Optimizing Antibiotic Treatment of Skin and Soft Tissue Infections 15th Annual Rocky Mountain Hospital Medicine Symposium November 6, 2017 Tim Jenkins, MD Director, Antibiotic Stewardship Program Denver Health q Durata Therapeutics Disclosure of off-label drug uses q Trimethoprim-sulfamethoxazole, clindamycin, doxycycline
q q q Explain the evolving epidemiology and microbiology of skin infections Identify recent evidence regarding the diagnosis, treatment, and prevention of common skin infections Implement strategies to improve the management of skin infections in clinical practice Goals for 2020: Establishment of antibiotic stewardship programs in all acute care hospitals Reduce inappropriate antibiotic use by 20% in hospitals Optimizing antibiotic use for each patient to: q q Maximize the chance for a good clinical outcome AND Minimize unintended consequences of antibiotics Selection of resistant organisms C. difficile infection Adverse drug events Drug interactions Microbiome disruption Health care costs
1488 adults with 24 hours of IV or oral antibiotic exposure at Johns Hopkins Hospital 298 (20%) 1 antibiotic-associated adverse event 42% gastrointestinal 24% renal 15% hematologic 287 (19%) antibiotic regimens not clinically indicated 20% associated with adverse event Tamma P. JAMA Intern Med 2017; 177:1308 Question 1 65yo man presents with severe right thigh pain since striking his thigh on a countertop yesterday. He has a history of pulmonary embolus for which he takes warfarin. One week ago he was hospitalized for a left arm abscess. After drainage and IV antibiotics, he was discharged with a 10-day course of an unknown antibiotic. There is a large area of induration and ecchymosis over the thigh. Ultrasound shows a large hematoma. His INR is 8.6. He denies any change in his warfarin dose or dietary changes. Which antibiotic had he most likely been prescribed? A. Clindamycin B. Doxycycline C. Trimethoprim-sulfamethoxazole D. Cephalexin
Epidemiology and microbiology Magill S. JAMA 2014; 312:1438 Hospital admission and mortality rates for skin infections, 2005-2011 Kaye KS et al. PLoS ONE 2015;10:e0143276
Microbiology of inpatient skin infections 533 cases of cellulitis, wound infection, or abscess from 7 Colorado hospitals N =533 Any microorganism identified 202 (38) Any gram-positive pathogen 190 (94) Staphylococcus aureus 127 (63) MSSA 58 (29) MRSA 64 (32) Streptococcal species 59 (29) Aerobic gram-negative organism 20 (10) Only gram-negative organism(s) identified 4 (2) Anaerobic organism(s) 17 (8) Jenkins T. Infect Control Hosp Epidemiol 2014; 35:1241 Microbiology of cellulitis in era of CA-MRSA q 2 studies of >200 patients hospitalized for cellulitis (California 1 and Norway 2 ) q 3/4 confirmed etiology of β-hemolytic streptococci by serology or culture q Of patients only treated with β-lactam antibiotic, 96% cured 1 1) Jeng A. Medicine 2010; 89: 217-26 2) Bruun T. Open Forum Infect Dis 2017 Diagnosis of cellulitis
Question 2 56yo obese woman admitted with 2 days of progressive bilateral lower extremity redness, swelling, and pain. She has been fatigued but denies fever, chills, feeling ill, SOB, or CP. She had a LLE DVT 3 months prior for which she is on rivaroxaban. On exam she has bilateral erythema from the ankles to the mid-calf (more intense on the left) with edema and tenderness to palpation. There is scaling skin over the shins and patchy hyperpigmentation. What is the most appropriate next step? A. Order a LLE ultrasound B. Obtain Dermatology consultation C. Start vancomycin D. Start cefazolin Frequent misdiagnosis of cellulitis Adapted from Weng QY. JAMA Dermatol 2017; 153:141
Raff AB. JAMA 2016; 316:325 Beware of pseudocellulitis Know common causes: Stasis dermatitis Contact dermatitis Insect bite reaction Gout Hematoma Deep venous thrombosis Antibiotics and skin abscesses Question 3 A 22yo healthy man you are seeing in the ED has a 3x4cm left upper extremity skin abscess. He notes several members of his wrestling team have had similar infections recently. The abscess is incised and 2cc of pus is drained. What is the most appropriate antibiotic therapy? A. Trimethoprim-sulfamethoxazole B. Doxycycline C. Cephalexin D. No antibiotic is necessary
Infectious Diseases Society of America guideline for management of skin infections Give antibiotics after abscess drainage if: Fever Other evidence of systemic involvement Markedly impaired host defenses Inadequate response to drainage alone Stevens D. Clin Infect Dis 2014;59:e10-e52 786 participants (281 children) with abscess 5cm Randomized to 10 days of: Clindamycin 300mg TID TMP-SMX 1DS BID Placebo Daum RS. NEJM 2017; 376: 2545 Clinical cure 7 10 days after end of treatment in the intention to treat population Clindamycin % TMP-SMX % Placebo % All participants* 83.1 81.7 68.9 Children 89.1 82.4 68.5 Adults 79.4 81.4 69.0 S. aureus isolated 83.5 83.2 63.8 No S. aureus isolated Primary outcome 83.8 81.9 83.1 *p<.001 for difference between clindamycin and placebo and between TMP-SMX and placebo NNT = 7 to prevent one clinical failure
Adverse events Clindamycin % TMP-SMX % Placebo % Any adverse event 21.9 11.1 12.5 Diarrhea 16.2 5.4 6.7 Nausea 2.3 4.2 2.4 1 patient in TMP-SMX group had serious antibiotic-related adverse event (hypersensitivity reaction) Retrospective analysis of 269 patients hospitalized for cellulitis or abscess Compared outcomes between: Vancomycin alone Vancomycin plus clindamycin Wargo K. Clin Infect Dis 2015 ;61:1148 Primary outcome Hospital length of stay in days Vancomycin monotherapy Vancomycin and clindamycin All cases (mean ± SD) 4.0 ± 2.0 3.7 ± 1.4.137 Abscesses only 4.4 ± 2.3 3.6 ± 1.5.016 P Clindamycin group: 18% reduction in LOS after adjustment for treatment, I&D status, diabetes, outpatient antibiotics, and corticosteroid therapy
Summary Antibiotics and skin abscesses q Antibiotics after abscess drainage in outpatients improves outcomes q Benefit seen in S. aureus abscesses q Clindamycin less well tolerated than TMP-SMX q Whether adjunctive clindamycin for inpatients improves outcomes requires further study Antibiotic choice for cellulitis Question 4 45yo woman presents complaining of RLE erythema, swelling, and pain that began suddenly 12 hours ago. She is unable to bear weight due to the pain. She has a long history of poorly controlled diabetes mellitus (A1C 10.2). Her temperature is 38.7C and she has findings consistent with RLE cellulitis. There is no wound, purulence, or evidence of abscess. She has tinea pedis and onychomycosis.
What is the most appropriate initial therapy? A. Cefazolin B. Vancomycin C. Vancomycin + piperacillin-tazobactam D. Vancomycin + clindamycin Antibiotic selection for cellulitis q q q Uncertainty regarding optimal treatment since emergence of CA-MRSA In vitro and observational data suggest MRSA-active agents (TMP-SMX, doxycycline) not adequate for β- hemolytic streptococci Combination of β-lactam plus MRSA-active agent has become common practice (~15% of cases) 1,2 1) Hurley H. Am J Med 2013; 126; 1099 2) Jenkins T. Infect Control Hosp Epi 2014; 35:1241 Stevens D. Clin Infect Dis 2014; 59:e10-52
410 outpatients or inpatients from 20 hospitals in England with lower extremity cellulitis Randomized to: Flucloxacillin 500mg PO or IV QID 5 days + Clindamycin 300mg PO TID x 2 days Flucloxacillin + placebo BMJ Open 2017; 7:e013260 Outcomes Clinical improvement defined as afebrile and reduction in swelling or erythema at day 5 Incidence of diarrhea at day 10: 12.8% with clindamycin vs 5.3% with placebo (p =.04) 500 patients >12 years old with cellulitis (no wound or purulence) randomized to 7 days of: Cephalexin 500mg QID + TMP-SMX 2DS BID Cephalexin + placebo JAMA 2017; 317:2088
Outcomes and adverse events Clinical cure in 83.5% (TMP-SMX) vs. 85.5% (placebo) No significant difference in any secondary outcome: Need for hospitalization Recurrent or new site of skin infection Missed days or normal activity or school/work Days of pain medication Treatment-related adverse event: 42% (TMP-SMX) vs. 36% (placebo) Gastrointestinal disorder: 46% (TMP-SMX) vs. 39% (placebo) 524 patients with abscess (>5cm diameter), cellulitis, or both Randomized to: Clindamycin 300mg TID x 10 days TMP/SMX 1DS BID x 10 days Miller L. NEJM 2015; 372:1093 Cure rate Clindamycin group TMP-SMX group P All patients Intention to treat 212/264 (80%) 202/260 (78%).52 Per protocol population 212/237 (90%) 202/229 (88%).77 Cellulitis without abscess Intention to treat 110/136 (81%) 110/144 (76%).38 Per protocol population 110/121 (91%) 110/127 (87%).32 Adapted from Miller L. NEJM 2015; 372:1093
Summary Antibiotic selection for cellulitis q National guidelines recommend β-lactam monotherapy q Addition of MRSA-active agent to a β-lactam does not improve outcomes q Increased risk of adverse outcomes with addition of clindamycin q TMP-SMX is a reasonable treatment option for non-purulent cellulitis Duration of therapy Question 4 continued Your patient s cellulitis has markedly improved after 2 days of cefazolin. She states she is leaving the day after tomorrow for a 10-day family vacation to Cancun, Mexico. When writing your discharge prescription, what total duration of therapy should be completed? A. 5 days B. 7 days C. 10 days D. 14 days
Duration of therapy for cellulitis Randomized trial of 5 vs 10 days of levofloxacin for cellulitis Signs/symptoms scores at follow up (n = 87) 98% in each group had resolution of symptoms within 14 days and absence of relapse within 28 days (p >.05) Hepburn M. Arch Int Med 2004; 164:1669 Randomized trial of tedizolid for 6 days vs. linezolid for 10 days *Tedizolid non-inferior at both time points Prokocimer P. JAMA 2013; 309:559 IDSA guideline recommendations Duration of therapy Cellulitis q 5 days if clinically responding (strong recommendation, high-quality evidence) Cutaneous abscess q No specific recommendations Stevens D. Clin Infect Dis 2014; 59:e10
Summary of IDSA guideline treatment recommendations Short course of a single antibiotic targeted toward gram-positive pathogens Stevens D. Clin Infect Dis 2014; 59:e10-52 Single-dose treatment of skin infections Oritavancin and dalbavancin q Lipoglycopeptides with prolonged half-life à once-weekly dosing q Single dose as effective as 7-14 day courses of vancomycin and/or linezolid q Very expensive q Role to shorten or avoid hospitalization? Corey GR. NEJM 2014; 370:2180 Boucher HW. NEJM 2014; 370:2169 Dunne MW. Clin Infect Dis 2016; 62:545 Summary Duration of therapy q Existing evidence suggests prolonged antibiotic therapy does not improve outcomes q National guidelines support short courses of therapy q Role of long half-life agents unclear
Question 5 59yo man is hospitalized with his third episode of RLE cellulitis in the last 6 months. The prior two episodes completely resolved with appropriate short courses of beta-lactam therapy. On exam he has cellulitis without purulent drainage or abscess. There are no wounds, excoriations, skin changes suggestive of venous stasis, or tinea pedis. You start cefazolin and he improves over the next several days. What is the most appropriate discharge therapy? A. Cephalexin to complete 5-day course B. Complete cephalexin course then start longterm oral penicillin C. Complete cephalexin course then perform S. aureus decolonization D. Cephalexin to complete 14-day course Prevention of recurrent infections
274 patients with 2 episodes of lower extremity cellulitis Randomized to 12 months of: PCN 250mg PO BID Placebo NEJM 2013; 368:1695 Proportion of patients recurrence-free over time Thomas KS. NEJM 2013; 368:1695
Goals for 2020: Establishment of antibiotic stewardship programs in all acute care hospitals Reduce inappropriate antibiotic use by 20% in hospitals Broad-spectrum antibiotic use before and after the intervention Jenkins T. Arch Int Med 2011; 171:1072 Duration of therapy before and after the intervention Median duration of therapy decreased from 13 days to 10 days (p <.001)
q Ensure correct diagnosis q Appropriate spectrum of antibiotics Cellulitis: cefazolin monotherapy Abscess: MRSA-active agent q Short durations of therapy q Prevent infections Questions? timothy.jenkins@dhha.org