Conflicts of Interest • None to declare MRSA Guidelines and Clinical Controversies: A practical overview A practical overview Tim T.Y. Lau , PharmD, FCSHP Pharmacotherapeutic Specialist in Infectious Diseases , Pharmaceutical Sciences, Vancouver General Hospital Clinical Associate Professor , Faculty of Pharmaceutical Sciences and Associate Member , Faculty of Medicine, The University of British Columbia November 2011 1 1 2 2 Objectives Questions 1. To describe the epidemiology of MRSA 1. What is MRSA? 2. To review the differences between HA-MRSA and CA- 2. What is the difference between HA-MRSA and MRSA CA-MRSA? 3. To become familiar with the antibiotics used in the 3. What antibiotics are effective against MRSA? treatment of MRSA 4. How do we treat common MRSA infections? 4. To recognize the common infections associated with MRSA infections 5. Is vancomycin still a good drug for MRSA? 5. To be acquainted with the guidelines on the treatment 6. What are some of the clinical controversies in of MRSA infections MRSA treatment? 6. To review the clinical controversies associated with treatment 3 3 4 4 Clinical Controversies 1. What is MRSA? 1. What is the evidence for I&D alone vs. I&D and antibiotics • Methicillin-resistant Staphylococcus aureus for treating MRSA cutaneous abscess? (MRSA) 2. What is the evidence for adding rifampin in MRSA skin and – Background soft tissue infections (SSTI)? (Enright et al. Proc Natl Acad Sci USA 2002;99:7687.) • In 1959, methicillin introduced 3. What is the evidence for decolonization in recurrent MRSA • In 1961, MRSA first reported; hospital-associated SSTI? • In mid-1990s, infections in healthy individuals in community; 4. What is the evidence for combination therapy in MRSA no healthcare risk factors endocarditis? • Presently, world-wide 5. Is linezolid better than vancomycin for MRSA pneumonia? – In 2005, 95,000 cases invasive MRSA in US (Klevens et al. JAMA 2007;298:1763.) 6. Is vancomycin still a good drug for MRSA? 5 5 6 6
1. What is MRSA? 1. What is MRSA? – Mechanism – Colonization (Oliveira et al. Microb Drug Resist 2001;7:349.) (Sanford et al. CID 1994;19:1123.) • Resistance mediated by PBP-2a • Anterior nares, skin (hands, axillae, perineum), and • Encoded by mecA gene on mobile staphylococcal open wounds chromosome cassette (SCCmec) – Increases risk of infection • 6 major clones SCCmec I-VI – Durability from few days to several years • Pulsed-field gel electrophoresis (PFGE) pattern – Transmission (Davis et al. CID 2004;39:776.) • Contaminated hand or environmental surfaces – HA-MRSA hands of healthcare workers Spach DH. Methicillin-Resistant Staphylococcus aureus (MRSA) Skin and – CA-MRSA direct contact with colonized or infected Soft Tissue Infections, 2011. individuals (http://depts.washngton.edu/hivaids/derm /case6/index.shtml) 7 7 8 8 1. What is MRSA? 1. What is MRSA? – Infections – Outcomes (Cosgrove et al. Infect Control Hosp Epidemiol 2005;26:166.) • Skin and soft tissue infections (SSTI) • Higher mortality • Bacteremia and infective endocarditis (IE) • Higher co-morbidities • Pneumonia (Blot et al. Arch Intern Med 2002;162:2229.) – Acute renal failure, hemodynamic instability • Bone and joint infections • Longer hospital stay • Central nervous system (CNS) infections • Higher healthcare costs 9 9 10 10 2. What is the difference between 2. What is the difference between HA-MRSA and CA-MRSA? HA-MRSA and CA-MRSA? • HA-MRSA vs. CA-MRSA • HA-MRSA vs. CA-MRSA – Differences in clinical and molecular epidemiology • Molecular epidemiology (Naimi et al. JAMA 2003;290:2976.) • Clinical epidemiology (Klevens et al. JAMA 2007;298:1763.) • Panton-Valentine Leukocidin (John et al. J Infect Dis 2008;197:175.) – Cytotoxin leukocyte destruction and tissue necrosis; virulence – Encoded by lukSF-PV usually on SCCmec IV and V – Epidemiologic association with SSTI 11 11 12 12
2. What is the difference between 3. What antibiotics are effective HA-MRSA and CA-MRSA? against MRSA? • HA-MRSA vs. CA-MRSA • HA-MRSA • CA-MRSA – Evolving epidemiology – Vancomycin – Vancomycin – Co-trimoxazole ? – Co-trimoxazole • HA-MRSA and CA-MRSA classifications – Rifampin* – Tetracyclines (Miller et al. CID 2007;44:471.) – Fusidic acid * (SAP) – Clindamycin? – No longer clearly defined – Rifampin* • CA-MRSA incidence surpass HA-MRSA – Fusidic acid * (SAP) (Liu et al. CID 2008;46:1637.) • CA-MRSA may replace hospital-acquired strains Daptomycin (Popovich et al. CID 2008;46:787.) � Linezolid � Tigecycline • Telavancin * Used in combination with � Quinupristin-dalfopristin (SAP) other agents � Ceftaroline (US) 13 13 14 14 3. What antibiotics are 3. What antibiotics are effective effective against MRSA? against MRSA? • Daptomycin (Liu et al. CID 2011;52:1) • Newer agents • Traditional agents – Class: Cyclic lipopeptide – Daptomycin – Clindamycin – MOA: Disrupts cell membrane via calcium-dependent – Linezolid – Co-trimoxazole (TMP- binding; bactericidal SMX) – Tigecycline – Activity: Staph (MRSA), Strep , Enterococcus (VRE) – Rifampin – Ind: Bacteremia + right-sided IE ; complicated SSTI – PK: 90% albumin; soft tissue; t 1/2 8 h – Tetracycline – Elim: Renal; 80% unchanged – Vancomycin – Interact: HMG-CoA reductase inhibitors may increase CK – Dose: SSTI - 4 mg/kg IV Daily; Bacteremia - 6 mg/kg IV Daily (CrCl <30 mL/min – Q48H) – ADR: GI, CK elevation, myopathy, eosinophilic pneumonia 15 15 16 16 3. What antibiotics are effective 3. What antibiotics are effective against MRSA? against MRSA? • Daptomycin • Linezolid (Liu et al. CID 2011;52:1) – Class: Oxazolidinone – Monitoring: – MOA: Inhibits protein synthesis at 50S ribosomal subunit; • Baseline and weekly CK; muscle pain or weakness bacteriostatic – Clinical Highlights: – Activity: Staph (MRSA), Strep , Enterococcus (VRE) • Persistent MRSA bacteremia – Ind: Nosocomial pneumonia, complicated SSTI • Inactivated by pulmonary surfactant – PK: F100%; 30% protein; CSF/lung/soft tissue/bone; t 1/2 6 h • Prior vancomycin and MRSA with elevated vancomycin MIC – Elim: Hepatic oxidative metabolism associated with reduce susceptibility to daptomycin – Interact: Weak MAOI; avoid SSRI (Sakoulas et al. Antimicrob Agents Chemother 2006;50:1581.) – Dose: 600 mg PO /IV Q12H • Higher doses may be used – ADR: GI, myelosuppression , optic/peripheral, neuropathies , • Avoid HMG-CoA reductase inhibitors; may increase CK/myopathies lactic acidosis 17 17 18 18
3. What antibiotics are effective 3. What antibiotics are effective against MRSA? against MRSA? • Linezolid • Tigecycline (Liu et al. CID 2011;52:1) – Class: Glycylcyline – Monitor: – MOA: Inhibits protein synthesis at 30S ribosomal subunit; • CBC weekly (if >7-10 d) bacteriostatic – Activity: Staph (MRSA), Strep , Enterococcus (VRE), Gram- – Clinical Highlights: negative ( except Proteus , Pseudomonas ), anaerobes – Ind: Intraabdominal, community-acquired pneumonia, • Always use PO unless not absorb or tolerate GI route complicated SSTI • Drug interactions with SSRIs – PK: 70% protein; lung/biliary tract/soft tissue • Monitor CBC weekly with prolonged use – Elim: Glucuronidation; biliary excretion; 30% renal • Pharmacare limited coverage drug – Dose: 100 mg IV load, 50 mg IV Q12H (Child-Pugh C - ½ dose) – VRE – ADR: N&V – MRSA unresponsive or intolerant to vancomycin 19 19 20 20 3. What antibiotics are effective 3. What antibiotics are effective against MRSA? against MRSA? • Tigecycline • Clindamycin (Liu et al. CID 2011;52:1) – Monitoring: – Clinical Highlights: • Baseline LFTs in hepatic insufficiency • CA-MRSA 60-70% susceptible – Clinical Highlights: • Not approved for MRSA infections; bacteriostatic • Polymicrobial MRSA infection • Good bioavailability • High Vd achieves high tissue concentrations and low serum levels (<1 • Use in SSTI, bone and joint infections, and pneumonia mg/L); use cautiously in bacteremia (Rodvold et al. J Antimicrob Chemother 2006;58:1221.) • Dose • In serious infections, consider alternative increase in all-cause mortality – SSTI – 300-450 mg PO TID in Phase 3 and 4 trials – Severe - 600 mg PO/IV Q8H – Pooled analysis all 13 Phase 3 and 4 trials with comparator • Adverse effects » Death 4.0% (150/3788) tigecycline vs. 3.0% (110/3646) – GI upset, diarrhea comparator; cause not established 21 21 22 22 3. What antibiotics are effective 3. What antibiotics are effective against MRSA? against MRSA? • Co-trimoxazole (TMP-SMX) (Liu et al. CID 2011;52:1) • Rifampin (Liu et al. CID 2011;52:1) – Clinical Highlights: – Clinical Highlights: • CA-MRSA 95-100% susceptible • Adjunct therapy for staphylococcal prosthetic infections • Not approved for staphylococcal infections • Penetrate biofilms • Few studies in MSSA bone and joint infections • Lack of clinical studies in MRSA • Possible benefit in invasive staphylococcal infections • Variable doses • Dose – 600 mg daily – 450 mg BID – SSTI – 2DS PO BID; severe – 3.5-5 mg/kg/dose PO/IV Q8-12H – 300 TID • Adverse effects • Avoid monotherapy; rapid resistance – Increased risk of hyperkalemia in renal insufficiency • Drug interactions – Bone marrow suppression • Monitor baseline LFTs 23 23 24 24
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