Disclosures Treatment of Skin and Soft Tissue Infections Allergan - - PDF document

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2/1/2017 Disclosures Treatment of Skin and Soft Tissue Infections Allergan research grant Genentech research grant Henry F. Chambers, MD Professor of Medicine, UCSF Microbiology Abscess, Cellulitis Purulent (abscess)

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2/1/2017 1

Treatment of Skin and Soft Tissue Infections

Henry F. Chambers, MD Professor of Medicine, UCSF

Disclosures

  • Allergan – research grant
  • Genentech – research grant

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

Abscess, Cellulitis

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2/1/2017 2

  • S. aureus Skin and Soft Tissue

Infections

  • 95% of all S. aureus infections
  • Community MRSA (methicillin-

resistant S. aureus) causes > 50% of SSTIs

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)

Study Subjects and Culture Results

Single Abscess < 5 cm All Subjects (n=786)

Male, n (%) 448 (57.0) > 18 years, n (%) 505 (64.2) Positive culture, n (%) 718 (91.3)

  • Staph. aureus, n (%)

527 (67.0) MRSA, n (%) 388 (49.8)

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2/1/2017 3

Clinda 300 mg tid TMP/SMX 160/800 bid 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 – similar results but higher cure rates

Efficacy at Test of Cure*

Single Abscess < 5 cm

* 10-14 days after 10-day course of therapy

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

ITT

∆ cure rates

  • 1.3%
  • 14.2%
  • 12.9

95% CI

  • 8.4% - 5.7%
  • 22.0% - -6.4% -20.8% - -5.0%

p-value 0.7324 0.0001 0.0008

Evaluable – similar results

Efficacy at Test of Cure

Single Abscess < 5 cm Clinda (n) TMP/SMX (n) Placebo (n)

  • Staph. 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-Staph. aureus

Cure rate 90.5% (57) 90.8% (59) 90.8% (69) p-value vs Placebo 1.0000 1.0000

  • Efficacy at Test of Cure
  • Staph. aureus, Single Abscess – Evaluable Population

Reasons for Clinical Failure - ITT

Clinda (n=266) T/S (n=263) Placebo (n=257) Failures, N 45 48 80 Missed TOC, N 28 31 37 Worse 1o lesion, N 3 2 5 New infection, N 6 9 32 Rescue meds, N 12 15 33 All other, N 9 6 4

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SLIDE 4

2/1/2017 4 Reasons for Clinical Failure – OMFU

Clinda (n=266) T/S (n=263) Placebo (n=257) Failures, N 57 71 96 Missed TOC, N 32 37 39 Worse 1o lesion, N 1 1 New infection, N 13 26 46 Rescue meds, N 12 15 33 All other, N 12 68 6

Other Outcomes

Single Abscess < 5 cm

  • Cures rates similar for children and adults
  • MRSA and MSSA cure rates similar

New Engl J Med 374:823, 2016

Main Results

  • TMP/SMX 320/1600 mg bid vs Placebo, 7d
  • Cure rates of 73.6% versus 80.5%

– 6.9% higher (95% CI 2.1 – 11.7) for TMP/SMX

  • TMP/SMX with higher rate of secondary

benefits

  • Adverse event rates similar

New Engl J Med 374:823, 2016

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2/1/2017 5

Clin Infect Disease 2016 Mar 29. pii: ciw177. [Epub ahead of print]

Key Points

  • 500 subjects with wound infections treated as
  • ut-patients

– 2 DS TMP/SMX vs Clinda 300 mg qid, 7d

  • 65% S. aureus, 40% MRSA
  • Overall cure rate 92%, <1% difference between

the two.

  • Fewer recurrences/new infections with clinda

Clin Infect Disease 2016 Mar 29. pii: ciw177. [Epub ahead of print]

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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SLIDE 6

2/1/2017 6 Patient Characteristics

Cellulitis, Abscess > 5 cm, Mixed, Multiple

All Subjects (n=534)

Male, n (%) 247 (52.3) > 18 years, n (%) 369 (70.4) I&D performed, n (%) 233 (44.5) Purulent drainage, n (%) 237 (45.2) Positive culture, n (%) 277 (52.9)

  • S. aureus, n (%)

219 (41.8) MRSA, n (%) 167 (31.9)

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%

Clinda 300 mg tid TMP/SMX 160/800 mg bid

ITT

Cure 212/264 202/260 Cure rate 80.3% 77.7% 95% CI 75.2% - 85.4% 72.3% - 83.1%

Evaluable – similar results, higher cure rates

Efficacy at Test of Cure*

Cellulitis, Larger Abscess > 5 cm, Mixed, Multiple

* 10-14 days after 10-day course of therapy

TMP-SMX vs Clinda

ITT

∆ cure rates

  • 2.6%

95% CI

  • 10.2% - 4.9%

p-value 0.52

Evaluable

∆ cure rates

  • 1.2%

95% CI

  • 7.6% - 5.1%

p-value 0.77

Efficacy at Test of Cure

Cellulitis, Larger Abscess > 5 cm, Mixed, Multiple

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SLIDE 7

2/1/2017 7

Efficacy at Test of Cure: Cellulitis vs Abscess

Evaluable Population Clindamycin TMP/SMX

Cellulitis

Cure rate 110/121 (90.9%) 110/127 (86.6%) ∆ Clinda – TMP/SMX (95% CI) 4.3% (-4.6% – 13.1%)

Abscess

Cure rate (%) 63/73 (86.3%) 64/72 (88.9%) ∆ Clinda – TMP/SMX (95% CI)

  • 2.6 (-15.0 – 9.8)

Logistic Regression Model: Treatment effect: p = 0.87 Disease group: p = 0.81 Interaction: p = 0.36

Other Outcomes

Cellulitis, Larger Abscess > 5 cm, Mixed, Multiple

  • 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* 25/170 (14.7%) 6/13 (46.2%) Larger abscess, cellulitis** 7/84 (8.3%) 4/15 (26.6%) Combined results¶ 32/254 (12.6%) 10/28 (35.7%) ∆ R-S (95% CI) 23.1% (6.0% - 43.6%)

*p = 0.01, **p = 0.06, ¶p = 0.003

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, cellulitis, mixed, multiple** 11/102 (10.7%) 20/92 (21.7%) n/a Combined results¶ 26/323 (8.0%) 49/307 (16%) 22/177 (12.4%) ∆ TMP/SMX-Clinda (95% CI) 7.9% (2.6% to 13.3%)

Clinda v TMP/SMX: *p = 0.025, **p = 0.049, ¶p = 0.002

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SLIDE 8

2/1/2017 8

Adverse Events - Combined

Clinda TMP/SM X 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%)

Clinda vs TMP/SMX: *p = 0.008, **p = 0.055 ¶ p = 0.04

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

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

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
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SLIDE 9

2/1/2017 9

Clin Infect Dis 56:1754, 2013

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%) ∆ TMP/SMX-Placebo (95% CI) 2.7% (-9.3% - 15%) Progression to abscess 5/73 (6.8%) 5/73 (6.8%) ∆ TMP/SMX-Placebo (95% CI) 0% (-8.2% - 8.2%) Cure rate, purulent lesions 75% 91% Cure rate, non-purulent lesions 86% 81%

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

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SLIDE 10

2/1/2017 10 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 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 1500 mg once over 30 min 1 day $3000

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SLIDE 11

2/1/2017 11 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 85.5 v 86.0

  • 0.5 (-5.8, 4.9)

Tedizolid (IV) Linezolid 666 88.0 v 87.7 0.3 (-4.8, 5.3) Oritavancin Vancomycin 954 79.6 v 80.0

  • 0.4 (-5.5, 4.7)

Dalbavancin Vancomycin 1312 91.4 v 91.0 0.4 (-2.8, 3.6)

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

Area = 103 cm2 (16.2 in2) Area = 4.52 cm2 (0.71 in2)

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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2/1/2017 12

Case 4

  • 46 yo male diabetic,

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

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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2/1/2017 13

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

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