TABLE 4.
Randomized controlled trials involving skin and soft tissue infectionsa
| Type of SSTI and authors of study, yr (reference) | Population | Study design | No. of patients | Treatment(s) | Outcome | Description |
|---|---|---|---|---|---|---|
| Impetigo | ||||||
| Oranje et al., 2007 (339) | Children and adults with impetigo | Observer-blind RCT | 519 | 1% retapamulin ointment twice daily for 5 days vs 2% sodium fusidate ointment 3 times daily for 7 days | 99.1% and 94.0% clinical efficacy in per-protocol populations | 60.5% were culture positive for S. aureus, of which 3.5% were positive for MRSA |
| Koning et al., 2008 (340) | Children and adults with impetigo | Double-blind RCT | 210 | 1% retapamulin ointment twice daily vs placebo, each for 5 days | Retapamulin was superior to placebo in clinical success at 7 days (86% vs 52%) and 14 days (76% vs 39%) | 69.5% were culture positive for S. aureus |
| Bowen et al., 2014 (316) | Children with impetigo | Investigator-blind RCT | 508 | Benzathine penicillin i.m. in a single dose vs TMP-SMX twice daily for 3 days or daily for 5 days | TMP-SMX was noninferior to penicillin in mITT (84.7% vs 85.3%) or evaluable populations when assessed for improvement or cure at day 7 | 81% were culture positive for S. aureus, and 90% were culture positive for S. pyogenes; 13.3% of S. aureus isolates were MRSA |
| Uncomplicated SSTI | ||||||
| Tack et al., 1997 (341) | Children with uncomplicated SSTI, mostly impetigo (57%), infected dermatitis (9%), wound infection (8%), and cellulitis (7%) | Investigator-blind RCT | 394 | 7 mg/kg cefdinir twice daily vs 10 mg/kg cephalexin 4 times daily, each for 10 days | No difference; high cure rate in both arms (98.3% vs 93.8%) in microbiologically evaluable population | 72.1% were culture positive for S. aureus |
| Bucko et al., 2002 (342) | Adults and children at least 12 yr of age with uncomplicated SSTI | Double-blind RCT | 1,685 | 200 mg or 400 mg cefditoren vs either 250 mg cefuroxime or 500 mg cefadroxil, each given twice daily for 10 days | Similar clinical cure rates at TOC visit (85%, 83%, 88%, and 85%, respectively) | 31.1% were culture positive for S. aureus, of which 8% were positive for MRSA |
| Giordano et al., 2006 (343) | Adults and children at least 13 yr of age with uncomplicated SSTI | Investigator-blind RCT | 391 | 300 mg cefdinir twice daily vs 250 mg cephalexin 4 times daily, each for 10 days | No difference in clinical cure rate at TOC visit in ITT (83% vs 82%) or CE (89% vs 89%) populations; no difference between MRSA and MSSA subgroups was found | 38.6% were culture positive for S. aureus, of which 52.3% were positive for MRSA |
| Rajendran et al., 2007 (344) | Adults with uncomplicated skin abscess who underwent drainage procedure | Double-blind RCT | 166 | 500 mg cephalexin 4 times daily vs placebo, each for 7 days | No difference; high cure rates in both arms (84.1% vs 90.5%) | 70.4% were culture positive for S. aureus, of which 87.8% were positive for MRSA |
| Duong et al., 2010 (345) | Children with uncomplicated skin abscess who underwent drainage procedure | Double-blind RCT | 161 | TMP-SMX (10–12 mg trimethoprim/kg/day divided into 2 doses, with a maximum dose of 160 mg trimethoprim/dose) vs placebo, each for 7–10 days | No difference; high success rates in both arms (94.7% vs 95.9%); more new lesions at 10 days in placebo-treated group (26% vs 13%) but not at 3 mo | 88.2% were culture positive for S. aureus, of which 90.8% were positive for MRSA |
| Schmitz et al., 2010 (346) | Adults with uncomplicated skin abscess who underwent drainage procedure | Double-blind RCT | 212 | 2 tablets of 160/800 mg TMP-SMX twice daily vs placebo, each for 7 days | Nonsignificant difference in treatment failure (17% vs 26%), higher incidence of subsequent new lesions within 30 days in placebo group (28% vs 9%) | 62.3% were culture positive for S. aureus, of which 73.5% were positive for MRSA |
| Pallin et al., 2013 (347) | Adults and children with cellulitis without abscess | Double-blind RCT | 146 | TMP-SMX vs placebo, each in addition to cephalexin, for 7–14 days | No difference in 30-day cure rates (62% vs 60%) | |
| Miller et al., 2015 (369) | Adults and children with uncomplicated cellulitis or skin abscess | Double-blind RCT | 524 | Clindamycin vs TMP-SMX, each for 10 days | No difference in cure rates at 14 days in ITT population (80.3% vs 77.7%) or evaluable population | Among suppurative lesions, S. aureus was found in 218 (42%), 178 (82%) of which were MRSA isolates; there was 14% clindamycin resistance and 0% TMP-SMX resistance among S. aureus isolates |
| Complicated SSTI and ABSSSIc | ||||||
| Stevens et al., 2000 (348) | Adults with cSSTI suspected to be due to a Gram-positive organism | Double-blind RCT | 819 | 600 mg linezolid i.v. every 12 h vs 2 g oxacillin i.v. every 6 h, each for 10–21 days (mean, 13.4 days), with transition to oral linezolid or dicloxacillin, respectively, when clinically improving | Similar cure rates in ITT population (69.8% vs 64.9%), CE population (88.6% vs 85.8%), and ME population (88.1% vs 86.1%) | 23.9% were culture positive for S. aureus |
| Arbeit et al., 2004 (349) | Adults with cSSTI due to Gram-positive organism and requiring hospitalization and i.v. therapy for ≥4 days | Pooled analysis of 2 evaluator-blind RCTs | 1,082 | 4 mg/kg/day daptomycin vs vancomycin or a penicillinase-resistant penicillin (cloxacillin, nafcillin, oxacillin, or flucloxacillin), each for 7–14 days | No difference in clinical success in ITT population (71.5% vs 71.1%) | S. aureus was cultured in samples from 58.0% of patients, of which 13.9% were positive for MRSA |
| Weigelt et al., 2005 (350) | Adults with cSSTI requiring hospitalization. | Open-label RCT | 1,180 | Linezolid vs vancomycin, each for a goal of 7–14 days (minimum, 4 days; maximum, 21 days) | No difference in clinical response in ITT population (92.2% vs 88.5%); linezolid was superior (71% vs 55%) in the subgroup with MRSA | 71% culture positive for S. aureus, of which 59% were positive for MRSA |
| Ellis-Grosse et al., 2005 (351)b | Adults with cSSTI | Pooled analysis of 2 double-blind RCTs | 1,116 | Tigecycline vs vancomycin-aztreonam, each for up to 14 days | No significant difference in cure rates in clinically evaluable populations (86.5% vs 88.6%) at TOC visit | 28.6% were culture positive for S. aureus, of which 20.4% were positive for MRSA |
| Breedt et al., 2005 (352)b | Adults with cSSTI | Double-blind RCT | 546 | Tigecycline vs vancomycin-aztreonam, each for up to 14 days | Tigecycline was noninferior in clinical response in the clinically evaluable mITT population | 24.2% were culture positive for S. aureus, of which 9.1% were positive for MRSA |
| Sacchidanand et al., 2005 (353)b | Adults with known or suspected cSSSI who required ≥5 days of i.v. antibiotics | Double-blind RCT | 573 | Tigecycline vs vancomycin-aztreonam, each for up to 14 days | Tigecycline was noninferior in clinical response in the CE population (82.9% vs 82.3%) at TOC visit | 20.0% were culture positive for S. aureus, of which 36.5% were positive for MRSA |
| Jauregui et al., 2005 (354) | Adults with cSSSI suspected or confirmed to harbor a Gram-positive pathogen | Double-blind RCT | 854 | 2:1 distribution of dalbavancin at 1,000 mg on day 1 and 500 mg on day 8 vs 600 mg linezolid every 12 h, each for 14 days (with each dalbavancin dose defined as 7 days of therapy) | Dalbavancin was noninferior in clinical success at TOC visit (88.9% vs 91.2%) | 57.6% were culture positive for S. aureus, of which 56.5% were positive for MRSA |
| Noel et al., 2008 (361) | Adults with cSSSI | Double-blind RCT | 828 | Ceftobiprole vs vancomycin-ceftazidime, each for 7–14 days | Ceftobiprole was noninferior in cure rate in clinically evaluable (90.5% vs 90.2%) or ITT populations at 7- to 14-day TOC visit | 45.4% were culture positive for S. aureus, of which 33% were positive for MRSA |
| Noel et al., 2008 (355) | Adults with cSSSI | Double-blind RCT | 784 | Ceftobiprole vs vancomycin, each for 7–14 days | Ceftobiprole was noninferior in cure rate in clinically evaluable (93.3% vs 93.5%) or ITT populations at 7- to 14-day TOC visit | 60.9% were culture positive for S. aureus, of which 37.1% were positive for MRSA |
| Stryjewski et al., 2008 (356) | Adults with cSSSI | Pooled analysis of 2 double-blind RCTs (ATLAS 1 and 2) | 1,867 | Telavancin vs vancomycin, each for 7–14 days | Telavancin was noninferior in cure among the clinically evaluable population (88.3% vs 87.1%) at 7- to 14-day TOC visit | 61.2% were culture positive for S. aureus, of which 62.7% were positive for MRSA |
| Krievins et al., 2009 (357) | Adults with cSSTI | Double-blind RCT | 92 | 0.8 or 1.6 mg/kg iclaprim vs 1 g vancomycin, each given twice daily for 10 days | No difference in clinical cure rates at TOC visit (92.9% for lower-dose iclaprim, 90.3% for higher-dose iclaprim, and 92.9% for vancomycin) | 57% were culture positive for S. aureus, of which 10% were positive for MRSA |
| ASSIST 1 and 2 (828) | Adults with cSSSI | Pooled results of 2 investigator-blind RCTs (ASSIST 1 and 2) | 991 | 0.8 mg/kg iclaprim i.v. twice daily vs 600 mg linezolid i.v. twice daily, each for 10–14 days | Iclaprim did not meet prespecified noninferiority criteria for clinical cure rate at TOC visit in ITT and PP populations | 59.6% were culture positive for S. aureus, of which 39.4% were positive for MRSA |
| Craft et al., 2011 (358) | Adults with ABSSSI suspected or proven to be caused by a Gram-positive organism | Double-blind RCT | 198 | 600 mg fusidic acid p.o. twice daily (n = 43), fusidic acid at 1,500 mg twice daily for 2 loading doses and then 600 mg twice daily (n = 78), or 600 mg linezolid p.o. twice daily (n = 77); study outcomes were reported only for the “loading-dose” and linezolid groups | Similar clinical success rates between fusidic acid loading-dose and linezolid groups, among ITT (86% vs 95%), mITT (88% vs 93%), CE (92% vs 99%), and ME (96% vs 98%) populations | 71.6% were culture positive for S. aureus, of which 70.3% were positive for MRSA |
| Friedland et al., 2012 (359) | Adults with cSSSI | Pooled analysis of 2 double-blind RCTs (CANVAS 1 and 2) | 1,378 | Ceftaroline vs vancomycin-aztreonam, each for 5–14 days | Ceftaroline was noninferior in cure rates in clinically evaluable (91.6% vs 92.7%) and mITT (85.9% vs 85.5%) populations | 53.3% were culture positive for S. aureus, of which 36.9% were positive for MRSA |
| Prokocimer et al., 2013 (360) | Adults with ABSSSI | Double-blind RCT | 667 | 200 mg tedizolid daily for 6 days vs 600 mg linezolid twice daily for 10 days | Tedizolid was noninferior in early clinical response (79.5% vs 79.4%); results at the end of treatment and 1–2 wk posttherapy were also similar | 51.9% were culture positive for S. aureus, of which 51.4% were positive for MRSA |
| Moran et al., 2014 (373) | Patients aged ≥12 yr with ABSSSI | Double-blind RCT | 666 | 200 mg tedizolid i.v. daily for 6 days vs 600 mg linezolid i.v. twice daily for 10 days, with optional oral step-down therapy | Tedizolid was noninferior in early clinical response (85% vs 83%) | 48.8% were culture positive for S. aureus, of which 33.5% were positive for MRSA |
| Corey et al., 2014 (374) | Adults with suspected or proven ABSSSI requiring at least 7 days of i.v. therapy | Double-blind RCT | 954 | 1,200 mg oritavancin i.v. in a single dose vs vancomycin twice daily for 7–10 days | Oritavancin was noninferior in the mITT population (82.3% vs 78.9%) in a composite outcome of (i) cessation of spreading or reduction in lesion size, (ii) absence of fever, and (iii) no rescue antibiotic | 60.8% were culture positive, of which 73.8% were positive for S. aureus (47.7% MRSA, 52.3% MSSA) |
| Boucher et al., 2014 (372) | Adults with ABSSSI requiring at least 3 days of i.v. therapy | Pooled analysis of 2 double-blind RCTs (DISCOVER I and II) | 1,312 | Dalbavancin i.v. on days 1 and 8 vs vancomycin for at least 3 days +/− linezolid to complete 10–14 days of therapy | Dalbavancin was noninferior in early clinical response (79.7% vs 79.8%) | 50.8% were culture positive, of which 77.0% were positive for S. aureus (30.6% MRSA, 69.4% MSSA) |
a
SSTI, skin and soft tissue infection; cSSTI, complicated skin and soft tissue infection; ABSSSI, acute bacterial skin and skin structure infection; cSSSI, complicated skin and skin structure infection; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; TMP-SMX, trimethoprim-sulfamethoxazole; i.m., intramuscular; RCT, randomized controlled trial; ITT, intention to treat; mITT, modified intention to treat; TOC, test of cure; CE, clinically evaluable; ME, microbiologically evaluable; p.o., orally; PP, per protocol.
b
Note that tigecycline has subsequently received an FDA black box warning for an increased risk of death compared to other antibacterial drugs.
c
The FDA has released periodic guidance on clinical trial design for drug development for skin and skin structure infections. The studies enrolling patients with “cSSTI” were performed in accordance with the initial 1998 version of this guidance. This FDA guidance was updated in 2010 and included the newer designation ABSSSI. The oritavancin and dalbavancin trials were performed in accordance with this version of the guidelines. For a comparison of these guidelines, see reference 376. The guideline was updated again in October 2013 (375).