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Treatment Options for Mrsa Infections TREATMENT OPTIONS FOR MRSA INFECTIONS Arjana© Tambic by author Andrasevic University Hospital for Infectious Diseases ESCMID OnlineZagreb, Lecture Croatia Library © by author ESCMID Online Lecture Library Managing MRSA Infection in Europe – Opinions and Practice An Interactive Workshop © by author ESCMIDECCMID, Online Helsinki Lecture Library 18 May, 2009 Which is the most frequent infection caused by MRSA in your practice? Pneumonia Expert Panel (N = 13) ECCMID Delegates (N = 415) Osteomyelitis Bloodstream © by author SkinESCMID and soft Online Lecture Library tissue 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% ECCMID 2009 Which is the Most Common Focus of MRSA Bloodstream Infections in Your Practice? 5.5% BJI ECCMID Delegates (N = 400) 29.5% SSTI Urinary catheters (3.0%) 49.0% Bone/joint (5.5%) IV/vascular lines © by author Skin and soft tissue (29.5%) Respiratory tract (13.0%) ESCMID Online Lecture LibraryIV/vascular lines (49.0%) 13% Respiratory tract ECCMID 2009 Should All Patients With a Clinical Suspicion of HCAP/HAP/VAP Be Treated With an Antimicrobial Agent Active Against MRSA? Expert Panel (n = 13) ECCMID Delegates (n = 321) 30.8% 19.9% Yes Yes © by author 69.2% 80.1% No ESCMID Online LectureNo Library 0% 50% 100% 0% 50% 100% ECCMID 2009 If the Answer to the Previous Question is NO, Then Which Categories of Patients With a Clinical Suspicion of HCAP/HAP/VAP Should Be Treated With an Antimicrobial Agent Active Against MRSA? (choose all that apply) Patients previously identified as colonised or infected by MRSA ECCMID Delegates (n = 267) Patients with prior hospitalisation in high-risk settings such as nursing homes with high (> 20%) local MRSA Expert Panel (n = 13) prevalance Patients with the late-onset infection and/or prior antimicrobial treatment when ICU MRSA prevalence is high (>20%) Patients with MRSA present in the© nasopharynx by author All of the above. ESCMID Online Lecture Library None of the above. Wait for culture results. 0 10 20 30 40 50 60 70 80 90 100 ECCMID 2009 % When MRSA Pneumonia (HCAP/HAP/VAP) is Confirmed, What Do You Regard as the Most Appropriate Treatment Regimen? Linezolid ECCMID Delegates (n = 315) Vancomycin Expert Panel (n = 13) Teicoplanin Daptomycin Quinupristin/dalfopristin © by author Tigecycline ESCMID Online Lecture Library Other 0 10 20 30 40 50 60 70 80 90 100 ECCMID 2009 % For a cSSTI Caused by MRSA, What Would Be Your Initial IV Treatment? ECCMID Delegates (n = 325) Vancomycin Expert Panel (n = 13) Teicoplanin Linezolid Daptomycin © by author Quinupristin/dalfopristin ESCMIDTigecycline Online Lecture Library Other 0 10 20 30 40 50 60 70 80 90 100 % ECCMID 2009 For a Confirmed MRSA Bacteraemia, What is Your First-Line Treatment? Tigecycline Quinupristin/dalfopristin Daptomycin Expert Panel (n = 13) ECCMID Delegates (n = 316) Linezolid Glycopeptide + another drug © by author Teicoplanin ESCMID Online Lecture Library Vancomycin 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% ECCMID 2009 Vancomycin • Vancomycin is the standard of care for treating MRSA1 • Limitations1,2 – Slow bactericidal activity – Inconsistencies in tissue distribution based on the degree of tissue inflammation – Variable tissue penetration – Toxicity – Complicated dosing and blood level monitoring required • Recommend vancomycin trough levels - CNS infection: 15-20© mg/L by author - MRSA bacteraemia and endocarditis: 10-15 mg/L - MRSA pneumonia: 15-20 mg/L ESCMID Online Lecture Library – MIC creep 1. Sakoulas G, et al. J Clin Microbiol. 2004;42:2398-2402. 2. Rybak M. Clin Infect Dis. 2006;42:S35-S39. Vancomycin “MIC creep” © by author ESCMID Online Lecture Library I. Gould et al. Int J Antimicrob Agents 2008;31:1-9. Vancomycin: Minimal inhibitory concentrations (MICs) and clinical success © by author ESCMID Online Lecture Library I. Gould et al. Int J Antimicrob Agents 2008;31:1-9. Vancomycin Break-Point Concentrations Vancomycin (mg/L) 1 2 4 8 16 32 CLSI, (old) VSSA VISA VRSA CLSI, 2006 VSSA© by authorVISA VRSA EUCASTESCMID OnlineVSSA Lecture LibraryVRSA © byVSSA author (VISA) & VRSA ESCMID Online Lecture Library Do You Use the Glycopeptide MIC Routinely to Guide Your Choice of Treatment? Expert Pannel (N(n=13) = 13) ECCMID Delegates (N = 315) Expert Panel ECCMID Delegates Yes 84,6% Yes 55.9% No 15,4% © by authorNo 44,1% 0% ESCMID50% Online100% Lecture0% Library50% 100% At which Vancomycin MIC Level for MRSA (by E Test) Would You Replace Vancomycin With An Alternative Antibiotic? 4.0 mg/L Expert Panel (n = 13) ECCMID Delegates (n = 282) 2.0 mg/L 1.5 mg/L © by author 1.0 mg/L ESCMID Online Lecture Library 0.5 mg/L 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% In Your Opinion, How Does Combination Therapy Compare with Monotherapy to Treat Serious MRSA Infection? (choose all that apply) Expert Panel (n = 13) ECCMID Delegates (n = 313) Other Glycopeptides alone do NOT provide adequate therapy for serious infection Combination therapy shortens duration Less likely for resistance to develop No, not better than monotherapy No, no enough© evidence by author In some cases, but not enough evidence for routine use ESCMIDIncreasing Online risk of toxicity Lecture Library More effective than monotherapy 0% 10% 20% 30% 40% 50% 60% 70% 80% Antibiotic development Glycycline, 2005 Lipopeptides, 2005 Ketolide, 2001 Oxazolidinone, 2000 Carbapenem, 1985 Quinolones, 1962 Streptogramins, 1962 Fluoroquinolone, 1983 Glycopeptide, 1958 Chephalosporine, 1953 Macrolide, 1952 Chloramphenicol, 1949 Tetracycline, 1948 Polymyxine, 1948 Aminoglycoside, ©1944 by author Penicillin, 1943 Sulfonamide, 1936 ESCMID Online Lecture Library Salvarsan,1910 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 Linezolid Oxazolidinone (inhibitor of bacterial protein synthesis) Spectrum: G+ bacteria including MRSA, VRE Linezolid resistance rare in MSSA and MRSA Excellent oral bioavailability EMEA approved© for by the author treatment of • Complicated SSTIs due to MRSA ESCMID• Nosocomial Online pneumonia Lecture Library ZEPHyR study linezolid vs vancomycin in the treatment of nosocomial pneumonia caused by MRSA • a double-blind, randomized, non-inferiority with a nested superiority hypothesis study, n=1225, n=448 culture +MRSA, n=348 evaluable EOS • superiority of linezolid in primary end point: clinical success rate P=.042 100 95% CI: 0.5, 21.6 80 57.6% 60 46.6% 40 © by author Clinical Clinical Cure Patients (%) With 20 95/165 81/174 ESCMID0 Online Lecture Library Linezolid Vancomycin 600 mg IV q12h 15 mg/kg IV q12h Wunderink et al. Clinical Infectious Diseases 2012;54(5):621–9 21 Daptomycin • Unique mechanism of action – Disruption of bacterial membrane potential (G+ bacteria) – Bactericidal effect – No cross resistance with other antibiotic classes • Revival of an old drug: PK/PD→ less side effects with 1x daily dosing • Clinical indications© by author – Complicated skin & soft tissue infections (cSSTI) ESCMID– Right-sided endocarditis Online Lecture Library – Bacteraemia related to cSSTI and endocarditis – NOT suitable for pneumonia Phase III clinical trials of daptomycin in cSSTIs: study design Investigator assigns comparator agent Penicillinase-resistant Vancomycin penicillin (PRP) (VAN) Randomization© by to authortreatment group Comparator Comparator Daptomycin Daptomycin ESCMID Online(PRP) Lecture Library(VAN) Arbeit et al. Clin Infect Dis 2004;38:1673–1681 Phase III clinical trials of daptomycin in cSSTIs Clinical success* in S. aureus infected patients: ME population Daptomycin 100 Comparator 85.9 87.0 75.0 80 69.4 60 40 Patients (%) Patients © by author 20 0 ESCMIDMSSA Online (n=405) LectureMRSA (n=64) Library 95% CI: –5.6 to 7.8 –28.5 to 17.4 *Cure or improvement sufficient to stop antibiotic treatment ME, microbiologically evaluable Arbeit et al. Clin Infect Dis 2004;38:1673–1681 endocarditis daptomycin: 6 mg/kg; 1x daily © by author ESCMID Online Lecture Library Phase III S. aureus bacteraemia and infective endocarditis study: Success rates at 6-week test of cure by final diagnosis 70 Daptomycin Comparator 60 56.3 55.2 50 43.3 42.1 43.8 40 37.7 30 22.2 Success rate (%) Success rate 20 11.1 10 © by author 18/32 16/29 26/60 23/61 8/19 7/16 1/9 2/9 0 Uncomplicated Complicated Right-sided Left-sided ESCMIDbacteraemia Online bacteraemia Lecture endocarditis Library endocarditis* mITT population *Limited data in LIE preclude determination of efficacy Fowler et al. NEJM 2006;355:653–665 Tigecycline • Glycylcycline class – semisynthetic derivatives of tetracycline antibiotics with the maintained antibacterial effect but greater stability against mechanisms of tetracycline resistance • Broad spectrum of activity: – Gram-positive pathogens, including MRSA and VRE – Gram-negative pathogens, including ESBL producers (intrinsic resistance in P.aeruginosa, Proteeae – Anaerobic pathogens • Tigecycline monotherapy© by cure authorrates non-inferior to vancomycin plus aztreonam • Clinical indications ESCMID– Complicated skin Online & soft tissue infectionsLecture (cellulitis Library, wound infection, abscesses,ulcers, and burns) – Complicated abdominal infections MRSA Oral Treatment • MRSA infections that are treated ambulatory – Mild infections (skin infections, UTIs) – Infections that need long-term therapy (osteomyelitis) • MRSA infections© in hospitaliby authorsed patients – switch to oral therapy ESCMID Online Lecture Library Are oral antibiotics ever justified for the initial treatment of proven MRSA infection in the following? (choose all that apply) Bone and joint ECCMID Delegates (n=344) infections Expert Panel (n=13) Pneumonia Bacteraemia Complicated
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