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Options for Complicated Skin and Skin Structure Infections

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Options for Complicated Skin and Skin Structure Infections Options for Complicated Skin and Skin Structure Infections Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown Univ. Disclosures I have served as a consultant to, researcher/investigator for, or spoken for: • Astra Zeneca • Forest • Astellas • Pfizer • Bayer • Tetraphase • Cubist • Theravance Currently Used Therapy for MRSA FDA-approved Nosocomial cSSSI Evidence Evidence Bacteremia Evidence agent Pneumonia Ceftaroline (IV) ✔ AI Daptomycin (IV) ✔ AI ✔ AI Linezolid (IV/PO) ✔ AI ✔ AII Telavancin (IV) ✔ AI Tigecycline (IV) ✔ Vancomycin (IV) ✔ AI ✔ AII ✔ AII Oral Generics (no FDA-approved indication) • Tetracyclines - Doxycycline, minocycline • Trimethoprim/sulfamethoxazole • Clindamycin Liu C, et al. Clin Infect Dis. 2011;52(2):1-38. Tigecycline Boxed Warning Issued 9/27/13: Health care professionals should reserve Tygacil for use in situations when alternative treatments are not suitable Additional analysis shows an increased risk of death when intravenous (IV) Tygacil (tigecycline) is used for FDA-approved uses as well as for non-approved uses • In a 2010 Drug Safety Communication, the FDA informed the public that a meta-analysis of 13 Phase 3 and 4 trials showed a higher risk of death among patients receiving Tygacil compared to other antibacterial drugs (adjusted risk for death was 0.6% with 95% confidence interval) – The increased risk was greatest in patients treated for ventilator-associated pneumonia, a use for which FDA has not approved the drug • Since issuing the 2010 DSC, the FDA analyzed data from 10 clinical trials conducted only for FDA-approved uses (cSSSI, cIAI, CABP), including trials conducted after the drug was approved (adjusted risk for death was 0.6% with 95% confidence interval) – This analysis showed a higher risk of death among patients receiving Tygacil compared to other antibacterial drugs when used for FDA-approved uses as well as for non-approved uses • In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions http://www.fda.gov/Drugs/DrugSafety/ucm369580.htm Accessed 9/30/13. Dosing and Monitoring Vancomycin ASHP/IDSA/SIDP Recommendations • Loading Dose: 25-30 mg/kg IV (actual body weight) over 2 hours in seriously ill patients with suspected MRSA infection may be considered (C-III). • Maintenance Dose: 15-20 mg/kg (actual body weight) every 8-12 hours, not to exceed 2 g/dose in patients with normal renal function (B-III) • Trough serum vancomycin concentrations should always be maintained above 10 mg/L to avoid the development of resistance (B-III) • For complicated infections caused by S. aureus, total trough serum vancomycin concentration of 15-20 mg/L is recommended (B-II) Rybak et al. Am J Health-Syst Pharm 2009;66:82-98 Clinical Outcome: Vancomycin MIC 2.69 (1.60,4.51) 1.64 (1.14,2.37) 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Low MIC failure High MIC failure Low MIC mortality High MIC mortality Van Hal SJ et al. Clin Infect Dis 2012;54:755-71 Resistance: Prior Vancomycin Use Predicts High MICs No prior vancomycin Prior vancomycin 80 74 Logistic Regression Analysis of Risk Factors Associated with Vancomycin MIC ≥ 1.5 mcg/ml 70 63 60 Variable AOR P P = 0.002 value 50 (95% CI) 40 35 Vancomycin last 9.4 0.04 30 days (1.1-80.7) 30 Percent Isolates of Percent 20 16 ICU-acquired 5.3 0.02 11 10 bacteremia (1.4-20.4) 2 0 0,5 1 2 Vancomycin MIC (mcg/ml) Moise et al, J Antimicrob Chemo 2008;61:85–90 Lodise et al, J Antimicrob Chemo 2008;62:1138-41 Vancomycin • Increased doses of vancomycin does not necessarily improve outcomes – The percentage of MRSA isolates with vancomycin MIC >2.0 μg/mL increased from 3% in 2005 to 11% in 2009 – Vancomycin success rates at higher MICs are 5-fold lower • First case report of infection with VRSA reported in Europe from a patient in Portugal – Genetic background similar to that of VRSA isolated in USA but no epidemiological link with the USA to the patient or healthcare providers Hawser et al. International Journal of Antimicrobial Agents. 2011;37(3):219-24. Sakoulas G et al. J Clin Microbiol. 2004;42:2398-2402 Linezolid vs Vancomycin in Documented MRSA cSSTIs The largest culture-confirmed MRSA cSSTI trial to date compared the efficacy and safety of ZYVOX with that of vancomycin Study Design • Phase 4, prospective, randomized (1:1), open-label, multinational, multicenter, comparator-controlled trial Scope • 1077 randomized patients from 102 centers in 12 countries Primary End Point • Clinical efficacy at end of study (EOS) in per-protocol (PP) population Secondary End Points • Clinical efficacy at end of treatment (EOT) in PP population • Clinical efficacy at EOT and EOS in modified intent-to-treat population • Microbiologic outcomes • Safety Linezolid vs Vancomycin in Patients With Culture-Confirmed MRSA cSSTIs: Clinical Success (Per-Protocol Subjects) Results of a prospective, randomized, open-label, multicenter study versus vancomycin in patients with culture-confirmed MRSA (intent-to-treat population=1052 patients) P=NS Linezolid 600 mg IV q12h P=NS Vancomycin 15 mg/kg IV q12h; titrate per ClCr and trough levels Clinical Success (%) Clinical Success 219/239 193/220 191/227 167/209 *Primary analysis was a noninferiority comparison, with nested superiority hypothesis. Success rate was defined as the rate of patients assessed or classified as cured or improved. Itani KM, et al. Am J Surg. 2010;199(6):804-816. Linezolid vs Vancomycin in Patients With Culture-Confirmed MRSA cSSTIs: Clinical Success (Modified Intent-to-Treat [mITT] Subjects) Results of a prospective, randomized, open-label, multicenter study versus vancomycin in patients with culture-confirmed MRSA (intent-to-treat population=1052 patients) P=NS Linezolid 600 mg IV q12h P=.048 Vancomycin 15 mg/kg IV q12h; titrate per ClCr and trough levels Clinical Success (%) Clinical 254/284 243/287 223/276 196/266 Clinical success in mITT population at EOT and EOS are secondary end points. Success rate was defined as the rate of patients assessed or classified as cured or improved. Itani K et al. Clinical Microbiology and Infection 2008;14(suppl 7):S16. Abstract 080. Daptomycin – Outcomes with Higher Doses (1) CPK values ≥ 3 times the upper limit of normal (ULN) based on two serial measurements during therapy, and one of two levels ≥ 5 times the ULN or (2) CPK levels ≥ 5 times the ULNon two serial measurements if abnormal CPK levels at baseline [26]. he ULN of CPK value at NTUH is 160 IU/L. Telavancin: Current Indications FDA-approved indications (2009 - 2011): • Treatment of adult patients with complicated skin and skin structure infections - Caused by susceptible Gram-positive bacteria - Including Staphylococcus aureus, both MRSA and MSSA • Hospital-acquired and ventilator-associated bacterial pneumonia(HABP/VABP) caused by susceptible isolates of Staphylococcus aureus, when alternative treatments are not suitable EMA-approved indication (2011): • Treatment of adults with nosocomial pneumonia, including ventilator associated pneumonia - Known or suspected to be caused by MRSA; - Only in situations where it is known or suspected that other alternatives are not suitable Ceftaroline Ceftaroline is a cephalosporin with in vitro activity against Gram-positive and Gram-negative bacteria1 • The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs)1 • Ceftaroline is bactericidal against S. aureus due to its affinity for PBP2a1 – Ceftaroline has the ability to bind to PBP2a, the mutant protein that produces methicillin resistance in S. aureus2 • Ceftaroline is bactericidal against S. pneumoniae due to its affinity for PBP2x1 1. TEFLARO (ceftaroline fosamil) [prescribing information]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2012. 2. Moisan H, Pruneau M, Malouin F. J Antimicrob Chemother. 2010;65:713-716. Ceftaroline Indications CABP ABSSSI • Gram-positive bacteria • Gram-positive bacteria – S. pneumoniae (including – S. aureus (including cases with concurrent methicillin-susceptible and bacteremia) -resistant isolates) – S. aureus (methicillin- – S. pyogenes susceptible isolates only) – S. agalactiae • Gram-negative bacteria • Gram-negative bacteria – H. influenzae – E. coli – K. pneumoniae – K. pneumoniae – K. oxytoca – K. oxytoca – E. coli Anti Gram-positive Agents in the Pipeline Class Company Drug Status (clinical) Timing Fluoroquinolones III (ABSSSI) II First PIII for ABSSSI started in Rib-X delafloxacin 1H2013 (CAP) TaiGen nemonoxacin II (CAP/dfi) Furiex JNJ-Q2 III CAP/ABSSSI Entering PIII Lipogycopeptides (*) NDA late September/projected Durata dalbavancin III ABSSSI launch 2H14 PIII completed – projected filing The MedCo oritavancin III (ABSSSI) 4Q13 in US; 2014 European filing Ketolides Additional data requested by FDA / Adv. Life Sci. cethromycin III (CAP) / anthrax operations suspended Cempra solithromycin III (CAP) 4Q13 Initiation of PIII trial in CABP Oxazolidinones Two PIII trials completed; NDA Trius tedizolid III (ABSSSI) filing projected 2H13 Rib-X radezolid II ABSSSI/CAP) Pleuromotulin (*) Nabriva BC-3781 II (ABSSSI) Peptidomimetic (**) Polymedics PMX-30063 II (ABSSSI) Fab inhibitor (**) Affinium AFN-1252 II (ABSSSI) Deformylase inhibitor (**) GSK GSK1322322 II (ABSSSI/CAP) * new target (not yet exploited) – dual site of action for oritavancin ** old target but not exploited in human systemic medicine Anti Gram-positive Agents in the Pipeline Class Company Drug Status (clinical) Timing Fluoroquinolones III (ABSSSI) II First PIII for ABSSSI started in 1H2013 Rib-X delafloxacin
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