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PHL 424 Antimicrobials 9th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Inhibitors of bacterial protein synthesis, Macrolides, contd. Therapeutic Uses: Erythromycin is the drug of choice for treating persons with B. pertussis disease and for postexposure prophylaxis of household members and close contacts Erythromycin is very effective in corynebacterial infections Erythromycin is useful as a penicillin substitute in penicillin-allergic individuals with infections caused by streptococci or pneumococci Chlamydial infections can be treated effectively with any of the macrolides During pregnancy, erythromycin is recommended as first-line therapy for chlamydial urogenital infections A macrolide or tetracycline is the drug of choice for mycoplasma infections Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin, 1 g, each administered twice daily for 10 to 14 days, is effective for treatment of peptic ulcer disease caused by H. pylori Penicillin is the drug of choice for the prophylaxis of recurrences of rheumatic fever. Erythromycin is an effective alternative for individuals who are allergic to penicillin Inhibitors of bacterial protein synthesis, Macrolides, contd. Side effects : Serious untoward effects are rarely caused by erythromycin Among the allergic reactions observed are fever, eosinophilia and skin eruptions, which may occur alone or in combination; each disappears shortly after therapy is stopped Cholestatic hepatitis is the most striking side effect (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral administration (due to a direct stimulation of gut motility) Drug interactions: Erythromycin and clarithromycin can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, corticosteroids and digoxin Azithromycin appears to be free of these drug interactions Inhibitors of bacterial protein synthesis, Clindamycin Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic produced by Streptomyces lincolnensis Lincomycin, although structurally distinct, resembles erythromycin in activity, but it is toxic and no longer used MOA: Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the aminoacyl translocation reaction (see MOA of macrolides) The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin Although clindamycin, erythromycin and chloramphenicol are not structurally related, they act at sites in close proximity, and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others There are no clinical indications for the concurrent use of these antibiotics Inhibitors of bacterial protein synthesis, Clindamycin, contd. Antimicrobial actions: Clindamycin generally is similar to erythromycin in its in vitro activity against susceptible strains of pneumococci and streptococci Some strains of streptococci that are macrolide-resistant remain susceptible to clindamycin Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin, but MRSA are resistant Essentially all aerobic G-ve bacilli are resistant Resistance mechanisms: 1. Mutation of the ribosomal receptor site 2. Modification of the receptor by a constitutively expressed methylase 3. Enzymatic inactivation of clindamycin 4. G-ve aerobic species are intrinsically resistant because of poor permeability of the outer membrane Resistance to clindamycin generally confers cross-resistance to macrolides Inhibitors of bacterial protein synthesis, Clindamycin, contd. Pharmacokinetics Clindamycin is nearly completely absorbed following oral administration. The presence of food in the stomach does not reduce absorption significantly It penetrates well into most tissues, with brain and CSF (even when the meninges are inflamed!) being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells The drug is about 90% protein-bound. It is metabolized by the liver, and both active drug and active metabolites are excreted in bile Therapeutic Uses: Clindamycin is indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci and staphylococci The high incidence of diarrhea and the occurrence of pseudomembranous colitis limit its use to infections in which it is clearly superior to other agents It is effective topically (or orally) for acne vulgaris and bacterial vaginosis It is particularly valuable for the treatment of infections with anaerobes It has replaced penicillin as the drug of choice for treatment of lung abscess and anaerobic lung and pleural space infections Inhibitors of bacterial protein synthesis, Clindamycin, contd. Side effects: Abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting and diarrhea Antibiotic-associated colitis that has followed administration of clindamycin and other drugs is caused by toxigenic C difficile. This potentially fatal complication must be recognized promptly and treated with metronidazole (the preferred therapy) Skin rashes occur in approximately 10% of patients treated with clindamycin Impaired liver function (with or without jaundice) and neutropenia sometimes occur It can inhibit neuromuscular transmission and may potentiate the effect of a neuromuscular blocking agent administered concurrently Inhibitors of bacterial protein synthesis, Aminoglycosides Aminoglycosides are a group of bactericidal antibiotics originally obtained from various streptomyces species and sharing chemical, antimicrobial, pharmacologic and toxic characteristics The group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin and others Streptomycin is the oldest and best-studied of the aminoglycosides Gentamicin, tobramycin and amikacin are the most widely employed aminoglycosides at present Neomycin and kanamycin are now largely limited to topical or oral use Inhibitors of bacterial protein synthesis, Aminoglycosides, MOA Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of G-ve bacteria to enter the periplasmic space. Their transport across the cytoplasmic membrane depends on electron transport (membrane electrical potential is required to drive permeation of these antibiotics) This transport is rate-limiting and can be inhibited by divalent cations (e.g., Ca2+ & Mg2+), a reduction in pH and anaerobic conditions. The last two conditions impair the ability of the bacteria to maintain the membrane potential, which is the driving force necessary for transport. Thus the antimicrobial activity of aminoglycosides is reduced markedly in the anaerobic environment of an abscess for example Inhibitors of bacterial protein synthesis, Aminoglycosides, MOA Once inside the cell, aminoglycoside binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA, leading to accumulation of abnormal initiation complexes, socalled streptomycin monosomes, blocking further translation of the message Inhibitors of bacterial protein synthesis, Aminoglycosides, MOA Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to: premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein (B) incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins (C) The resulting aberrant proteins may be inserted into the cell membrane, leading to altered permeability and further stimulation of aminoglycoside transport. This leads to leakage of small ions, followed by larger molecules and, eventually, by proteins from the bacterial cell. This progressive disruption of the cell envelope, as well as other vital cell processes, may help to explain the lethal action of aminoglycosides