Macrolides & Ketolides. Objectives. Protein Synthesis

Transcription

1 Macrolides & Ketolides Elizabeth D. Hermsen, Pharm.D. Infectious Diseases Research Fellow University of Minnesota College of Pharmacy bjectives Participant should be able to explain macrolide/ketolide mechanism of action. Participant should be able to identify one important pharmacodynamic parameter each for macrolides and ketolides. Participant should be able to list three reasons why ketolides may be beneficial over macrolides. Spring 24 PHAR Protein Synthesis Spring 24 PHAR

2 Mechanism of Action Spring 24 PHAR Structure: Macrolides vs. Ketolides N N N Carbamate Extension Increased potency via domain II N Telithromycin Acid Stability CH 3 Sugar Sugar Erythromycin Cladinose Keto Group Acid stability Lack of induction of MLS B resistance Spring 24 PHAR Structure: Acid Stability 1 Telithromycin 8 % Stable 6 4 Incubation at ph 1 at 37ºC 2 Azithromycin Clarithromycin Time (hours) Spring 24 PHAR

3 Spectrum of Activity Ery Clari Azi Teli S. aureus S. pyogenes S. pneumoniae S. viridans S. agalactiae H. influenzae M. catarrhalis M. pneumoniae L. pneumophilia C. pneumoniae B. pertussis N. meningitidis ± -- ± + Spring 24 PHAR Spectrum of Activity (cont.) While clarithromycin, azithromycin, and telithromycin have some activity versus certain anaerobes, these agents should not be used as monotherapy for anaerobic infections More studies necessary for ketolides Spring 24 PHAR Pharmacokinetics Ery Clari Azi Teli Half-life (hrs.) Bioavailability (%) V d (L/kg) ? Protein binding (%) Metabolism yes(3a4) yes* yes yes (3A4) Renal excretion (%) ** 15 *active metabolite formed ** ~5% excreted unchanged in biliary tract ~7% excreted in feces Spring 24 PHAR

4 Pharmacodynamics Concentration (mg/l) 1 5 MIC=.5 Cp-max AUC / MIC = 1 /.5 = 2 Cpmax / MIC = 1 /.5 = 2 T > MIC ~ 22hrs AUC = 1 mg h / L Time (hrs) 24 Spring 24 PHAR Pharmacodynamics (cont.) Macrolides T>MIC -- 5% azithromycin? Conc. time>mic Time MIC Ketolides concentration-dependent AUC/MIC Conc. Time MIC Van Bambeke F. IJAA. 21;18:S Spring 24 PHAR Adverse 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 all Spring 24 PHAR

5 Drug Interactions CYP3A4 inhibition erythromycin>clarithromycin Carbamazepine, cyclosporine, tacrolimus, digoxin, theophylline, warfarin, simvastatin, protease inhibitors (saquinavir, indinavir, ritonavir, etc.) Rifampin induces P45 increased clearance of erythromycin and clarithromycin Ritonavir and indinavir inhibit CYP3A4 increased AUC s for erythromycin and clarithromycin ph macrolides are more active at basic ph Spring 24 PHAR Percent of Pathogens Resistant to Antibiotics U.S. Trends in Gram-Positive Resistance to 22 MRSE 8% MRSA 55% PRSP 35% MacR SP 3% VRE 2% 1 VISA VRSA Spring 24 PHAR Mechanisms of Resistance: Macrolides Ribosomal (erm - erythromycin ribosomal methylase) ~3% erma, ermb, ermc, ermf Inducible or constitutive resistance to all macrolides, lincosamides, and group B streptogramins (MLS B ) Efflux pump ~7% mef streptococci; msr - staphylococci resistance varies Leclercq R. CID. 22;34: Spring 24 PHAR

6 Mechanisms of Resistance: Macrolides 23S rrna or ribosomal protein mutations L4 and L22 mutations S. pneumoniae Rare Drug modification mph, lnu staphylococci, E. faecium Rare Leclercq R. CID. 22;34: Spring 24 PHAR Mechanism of Resistance: Macrolides and Ketolides (erm) Macrolide/ Ketolide binding sites Spring 24 PHAR Resistance: Breaking it Down M K Macrolides Ketolides Spring 24 PHAR

7 Resistance: Breaking it Down M Mechanism of Action Made Simple crolides Macrolides Spring 24 PHAR K Ketolides Telithromycin Resistance: Breaking it Down Macrolides Ketolides T Spring 24 PHAR Resistance: Breaking it Down methylation methylation K M Macrolides have weaker affinity for domain II Ketolides bind more strongly than macrolides to domain II Spring 24 PHAR

8 Resistance: Breaking it Down M Macrolides cannot maintain activity against resistant strains K Ketolides hang on maintain activity even against macrolideresistant strains Spring 24 PHAR Resistance: Breaking it Down Efflux Increased MIC s Less effective versus ketolides Tight ribosomal binding, increased intrinsic activity, poor substrates? 23S rrna or ribosomal mutations Different L4 mutation Rare Spring 24 PHAR Spectrum of Activity Revisited Ery Clari Azi Teli S. pneumoniae erm (MLS B ) mef S. pyogenes erm (MLS B ) ± mef Spring 24 PHAR

9 Indications & Therapeutic Uses Ery Clari Azi AECB x x x CAP x x x Pharyngitis x x x Sinusitis --- x --- titis media x x* x* SSTI x x x *FDA approved for pediatrics only Spring 24 PHAR Indications & Therapeutic Uses: Telithromycin Specifically developed for use in respiratory tract infections (RTIs) ~1% worldwide morbidity/mortality related to RTIs 1 ~75% antibiotic consumption due to RTIs 1 upper RTIs -- common cause of absence from work or school lower RTIs -- can be fatal in high-risk groups Ball et al. Journal of Antimicrobial Chemotherapy. 22;49:31-4. Spring 24 PHAR Therapeutic Uses: H. infuenzae is the leading cause of AECB, followed by S. pneumoniae and M. catarrhalis MIC 9 (mg/l) Felmingham et al. Journal of Antimicrobial Chemotherapy. 21;48: Spring 24 PHAR H. influenzae (n=1) Teli Azi Clari 9

10 Therapeutic Uses: M. catarrhalis causes AECB, CAP, and sinusitis >9% produce MIC 9 (mg/l) Teli Azi Clari ß-lactamase M. catarrhalis (n=148) Felmingham et al. Journal of Antimicrobial Chemotherapy. 21;48: Spring 24 PHAR S. pyogenes is the most common cause of acute pharyngitis Therapeutic Uses: MIC 9 (mg/l) >128 Ery-S erma ermb Felmingham et al. Journal of Antimicrobial Chemotherapy. 21;48: Spring 24 PHAR Teli Azi Clari Therapeutic Uses: S. pyogenes MIC 9 (mg/l) >64 >16 32 Ery-S ermb erma mef Teli Azi Clari Nagai et al. Antimicrob Agents Chemother. 21;45(1): Spring 24 PHAR

11 Therapeutic Uses: S. pneumoniae is the most common bacterial pathogen in RTIs cause of ~5, cases of pneumonia/year in the U.S. 2-3 million cases of CAP/year in the U.S. ~1 million visits to physicians offices ~5, hospitalizations ~45, deaths Ball et al. Journal of Antimicrobial Chemotherapy. 22;49:31-4. Felmingham et al. Journal of Antimicrobial Chemotherapy. 21;48: Spring 24 PHAR Therapeutic Uses: S. pneumoniae >64 >64 MIC 9 (mg/l) Teli Azi Clari Pen-S Pen-R Ery-S Ery-R Felmingham et al. Journal of Antimicrobial Chemotherapy. 21;48: Spring 24 PHAR Therapeutic Uses: S. pneumoniae >64 16 >64 32 MIC 9 (mg/l) Ery-S ermb mef L4 Teli Azi Clari Nagai et al. Antimicrob Agents Chemother. 21;45(1): Spring 24 PHAR

12 Dosing Regimens Ery (po/iv) Clari (po) Azi (po/iv) AECB 25mg qid 5mg q12* Z pack** x1d x7-14d CAP 25mg qid 25mg q12 Z pack x14d x7-14d Pharyngitis 25mg qid 25mg q12 Z pack x1d x1d Sinusitis --- 5mg q x14d titis media 4/12mg 7.5mg/kg 3mg/kg q6h x1d q12 x1d x1 SSTI 25mg qid 25mg q12 Z pack x1-14d x7-14d *for H. influenzae, 25mg for S. pneumonia and M. pneumoniae **5mg on day 1, 25mg days 2-5 Spring 24 PHAR Cost Erythromycin Ery-Tab 5mg bid x1d $9.32 ERYC 25mg qid x1d $32.99 E-Mycin 25mg qid x1d $19.99 Clarithromycin Biaxin 5mg bid x1d $ mg bid x1d $88.99 Azithromycin Zithromax Z-Pak $ Spring 24 PHAR What does this all mean? Pharmacodynamics of ketolides support once-daily dosing Comparable adverse effects for ketolides versus macrolides Ketolides show good activity versus common respiratory tract pathogens Ketolides represent good empirical choice for RTIs due to coverage and efficacy versus resistant microorganisms Ketolides may serve as alternative to fluoroquinolones Spring 24 PHAR

13 HWEVER New class -- concerns about unknown toxicities and drug interactions, general lack of experience Not in guidelines for CAP as a ketolide Questions about use as a first-line agent? Two tablets -- possible non-adherence nly available in oral formulation concerns about activity versus H. influenzae and ermb S. pyogenes Cost? Spring 24 PHAR bjectives Participant should be able to explain macrolide/ketolide mechanism of action. Participant should be able to identify one important pharmacodynamic parameter each for macrolides and ketolides. Participant should be able to list three reasons why ketolides may be beneficial over macrolides. Spring 24 PHAR