibiting dihydropteroate synthase o RESISTANCE: common; plasma-mediated; decreased intracellular accumulation, increased PABA production by bacteria, or decreased sensitivity to the sulfonamide o used against both g(+) and g(-) organisms Chlamydia and Nocardia specifically in UTIs, ocular infections, burn infections, ulcerative colitis, rheumatoid arthritis, toxoplasmosis, etc. o toxicity includes hypersensitivity with rash and fever GI n/v

 hematotoxicity nephrotoxicity drug interactions Trimethoprim o MOA: selective inhibitor of bacterial DHFR inhibiting folic acid synthesis specifically in bacteria o RESISTANCE: production of dihydrofolate reductase with reduced affinity for the drug o effective orally in the treatment of UTI and respiratory, ear, and sinus infections caused by H. influenza and M. catarrhalis o in immunocompromised ppl it is used for infections due to Aeromonas hydrophilia and is DOC for pneumocystosis pneumonia o toxicity can be megaloblastic anemia, leukopenia, granulocytopenia administer folic acid with this drug TRIMETHOPRIM-SULFAMETHOXAZOLE COMBINED SEQUENTIAL BLOCKADE OF FOLATE SYNTHESIS LEADING TO BACTERIAL CELL DEATH DNA Synthesis Inhibitors Fluoroquinolones o MOA: inhibit topoisomerase II (DNA gyrase) especially in g(-) to block relaxation of supercoiled DNA and topoisomerase IV especially in g(+) to interfere with separation of replicated chromosomal DNA during cell division o RESISTANCE: decreased intracellular accumulation due to efflux pumps or porins (in g(-)); also changes in sensitivity via point mutations in antibiotic binding regions (i.e. gyrA gene mutation leads to gonococcal resistance) o 1st gen Norfloxacin o 2nd gen ciprofloxacin and ofloxacin greater activity against g(-) as well as activity against g(+) cocci, mycobacteria, and atypical pneumonia o 3rd gen levofloxacin, gemifloxacin, moxifloxaciin aka respiratory fluoroquinolones greater activity against g(+), less against g(-) gemi and moxi are most recently introduced and have enhanced activity against anaerobes levo works against community-acquired pneumonia cant use moxi for UTIs because not excreted in urine o toxicity includes: GI distress most commonly skin rashes headaches dizziness insomnia abnormal liver function tests phototoxicity tendinitis, tendon rupture not for kids or pregnant women newer fluoroquinolones prolong QTc 2. Identify the drug of choice, and its significant adverse effects, used to treat most protozoal infections producing diarrhea. DOC: Metronidazole MOA: acts an electron sink in protozoa and disrupts DNA with its reactive intermediate

EFFECTS: o rare adverse effects, rarely worth discontinuing the drug o contraindicated with alcohol causes disulfiram-like reaction o also contraindicated in CNS disease and pregnancy because can get high concentrations in the CSF

3. List three drugs used to treat diarrhea and describe the mechanisms of action and uses for each of the drugs. (copied word-for-word from document) 1) Bismuth Subsalicylate (Pepto-Bismol, Kaopectate) inflammatory prostaglandins stimulate intestinal motility and diarrhea, inhibitors of cyclooxygenase are antimotility; salicylate component completely absorbed; bismuth may stimulate absorption of fluids and electrolytes across intestinal wall may prevent colonization with foreign E. coli; protection from travelers diarrhea weak antacid properties constipating, high doses, like aspirin, may cause tinnitus; may cause temporary black tongue and stools

Opioids -- 2) Loperamide and 3) Diphenoxylate+atropine act on mu opiate receptors in the submucosal and myenteric plexus alter G-I motility by o increasing segmental contractions, decreasing propulsive peristalsis, increasing transit time, decrease secretions from stomach, pancreas sand intestine, delays digestion; increases absorption of Na and water requires smaller dose of opioids to affect gut than to produce analgesia or euphoria, but physical dependency still limits clinical use of some drugs; treats symptoms but not underlying cause loperamide (Imodium) o acute non-specific diarrhea and chronic diarrhea associate with inflammatory bowel disease; non-addictive; no physical dependence demonstrated even after more than two years of use ; unclear if crosses blood brain barrier; may cross and get transported back diphenoxylate + atropine (Lomotil) o low dose has few systemic side effects, atropine added to reduce potential of abuse; prodrug metabolized to active compound difenoxin