MRSA What Are Our Treatment Options and How Do We Choose the Right One? Kristi Traugott, PharmD, BCPS Clinical Pharmacy Specialist Infectious Diseases University Health System San Antonio, TX October 25, 2014 Patient Case 45 yo M with PMH of uncontrolled DM2, HTN, HLP, and obesity comes to ER with complaints of fever to 102.9 o F, malaise and painful, eyrthematous pustule on his groin. History of multiple pustules he has self-drained over past year in similar area Within a few hours of presentation becomes hypotensive and disoriented ESKAPE Bugs Enterococcus sp Staphylococcus aureus Klebsiella pneumoniae Acinetobacter Psuedomonas Enterobacter/Enterobacteriacae Boucher HW, et al. Clin Infect Dis. 2009;48:1-12 Objectives Describe the epidemiology of methicillin resistant Staphylococcus aureus (MRSA) Identify the available antimicrobials for the treatment of MRSA infections Describe what disease state and patient factors would aid in guidance to the most appropriate treatment of patients with MRSA infections What is MRSA? Methicillin resistant Staphylococcus aureus Gram positive cocci in clusters β hemolytic colonies 1
% Methicillin Resistant 11/4/2014 What is MRSA? Methicillin resistant Staphylococcus aureus Causes serious infections Community acquired Hospital acquired EPIDEMIOLOGY Common type of infections Cellulitis/abscesses Bacteremia/endocarditis Pneumonia Staphylococcus Resistance Staphylococcus Resistance Drug Year Introduced Years to Report of Resistance Years Until 25% Resistance in Hospital Years Until 25% Resistance in Community Penicillin 1941 1-2 6 15-20 Methicillin 1961 < 1 25-30 40-50 Vancomycin 1956 40?? Penicillin resistance β-lactamases Methicillin resistance change target site MecA gene PBP2 to PBP2a Vancomycin resistance change target site VanA, VanB acquired from VRE D-ala D-ala to D-ala D-lactate Chambers HF. Emerg Infect Dis. 2001; 7:178-182 Staphylococcus Resistance University Hospital MRSA Rates 80 70 60 50 40 30 20 10 0 Year Chambers HF. Emerg Infect Dis. 2001; 7:178-182 Internal Data: University Health System 2
MRSA Infections 2005-2011 CDC Threat Report: http://www.cdc.gov/drugresistance/threat-report-2013/ CDC Threat Report: http://www.cdc.gov/drugresistance/threat-report-2013/ Alphabet Soup ANTIMICROBIALS Abbv GNR MRSA VISA VRSA VRE Definition Gram Negative Rod Methicillin Resistant Staphylococcus aureus Vancomycin Intermediate Staphylococcus aureus Vancomycin Resistant Staphylococcus aureus Vancomycin Resistant Enterococcus MRSA Drug Review MRSA Drug Review Antimicrobial Spectrum Route Pearl Vancomycin Telavancin Daptomycin Linezolid Quinupristin/ dalfopristin Gram positive (staph, strep, diphth, peptostrep, actinomyces) NO VRE, VISA, VRSA, GNR Gram positive similar to vanco More potent (VISA?) Gram positive similar to vanco but add VRE, VISA, VRSA Gram positive similar to vanco but add VRE, VISA, VRSA Gram positive inclusing MRSA and VRE (E. faecium ONLY) /PO Mainstay for serious infection Vanco on steroids; lots of AE Muscle toxicity, inactivated by lung surfactant, $$$ Thrombocytopenia, neuropathies, $$$ Myopathies, not used much, $$$ Antimicrobial Spectrum Route Pearl Ceftaroline Clindamycin Doxy/mino Tigecycline Trimeth/sulfa Gram positive (MRSA) + gram negative (NO Pseudomonas) Gram positive (MRSA) + above the diaphragm anaerobes Gram positive (MRSA) + gram negative (NO Pseudomonas) Gram positive (MRSA) + gram negative (NO Pseudomonas) + anaerobes Gram positive (MRSA) + gram negative (NO Pseudomonas) /PO /PO /PO First BL with MRSA activity; vanc + ceftriaxone spectrum,$$ Increasing MRSA resistance; inducible resistance Great MRSA but lack strep coverage Severe N/V; BBW of increased mortality, $$$ Great MRSA but lack strep coverage 3
New Gram Positive Agents NEWLY APPROVED GRAM POSITE AGENTS Approval Date Generic Brand Company 5/23/2014 Dalbavancin Dalvance Durata Pharmaceutical 6/20/2014 Tedizolid Sivextro Cubist Pharmaceutical 8/6/2014 Oritavancin Orbactiv The Medicines Company Tedizolid Dalbavancin Oritavancin MOA Tedizolid Protein synthesis inhibitor Spectrum Staph (MRSA, MSSA), Strep, Enterococcus (VRE) Linezolid resistant isolates? Mutations in chromosomal genes encoding 23S rrna or ribosomal proteins (L3 or L4) vs cfr gene Claim to fame? Less toxicity and drug interactions Sivextro [package insert]. Cubist Pharmaceuticals, Lexington, MA; 2014 Tedizolid ESTABLISH TRIALS 4
Response Rate (%) 11/4/2014 Tedizolid Efficacy Tedizolid Safety 100 90 80 70 60 50 40 30 20 80 79 85 83 69 72 87 88 Tedezolid Linezolid Outcome Tedizolid n=331, n(%) ESTABLISH-1 Linezolid n=335, n(%) Tedizolid n=331, n(%) ESTABLISH-2 Linezolid n=327, n(%) 1 AE 135 (40.8) 145 (43.3) 148 (45) 141 (43) Nausea 28 (8.5) 45 (13.4) 26 (8) 36 (11) Headache 21 (6.3) 17 (5.1) 20 (6) 22 (7) Vomiting 9 (2.7) 20 (6.0) 10 (3) 17 (5) Pruitius 3 (0.9) 8 (2.4) -- -- Dyspepsia 2 (0.6) 7 (2.1) -- -- 10 0 ESTABLISH-1 ESTABLISH-2 ESTABLISH-1 ESTABLISH-2 Early Clinical Response End of Therapy Prokocimer, et al. JAMA. 2013;309(6):559-69 Moran, et al. Lancet Infect Dis. 2014;14:696-705 Prokocimer, et al. JAMA. 2013;309(6):559-69 Moran, et al. Lancet Infect Dis. 2014;14:696-705 Tedizolid Safety Tedizolid Pharmacokinetics Maximum % decrease over 21 days (mean/individual) Dose Platelets (%) Neutrophils (%) Placebo -5/-23-2/-57 200 mg tedizolid daily -15/-38-18/-51 300 mg tedizolid daily -23/-43-4/-44 400 mg tedizolid daily -38/-50-37/-66 600 mg linezolid daily -22/-54-38/66 Parameter Tedizolid Linezolid Dose 200 mg daily 600 mg BID Bioavailability 91% 100% Cmax(mcg/mL) 3.0 21.2 T ½ 12 hours 4-5 hours AUC 0-24 (mcg*hr/ml) 29.2 138 Protein Binding 70-90% 31% Vd (L) 67-80 40-50 Metabolism Liver; not CYP450 Oxidation (metabolites) Excretion 82% feces, 18% urine 65% non-renal, 30% renal Prokocimer, et al. Presented at: ICACC/IDSA 2008. Zyvox [package insert]. Pfizer Inc, NY, NY; 2014 Sivextro [package insert]. Cubist Pharmaceuticals, Lexington, MA; 2014 Tedizolid Pharmacokinetics Tedizolid in Neutropenia Parameter Tedizolid Linezolid Dose 200 mg daily 600 mg BID Bioavailability 91% 100% Cmax(mcg/mL) 3.0 21.2 T ½ 12 hours 4-5 hours AUC 0-24 (mcg*hr/ml) 29.2 138 fauc 0-24 (mcg*hr/ml) 2.9 95 Protein Binding 70-90% 31% Vd (L) 67-80 40-50 Metabolism Liver; not CYP450 Oxidation (metabolites) Excretion 82% feces, 18% urine 65% non-renal, 30% renal MIC 50 /MIC 90 0.25/0.25 1/2 In granulocytopenic mice (neutrophil count <100 cells/ml), bacterial stasis was achieved at a humanequivalent dose of approximately 2000 mg/day In non-granulocytopenic animals, stasis was achieved at a human-equivalent dose of approximately 100 mg/day The safety and efficacy for the treatment of neutropenic patients have not been evaluated Zyvox [package insert]. Pfizer Inc, NY, NY; 2014 Sivextro [package insert]. Cubist Pharmaceuticals, Lexington, MA; 2014 Prokocimer, et al. Antimicrob Agents Chemother. 2012;56:4608-13 Sivextro [package insert]. Cubist Pharmaceuticals, Lexington, MA; 2014 5
Response Rate (%) Response Rate (%) 11/4/2014 Tedizolid vs Linezolid Similar spectrum Tedizolid may pick up some linezolid R isolates Less drug interactions Less toxicity? Lower dose Large studies for only 6 days Linezolid goes generic 2015! Dalbavancin/Oritavancin MOA: Lipoglycopeptide antibacterials that inhibit cell wall synthesis and disrupt cell membrane integrity Spectrum Dalbavancin Staphylococcus (MRSA) Streptococcus (Viridans, S. pneumo, beta streps) Enterococcus (vanco susc isolates only) Oritavancin Staphylococcus (MRSA) Streptococcus (Viridans, S. pneumo, beta streps) Enterococcus (vanco susc AND resistant isolates) Discover-1 and Discover-2 Dalbavancin Efficacy Dalbavancin 1g day 1 + 500 mg day 8 Vancomycin X 3 days Optional switch to PO linezolid 10-14 days 100 90 80 70 60 50 40 30 20 10 0 94 91 93 87 83 82 77 78 DISCOVER-1 DISCOVER-2 DISCOVER-1 DISCOVER-2 Dalbavancin Vanc/LZD Early Clinical Response End of Therapy Boucher, et al. New Engl J Med. 2014;370:2169-79 Boucher, et al. New Engl J Med. 2014;370:2169-79 SOLO-1 and SOLO-2 Oritavancin Efficacy 100 Oritavancin 1200 mg X 1 90 80 70 60 82 82 79 81 80 80 84 86 50 40 Oritavancin Vancomycin Vancomycin X 7-10 days 30 20 10 0 SOLO-1 SOLO-2 SOLO-1 SOLO-2 Early Clinical Response End of Therapy Corey, et al. N Engl J Med. 2014;370:2180-90 Corey, et al. Presented at: ICAAC 2013 Corey, et al. N Engl J Med. 2014;370:2180-90 Corey, et al. Presented at: ICAAC 2013 6
Dose Dalbavancin and Oritavancin Pharmacokinetics Parameter Dalbavancin Oritavancin 1000 mg day 1 500 mg day 8 over 30 min infusion 1200 mg X 1 over 3 hrs Use of UFH is CI for 48 hrs bc aptt remain falsely elevated for ~48hs Cmax(mcg/mL) 287 138 T ½ 346 hours 245 hours AUC 0-24 (mcg*hr/ml) 3185 1110 Protein Binding 93% 85% Vd (L) 36 87.6 Shown to artificially prolong PT and INR for up to 24h, making monitoring of warfarin unreliable for up to 24 hours Metabolism Very little None Excretion Feces and urine Feces and urine Drug/Drug Interactions None Yes! Inducer and Inhibitor Drug/Lab Interactions None YES!! Dalbavancin/Oritavancin: Unanswered Questions Gram positive agents with LONG T ½ Change treatment paradigm? Who are these patients? Cost effective? Dalba ~$4500/course, Orita ~$2900 Are there issues with resistance and long term low drug levels? Dalvance [package insert]. Durata Therapeutics, Chicago, IL; 2014 Orbactiv [package insert]. The Medicines Co, Parsippany, NJ; 2014 Liu C, et al. Clin Infect Dis. 2011;52:1-38 CLINICAL INFECTIONS www.idsociety.org Go to guidelines section Skin and Soft Tissue Infections Non-purulent vs purulent cellulitis Empiric tx: β-hemolytic strep Empiric tx: MRSA Skin and Soft Tissue Infections Incision and drainage is primary treatment if abscess Simple abscesses or boils this alone is adequate Antibiotic therapy recommended: Severe/extensive disease Rapid progression Systemic symptoms Comorbidities/immunosuppression No drainage Lack of response to I&D Don t forget to get cultures!!! 7
Skin and Soft Tissue Infections Skin and Soft Tissue Infections Outpatient Inpatient Outpatient Outpatient Clindamycin TMP-SMX ± β-lactam Doxy/mino ± β-lactam Linezolid/tedizolid Vancomycin Linezolid/tedizolid Daptomycin Telavancin Ceftaroline Clindamycin **Consider addition of β-lactam if nonpurulent** Clindamycin Increasing MRSA resistance Inducible resistance C. diff? TMP-SMX ± β-lactam Sulfa allergy? Renal failure? Sun sensitivity Doxy/mino ± β-lactam Sun sensitivity N/V Linezolid/tedizolid Cost, cost, cost, cost Long term-toxicities (linezolid) Skin and Soft Tissue Infections Recurrent MRSA SSTI Inpatient Vancomycin Typical mainstay of therapy Linezolid/tedizolid Easy PO transition Cost, cost, cost Decrease toxin production Daptomycin Cost, cost, cost Skeletal muscle toxicity Inpatient Telavancin Ceftaroline Broader spectrum Clindamycin Decrease toxin production **Consider addition of β-lactam if nonpurulent** Personal hygiene and appropriate wound care Environmental hygiene Decolonization (if recurrent despite above practices) Nasal decolonization mupirocin BID X 5-10 d Body decolonization chlorhexidine or dilute bleach baths Do not treat colonization with antimicrobial therapy Bacteremia and Endocarditis MRSA bacteremia is a BIG DEAL!!! High morbidity and mortality Can cause metastatic infections Endocarditis Epidural abscess Vertebral osteomyelitis Liver/kidney/spleenic abscesses Source identification and control extremely important!! Get follow up cultures!! Bacteremia and Endocarditis Duration of therapy Uncomplicated: at least 2 weeks No endocarditis or prostheses, clearance of blood cultures 2-4d, defervescence w/in 72h, no evidence of metastatic infection Complicated: 4-6 weeks Do not meet above criteria 8
Bacteremia and Endocarditis Treatment: vancomycin or daptomycin Vancomycin High trough levels: 15-20 Daptomycin Non-inferior to standard therapy Development of resistant on daptomycin therapy Use higher doses: 8-10 mg/kg/d Good safety data for higher doses Bacteremia and Endocarditis Treatment Addition of rifampin or low dose gentamicin no longer recommended Rifampin increased duration of bacteremia Gentamicin no clinical benefit with increased risk of nephrotoxicity Daptomycin alone: 7% Vancomycin + gentamicin: 19% Anti staphylococcal penicillin + gentamicin: 17% Fowler VG, et al. N Engl J Med. 2006; 355:653-65 Levin DP, et al. Ann Intern Med. 1991; 115:674-80 Cosgrove SE, et al. Clin Infect Dis. 2009;48:713-21 Bacteremia and Endocarditis Pneumonia Persistent bacteremia Search for and remove foci of infection!!! Susceptible to daptomycin: High dose daptomycin + low dose gentamicin, rifampin, linezolid, TMP-SMX, beta-lactam Reduced susceptibility to vancomycin and daptomycin: Quinupristin-dalfopristin, TMP-SMX, linezolid, telavancin as single agent or combination Ceftaroline? Typical MRSA PNA patient Requires ICU admission, necrotizing or cavitary infiltrates and/or empyema Preceding or concurrent influenza-like illness Frequent colonizer Treatment Vancomycin or linezolid first line Telavancin, ceftaroline, clindamycin, TMP-SMX second line NO DAPTOMYCIN!!! Pneumonia Treatment vancomycin or linezolid Vancomycin Was std of care Poor penetration (trough 15-20) Linezolid Several studies vs vancomycin ZEPHYR trial MRSA nosocomial pneumonia Linezolid superior to vancomycin in clinical success 57.6% vs 46.6%, p = 0.04 No difference for 60 day mortality Never use daptomycin Ceftaroline? Tedizolid?? HOW DO WE PROTECT OURSELVES AND PATIENTS? Wunderink RG, et al. Clin Infect Dis. 2012; 54:621-29 9
Prevention Is Important!! Prevention 24-yo quadriplegic M (traumatic spinal cord injury) found to be colonized with MRSA No history of MRSA infection or colonization Health care worker performed abdominal exam and for infection control demonstration cultured ungloved hand Before alcohol hand sanitizer After alcohol hand sanitizer Donskey CJ, et al. N Engl J Med. 2009;360:e3 Prevention Questions?? Donskey CJ, et al. N Engl J Med. 2009;360:e3 10