CHEMOTHERAPY

March 12, 2012

CHEMOTHERAPY:
It is the use of drug to eradicate pathogenic organisms and neoplastic cells in the treatment of infectious diseases and cancer respectively. PRINCIPLE: The chemotherapy is based on principle of selective toxicity, which inhibits function of invading organisms or neoplastic cells that will qualitatively and quantitatively effect the function of normal host cell.
Chemotherapy

Antimicrobial

Antiparasitic

Antineoplastic

Antibacterial

Antiviral

Anti fungal

Naturally occurring and naturally affecting these compounds

ANTIBIOTICS:
These are chemicals produced by one microbe and inhibit growth of another microbe.

ANTIBIOSIS:
It is a process in which growth of microbe is inhibited when another type of microbe is introduced in the culture (Louis Pasteur) Penicillin is produced by fungus and inhibits growth of staphylococci. (Alexander Fleming) Paul Ehrlich is the father of chemotherapy; he gave sulfonamide for systemic infections.

On the basis of site or mechanism of action it is classified as: Cell wall inhibitor Cell membrane inhibitor Protein synthesis inhibitor Metabolic and nucleic acid inhibitor Antimicrobial activity is divided into four: Bactericidal/ bacteriostatic Spectrum study activity Concentration Time dependent effect

BACTERICIDAL/ BACTERIOSTATIC:
Bactericidal is more effective than bacteriostatic. BACTERICIDAL Rapid response More effective Clinical improvement is more Less likely to exhibit microbial resistance Lethal changes in microbial metabolism or blocks activities which are vital for microbes E.g. Penicillin and Streptomycin BACTERIOSTATIC Slow response Less effective Clinical improvement is less Elicit microbial resistance Usually inhibit metabolic reactions that are important for bacterial growth, but not necessary for cell viability. E.g Tetracycline

March 13, 2012 Penicillin is a cell wall inhibitor, and it is an example of bactericidal antibiotics. Tetracycline and streptomycin are protein inhibitors, but tetracycline is reversible, while streptomycin is irreversible therefore, belong to bacteroistatic and bactericidal antibiotics respectively; because action of tetracycline will end once drug therapy is stopped.

ANTIMICROBIAL SPECTRUM:
Narrow spectrum- it means the antimicrobial agent is active against single organism or a small group of microbes like gram positive bacteria. These drugs are prescribed in case of infection of known/ specific organism. And if broad spectrum drug is given it will harm normal flora and cause superinfection (infection due to damage of normal flora of gut and respiratory tract). Broad spectrum- they are active against wide range of pathogens. If the infection is serious and pathogen is unknown then broad spectrum drugs are prescribed. In this case, imipenem is given as prophylactic treatment (initial therapy). Extended spectrum- they have intermediate range of activity. At low concentration inhibit only a group of organism, and as dose is increased they act as broad spectrum.

CONCENTRATION AND TIME DEPENDENT EFFECT:

These factors can affect the efficacy, frequency and dosage of drug. A. MIC (Minimal Inhibitory Concentration) - lowest concentration of drug that inhibit bacterial growth. On the basis of MIC, we can find susceptible and resistant strains. B. CDKR (Concentration Dependent Killing Rate) - some aminoglycosides (tobramycin) belong to this class, and fluoroquinolones are active against large no of gram +ve, -ve, Pseudomonas aeruginosa, Enterobacteriaceae. C. PAE (Post Antibiotic Effect)- when antibiotic is removed from bacterial culture; the persistent effect of antibiotic is called PAE. Most antibiotics exhibit PAE against gram +ve bacteria, and aminoglycosides show against gram ve bacteria. The effect between 2 doses is also called PAE. As aminoglycoside has PAE and CDKR properties, its dosage frequency is OD. High PAE, elimination of bacteria is more, and PAE prevent remaining bacteria from replication. March 14, 2012

BROTH DILUTION TEST:

This test gives MIC value, and also gives idea about susceptible and resistant strain.

DISK DIFFUSION METHOD:

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The test organism is streaked over the agar, and then we compare zone of inhibition to standard zone.

TEST METHOD:
Instead of test tubes, we use antimicrobial strip graded according to concentration. The zone of inhibition appears in the form of tear, and point at which zone of inhibition end is known as MIC. RESISTANCE: It can be innate or acquired. Reason of resistance is mutation and transfer of plasmid. Mutation can be loss of gene or changes in its development. Microbes mutate, if antibiotics are given in sub-optimal concentration or exposed for long period of time. Therefore, it is preferred to test the strains of infection, which help in drug selection, dosage and duration for which drug is given. March 20, 2012 Resistance is always acquired.

MECHANISM OF RESISTANCE: Inactivation of drug by microbial enzymes like -lactamase. Decrease accumulation (concentrate ion of drug necessary for action will not accumulate) e.g. cell membrane of gram ve bacteria have P-glycoprotein, which is an important part of bacterial cell membrane, it initiates resistance by decreasing accumulation of antibiotic in bacterial cell. Increase fluoroquinolones efflux from DNA. Reduce affinity of target macromolecule e.g. reduce affinity of RNA polymerase for Rifampicin. SELECTION OF ANTIMICROBIAL DRUGS: Antimicrobial is selected on the basis of infection and pharmacological properties of available drugs. These are known as drug based factors. Other factors influencing choice of drugs are host factors which are: 3

Pregnancy- tetracycline (protein synthesis inhibitor) causes discoloration of teeth of infants if taken during pregnancy. Therefore, penicillin and cephalosporins are preferred during pregnancy. Drug allergy- some people are susceptible to hypersensitivity reaction due to penicillin. Penicillin must be avoided in this condition. Age and immune factor- diabetes, cancer chemotherapy, HIV and age impair immunity; such individuals are called immunocompromised patients. The dose of antibiotic is larger than the dose of normal individual, and duration of therapy is also prolonged. Renal impairment- drugs excreted from kidney are not given to patients having compromised renal function e.g. aminoglycosides (Amikacin, dose must e reduced if creatinine level is high). Hepatic insufficiency- patients suffering from liver disorder should not take drugs metabolized through liver. Neonates can not metabolize chloramphenicol, so the dose/kg of body weight is less than the dose of children and adults. It causes gray baby syndrome.

PHARMACOKINETIC PROPERTIES: Oral bioavailability Distribution to particular site of infection Route of elimination Elimination half-life Peak serum concentration (serum concentration required for effect of drug) Peak serum concentration of any antimicrobial drug must be greater than MIC. The concentration of drug in tissues is always lower than serum. Route of elimination affect drug selection. Drug excreted through kidneys are more effective in UTI (Urinary Tract Infection) e.g. aminoglycosides. Aminoglycosides accumulate in patients with compromised renal function, for such patients dose of drug is reduced. March 21, 2012 ADVERSE EFFECT PROFILE: We should consider risk to benefit ratio for e.g. -lactam and macrolide show less incidence of organ toxicity therefore, they can be selected for minor infections. Aminoglycosides cause relatively high incidence of severe adverse effects. They are reserved for serious or life threatening infections. COMBINATION THERAPY: There are four different effects when antimicrobial agents are given in combination: Additive- When combine effect is equal to the sum of independent effect. Synergistic- When combine effect is greater than the sum of independent effect. Antagonist- When combine effect is less than the effect of either drug alone.

Indifferent- When combine effect is similar to the greatest effect produced by either drug alone.

Chloramphenicol and tetracycline are bacteriostatic. They antagonize bactericidal effects of other antibiotics. As bactericidal drugs inhibit growth of rapidly replicating bacteria, while bacteriostatic drugs cease the growth of bacteria thus, the effect is inhibited. TREATMENT OF INFECTION BY SINGLE ANTIMICROBIAL AGENT: When infection is due to one microbe single drug is prescribed. COMBINATION THERAPY: When two bactericidal drugs act by different mechanisms, they are given in combination to give additive or synergistic effect against susceptible bacteria. Penicillin and aminoglycosides combination is used against gram ve P. aeruginosa, Staphylococci and enterococci. Some antimicrobial drugs give synergistic against some bacteria for e.g. sulfonamide and trimethoprim inhibit sequential step in folate synthesis and give activity against many strains that are resistant to either drug.

March 26, 2012 TREATMENT OF MIX INFECTIONS: If infection is caused by more than 1 microorganism combination of antibiotics are prescribed to treat the patient. Intra-abdominal infection is caused by aerobic (E.Coli) and anaerobic (Bacteroides fragilis) gram ve bacilli. Aminoglycosides are given against E.Coli and Clindamycin against B. fragilis. EMPIRIC TREATMENT: More than 1 antibiotics are often used to treat patients with series infections until the causative organism can be identified, and its sensitivity to antimicrobial drug can be determined is called its empiric treatment (initial treatment). 5

E.g. Urethritis caused by Neisseria gonorrhoeae and Chlamydia trachomatis, cephalosporin (Ceftriaxone) and tetracycline are used to treat the infection caused by these microbes respectively. PROPHYLACTIC TREATMENT: The prevention of infection requires the sterilization of diagnostic and surgical instruments. Antimicrobial drugs administered prophylactically either to reduce incidence of infection or to prevent the disease transmission through close contact with infected person. Prevention of infection during invasive procedure e.g. to prevent endocarditis in valvular heart patients, amoxicillin is administered for dental, oral and respiratory tract treatment. Prevention of disease transmission in person at risk e.g. influenza A is prevented by administrating amantadine and rimantadine. Malaria is prevented by administering chloroquine or mefloquine, meningococcal disease is prevented by rifampin and for TB isoniazid is given. March 28, 2012

Peptidoglycans of gram +ve are thick for pollens or ion channels that allow selective drug to enter in gram ve bacilli. Endotoxins have 1 portion of lipopolysaccharide that is only in gram ve. Endotoxins activate immunological reactions and cause fever, platelet aggregation and increase vascular permeability and other adverse effects. When endotoxins come in contact with host cells cause fever. There are specific amino acids that target only cytoplasmic membrane. Daptomycin is cell wall inhibitors. Cell wall consists of peptidoglycans and is constructed by repeated units of N-acetylglucosamine (GlcNAc or NAG) and N-acetylmuramic acid (MurNAc or NAM) connected by glycosidase disaccharide linkage. Disaccharides are cross-linked to form peptidoglycans. L-alanine, D-alanine and peptidoglycans are important amino acids of cell wall. The cell wall inhibitors act on cell wall and cause bactericidal action by breaking/ destroying parts of cell wall. -LACTAM: MECHANISM OF ACTION: -lactam ring is present in their structure therefore, these antibiotics are called -lactam. PBP gives catalytic property needed by cell wall so -lactam inhibits property of PBP. It also inhibits crosslinkage of peptidoglycans which is held by PBP. Inhibition of PBP leads to autolysis of bacteria. BACITRACIN AND FOSFOMYCIN: They are cell wall inhibitors and peptidoglycans synthesis inhibitors by blocking specific steps in formation of disaccharide precursor (GlcNAc, MurNAc) and inhibits dephosphorylation step or inhibits cross linking by phosphorylation. 6

Bacitracin is derived from Bacillus subtilis and is active against gram +ve bacteria including staphylococci and streptococci and is used in minor skin and ocular infections and in combined form with polymyxin and neomycin in ocular ointments and drops. SIDE EFFECTS: Nephrotoxicity and not given systemically. PHOSPHOMYCIN: Same as Bacitracin active against enterococci and gram ve bacteria including E.coli, klebsiella specie and proteus specie specific for uncomplicated UTI caused by E.coli and Enterococcus faecalis. It is administered orally, single dose, excreted unchanged in urine. Half-life is 6 hr sometimes cause diarrhea but tolerable. VANCOMYCIN: It prevents bonding during cross linking of peptidoglycans strength. April 2, 2012 It is active against gram +ve and penicillin resistant strains. It is also given for Staphylococci endocarditis, Enterococci endocarditis, Staphylococcal osteomyelitis, serious infections and diarrhea caused by Clostridium difficile. MECHANISM OF ACTION: Cell wall synthesis inhibitors and inhibits cross-linkage (GlcNAc MurNAc). ADVERSE EFFECT: Nephrotoxicity and ototoxicity. Ototoxicity is of two types vestibular ototoxicity (ataxia, vertigo and nausea) and cochlear ototoxicity (tinnitus and loss of hearing). It also causes erythematous rash (red man or red neck, characterized by red patches on upper part of the body). PHARMACOKINETICS: It is poorly absorbed from gut therefore, administered parentally in serious infections, excreted through kidney by glomerular filtration.

PENICILLIN:
They are divided into: Narrow spectrum (Penicillin-G, Penicillin-V) Penicillinase resistant penicillin Extended spectrum It belongs to class of -lactam antibiotics i.e. basic structure is -lactam rings, thiazolidine ring and R (alkyl group), any substitution in R group leads to change in type of penicillin. Narrow spectrum drugs have small R group, broad spectrum has large group and extended spectrum has intermediate R group. Penicillin ca be divided on the basis of its origin Natural (penicillin-G and penicillin-V, obtained from penicillium) Semi-synthetic (6-amino penicillanic acid, organic acid and removal or substitution of R group). PHARMACOKINETICS: Acid stable penicillin (amoxicillin, dicloxacillin, Penicillin-V) Acid labile penicillin (piperacillin and ticarcillin) Intermediate sensitivity (Penicillin-G) Route of administration depends on pharmacokinetic property. Acid stable penicillin is stable in gastric environment therefore, given orally. Acid labile are given parentally. Intermediate drugs in low doses are hydrolyzed by acid and in high doses are resistant to gastric acid. Penicillin is distributed to all organs of body except CNS, but it can be given for the treatment of meningitis. Penicillin can enter CNS when meninx is inflamed. Excreted by renal tubular secretion. 7

Half-life is 0.5-1.3 hr. More secretion more excretion. Probenecid inhibits renal tubular secretion of penicillin. It shows excretion and prolongs half-life of the drug. Penicillin G long acting I/M preparations (These drugs are released slowly and have long duration of action). o Procaine penicillin G o Benzathine penicillin G April 3, 2012 SPECTRUM AND INDICATION: NARROW SPECTRUM (Penicillin G and Penicillin V) Streptococci (Pneumococci) Meningococci Spirochetes (Treponema pallidum) Clostridium perfringens (cause gas gangrene) Staphylococci and gonococci (some strains show resistance against penicillin G and penicillin V) PENICILLINASE RESISTANT PENICILLIN (Dicloxacillin (oral) and Nafcillin (parenteral)) Staphylococcal infection endocarditis and osteomyelitis, the strains that are resistant to these penicillins are called Methicillin resistant Staphylococcus aureus (MRSA). Methicillin was the original drug of this class of penicillin. Due to Nephrotoxicity (it causes nephritis) of methicillin some changes were made in it. MRSA show cross-resistance against nafcillin. EXTENDED SPECTRUM PENICILLIN: Aminopenicillin o Amoxicillin and ampicillin Antipseudomonal penicillin o Piperacillin and ticarcillin Amino penicillin is active against streptococci, enterococci and limited sensitivity for gram ve bacteria. Due to limited sensitivity for gram ve bacterial aminopenicillin usually combines with lactamase inhibitors (this enzyme hydrolyze the -lactam ring and microbe show resistance against -lactam antibiotics). Amoxicillin and clavulanate (Augmentin) Ampicillin and Sulbactam (UnaSyn) These combinations are used for -lactamase producing pathogens. Amoxicillin can be used for respiratory tract infection. Augmentin is given for infection caused by Haemophilus influenza, Moraxella catarrhalis (Penicillinase producing pathogens). Streptococcus pneumoniae (Pneumonia) can be treated with high dose of amoxicillin, and to avoid high dose combination of amoxicillin and clavulanate can be given. Sustained release tablet (Augmentin XR) contains 1000 mg amoxicillin and 62.5 mg clavulanate. These are used for adult respiratory tract infection. Augmentin ES-60 is a liquid suspension containing 90 mg amoxicillin and 6.4 mg clavulanate /kg/day for the treatment of pediatric respiratory tract infection and otitis media. Amoxicillin and clavulanate combination is used for bind wound infection if caused by Pasteurella multocida and Staphylococcus aureus. Amoxicillin is used prophylactically for the treatment of endocarditis. Ampicillin and Sulbactam is used for diabetic wound ulcer. Ampicillin and aminoglycosides can be used to treat endocarditis, if the pathogen is enterococci. April 9, 2012

Antipseudomonal penicillin is active against pseudomonas and other gram ve aerobic bacilli (serratia and citrobacter). Antipseudomonal penicillin and aminoglycoside Antipseudomonal penicillin and -lactam inhibitors (tazobactam) These drugs are used for nosocomial pneumonia, which is a mixed infection caused by gram +ve and anaerobic bacilli. BACTERIAL RESISTANCE: The resistance of antimicrobial is due to following factors: -lactamase Reduced affinity of drug for binding with PBP (Penicillin Binding Protein) Reduced affinity of antibiotic to enter through porins (porins become impermeable to drug) -LACTAMASE: -lactamase is excreted out through outer layer of gram +ve bacteria (extracellular enzyme). It forms outer layer and in gram ve bacteria, it is released as periplasmic enzyme. Staphylococcus was the first pathogen which showed resistance against drugs containing -lactam ring. Some monococci, gram ve bacteria, Haemophilus influenza, Enterobacteriaceae including Klebsiella pneumoniae and E.Coli show resistance against penicillin. ADVERSE EFFECTS: Drug induced hypersensitivity reaction (penicillin degrades into penicilloic acid, this acid combines with body proteins to form antigen and initiate antibody formation, and it causes hypersensitivity reaction). Immediate hypersensitivity reaction (this is mediated by IgE and leads to urticaria and anaphylactic shocks) Other hypersensitivity reaction causes nephritis, skin rash and hepatitis. Treatment is done by giving penicillin antigen product; it is administered via IM route, and it may cause erythema at site of infection. -LACTAMASE INHIBITORS: Amoxicillin and clavulanate (Augmentin) Ampicillin and Sulbactam (UnaSyn) Piperacillin and tazobactam (given parentally, trade name is zosyn) Ticarcillin and clavulanate (Timentin given parentally)

CEPHALOSPORINS:
On the basis of spectrum, these drugs are divided into: 1st generation- gram +ve and limited gram ve (Cefazolin and cephalaxin) 2nd generation- gram +ve and few gram ve (Cefolatin, cefoxitin, cefprozil and cefuroxime) 3rd generation- less gram +ve and more gram ve (Cefdinir, cefotaxime, ceftazidime and ceftriaxone) 4th generation- gram +ve and gram ve (Cefepime) Activity against gram ve is difficult to attain as compare to gram +ve. April 11, 2012 As generation of cephalosporin increases, more resistance against -lactamase is observed. 4th generation drugs are most resistant against -lactamase. Cephalosporin is also -lactam antibiotic. It has -lactam, dihydrothiozolidine ring and at least 2 R group (1st generation drugs have 2 R groups, while other generations have 3 R groups). 9

It is less likely to provoke hypersensitivity reactions. Given through different routes INDICATION: 1st generation: Most streptococci and methicillin sensitive staphylococci, activity against some gram ve like E.Coli, Klebsiella pneumonia. Cephalaxin is administered orally, and it is used for skin and soft tissue infections caused by gram +ve cocci and uncomplicated UTI. Many strains are now resistant to cephalaxin. Cefazolin is administered parentally, and it is used to treat serious infection like surgical prophylaxis of infection caused by staphylococci and aerobic gram ve bacilli. 2nd generation Similar activity against gram +ve as of 1st generation, but have more activity against gram ve. Additional activity against Haemophilus influenza (resistant to amoxicillin therefore, this drug is used for treating the infection). Orally administered drugs are cefprozil and cefuroxime axetil, which are used against H. influenza causing otitis media. Cefuroxime sodium is parentally administered, used as empiric therapy for community acquired pneumonia. Cefolatin is active against aerobic and anaerobic gram ve bacilli including Bacteroid fragilis. It is used to treat intra-abdominal gynecological and bilary tract infection caused by these organisms. Cefoxitin is similar to Cefolatin, which is used for surgical prophylaxis of infections caused by gram ve. 3rd generation More activity against gram ve including Enterobacteriaceae, H. influenza and Moraxella catarrhalis (physicians usually prescribe 3rd generation drugs for treating H. influenza, but this is wrong practice; initially 2nd generation drug must be prescribed). Ceftazidime is active against Pseudomonas aeruginosa. Cefotaxime and ceftriaxone are active against gonococci and used as single dose treatment in gonorrhea. Single dose of ceftriaxone (IM) is given for gonorrhea caused by gonococci. Other indications are otitis media, pneumonia and meningitis, UTI and intra-abdominal infection. Cefdinir have same indication as cefotaxime and ceftriaxone. 4th generation Cefepime is more resistant to -lactamase. It rapidly penetrates in gram ve bacteria and targets multiple penicillin binding proteins. It is active against many Enterobacteriaceae including Citrobacter freundii, Enterobacter cloacae. Activity against gram +ve is similar to 3rd generation. ESBL (Extended Spectrum -Lactamase): In some strains, alkyl group of -lactamase is substituted with amino acid, amino acid substitution enable them to hydrolyze wide range of substrate including 3rd generation drugs. BACTERIAL RESISTANCE: Bacteria show resistance against cephalosporin by same mechanisms, as of penicillin. The resistance is less than that of penicillin. Due to ESBl, 3rd generation drugs show resistance, but 4th generation drugs are sensitive.

ADVERSE EFFECTS:

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Little toxicity, have excellent safety record. It exhibits cross-sensitivity and evoke mild hypersensitivity reactions. Person having mild hypersensitivity reaction due to penicillin usually not shows cross-sensitivity reaction to penicillin, but person of severe hypersensitivity like anaphylactic shock has greater risk of cross-reaction. Also causes platelet dysfunction and bleeding. It potentiates the effects of anticoagulants and anti-platelet drugs. April 16, 2012

MONOBACTAM (AZTREONAM):
Monocyclic -lactam antibiotics are active against aerobic gram ve bacilli including strains of Enterobacter, citrobacter, klebsiella, proteus specie and P. aeruginosa. It is used to treat serious infection, also susceptible against multidrug resistant infections. It is administered via IV route, extensively metabolized and excreted through kidney (renal excretion). Adverse effects are hypersensitivity reactions and rarely show cross sensitivity reaction with penicillin. Its dose must be reduced in case of renal infection.

CARBAPENEM (IMIPENEM, MEROPENEM AND ERTAPENEM):

Carbapenem are synthetic -lactam antibiotics that differ in structure from the penicillin in that the sulfur atom of the thiazolidine ring is replaced by a carbon atom. It is bactericidal in nature, and active against wide range of gram +ve and ve and aerobic and anaerobic bacilli. Imipenem has affinity for PBP-2, while meropenem has affinity for PBP-2 and PBP-3, so it is more active than imipenem. Meropenem is active against many Enterobacteriaceae, P. aeruginosa and other gram -ve organisms. Both are active against ESBL and both treat serious systemic infections including endocarditis, pneumonia, UTI, pelvic, skin, soft tissue and intra-abdominal infections. It is also useful against multidrug resistant infections. Imipenem is usually available in combination with cilastatin, as imipenem is excreted through renal tubules, and it is degraded by renal tubular dipeptidase. Cilastatin inhibits this degradation. Carbapenem is also active against cephalosporin resistant nosocomial bacteria i.e. citrobacter and Enterobacter species.

PROTEIN SYNTHESIS INHIBITORS:

Various streptomyces species were obtained from different samples of soil and yielded new class of drugs including aminoglycoside, tetracycline and streptomycin. Protein synthesis inhibitors are classified into two groups: 30S subunit inhibitor o Aminoglycoside Amikacin Gentamicin Tobramycin Neomycin Streptomycin o Tetracycline o Spectinomycin 50S subunit inhibitors o Macrolide o Ketolide o Others Clindamycin Chloramphenicol Quinupristin Dalfopristin 11

o Linezolid Tetracycline inhibits the attachment of tRNA at site A. aminoglycoside and Spectinomycin place wrong amino acid at site A. macrolide, chloramphenicol and dalfopristin inhibit peptidyl transferase. After attachment of correct tRNA at site A, it moves to site B by translocation, which leads to formation of DNA, macrolide and Clindamycin inhibit this step. April 17, 2012

AMINOGLYCOSIDE:
Amino sugars attached through glycoside bond. It is highly ionized and readily become protonated in plasma or body fluids. These are highly basic in nature. Due to their nature poorly absorbed from gut. It must be administered parentally. Volume of distribution of aminoglycoside is equal to extracellular fluid, as due to its ionic nature it cant penetrate body cells. It can be given for treatment of meningitis. It can not cross blood brain barrier in normal individuals, but in case of meningitis it enters CNS. It is not metabolized. It is excreted by GFR, and renal clearance is equal to creatinine clearance. In case of any renal insufficiency, the creatinine clearance reduces, and to overcome this problem either dose of drug is reduced or intermittent time is increased. The standard dose regimen is Q8H, but in patients of renal insufficiency it is Q12H. SPECTRUM: It has more activity against aerobic gram ve. As it is toxic, therefore, any less toxic antibiotic is preferred. It is usually used for prophylaxis and treatment of serious infection. BACTERIAL RESISTANCE: The resistance caused by inactivation of drug by bacterial enzymes acetylase, adenylase and phosphorylase. These enzymes add acetyl, adenyl and phosphoryl group in amino acids of aminoglycoside. This alter structure of aminoglycoside, and as a result drug can not enter bacterial cell. Decrease binding of drug with 30S ribosomal subunit. Decrease uptake of drug via porins. ADVERSE EFFECTS: Nephrotoxicity and ototoxicity, it may also cause drug induced renal failure, and leads to decreased renal function. Ototoxicity is of two types: vestibular (accumulation of aminoglycoside in labyrinth. It is characterized by dizziness, impaired vision, vertigo, nausea, vomiting, problems with postural balance and walking) and cochlear (accumulation of aminoglycoside in hair cells of cochlea, characterized by tinnitus, hearing impairment and irreversible deafness). STREPTOMYCIN: It is least toxic of all aminoglycosides, and also least active against P. aeruginosa and other gram ve bacilli. It is used to treat multi drug resistant infections, tuberculosis and infection caused by Yersinia pestis (Plague). OTHER AMINOGLYCOSIDES: Tobramycin is most active against P. aeruginosa. Gentamicin is most active against Enterobacteriaceae. It is used in combination with penicillin. It is used to treat serious enterococcal, staphylococcal and streptococcal infections. Neomycin is most nephrotoxic. Its use is limited to topical treatment of superficial infections. Usually neomycin is combined with vancocin (active against gram +ve) and polymyxin (only drug having action against cell membrane of gram ve bacteria) (-lactam antibiotics).

TETRACYCLINE:
Drugs are doxycycline, minocycline and tetracycline. These are anthracene derivatives. SPECTRUM:

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These are broad spectrum antibiotics. Act against gram +ve and ve bacilli, rickettsiae spirochetes and chlamydia. Tetracycline is drug of choice for rocky mountain spotted fever and other infections caused by rickettsiae, lyme disease caused by Borrelia burgdorferi and relapse fever caused by Borrelia recurrentis. Tetracycline can be used as an alternative of macrolide. It can be given in most genital infections for pelvic inflammatory disease caused by chlamydia, in this condition drug is administered via IV route.

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