2/14/16 Skin and Soft Tissue Infections Henry F. Chambers, MD Professor of Medicine, UCSF Disclosures • AstraZeneca – advisory board • Cubist/Merck – research grant • Genentech – advisory board • Merck – stock • Theravance – advisory board 1
2/14/16 Microbiology • Purulent (abscess) – MSSA, MRSA • Non-purulent (cellulitis) – Approx. 75% beta-hemolytic streptococci (GAS, other BHS) (based on serology, clinical response*) • Necrotizing (either of above) – Monomicrobial (MSSA, MRSA, GAS, Clostridia sp., Vibrio sp., Gram-negatives) – Polymicrobial: Mixed Gram+/Gram-, aerobes and anaerobes * Jeng, et al. Medicine 89:271, 2010 S. aureus Skin and Soft Tissue Infections • 95% of all S. aureus infections • Community MRSA (methicillin-resistant S. aureus ) causes > 50% of SSSIs • Usually pus is present (i.e., purulence) 2
2/14/16 Most Common CA-MRSA (and MSSA) Skin Infections Abscess 59% Cellulitis 42% Folliculitis 7% Impetigo 3% Rare cause of necrotizing fasciitis Fridkin, et al, New Engl J Med 2005;352:1436 Abscess, Cellulitis 3
2/14/16 Case 1 An 18 year high school senior male is seen in your office for an approximately 2 cm abscess of the right buttock with 5 cm diameter of surrounding erythema. No allergies. He is afebrile, other vital signs are normal, and exam is normal except for the abscess. Which of the following is the most appropriate management? 1. Incision and drainage 2. Incision and drainage + cephalexin 3. Incision and drainage + TMP/SMX 4. Incision and drainage + clindamycin Randomized, Double-Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin- Resistant Staphylococcus aureus Study Sponsor: Division of Microbiology and Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health PI: Henry F. Chambers, MD Co-Investigators: Loren Miller, MD (UCLA Harbor); Robert Daum, MD (University of Chicago) 4
2/14/16 Study Schema Skin, soft tissue infection Hospitalization, diabetes, immunocompromised, SIRs, other exclusions No Yes Eligible Ineligible Single abscess < 5 cm No Yes Other stratum Randomize Clindamycin TMP/SMX Placebo 300 mg tid x 10d 160/800 mg bid x 10d Outcome Measures • Primary – Cure rates of clindamycin, TMP/SMX, and placebo, each in conjunction with surgical drainage for the treatment of patients with limited abscess at Test of Cure (TOC) visit in evaluable and ITT populations. • Secondary – Cure rates in adults and children, cure rates for MRSA and MSSA, rates of recurrence after apparent cure 5
2/14/16 Patient Characteristics – Abscess < 5 cm Clinda TMP/SMX Placebo (n=266) (n=263) (n=257) Male, n (%) 140 (52.6) 152 (57.8) 152 (60.7) Age (Years) Mean (SD) 24.8 (17.8) 25.6 (18.1) 26.2 (18.7) Age groups < 1 – 8 years, n (%) 62 (23.4) 60 (22.8) 61 (23.8) > 18 years, n (%) 165 (62.0) 172 (71.5) 168 (65.4) Positive culture, n (%) 244 (91.7) 241 (91.6) 233 (90.6) S. aureus , n (%) 188 (77.0) 179 (74.3) 161 (69.1) MRSA, n (%)* 142 (75.5) 130 (72.6) 116 (72.0) Efficacy at Test of Cure Single Abscess Clinda TMP/SMX Placebo ITT 221/266 215/263 177/257 Cure 83.1% 81.7% 68.9% Cure rate 78.3% - 87.9% 76.8% - 86.7% 62.9% - 74.9% 95% CI Evaluable 221/238 215/232 177/220 Cure 92.9% 92.7% 80.5% Cure rate 89.3% - 96.4% 89.0% - 96.3% 74.8% - 86.1% 95% CI 6
2/14/16 Efficacy at Test of Cure Single Abscess TMP-SMX Placebo vs Placebo vs vs Clinda Clinda TMP/SMX ITT -1.3% -14.2% -12.9 Δ cure rates -10.1% - 7.5% -24.0% - -4.4% -22.8% - -3.0% 99% CI 0.7324 0.0001 0.0008 p-value Evaluable -0.2% -12.4% -12.2% Δ cure rates -6.7% - 6.3% -20.9% - -4.0% -20.7% - -3.7% 99% CI 1.0000 < 0.0001 0.0002 p-value Efficacy at Test of Cure Single Abscess – Evaluable Population Clinda (n) TMP/SMX (n) Placebo (n) S. aureus 94.4% (157) 93.1% (147) 76.1% (102) Cure rate 90.1% - 97.9% 88.9% - 97.4% 68.5% - 83.7% 95% CI <0.0001 <0.0001 -- p-value vs Placebo Non- S. aureus 90.5% (57) 90.8% (59) 90.8% (69) Cure rate 82.4% - 98.5% 83.0% - 98.6% 83.6% - 97.9% 95% CI 1.0000 1.0000 -- p-value vs Placebo 7
2/14/16 Other Outcomes Single Abscess • Cures rates similar for children and adults • MRSA and MSSA cure rates similar Case 2 28 year old female, otherwise healthy, is seen in your office with a tender lesion over her L lateral calf which she first noticed 2 days ago and is now more painful and has increased in size. No drug allergies. She is afebrile, other vital signs are normal and the exam is remarkable only for a 6.5 x 8 cm non-purulent, non-fluctuant, erythematous lesion that is tender and slightly swollen. Which antibiotic would you recommend? 1. No antibiotic needed 2. Cephalexin 3. TMP/SMX 4. Clindamycin 8
2/14/16 Study Schema Skin, soft tissue infection Hospitalization, diabetes, immunocompromised, SIRs, other exclusions No Yes Eligible Ineligible Single abscess < 5 cm No Yes Randomize Other stratum Clindamycin TMP/SMX 300 mg tid x 10d 160/800 mg bid x 10d Outcome Measures • Primary – To compare the cure rate of clindamycin to that of TMP/SMX for the treatment of patients with cellulitis or larger abscess at TOC visit, evaluable and ITT populations. • Secondary – To compare cure rates of clindamycin and of TMP/SMX, and their difference, for cellulitis or larger abscess, evaluable and ITT populations Miller, at al. New Engl J Med 372:1093, 2015 9
2/14/16 Patient Characteristics Clindamycin (n=264) TMP/SMX (n=260) Male, n (%) 135 (51.1) 139 (53.5) Age groups < 1 – 8 years, n (%) 51 (19.3) 47 (18.1) 9-17 years, n (%) 30 (11.4) 27 (10.4) > 18 years, n (%) 183 (69.3) 186 (71.5) I&D performed, n (%) 122 (46.2) 111 (42.7) Purulent drainage, n (%) 124 (47.0) 113 (43.5) Positive culture, n (%) 144 (54.5) 133 (51.2) S. aureus , n (%) 109 (75.7) 110 (82.7) MRSA, n (%)* 84 (77.0) 83 (75.4) *90% USA300 Lesion Types • Abscess only 30.6% – Mean Volume: 21.9 cm 3 (max 628 cm 3 ) – Area of erythema: 44 cm 2 (range 0-528 cm 2 ) • Cellulitis only 53.6% – Area of erythema: 60.5 cm 2 (range 0-1131 cm 2 ) • Mixed 15.7% 10
2/14/16 Efficacy at Test of Cure Cellulitis, Larger Abscess Clindamycin TMP/SMX Evaluable Population Cure rate 212/237 202/229 (89.5%) (88.2%) Δ Clinda – TMP/SMX (95% CI) 1.2% (-5.1% – 7.6%), p = 0.773 ITT Population Cure rate (%) 212/264 202/260 (80.3%) (77.7%) Δ Clinda – TMP/SMX (95% CI) 2.6% (-4.9% – 10.2%), p = 0.520 Efficacy at Test of Cure: Cellulitis vs Abscess Evaluable Population Clindamycin TMP/SMX Cellulitis Cure rate 110/121 110/127 (90.9%) (86.6%) Δ Clinda – TMP/SMX (95% CI) 4.3% (-4.6% – 13.1%) Abscess Cure rate (%) 63/73 64/72 (86.3%) (88.9%) Δ Clinda – TMP/SMX (95% CI) -2.6 (-15.0 – 9.8) Logistic Regression Model: Treatment effect: p = 0.866 Disease group: p = 0.810 Interaction: p = 0.363 11
2/14/16 Other Outcomes Cellulitis, Larger Abscess • Cures rates similar for children and adults • MRSA and MSSA cure rates similar Clindamycin Resistance is Associated with Treatment Failure Stratum Sensitive Resistant Abscess < 5 cm* 5/156 (3.2%) 5/13 (38.5%) Larger abscess, 8/84 (9.5%) 4/16 (25.0%) cellulitis** Combined results ¶ 13/240 (5.4%) 9/29 (31.0%) Δ R-S (95% CI) 25.6% (10.1% - 45.7%) *p = 0.0002, **p = 0.0978, ¶ p = 0.0001 12
2/14/16 Recurrences at 1 Month in Cured Patients Stratum Clinda TMP/SMX Placebo Abscess < 5 cm* 15/221 29/215 22/177 (6.8%) (13.5%) (12.4%) Larger abscess, 11/102 20/92 n/a mixed lesions** (10.7%) (21.7%) Combined results ¶ 26/323 49/307 22/177 (8.0%) (16%) (12.4%) Δ TMP/SMX-Clinda 7.9% (2.6% to 13.3%) (95% CI) *p = 0.0254, **p = 0.0493, ¶ p = 0.0019 Adverse Events Stratum Clinda TMP/SMX Placebo (N) (N) (N) Abscess < 5 cm 265 261 255 Diarrhea 46 17 20 Any GI 60 33 40 Rash 10 1 6 Larger abscess, 259 258 n/a cellulitis Diarrhea 27 28 n/a Any GI 38 44 n/a Rash 5 4 n/a 13
2/14/16 Adverse Events - Combined Clinda TMP/ Placebo SMX Number of subjects 524 519 255 Diarrhea* 73 (13.9%) 45 (8.7%) 20 (7.8%) Any GI** 98 (18.7%) 74 (14.2%) 40 (15.7%) Rash ¶ 15 (2.9%) 5 (1%) 6 (2.4%) *p = 0.0082, **p = 0.0553 ¶ p = 0.0395 Other Safety Data • Clindamycin (n=524) – 2 hospitalizations for infection: 1 peri-rectal and 1 recurrent abscess at OMFU in IVDU • TMP/SMX (n=519) – 6 hospitalizations for worsening cellulitis or abscess – 1 drug-related SAE: rash, hepatitis, thrombocytopenia • Placebo (n=255) – 1 hospitalization for a peri-rectal abscess 14
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