Skin and Soft Tissue Infections Henry F. Chambers, MD Professor of - - PDF document

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Skin and Soft Tissue Infections Henry F. Chambers, MD Professor of - - PDF document

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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

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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
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Microbiology

  • Purulent (abscess)

– MSSA, MRSA

  • Non-purulent (cellulitis)

– Approx. 75% beta-hemolytic streptococci (GAS,

  • ther 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)
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Most Common CA-MRSA (and MSSA) Skin Infections Abscess 59% Cellulitis 42% Folliculitis 7% Impetigo 3%

Fridkin, et al, New Engl J Med 2005;352:1436

Rare cause of necrotizing fasciitis

Abscess, Cellulitis

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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)

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Study Schema

Skin, soft tissue infection Hospitalization, diabetes, immunocompromised, SIRs, other exclusions Yes No Ineligible Eligible Single abscess < 5 cm Clindamycin 300 mg tid x 10d TMP/SMX 160/800 mg bid x 10d Other stratum Yes No Randomize Placebo

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

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Patient Characteristics – Abscess < 5 cm

Clinda (n=266) TMP/SMX (n=263) Placebo (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)

Clinda TMP/SMX Placebo

ITT

Cure 221/266 215/263 177/257 Cure rate 83.1% 81.7% 68.9% 95% CI 78.3% - 87.9% 76.8% - 86.7% 62.9% - 74.9%

Evaluable

Cure 221/238 215/232 177/220 Cure rate 92.9% 92.7% 80.5% 95% CI 89.3% - 96.4% 89.0% - 96.3% 74.8% - 86.1%

Efficacy at Test of Cure

Single Abscess

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TMP-SMX vs Clinda Placebo vs Clinda Placebo vs TMP/SMX

ITT

Δ cure rates

  • 1.3%
  • 14.2%
  • 12.9

99% CI

  • 10.1% - 7.5% -24.0% - -4.4% -22.8% - -3.0%

p-value 0.7324 0.0001 0.0008

Evaluable

Δ cure rates

  • 0.2%
  • 12.4%
  • 12.2%

99% CI

  • 6.7% - 6.3%
  • 20.9% - -4.0% -20.7% - -3.7%

p-value 1.0000 < 0.0001 0.0002

Efficacy at Test of Cure

Single Abscess Clinda (n) TMP/SMX (n) Placebo (n)

  • S. aureus

Cure rate 94.4% (157) 93.1% (147) 76.1% (102) 95% CI 90.1% - 97.9% 88.9% - 97.4% 68.5% - 83.7% p-value vs Placebo <0.0001 <0.0001

  • Non-S. aureus

Cure rate 90.5% (57) 90.8% (59) 90.8% (69) 95% CI 82.4% - 98.5% 83.0% - 98.6% 83.6% - 97.9% p-value vs Placebo 1.0000 1.0000

  • Efficacy at Test of Cure

Single Abscess – Evaluable Population

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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
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Study Schema

Skin, soft tissue infection Hospitalization, diabetes, immunocompromised, SIRs, other exclusions Yes No Ineligible Eligible Single abscess < 5 cm Clindamycin 300 mg tid x 10d TMP/SMX 160/800 mg bid x 10d Other stratum Yes No Randomize

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

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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 cm3 (max 628 cm3) – Area of erythema: 44 cm2 (range 0-528 cm2)

  • Cellulitis only 53.6%

– Area of erythema: 60.5 cm2 (range 0-1131 cm2)

  • Mixed 15.7%
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Efficacy at Test of Cure

Cellulitis, Larger Abscess

Clindamycin TMP/SMX Evaluable Population Cure rate 212/237 (89.5%) 202/229 (88.2%) Δ Clinda – TMP/SMX (95% CI) 1.2% (-5.1% – 7.6%), p = 0.773 ITT Population Cure rate (%) 212/264 (80.3%) 202/260 (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 (90.9%) 110/127 (86.6%) Δ Clinda – TMP/SMX (95% CI) 4.3% (-4.6% – 13.1%) Abscess Cure rate (%) 63/73 (86.3%) 64/72 (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

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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, cellulitis** 8/84 (9.5%) 4/16 (25.0%) 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

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Recurrences at 1 Month in Cured Patients

Stratum Clinda TMP/SMX Placebo

Abscess < 5 cm* 15/221 (6.8%) 29/215 (13.5%) 22/177 (12.4%) Larger abscess, mixed lesions** 11/102 (10.7%) 20/92 (21.7%) n/a Combined results¶ 26/323 (8.0%) 49/307 (16%) 22/177 (12.4%) Δ TMP/SMX-Clinda (95% CI) 7.9% (2.6% to 13.3%)

*p = 0.0254, **p = 0.0493, ¶p = 0.0019

Adverse Events

Stratum Clinda (N) TMP/SMX (N) Placebo (N)

Abscess < 5 cm 265 261 255 Diarrhea 46 17 20 Any GI 60 33 40 Rash 10 1 6 Larger abscess, cellulitis 259 258 n/a Diarrhea 27 28 n/a Any GI 38 44 n/a Rash 5 4 n/a

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Adverse Events - Combined

Clinda TMP/ SMX Placebo

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

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Clindamycin vs TMP/SMX for uSSSI

Summary

  • Clindamycin and TMP/SMX were superior to placebo:

12% higher marginal cure rates for abscess < 5 cm

  • Clindamycin and TMP/SMX had similar efficacies

– For patients with abscesses only – For patients with cellulitis only or mixed infections

  • Efficacies similar in children and adults, MRSA, MSSA
  • Recurrent infections more common in subjects treated

with TMP/SMX

  • Side effects were similar, almost all mild or moderate
  • Either clindamycin or TMP/SMX is acceptable for

treatment of abscess or cellulitis

A Randomized, Double-Blind Trial of Trimethoprim- sulfamethoxazole (TMP/SMX) vs. Placebo for Patients with an Incised and Drained Cutaneous Abscess

Study Sponsor: Division of Microbiology and Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Principal Investigators: David A. Talan, MD and Gregory J. Moran, MD Olive View-UCLA Dept. of Emergency Medicine and Division of Infectious Diseases, David Geffen School of Medicine at UCLA

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Study Schema

Skin, soft tissue infection Hospitalization, immunocompromised, pregnancy SIRs, other exclusions Cellulitis Abscess > 2 cm I&D TMP/SMX 320/1600 mg bid x 7d Infected wound Placebo x 7d TMP/SMX Clinda Cephalexin + Placebo Cephalexin + TMP/SMX

Efficacy at Test of Cure

TMP/SMX Placebo Evaluable Population Cure rate 487/524 (92.9%) 457/533 (85.7%) Δ TMP/SMX-Placebo (95% CI) 7.2% (3.2% - 11.2%), p < 0.001 ITT Population Cure rate 507/630 (80.5%) 454/617 (73.6%) Δ TMP/SMX-Placebo (95% CI) 6.9% (2.1% - 11.7%), p = 0.004

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Case 3

An 28 year old female, otherwise healthy, presents 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. What antibiotic would you recommend?

  • 1. Cephalexin
  • 2. Cephalexin + TMP/SMX

Clin Infect Dis 56:1754, 2013

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Study Design

  • Randomized, double blind, placebo

controlled trial (n=146)

– Cephalexin (500-1000 mg qid) + placebo – Cephalexin + TMP/SMX (320/1600 to 640/3200 mg in 3-4 divided doses – Up to 24 h prior therapy allowed

  • Duration 7-14 days
  • TOC at 1 month

Outcomes

Cephalexin +TMP/SMX Cephalexin + Placebo Cure rate 62/73 (85%) 60/82 (82%) Δ TMP/SMX-Placebo (95% CI) 2.7% (-9.3% - 15%) Progression to abscess 5/73 (6.8%) 5/73 (6.8%) Δ TMP/SMX-Placebo (95% CI) 0% (-8.2% - 8.2%) Cure rate, purulent lesions 75% 91% Cure rate, non-purulent lesions 86% 81%

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Study Schema

Skin, soft tissue infection Hospitalization, immunocompromised, pregnancy SIRs, other exclusions Cellulitis Abscess > 2 cm I&D TMP/SMX 320/1600 mg bid x 7d Infected wound Placebo x 7d TMP/SMX Clinda Cephalexin + Placebo Cephalexin + TMP/SMX

NO DIFFERENCE!

Complicated Acute Bacterial Skin and Skin Structure Infections

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FDA APPROVED AGENTS FOR TREATMENT OF ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS (ABSSSI )

FDA Approved Agents for Treatment of ABSSSI

Agent Dose Duration Cost/day

Daptomycin IV 4 mg/kg q24h, push 7-14 days $350 Linezolid PO/IV 600 mg q12h 10-14 days $280 Vancomycin 15-20 mg/kg q8-12h 7-14 days $16 Telavancin IV 10 mg/kg q24h 7-14 days $310 Ceftaroline IV 600 mg q12h 5-14 days $250 Tedizolid PO/IV 200 mg 6 days $235 Oritavancin IV 1200 mg once over 3h 1 day $2900 Dalbavancin IV 1000 mg x1, 500 mg x1

  • ne wk later, over 30 min

8 days $3000/ $1500

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RCTs for Treatment of ABSSSI

Agent Comparator N Cure rates (%) Difference (95% CI)

Telavancin Vancomycin 1867 76.5 v 74.2 2.3 (-1.6, 6.2) Ceftaroline Vancomycin 1378 85.9 v 85.5 0.3 (-3.4, 4.0) Tedizolid (PO) Linezolid 667 79.5 v 79.4 85.5 v 86.0 0.1 (-6.1, 6.2)

  • 0.5 (-5.8, 4.9)

Tedizolid (IV) Linezolid 666 85.2 v 83.5 88.0 v 87.7 2.6 (-3.0, 8,2) 0.3 (-4.8, 5.3) Oritavancin Vancomycin 954 82.3 v 78.9 79.6 v 80.0 3.4 (-1.6, 8.4)

  • 0.4 (-5.5, 4.7)

Dalbavancin Vancomycin 1312 79.7 v 79.8 91.4 v 91.0

  • 0.1 (-4.5, 4.2)

0.4 (-2.8, 3.6)

Yellow = primary endpoint of cessation of spread or reduction in baseline lesion, no fever, no rescue therapy per 2013 FDA guidance

Lesion Size§

Orit Dalba TDZ (PO/IV) Ceftar T/S- Clinda N 954 1312 1333 1378 554 Area, mean (cm2) 237 345 189, 235 118 40 Area, range (cm2) 47- 3417 26- 5100 27- 5773, 120-483* 0.03- 4743 0- 1367

§ Current FDA guidance specifies enrollment of subjects

with lesion size > 75 cm2 * IQR

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Lesion Sizes

Orit Dalba TDZ (PO, IV) Ceftar T/S- Clinda N 954 1312 1333 1378 554 Area, mean (cm2) 237 345 189, 235 118 40 Area, mean ($100 units) 2.3 3.3 1.8, 2.3 1.1 0.4 Area, mean (25 ¢ units) 52 76 42, 52 26 9

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Case 4

  • 46 yo male diabetic

presents with severe L thigh pain

  • T = 38.9, P = 128,

RR = 20, BP = 110/65

  • Leg exam as shown

What empiric therapy would you

  • rder in this case?
  • 1. Vancomycin
  • 2. Vancomycin + piperacillin/tazobactam
  • 3. Vancomycin + ceftriaxone + metronidazole
  • 4. Meropenem
  • 5. Vancomycin + piperacillin/tazobactam +

clindamycin

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Treatment of More Serious ABSSSIs

  • Purulent

– Empiric: Vancomycin or other anti-MRSA agent as above – MSSA: nafcillin or cefazolin

  • Non-purulent (moderate)

– Penicillin (IV), ceftriaxone, cefazolin

  • Non-purulent (severe), necrotizing

– Vancomycin + pip/tazo or carbapenem + clindamycin (IVIG???) – Surgical consultation!!!

Stevens, et al. IDSA Guidelines, Clin Infect Dis. 59:e10, 2014.

Definitive Therapy of Necrotizing Infection

  • MSSA: Nafcillin or cefazolin
  • MRSA: Vancomycin or other MRSA agent
  • Group A streptococcus: Penicillin + clindamcyin
  • Closdrium sp.: Penicillin + clindamycin
  • Vibrio sp.: Doxycycline + ceftriaxone
  • Aeromonas: Doxycycline + ciprofloxacin or ceftriaxone
  • Polymicrobial: Piperacillin/tazobactam or carbapenem
  • r 3rd gen cephalosporin + metronidazole (+ vancomycin

if MRSA)

Stevens, et al. IDSA Guidelines, Clin Infect Dis. 59:e10, 2014.

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Summary

  • We now know how to treat SSTIs
  • Uncomplicated, outpatients cellulitis or abscess

– Cephalexin (cellulitis only) – Clindamycin, TMP/SMX (cellulitis or abscess) – Average benefit of antibiotics + I&D versus I&D alone for abscess 6-12% (e.g., 90% vs 80% cure rates)

  • More complicated or in-patient

– Vancomycin versus numerous more expensive

  • ptions

– Alternatives to vancomycin may be cost-effective in avoiding/minimizing hospitalization

Other References

  • Ceftaroline

– Corey, et al. Clin Infect Dis 51:641, 2010

  • Telavancin

– Stryjewski, et al. Clin Infect Dis 46:1683, 2008

  • Tedizolid

– Prokocimer, et al. JAMA 309:559, 2013 – Moran, et al. Lancet ID 14:696, 2014

  • Dalbavancin

– Boucher, et al. New Engl J Med 370:2169, 2014

  • Oritavancin

– Corey, et al. New Engl J Med 370:2180, 2014