Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

Abstract

A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials. Over the past decade, robust clinical, scientific, and regulatory debate has emerged for initiatives to improve the design, execution, and analysis of antibacterial clinical trials (1-4). New trials for acute bacterial skin and skin structure infections (ABSSSI), previously referred to as complicated skin and skin structure infections (cSSTI), remain important, given the rise in incidence of methicillin-resistant Staphylococcus aureus infections and reports of treatment failure (5-8). Per guidance from the U.S. Food and Drug Administration (FDA), patient eligibility for enrollment in ABSSSI trials should be restricted to those with erysipelas, cellulitis, major cutaneous abscesses, and wound infections having a minimal lesion surface area involvement of 75 cm 2 (9). For trial endpoints, the traditional test-of-cure (TOC) endpoint, with the treatment success defined as total resolution of the infection at 7 to 14 days posttreatment, remains aligned with the European regulatory guidance, yet the treatment success for the primary efficacy endpoint aligned with the FDA guidance is defined as cessation of lesion spread after 48 to 72 h of treatment (9-11). Revisions to the enrollment and endpoint criteria in recent regulatory guidance for ABSSSI trials necessitate reevaluation of the...

Bacterial Motility and Its Role in Skin and Wound Infections

“…Moreover, bacteria that would not be pathogenic with an undamaged skin barrier can penetrate through damaged skin and become virulent. In general, most acute infections are superficial and relatively easy to treat with appropriate antibiotics [ 7 ], whereas chronic infections, in particular chronic wound infections, often pose many difficulties in effective treatment, and in the era of multi-drug resistance, they are a major social and economic problem [ 8 ]. The most common aetiological factors in chronic wounds are Staphylococcus aureus , P. aeruginosa , Acinetobacter baumannii , Proteus mirabilis , Escherichia coli , and Corynebacterium spp.…”