-1-Lecture 14: Tetracyclins, Chloramphenicol and MacrolidesDolly Mehta, Ph.D. Knowledge Objectives1. 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. Whichdrugs are broad spectrum, and which have specific or unique uses.Drug Listtetracyclinedoxycyclinepolymyxinchloramphenicolerythromycinclindamycinclarithromycinazithromycin1MacrolidesErythromycinClarithromycin (Biaxin)A ithrom cin (Zithroma Zitroma )Azithromycin (Zithromax; Zitromax)Roxithromycin (Rulid)Dirithromycin (Dynabac)semi-synthetic derivatives of erythromycin5% of penicillin susceptible strains are macrolides resistant;50%it t t i b it tt lidKetolides (Telithromycin)50% penn-resistant strains may be resistant to macrolides Erythromycin (14-membered macrolide) Azithromycin (15-membered macrolide)OCH3ClarithromycinKetolides (Telithromycin)CladinoseÆ3-keto gr2Mechanism of actiona) Binds reversibly with 50S)fb) Inhibit translocation of peptide chain to P siteMechanism of ResistanceEfflux pumpRibosomal protectionEsterasesRibosomal protectiona) Mutation in 50S b) erm genes methylasesLactone ring ofMacrolidesModify ribosome/drug bindingInactivation of macrolides3Efflux pumpsrequires energycoded by mrsA genes (Group A staphylococci)mefA genes (Group A streptococci) or mefE genes S pneumoniea)or mefE genes S. pneumoniea)Methylases (decreases drug binding)Inducible or constitutivecoded by ermA, ermB and ermCI d ibl ill id i l lid•constitutive expression of erm leads to : MLSB(macrolide-lincosamide-streptogramin B)•Inducible erm will provide to resistance to only macrolidesABSORPTIONErythromycin: Incompletely but adequately absorbedsensitive to Gastric acid; administered as enteric-coated tabletsClarithromycin: 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 activeAzithromycin: Oral dose rapidly absorbed; antaacids decreasespeak serum drug concentrationuces but NOT overall-bioavailability ; the metabolites are not active; Should NOTbe given with food4Erythromycin: • distributes readily in intracellular bodily fluids and tissues tbi dCSFDISTRIBUTIONexceptbrain and 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 milkplasma) 50% of serum can be in milkClarithromycin: • distributes widely and achieve high intracellular concentration; phagocytes •Protein binding ranges from 40-70%.•Tissue concentration> serum concentrationTissue concentration> serum concentration in middle ear conc is 50% higher than that in of serum Azithromycin: • extensive tissue distribution•Protein binding is 50% at low plasma conc and less at higher gp gconcentrations•Tissue concentration> serum concentration in middle ear conc is 50% higher than that in of serumTissue fibroblasts act as a natural reservoir5EliminationErthromycin: only 2-5% of oral drug is excreted in urine; concentrated and metabolized in liver CYP’sÆdemethylationÆexcreted in bile;excreted in bile; short half life (1.6 hr) may prolong in anuria (dose adjustment not necessary) Clarithromycin: Both renal and non-renalliver CYP induces N-demethylation and hydroxylation; 2040% t d h d i i20-40% excreted unchanged in urine half life (3-7); 14-hydroxy metabolite (5-9 hr) may prolong in anuria (dose adjustment not necessary; only if high creatinine levels) Metabolism6Azithromycin: Some hepatic metabolism to inactive metabolite; excreated by bile; 12% by urinehalf life 48-68 hrs; because of extensive tissue sequesteration and binding Spectrum of ActivityErythromycin: widely prescribed for gram (+) infections caused by staphylococcal and streptococcal speciesalso effective against Legionella and Mycoplasma species. ClarithromycinGram-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.7Azithromycinincreased gram-negative coverage than erythro or clarithromycin.more active than clarithromycin against H. influenzaeSalmonella and Shigella species are susceptible, as have other diarrheal pathogens such as Yersinia and Campylobacter.also has good activity against Legionella and Mycoplasma species.ll t ti it i t Chl di t h tiexcellent activity against Chlamydia trachomatis.Untoward effectGI irritation common and unpleasantProlong QT interval Æventricular arrhythmias due to blockage fK+ t(h thltd HERG)hypersensitive reactions such as skin rashestransient hearing disturbancesof K+ current (human ether-a-go-related gene HERG) ~less with azithromycin at clinical dosesCholestatic Hepatitis primarily by erythromycin estolatePyloric stenosis in children of mother who took erythromycin during late pregnancy/nursing8Drug Interactions of MacrolidesMainly Erythromycin and (to a lesser extent Clarithromycin)(use caution with Azithromycin) Li d i i d b )PXRTATACYP3A4Ligand i.e.inducers, subs)metabolizeCorticosteroidsCyclosporinDigoxinwarfarinTherapeutic UseMycoplasma pneumoniae infectionsLegionnaires DiseaseChlamydial infections (any macrolides)DiphtheriaPertussis (erythromycin)Strep/Staph Infections; alternatives in patients allergic to Penn9Campylobacter/ Helibacter InfectionsTetanus: in patients allergic to PennMycobacterial Infections: Clathri/Azithro Ist choice in AIDS or in non-HIVProphylactic use: erythromycin can be used for rheumatic feverbacterial endocarditis, RTI in patients allergic to Pennicillinbacterial endocarditis, RTI in patients allergic to PennicillinKetolides: Telithromycin (Ketek) Mechanism of action: target is the ribosome;Absorption, distribution, eliminationwell-absorbed, 60-70% bound to proteins, penetrates target is the ribosome; structural modification neutralizes the common resistance mechanisms that makes macrolide ineffective such as methylases (inducible), drug efflux pumpsppwell in tissues (2-20 times more in tissue than plasma); Half life~9.8 hrs; Cleared by hepatic mechanism; 50% by CYP3A4
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