48 th Annual Meeting. IDWeek and ICAAC: The Cliffs Notes Version. Skin and Soft Tissue Infections. Skin and Soft Tissue Infections.

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1 48 th Annual Meeting IDWeek and ICAAC: The Cliffs Notes Version Yanina Pasikhova Pharm.D., BCPS-AQ ID, AAHIVP Infectious Diseases Pharmacist Moffitt Cancer Center Navigating the Oceans of Opportunity Skin and Soft Tissue Infections Skin and soft tissue infections (SSTIs) Common reason for seeking care Ambulatory setting Emergency departments Urgent care Trimethoprim / sulfamethoxazole (TMP/SMX) and clindamycin Recommended by current guidelines Limited clinical data to support these recommendations Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005; 41: Disclosure Skin and Soft Tissue Infections I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Clindamycin vs. TMP/SMX for Soft Tissue Infections Cellulitis or abscess > 5cm s/p I&D Clindamycin 300mg PO TID vs. TMP/SMX DS 1PO BID 10 days Test of cure at 14 days, total follow up 45 days Cure Clindamycin 80.3% vs. TMP/SMX 77.7% P=0.77 Adverse events Similar L. Miller et al. A Multi-Center Randomized Double Blind Controlled Trial of Clindamycin (CLINDA) versus Trimethoprim- Sulfamethoxazole (TMP-SMX) for Uncomplicated Skin and Soft Tissue Infection (SSTI). ICAAC 2013 Abstract L-337 Objectives Skin and Soft Tissue Infections Describe key studies presented at the most recent IDWeek and ICAAC meetings and their applications to clinical practice Discuss new research in the management of Clostridium difficile infection Explain the role of combination therapy in the empiric treatment of Gram-negative bacteria One month follow up No difference in overall failure rates 16.7% vs. 21.7% p=0.19 Recurrence accounted for 25-36% of overall failure Trend towards fewer recurrences in the clindamycin group 9.0% vs. 15.3% p=0.051(ns) Clindamycin and TMP/SMX appear to be viable options for management of SSTIs L. Miller et al. Recurrent Infections after Treatment of Uncomplicated Skin and Soft Tissue Infection (ussti) Among Patients Enrolled in A Multi-Center Randomized Double Blind Controlled Trial of Clindamycin (CLINDA) versus Trimethoprim- Sulfamethoxazole (TMP-SMX) SSTI. IDWeek 2013 Abstract 625 1

2 Vertebral Osteomyelitis Pyogenic vertebral osteomyelitis (VO) Most common form of vertebral infection Pathophysiology Direct spinal trauma / postoperatively Infections in adjacent structures Hematogenous spread of bacteria Treatment duration 6-12 weeks No randomized controlled trials No guidelines Anticipated release Summer 2014 is a significant cause of infections Methicillin-resistant (MRSA) Guidelines for treatment of MRSA infections IDSA 2011 Important to continuously assess Compliance with the guidelines Treatment outcomes Vertebral Osteomyelitis : MSSA Treatment duration of vertebral osteomyelitis (VO) 6 vs 12 weeks National, open blind, randomized controlled noninferiority, multicenter trial n=359 No significant difference between both groups Duration of parenteral antibiotics Length of hospitalization stay Choice of oral antibiotics Adverse events A. Dinh et al. Treatment Duration Of Vertebral Osteomyelitis, a Clinical Trial Comparing 6 Versus 12 Weeks Of Antibiotic Therapy. ICAAC 2013 Abstract L-338 Cefazolin (CEF) vs Oxacillin (OX) for Methicillin- Sensitive (MSSA) bloodstream infections (BSI) Retrospective, single centered observational study Clinical outcomes of high-burden infections Endocarditis (IE) Endovascular infections n=110 (CEF 95 vs OX 15) High burden: CEF 33.7% and OX 40% S. Nevrekar et al. Treatment Outcomes of Cefazolin versus Oxacillin for High Burden Methicillin-Sensitive Staphylococcus aureus (MSSA) Bloodstream Infections (BSI). IDWeek 2013 Abstract 1731 Vertebral Osteomyelitis : MSSA Cure = absence of clinical and biological signs related to VO without the need for additional or alternative antibiotic therapy 1 year after treatment Cure 6-weeks 91% (159/171) vs. 12-weeks 91% (160/176) 6 weeks of antibiotic therapy for VO appears to be sufficient No difference between two groups Clinical cure for high burden infections CEF 84% and OXA 67% Clinical cure for IE CEF 76% and OXA 67% Adverse events CEF appears to be effective in high burden MSSA BSI Further studies needed A. Dinh et al. Treatment Duration Of Vertebral Osteomyelitis, a Clinical Trial Comparing 6 Versus 12 Weeks Of Antibiotic Therapy. ICAAC 2013 S. Nevrekar et al. Treatment Outcomes of Cefazolin versus Oxacillin for High Burden Methicillin-Sensitive (MSSA) Bloodstream Infections (BSI). IDWeek 2013 Abstract

3 Cost of bacteremia Clinical and economic burden of hospitalized cases Cost-of-illness analysis Patients diagnosed with bacteremia (SAB) within 72 hours of admission n=303 MRSA 39 MSSA 264 MRSA surveillance culture and MRSA-ventilator associated pneumonia (VAP) Retrospective, multi-center study n=186 Purpose Determine if a relationship exists between admission nasal MRSA-PCR test and developing MRSA-VAP N. Thampi et al. Cost-of-illness analysis of bacteremia. IDWeek 2013 Abstract 374 B. Mullins et al. Methicillin-Resistant (MRSA) Surveillance Culture as a Predictor for MRSA-Ventilator Associated Pneumonia. IDWeek 2013 Abstract 349 MRSA vs. MSSA Longer median length of stay 22 vs. 12 days, p= 0.03 Similar comorbidities Similar rates of ICU admissions Median cost per case MRSA: $25,171 (95% CI $12,323-$38,019) MSSA $15,313 (95% CI $11,977-$18,650) p = 0.2 MRSA PCR test as a predictor of MRSA-VAP Sensitivity 70.0% Specificity 94.9% Positive predictive value 43.8% Negative predictive 98.2% Empiric MRSA coverage may not be warranted in patients with suspected VAP that are not MRSA colonized N. Thampi et al. Cost-of-illness analysis of bacteremia. IDWeek 2013 Abstract 374 B. Mullins et al. Methicillin-Resistant (MRSA) Surveillance Culture as a Predictor for MRSA-Ventilator Associated Pneumonia. IDWeek 2013 Abstract 349 Compliance with IDSA guidelines in the treatment of bacteremia (SAB) Infectious diseases consult (IDC) vs no IDC (nidc) IDC was associated with higher compliance for Documentation of bacteremia clearance (91% vs. 75%) Echocardiography (83% vs. 42%) Beta-lactam use in methicillin sensitive SAB (94% vs. 70%) Appropriate length of therapy (76% vs. 31%) Pharmacokinetic (PK) and pharmacodynamic (PD) need to be understood Appropriate dosing recommendations Optimal dosing of antimicrobials is not well described in certain patient populations Obese Critically ill Burn W.K. Chung et al. Infectious Diseases consultation improves adherence to IDSA Treatment Guidelines in the Treatment of bacteremia. IDWeek 2013 Abstract 357 3

4 Daptomycin (D) dosing for the treatment of Vancomycin- Resistant Enterococcal (VRE) Bacteremia in Morbidly Obese Patients Retrospective study of 47 patients Patients BMI>30 kg/m 2 VRE bacteremia treated with D 6mg/kg ABW vs AdjBW Outcomes similar in both groups 30-day mortality, LOS, time to microbiologic clearance and recurrent bacteremia J.L. Nagel et al. Evaluation of Adjusted-Dose versus Full Dose Daptomycin for the Treatment of Vancomycin-Resistant Enterococcal (VRE) Bacteremia in Morbidly Obese Patients. ICAAC 2013 Abstract K-169 Clostridium difficile Clostridium difficile infection (CDI) Most common cause of hospital acquired diarrhea Cost of $1 billion annually Risk factors Multiple antibiotics > 10 d of antibiotics Age > 10-fold increased risk for y/o PPI Optimal method for diagnosis is unclear Iv EC, Iii EC, Johnson DA. Clinical update for the diagnosis and treatment of Clostridium difficile infection. World J Gastrointest Pharmacol Ther Feb 6;5(1):1-26. Clostridium difficile Prolonged infusion (PI; continuous or extendedinfusion) vs intermittent bolus (IB) dosing in critically ill patients Pharmacokinetic and/or clinical advantage 68 ICUs in 10 European countries Piperacillin, meropenem and doripenem Drug concentration at 50 and 100% of dosing interval n=224 IB 63% PI 37% M-H. Abdul-Aziz et al. The DALI Study: Defining Antibiotic Levels in Intensive care unit patients - Prolonged Infusion of Beta-Lactam Antibiotics in Critically Ill Patients ICAAC 2013 Abstract A-010 Non-toxigenic Clostridium difficile (NTCD) as prevention of recurrence of CDI Phase 2 study Placebo or VP20621spores 1-2 days after completion of metronidazole or vancomycin Monitored for recurrent CDI 3 unformed stools within 24 hours Positive C. difficile stool assay No other likely cause of diarrhea S. Villano et al. Therapeutic Use of an Oral Suspension of VP20621, Spores of a Non- Toxigenic Clostridium difficile (NTCD) Strain, for Prevention of Recurrence of C. difficile Infection (CDI). IDWeek2013 Abstract LB-7 Clostridium difficile Drug concentrations PI consistently higher vs. IB dosing Clinical outcomes Clinical cure IB 66% vs PI 62%, p = 0.63 Mortality IB 28% vs PI 30%, p = 0.87 Infection-related mortality rates IB 22% vs PI 17%, p = Further studies need to be done to asses if PI of beta lactams offer a clinical benefit M-H. Abdul-Aziz et al. The DALI Study: Defining Antibiotic Levels in Intensive care unit patients - Prolonged Infusion of Beta-Lactam Antibiotics in Critically Ill Patients ICAAC 2013 Abstract A-010 n=168 Similar adverse events Mild- moderate headache was the only significant difference (2% placebo vs. 10%VP20621) CDI recurrence 30% placebo vs. 11% VP20621, p<0.01 Clinical implication New methods for preventing CDI recurrence are in development S. Villano et al. Therapeutic Use of an Oral Suspension of VP20621, Spores of a Non- Toxigenic Clostridium difficile (NTCD) Strain, for Prevention of Recurrence of C. difficile Infection (CDI). IDWeek2013 Abstract LB-7 4

5 Enterobacteriaceae Common cause of infections in health-care settings as well as in the community Infections with carbapenem resistant Enterobacteriaceae (CRE) Increasingly recognized in the last decade Mortality rates >40% Spread rapidly Limited treatment options Choice of antibiotics for initial double-coverage Increases chance of covering resistant isolate Assessment of dual-resistance for antibiotic pairs Retrospective study Blood cultures with Gram-negative organisms Analyzed antimicrobial sensitivity Rates of dual-resistance for all pairwise combinations MMWR / March 8, 2013 / Vol. 62 / No. 9 D. Nuckchady et al. Choice of Antibiotics for Initial Double-Coverage of Suspected Gram-Negative Bacteremia. IDWeek 2013 Abstract 1336 Fosfomycin (FOS) against CRE 80.9% of isolates were susceptible FOS against urinary tract isolates of Escherichia coli Canada % of isolates were susceptible FOS appears to be a viable option for treatment of urinary tract infections T. Keepers et al. Activity of Fosfomycin Against Carbapenem Resistant Enterobacteriaceae. IDWeek 2013 Abstract 738 J. A. Karlowsky et al. In Vitro Activity of Fosfomycin Against Urinary Tract Isolates of Escherichia coli Isolated From Patients Across Canada from 2010 to ICAAC 2013 Abstract E-1683 Addition of aminoglycosides to a beta-lactam Lowest dual-resistance and greatest added benefit Superior to quinolones Reduction in resistance Ceftriaxone +gentamicin 22% vs ceftriaxone + ciprofloxacin 13% Aztreonam and amikacin 19%vs ceftazidime + ciprofloxacin 3% Performing such analysis can help identify appropriate empiric therapy D. Nuckchady et al. Choice of Antibiotics for Initial Double-Coverage of Suspected Gram-Negative Bacteremia. IDWeek 2013 Abstract 1336 Development of in vitro resistance to ertapenem and other carbapenems after ertapenem exposure Patient isolates of K. pneumoniae, P. aeruginosa, E. coli, S. marcescens, A. baumanii, and Enterobacter spp. Ertapenem E-tests daily Meropenem, imipenem, and doripenem E-tests on days zero, five, ten, and fifteen Mean ertapenem MIC increased from 0.5 to 10 All meropenem, imipenem, and doripenem MICs increased The mechanisms of resistance determined All with (-) modified hodge test C. Handler et al. The Development of In Vitro Resistance of Selected Pathogens to Ertapenem and other Carbapenems. IDWeek 2013 Abstract 251 Minocycline (MC) and polymyxin B (PB) combination against Acinetobacter baumannii In vivo efficacy of the combination Neutropenic murine pneumonia model Humanized doses of antibiotics were administered to infected animals MC PB MC+PB D. R. Bowers et al. Assessment of Minocycline and Polymyxin B Combination against Acinetobacter baumannii. ICAAC 2013 Abstract A

6 Intracellular concentration and in vitro bactericidal effect of MC were enhanced by PB Bacterial burden in lung tissues at 24 hours Significantly reduced in combination group 4.63 ± 0.12 log cfu/g compared to either monotherapy MC 6.71 ± 0.55 log cfu/g PB 8.91 ± 0.10 log cfu/g Combination of MC and PB may have a role in the treatment of Acinetobacter baumannii D. R. Bowers et al. Assessment of Minocycline and Polymyxin B Combination against Acinetobacter baumannii. ICAAC 2013 Abstract A-1042 Questions? 6