Lecture 14 Tetracyclins Chloramphenicol and Macrolides Dolly Mehta Ph D Knowledge Objectives 1 Know the basic processes of bacterial protein synthesis 2 Know the mechanism of antimicrobial activity for tetracyclines chloramphenicol and the macrolides 3 Know the most common adverse effects of these drugs 4 Know the mechanisms of bacterial resistance for these drugs 5 Know the most common applications of these antibiotics for the treatment of disease Which drugs are broad spectrum and which have specific or unique uses Drug List tetracycline doxycycline polymyxin chloramphenicol erythromycin clindamycin clarithromycin azithromycin 1 Macrolides Erythromycin Clarithromycin Biaxin A ithrom cin Zithromax Azithromycin Zithroma Zitromax Zitroma semi synthetic derivatives of erythromycin Roxithromycin Rulid Dirithromycin Dynabac 5 of penicillin susceptible strains are macrolides resistant 50 penn resistant i t t strains t i may be b resistant i t t to t macrolides lid Ketolides Telithromycin Erythromycin 14 membered macrolide Azithromycin 15 membered macrolide OCH3 Clarithromycin Ketolides Telithromycin Cladinose 3 keto gr 1 Mechanism of action a Binds reversibly with 50S b Inhibit translocation off peptide chain to P site Mechanism of Resistance Efflux pump Ribosomal protection a Mutation in 50S Esterases b erm genes methylases Modify ribosome drug binding Lactone ring of Macrolides Inactivation of macrolides 2 Efflux pumps requires energy coded by mrsA genes Group A staphylococci mefA genes Group A streptococci or mefE genes S S pneumoniea Methylases decreases drug binding Inducible or constitutive coded by ermA ermB and ermC Inducible I d ibl erm will ill provide id to resistance i to only l macrolides lid constitutive expression of erm leads to MLSB macrolide lincosamide streptogramin B ABSORPTION Erythromycin Incompletely but adequately absorbed sensitive to Gastric acid administered as enteric coated tablets Clarithromycin Acid stable Oral dose rapidly absorbed but FIRST PASS metabolism reduces its bioavailability by 50 One of the metabolite 14 hydroxy clarithromycin is twice as active Azithromycin Oral dose rapidly absorbed antaacids decreases peak serum drug concentrationuces but NOT overallbioavailability the metabolites are not active Should NOT be given with food 3 DISTRIBUTION Erythromycin distributes readily in intracellular bodily fluids and tissues exceptt brain b i andd CSF concentration protein binding 70 80 in prostatic fluid 40 of serum in middle ear 50 of serum crosses placenta 5 20 of maternal plasma in fetal plasma 50 of serum can be in milk Clarithromycin distributes widely and achieve high intracellular concentration phagocytes Protein binding ranges from 40 70 Tissue Tissue concentration serum concentration in middle ear conc is 50 higher than that in of serum Azithromycin extensive tissue distribution Protein binding g is 50 at low pplasma conc and less at higher g concentrations Tissue concentration serum concentration in middle ear conc is 50 higher than that in of serum Tissue fibroblasts act as a natural reservoir 4 Elimination Erthromycin only 2 5 of oral drug is excreted in urine concentrated and metabolized in liver CYP s demethylation excreted in bile short half life 1 6 hr may prolong in anuria dose adjustment not necessary Clarithromycin Both renal and non renal liver CYP induces N demethylation and hydroxylation 20 40 excreted 20 40 t d unchanged h d in i urine i half life 3 7 14 hydroxy metabolite 5 9 hr may prolong in anuria dose adjustment not necessary only if high creatinine levels Metabolism 5 Azithromycin Some hepatic metabolism to inactive metabolite excreated by bile 12 by urine half life 48 68 hrs because of extensive tissue sequesteration and binding Spectrum of Activity Erythromycin widely prescribed for gram infections caused by staphylococcal and streptococcal species also effective against Legionella and Mycoplasma species Clarithromycin Gram positive activity superior than erythromycin and azithromycin especially against Streptococcus pyogenes and Streptococcus pneumoniae Gram negative coverage is also increased with clarithromycin Better than erythromycin against Legionella and Mycoplasma species 6 Azithromycin increased gram negative coverage than erythro or clarithromycin more active than clarithromycin against H influenzae Salmonella and Shigella species are susceptible as have other diarrheal pathogens such as Yersinia and Campylobacter also has good activity against Legionella and Mycoplasma species excellent ll t activity ti it against i t Chlamydia Chl di trachomatis t h ti Untoward effect GI irritation common and unpleasant Prolong QT interval ventricular arrhythmias due to blockage h ether a go related th l t d gene HERG off K currentt human less with azithromycin at clinical doses hypersensitive reactions such as skin rashes transient hearing disturbances Cholestatic Hepatitis primarily by erythromycin estolate Pyloric stenosis in children of mother who took erythromycin during late pregnancy nursing 7 Drug Interactions of Macrolides Mainly Erythromycin and to a lesser extent Clarithromycin use caution with Azithromycin Li d i e inducers Ligand i i d subs b CYP3A4 PXR TATA metabolize Corticosteroids Cyclosporin Digoxin warfarin Therapeutic Use Mycoplasma pneumoniae infections Legionnaires Disease Chlamydial infections any macrolides Diphtheria Pertussis erythromycin Strep Staph Infections alternatives in patients allergic to Penn 8 Campylobacter Helibacter Infections Tetanus in patients allergic to Penn Mycobacterial Infections Clathri Azithro Ist choice in AIDS or in non HIV Prophylactic use erythromycin can be used for rheumatic fever bacterial endocarditis RTI in patients allergic to Pennicillin Ketolides Telithromycin Ketek Mechanism of action target is the ribosome structural modification neutralizes the common resistance mechanisms that makes macrolide ineffective such as methylases inducible drug efflux pumps Absorption distribution elimination well absorbed 60 70 bound to p proteins p penetrates well in tissues 2 20 times more in tissue than plasma Half life 9 8 hrs Cleared by hepatic mechanism 50 by CYP3A4 and 50 by hepatic independent mechanism 9 Therapeutic Use RTI pneumococcal pneumonia Untoward effect Significant prolongation of QTc risk of ventricular arrhythmia drug interaction may be less than other macrolides Summary 50S Ribo inhibits transferases Bact develops resistance by modifying ribosomal target
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