1Macrolides & KetolidesElizabeth D. Hermsen, Pharm.D.Infectious Diseases Research FellowUniversity of MinnesotaCollege of PharmacySpring 2004 PHAR 6124 2Objectives• Participant should be able to explainmacrolide/ketolide mechanism of action.• Participant should be able to identifyone important pharmacodynamicparameter each for macrolides andketolides.• Participant should be able to list threereasons why ketolides may bebeneficial over macrolides.Spring 2004 PHAR 6124 3Protein Synthesis2Spring 2004 PHAR 6124 4Mechanism of ActionSpring 2004 PHAR 6124 5Structure: Macrolides vs. KetolidesCarbamate Extension• Increased potency via domain IIKeto Group• Acid stability• Lack of induction ofMLSB resistanceOOOCH3O OSugarOOAcid StabilityNO N N NOOOSugarOO CladinoseErythromycinTelithromycinSpring 2004 PHAR 6124 6Structure: Acid StabilityTime (hours)0 0.5 1 1.5 2 2.5 3 3.5 4Incubation at pH 1 at 37ºCTelithromycinAzithromycinClarithromycin020406080100% Stable3Spring 2004 PHAR 6124 7Spectrum of Activity Ery Clari Azi TeliS. aureus + + + +S. pyogenes + + + +S. pneumoniae + + + +S. viridans + + + +S. agalactiae -- + + +H. influenzae -- + + +M. catarrhalis + + + +M. pneumoniae + + + +L. pneumophilia + + + +C. pneumoniae + + + +B. pertussis + + + +N. meningitidis ± -- ± +Spring 2004 PHAR 6124 8Spectrum of Activity (cont.)• While clarithromycin, azithromycin, andtelithromycin have some activity versuscertain anaerobes, these agents shouldnot be used as monotherapy foranaerobic infections• More studies necessary for ketolidesSpring 2004 PHAR 6124 9Pharmacokinetics Ery Clari Azi TeliHalf-life (hrs.) 1.5 4 68 10Bioavailability (%) 25 50 35 60Vd (L/kg) 1.5 3 18 ?Protein binding (%) 70 70 50 70Metabolism yes(3A4) yes* yes yes (3A4)Renal excretion (%) 15 20 10** 15†*active metabolite formed** ~50% excreted unchanged in biliary tract†~70% excreted in feces4Spring 2004 PHAR 6124 10PharmacodynamicsAUC / MIC = 100 / 0.5 = 200AUC = 100 mg h / LMIC=0.5(mg/L)Time (hrs)Cp-max105Cpmax / MIC = 10 / 0.5 = 20024T > MIC ~ 22hrs ConcentrationSpring 2004 PHAR 6124 11Pharmacodynamics (cont.)• Macrolides– T>MIC -- 50%– azithromycin?• Ketolides– concentration-dependent• AUC/MICConc.TimeMICtime>MICTimeConc.MICVan Bambeke F. IJAA. 2001;18:S17-23.Spring 2004 PHAR 6124 12Adverse Reactions• Diarrhea and GI upset – all– Erythromycin>clarithromycin>azithromycin– telithromycin• Abnormal taste/smell – clarithromycin,telithromycin• Blurred vision – telithromycin• Hepatotoxicity – azithromycin, telithromycin( LFTs); erythromycin (cholestatic hepatitis)• Hypersensitivity – all5Spring 2004 PHAR 6124 13Drug Interactions• CYP3A4 inhibition –erythromycin>clarithromycin– Carbamazepine, cyclosporine, tacrolimus, digoxin,theophylline, warfarin, simvastatin, proteaseinhibitors (saquinavir, indinavir, ritonavir, etc.)• Rifampin induces P450 – increased clearanceof erythromycin and clarithromycin• Ritonavir and indinavir inhibit CYP3A4 –increased AUC’s for erythromycin andclarithromycin• pH – macrolides are more active at basic pHSpring 2004 PHAR 6124 14U.S. Trends in Gram-Positive ResistanceThornsberryC.NNIS.38thICAAC.1998;SanDiego,Calif;AbstractE22MMWRMorbMortalWklyRep.1997;46:624-636Percent of PathogensResistant to Antibiotics01020304050607080901001975 1980 1985 1990 1995 2000MRSE 80%MRSA 55%VRE 20%PRSP 35%VISA19971980 to20022002VRSA30%MacR SPSpring 2004 PHAR 6124 15Mechanisms of Resistance:Macrolides• Ribosomal (erm - erythromycin ribosomalmethylase)– ~30%– ermA, ermB, ermC, ermF– Inducible or constitutive– resistance to all macrolides, lincosamides, andgroup B streptogramins (MLSB)• Efflux pump– ~70%– mef – streptococci; msr - staphylococci– resistance variesLeclercq R. CID. 2002;34:482-92.6Spring 2004 PHAR 6124 16Mechanisms of Resistance:Macrolides• 23S rRNA or ribosomal protein mutations– L4 and L22 mutations – S. pneumoniae– Rare• Drug modification– mph, lnu– staphylococci, E. faecium– RareLeclercq R. CID. 2002;34:482-92.Spring 2004 PHAR 6124 17Mechanism of Resistance:Macrolides and Ketolides (erm)Macrolide/Ketolidebinding sitesSpring 2004 PHAR 6124 18Resistance: Breaking it DownKetolidesMacrolidesMK7Spring 2004 PHAR 6124 19Resistance: Breaking it DownMKKetolidesMacrolidesSpring 2004 PHAR 6124 20Resistance: Breaking it DownTelithromycinTelithromycinMacrolidesMacrolidesMMTTMechanism of Action Made SimpleMechanism of Action Made SimpleTelithromycinTelithromycinMacrolidesMacrolidesMMTTMechanism of Action Made SimpleMechanism of Action Made SimpleKetolidesMacrolidesSpring 2004 PHAR 6124 21Resistance: Breaking it DownKetolides bind morestrongly thanmacrolides todomain IIMacrolides haveweaker affinityfor domain IIMKmethylationmethylation8Spring 2004 PHAR 6124 22Resistance: Breaking it DownK MKetolides“hang on”—maintain activityeven againstmacrolide-resistant strainsMacrolidescannot maintainactivity againstresistant strainsSpring 2004 PHAR 6124 23Resistance: Breaking it Down• Efflux– Increased MIC’s– Less effective versus ketolides• Tight ribosomal binding, increased intrinsicactivity, poor substrates?• 23S rRNA or ribosomal mutations– Different L4 mutation– RareSpring 2004 PHAR 6124 24Spectrum of Activity Revisited Ery Clari Azi TeliS. pneumoniae + + + +erm (MLSB) -- -- -- +mef -- -- -- +S. pyogenes + + + +erm (MLSB) -- -- -- ±mef -- -- -- +9Spring 2004 PHAR 6124 25Indications & Therapeutic Uses Ery Clari AziAECB x x xCAP x x xPharyngitis x x xSinusitis --- x ---Otitis media x x* x*SSTI x x x*FDA approved for pediatrics onlySpring 2004 PHAR 6124 26Indications & TherapeuticUses: Telithromycin• Specifically developed for use inrespiratory tract infections (RTIs)– ~10% worldwide morbidity/mortality related toRTIs1– ~75% antibiotic consumption due to RTIs1– upper RTIs -- common cause of absence fromwork or school– lower RTIs -- can be fatal in high-risk groupsBall