SKIN AND SOFT TISSUE INFECTIONS OCTOBER 3-4, 2015

SKIN AND SOFT TISSUE INFECTIONS OCTOBER 3-4, 2015 Disclosures I have no financial conflicts of interest to disclose or report. Steven Tran, PharmD NEFSHP Fall Meeting 2015 Objectives for Pharmacists Review the signs and symptoms of skin and soft tissue infections Recommend evidence-based antibiotic regimens for the treatment of skin and soft tissue infections Evaluate ongoing treatment regimens for appropriate continuation of therapy Skin and Soft Tissue Infections (SSTI) Impetigo/Ecthyma Furuncles/Carbuncles/Abscesses Cellulitis/Erysipelas Wound Infections Necrotizing Infections Animal Bite Wounds SSTI with Neutropenic Fever Skin and Soft Tissue Infections (SSTI) Impetigo/Ecthyma Furuncles/Carbuncles/Abscesses Cellulitis/Erysipelas Wound Infections Necrotizing Infections Animal Bite Wounds SSTI with Neutropenic Fever Scratching the Surface Furuncles/Carbuncles/Abscesses Collection of pus within dermis or deeper with redness, edema and/or induration Food and Drug Administration. Guidance for Industry. 2013 Oct. Wound Infection Purulent drainage from wound with surrounding redness, edema and/induration Cellulitis/Erysipelas Diffuse skin infection with spreading area of redness, edema, and/or induration 1

Scratching the Surface Furuncles/Carbuncles/Abscesses Collection of pus within dermis or deeper with redness, edema and/or induration Cellulitis/Erysipelas Diffuse skin infection with spreading area of redness, edema, and/or induration Food and Drug Administration. Guidance for Industry. 2013 Oct. Wound Infection Purulent drainage from wound with surrounding redness, edema and/induration Skin and Soft Tissue Infections: A Focus Common reason for medical attention Outpatient setting Physician offices Hospital outpatient departments Emergency room visits Inpatient setting Hospital admissions Surgical site complications Suaya JA, et al. BMC Infectious Diseases. 2014 Jun. Dryden MS. Int J AntimicrobAgents. 2009 Jul. Millions 4 3.5 3 2.5 2 1.5 1 0.5 0 ED 1990s 2000s Inpatient The Bugs of Interest SENTRY: Complicated SSTIs Nonpurulent SSTI - Cellulitis Beta-hemolytic streptococci Purulent SSTI - Abscess Staphylococcus aureus, methicillin-sensitive and resistant Hospital-acquired SSTI or Site/Wound Infection S. aureus, p. aeruginosa, e. coli, enterococcus spp. SSTI with Recent Water Contact Aeromonas hydrophila, Vibrio vulnificus Necrotizing fasciitis S. pyogenes, S. aureus, enterobactericeae, klebsiella spp., pseudomonas spp., anaerobes % of Isolates 50 45 40 35 30 25 20 15 10 5 0 44.6 11.1 9.3 7.2 4.8 4.2 4.1 Rajan, S. Cleveland Clinic Journal of Medicine. 2012 Jan. Rajan, S. Cleveland Clinic Journal of Medicine. 2012 Jan. Bacteria on the Loose Methicillin-resistant S. aureus (MRSA) Presence first detected in 1961 Methicillin introduced 2 years earlier Major nosocomial pathogen Hospital-acquired MRSA (HA-MRSA) Frequent isolate from positive cultures Blood stream and site infections Increasing community prevalence Community-acquired MRSA (CA-MRSA) Respiratory and skin and soft tissue infections Infectious Disease Society of America (IDSA) Guidelines 2014 Guidelines for SSTI Update and refine 2005 guidelines Organization and weighting of recommendations Recognize the emergent issue of MRSA for SSTIs Provide systematic management to providers for different classifications of SSTI Evidence-based treatment options Simple diagnostic algorithms for appropriate therapy Christensen KL, et. Clin Infect Dis. 2009 Oct. Dryden MS. Int J AntimicrobAgents. 2009 Jul. 2

Nonpurulent SSTIs Nonpurulent SSTIs Pallin et al. (2013) Uncomplicated Cellulitis Background Multicenter from 2007 to 2011 Design Randomized, double-blind, placebo controlled trial Participants Inclusion Exclusion Emergency room Symptoms > 1 Uncomplicated cellulitis week Diabetes Abscess > 3 mm Purulence > 1 cc Intervention Outcome Cephalexin + placebo versus Cephalexin + trimethoprim/sulfamethoxazole Primary: Risk difference for cure at 1 month Follow-up at 2 weeks and 1 month Pallin et al. Clin Infect Dis. 2013 June. Pallin et al. (2013) Uncomplicated Cellulitis Statistics Intention-to-treat Results 153 (146) patients Control: previous antibiotic use, crowded contact, spider bite Intervention: healthcare worker, MRSA contact, cellulitis with edema Clinical cure Control: 60/73 (82%) Intervention: 62/73 (85%) 2.7% (95% CI, -9.3% to 15%) Subsequent per-protocol analysis 4 non-cellulitis patients 4.2 (95% CI, -7.4 to 16%) Pallin et al. (2013) Uncomplicated Cellulitis Discussion No benefit from trimethoprim-sulfamethoxazole IDSA guidelines Non-purulent cellulitis Microbiological data? CA-MRSA exotoxin? Diabetics excluded CA-MRSA risk factors Epidemiological correlations Duration of therapy Effectiveness versus efficacy Implications First evidence-based trial for IDSA guideline 2 ongoing trials Pallin et al. Clin Infect Dis. 2013 June. Stevens DL, et al. Clin Infect Dis. 2005 Nov. Pallin et al. Clin Infect Dis. 2013 June. Genestier, et al. J Clint Invest. 2005 May. Ruhe et al. Clin Infect Dis 2007 June. 3

Nonpurulent SSTIs Nonpurulent SSTIs Nonpurulent SSTIs Purulent SSTIs Schmitz et al. (2010) Background Uncomplicated Abscess Role of CA-MRSA coverage after incision and drainage (I/D) of uncomplicated skin abscesses Design Multi-center, double-blind, randomized placebo controlled trial Participants Inclusion Exclusion ED patients >16yo Immunocompromised Abscess with I/D Fever/systemic signs Previous antibiotics Deeper structure abscess Intervention Trimethoprim-sulfamethoxazole 160/800 mg BID for 7 days post-i/d versus placebo Outcome Schmitz GR et al. Ann Emerg Med. 2010 Sep. Primary: Treatment failure within 7 days Secondary: Development of new lesions, abscess, or pustule within 30 days Uncomplicated Abscess Schmitz et al. (2010) Results 220 patients enrolled 96 TMP-SMX, 116 placebo Culture results Primary outcome Placebo TMP-SMX MRSA 47/100 (47%) 50/84 (60%) MSSA 22/100 (22%) 13/84 (15%) S. viridans 5/100 (5%) 2/84 (2%) Coag neg staph 10/100 (10%) 1/84 (1%) Treatment failure at 7 days Schmitz GR et al. Ann Emerg Med. 2010 Sep. Placebo (n=102) 27 (26%) TMP-SMX (n=88) 15 (17%) P value 0.12 4

Uncomplicated Abscess Schmitz et al. (2010) Results 139 patients at 30-day follow-up Placebo (n=50) TMP-SMX (n=46) P value New lesion within 30 days 14 (28%) 4 (9%) 0.02 Discussion Similar rates of CA-MRSA Loss to follow-up for secondary outcome Previous trials Cephalexin post-i/d TMP-SMX in pediatrics Addition of TMP-SMX to I/D does not decrease failure rate Schmitz GR et al. Ann Emerg Med. 2010 Sep. Cefazolin versus Oxacillin/Nafcillin Cefazolin versus Oxacillin/Nafcillin Cefazolin versus Oxacillin Cefazolin versus Oxacillin Li et al. (2014) Complicated MSSA bacteremia Tolerability Outcomes Primary: rate of clinical cure at end of therapy Secondary: treatment failure, adverse events, discontinuation Results 59 patients treated with cefazolin 93% received 6 grams daily 34 patients treated with oxacillin 94% received 12 grams daily Clinical cure: 95% (C) versus 88% (O) (p = 0.25) 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 24% 47% 30% 3% 3% Cefazolin Oxacillin 21% Treatment Failure ADEs Discontinuation Li J, et al. Antimicrob. Agents Chemother. 2014 June. Li J, et al. Antimicrob. Agents Chemother. 2014 June. 5

Cefazolin versus Nafcillin Cefazolin versus Nafcillin 40.0% 35.0% 33.8% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 6.7% 13.9% 4.2% 3.3% 11.4% PAD Rash Renal impairment 1.6% Cefazolin Nafcillin 8.1% Liver abnormalities Youngster I, et al. Clin Infect Dis. 2014 April. Youngster I, et al. Clin Infect Dis. 2014 April. Cefazolin versus Nafcillin What About MRSA? 40.0% 35.0% 30.0% 25.0% 33.8% Daily Cost Cefazolin: $25 Nafcillin: $170 20.0% 15.0% 10.0% 5.0% 0.0% 6.7% 13.9% 4.2% 3.3% 11.4% PAD Rash Renal impairment 1.6% Cefazolin Nafcillin 8.1% Liver abnormalities Youngster I, et al. Clin Infect Dis. 2014 April. What About MRSA? Linezolid vs Vancomycin vs Daptomcyin Retrospective cohort review Acute SSTI for less than 2 weeks Linezolid, vancomycin, or daptomycin > 48 hours Outcome: hospital length of stay (LOS) Results: 219 total patients Daptomycin: n = 84 Linezolid: n = 45 Vancomycin: n = 90 Prolonged LOS: n = 30 Szczypniska E, et al. SpringerPlus. 2013 Dec. 6

Linezolid vs Vancomycin vs Daptomcyin Linezolid vs Vancomycin vs Daptomcyin Szczypniska E, et al. SpringerPlus. 2013 Dec. Szczypniska E, et al. SpringerPlus. 2013 Dec. Linezolid vs Vancomycin vs Daptomcyin No difference in length of stay for empiric treatment Vancomycin: 87% of troughs > 10 mg/ml MRSA Agent Daily Cost Daptomycin (4 mg/kg) $340 Linezolid $222 Vancomycin (1g q12h) $7 Antibiotics and Healthcare Every antibiotic prescribed has a potential health system impact caused by creation of selective pressures for multi-drug resistant organisms. Stan Deresinski, MD Szczypniska E, et al. SpringerPlus. 2013 Dec. Resistance Timeline Narrow Spectrum of Approval Quantity of Antibiotic Use Continuation of empiric coverage with multiple agents New agents for MRSA and multi-drug resistant organisms versus Quality of Antibiotic Use Effective use of current antibiotics Reserving newer therapies for resistant organisms CDC. Antibiotic Resistance Threat in the United States. 2013 April. Kanj SS et al. Mayo Clin Proc. 2011 Mar. Spellberg N, et al. Clin Infect Dis.2008 Jan. Owens RC et al. Pharmacotherapy. May 2004. Arnold FW et al. J Manag Care Pharm. June 2004 7

Food and Drug Administration (FDA) Guidance 2013: FDA and Industry Guidance for Industry: Developing Drugs for Treatment Acute bacterial skin and skin structure infections (ABSSSI) Resolution of signs and symptoms after completion of therapy Reliability of outcome measure? Previous research Treatment effects at 48-72 hours Applicable to modern circumstances and standards? Foundation for National Institutes of Health (FNIH): A Helping Hand Historical data suggests Antibacterial versus ultraviolet light Cessation of lesion spread for cellulitis: day 2 Clinical cure at 7 days Potential treatment response earlier in therapy? Effectiveness of modern agents vs. sulfonamides Food and Drug Administration. Guidance for Industry. 2013 Oct. Food and Drug Administration. Guidance for Industry. 2013 Oct. Snodgrass WR, Anderson T. BMJ. 1937 July. Snodgrass WR, Anderson T. BMJ. 1937 Dec. Corwin P et al. BMJ. 2005 Dec. Foundation for National Institutes of Health (FNIH): A Helping Hand Interim Evaluation Analysis of modern trials for lesion size and control Tigecycline, daptomycin, ceftaroline Response 48-72 hours after randomization Success defined as control of infected lesion spread Concerns Lack of rigorous justification for biomarker Lesion spread as related to functional status Future direction Evaluate content validity and measurement properties of endpoints Third phase of review: new trials based on interim recommendations Talbot GH, et al. Clin Infect Dis. 2012 Oct. FNIH and FDA: Development of Endpoints Bridge Recommendations Cellulitis/erysipelas, major cutaneous abscesses, wound infections >75 cm 2 lesion size <30% trial population: abscess Clinical Trials Non-inferiority design Primary outcome: lesion response at 48-72 hours Secondary outcome: resolution of ABSSSI 7-14 days after therapy Talbot GH et al. Clin Infect Dis. 2012 Oct. Food and Drug Administration. Guidance for Industry. 2013 Oct. Tedizolid Dalbavancin Oritavancin Approval June 2014 May 2014 August 2014 Indication Dose Adverse Effects Arsenal of New Antimicrobials ABSSSI MSSA/MRSA Strep. spp. E. faecalis 200 mg IV or PO daily x 6 days Nausea, vomiting, diarrhea ABSSSI MSSA/MRSA Strep. spp. 1000 mg IV x 1, then 500 mg IV 1 week later Nausea, rash, Red-Man Syndrome ABSSSI MSSA/MRSA Strep. spp. E. faecalis 1200 mg IV infusion x1 Nausea, vomiting, SSTI abscess formation Half-life 12 hours 204 hours 393 hours Boucher HW. N Engl J Med. 2014 Jun. Prokocimer P et al. JAMA. 2013 Feb. Corey GR et al. Clin Infect Dis. 2014 Oct. Moran GJ et al. Lancet Infect Dis. 2014 Aug. ESTABLISH-1 Group >18 yo ABSSSI with local or systemic signs of infection Intervention 200 mg PO tedizolid daily x 6 days 600 mg PO linezolid BID x 10 days Outcome Early response Sustained response Clinical success Results 667 patients Early response 0.1% [-6.1-6.2%] Sustained response 69.3% vs 71.9% Clinical success 85.5% vs 86.0% >12 yo ESTABLISH-2 ABSSSI with local or systemic signs of infection 200 mg IV tedizolid x daily 6 days 600 mg IV linezolid x BID 10 days Early response Sustained response Clinical success 666 patients Early response 2.6% [-3.0-8.2%] Sustained response 87% vs 88% Clinical success 92% vs 96% Prokocimer P et al. JAMA. 2013 Feb. Moran GJ et al. Lancet Infect Dis. 2014 Aug. 8

DISCOVER-1/2 Group ABSSSI with 1 systemic and 2 local signs IV tx for at least 3 days Intervention Dalbavancin 1 g IV on day 1, then 500 mg IV on day 8 Vancomycin 1g or 15 mg/kg IV q12h x 3-14 days SOLO-1/2 ABSSSI with 1 systemic and 2 local signs IV tx for at least 7 days Oritavancin 1200 mg IV x 1 over 3 hours Vancomycin 1g or 15 mg/kg IV q12h x 7-10 days DISCOVER-1/2 Group ABSSSI with 1 systemic and 2 local signs IV tx for at least 3 days Intervention Dalbavancin 1 g IV on day 1, then 500 mg IV on day 8 Vancomycin 1g or 15 mg/kg IV q12h x 3-14 days SOLO-1/2 ABSSSI with 1 systemic and 2 local signs IV tx for at least 7 days Oritavancin 1200 mg IV x 1 over 3 hours Vancomycin 1g or 15 mg/kg IV q12h x 7-10 days Outcome Early response Lesion reduction PTE clinical response Early response Lesion reduction PTE clinical response Outcome Early response Lesion reduction PTE clinical response Early response Lesion reduction PTE clinical response Results 659 DALBA, 653 VANCO Early response 79.7% vs 79.8% Lesion reduction 88.6% vs 88.1% PTE clinical response 96.0% vs 96.7% 978 ORITA, 981 VANCO Early response 81.2% vs 80.9% Lesion reduction 86.4% vs 84.1% PTE clinical response 81.2% vs 80.2% Results 659 DALBA, 653 VANCO Early response 79.7% vs 79.8% Lesion reduction 88.6% vs 88.1% PTE clinical response 96.0% vs 96.7% 978 ORITA, 981 VANCO Early response 81.2% vs 80.9% Lesion reduction 86.4% vs 84.1% PTE clinical response 81.2% vs 80.2% Boucher HW. N Engl J Med. 2014 Jun. Corey R, et al. Pennsylvania Convention Center. 2014 Oct. Corey GR et al. Clin Infect Dis. 2014 Oct. Corey GR et al. N Engl J Med. 2014 Jun. Boucher HW. N Engl J Med. 2014 Jun. Corey R, et al. Pennsylvania Convention Center. 2014 Oct. Corey GR et al. Clin Infect Dis. 2014 Oct. Corey GR et al. N Engl J Med. 2014 Jun. Roles of New Agents Tedizolid Shortened duration of therapy Less side effects Dalbavancin Convenient dosing Long half-life Oritavancin Convenient dosing Long half-life But how do they compare? Boucher HW. N Engl J Med. 2014 Jun. Prokocimer P et al. JAMA. 2013 Feb. Corey GR et al. Clin Infect Dis. 2014 Oct. Moran GJ et al. Lancet Infect Dis. 2014 Aug. Thom H et al. (2015) Background Design and Criteria ABSSSI: Systemic Review and Meta-Analysis Previous meta-analyses did not include newer agents and excluded the presence of indirect evidence for treatments Systematic literature review and network meta-analysis Adult patients with ABSSSI treated with: Vancomycin Linezolid Daptomycin Tigecycline Clindamycin Thom H et al. Curr Med Res Opin. 2015 Aug. Telavancin Dalbavancin Oritavancin Tedizolid Study data and outcomes must have conformed to new FDA guidelines on ABSSSI Exclusions: medical conditions affecting interpretation of early clinical response (ECR) e.g. neutropenia Intention to treat (ITT) and clinically evaluable (CE) patients Thom H et al. (2015) ABSSSI: Systemic Review and Meta-Analysis Outcome Clinical response Focus Test-of-cure (TOC) Early clinical response (ECR) Results 52 trials identified 26 trials included for TOC outcome 10 trials included enough data for ECR comparison Clindamycin/telavancin excluded due to lack of relationship data Thom H et al. Curr Med Res Opin. 2015 Aug. Thom H et al. (2015) ABSSSI: Systemic Review and Meta-Analysis Treatment TOC ITT* TOC CE* Ceftaroline 1.07 (0.77-1.51) 2.29 (0.21-2.48) Dalbavancin 1.01 (0.24-4.41) 1.16 (0.47-2.35) Daptomycin 2.18 (0.90-5.42) N/A Linezolid 1.55 (0.91-2.57) 1.65 (0.68-3.53) Oritavancin 1.06 (0.80-1.43) 1.24 (0.41-2.26) Tedizolid 1.51 (0.82-2.73) N/A Tigecycline 0.87 (0.61-1.26) 0.90 (0.31-1.79) *Treatment effects are presented as odds ratio versus vancomycin. Ratios >1 indicate superior outcome for the comparator. Thom H et al. Curr Med Res Opin. 2015 Aug. 9

Thom H et al. (2015) ABSSSI: Systemic Review and Meta-Analysis Discussion No statistically significant difference among approved agents for ABSSSI for TOC Limited ECR data suggests same results Previous two meta-analyses suggests superiority of linezolid over vancomycin No inclusion of indirect effects of treatment comparators Limitations Unable to assess MRSA or MSSA confirmed subgroups due to lack of data Several studies lacked information to assess ECR Conclusion Suggestion of equivalence for current use of agents for ABSSSI More ABSSSI studies are needed that confirm to recent FDA guidelines Thom H et al. Curr Med Res Opin. 2015 Aug. Narrowing Coverage to Suspected Pathogens De-escalation to Defined Therapy Antimicrobial Stewardship Right Drug Right Dose Right Duration Appropriate De-escalation Right Route of Delivery Antimicrobial Stewardship Program Principles of Stewardship Appropriate selection, dosing, route, and duration of antimicrobial therapy Optimize clinical outcomes Minimize unintended consequences of antimicrobial use: Drug toxicity Selection of pathogenic organisms Emergence of resistance Ensure quality assurance and patient safety Dellit TH, et al. Clin Infect Dis. 2007 Jan. Dellit TH, et al. Clin Infect Dis. 2007 Jan. 10

Pasquale et al. (2014) Antimicrobial Stewardship - ABSSSI Background Summa Health System Historical data from 2011 ABSSSI average LOS: 6.2 days 30-day ABSSSI readmission rate: 6.2% Design Retrospective observational chart review Participants Emergency department admits with ABSSSI Reviewed within 24 hours Cellulitis, abscess, surgical site/wound infections Intervention Evaluation of patient by clinical pharmacist and ID physician Prospective chart review and recommendation Outcome Length of stay and 30-day ABSSSI readmission rate Pasquale et al. (2014) Results 62 patients 22 (35%) diabetics Antimicrobial Stewardship - ABSSSI Cellulitis 47 (76%) Major or deep abscess 16 (26%) Surgical site infection 5 (8%) Diabetic Wound 2(3%) 85 Interventions; 81 accepted Dose change 27 (44%) De-escalation 23 (37%) Regimen change 20 (24%) ID consult 6(7%) Other 9 (11%) Pasquale TR, et al. Am J Health Syst Pharm. 2014 Jul. Pasquale TR, et al. Am J Health Syst Pharm. 2014 Jul. Pasquale et al. (2014) Antimicrobial Stewardship - ABSSSI Results Length of stay (days) 30-day all-cause readmission rate 30-day ABSSSI readmission rate ASP Group (n=62) Historical Group (n=1149) P- value 4.4 6.2 <0.001 6.5% 16.71% 0.050 3.33% 6.27% 0.483 Discussion Specific for ABSSSI Observational study Small patient size Implications Interventions are readily available in various forms Antimicrobial stewardship implementation and focus Pasquale TR, et al. Am J Health Syst Pharm. 2014 Jul. Intravenous to Oral Antibiotics Coverage IV Therapy PO Therapy Streptococcus/ MSSA Cefazolin Oxacillin/ Naficillin Ceftriaxone MRSA Vancomycin Linezolid Ceftaroline Daptomycin Polymicrobial Piperacillin/ tazobactam + vancomycin Amoxicillinclavulanate Cephalexin Clindamycin Doxycycline Minocycline TMP-SMX Clindamycin TMP-SMX + cephalexin or clindamycin Future Directions Duration of Antibiotic Therapy for Cellulitis (DANCE) Prospective, multicenter, non-inferiority trial in the Netherlands Short versus standard duration of inpatient cellulitis therapy Primary outcome: resolution of cellulitis at day 14 without recurrence at day 28 Flucloxacillin IV/PO for 10-14 days for all cellulitis cases Potential guidance for duration of therapy Similar studies for respiratory tract infections, urinary tract infections, and bacteremia Cranendonk DR, et al. BMC Infect Dis. 2014 May. 11

Future Directions Omadacycline Oral/IV, once-daily tetracycline derivative Gram (+), gram (-), atypical, anaerobic, MRSA ABSSSI, CABP, UTI undergoing phase 3 trials Iclaprim IV dihydrofolate reductase inhibitor initially denied approval in 2008 Phase 3 trials approved on April 2015 ABSSSI and HABP caused by gram (+) pathogens Other investigational antibiotics BC-3781 semisynthetic pleuromutilin derivative CEM-102/Fusidic acid oral agent with high dose regimen JNJ-Q2/Avarofloxacin targets topoisomerase II and IV TD-1792/1607 glycopetptide-cephalosporin heterodimers Conclusion Skin and soft tissue infections are common High antibiotic exposure for patients Appropriate empiric treatment with antibiotics, if indicated Identification of most common pathogens for SSTI classification Nonpurulent Streptococcus spp., MSSA Purulent MSSA/MRSA Bug-drug match Consider local antibiogram Conclusion Antimicrobial stewardship is essential Appropriate drug Appropriate dose Appropriate de-escalation of therapy Refer to culture/susceptibility if present Appropriate IV to PO conversion Review resolution of leukocytosis, fever, PO intake Appropriate duration of therapy 7-14 days inpatient, but reassess daily Acknowledgements Florian Daragjati, PharmD, BCPS Michele Loudy, PharmD, BCPS Kevin Epps, PharmD, BCPS (AQ-ID), BCNSP SKIN AND SOFT TISSUE INFECTIONS OCTOBER 3-4, 2015 Steven Tran, PharmD NEFSHP Fall Meeting 2015 12