New rules for clinical trials of patients with acute bacterial skin and skin-structure infections: do not let the perfect be the enemy of the good.
ABSTRACT Over the past decade, the United States has witnessed an epidemic of acute bacterial skin and skin-structure infections (ABSSSIs) caused primarily by community-acquired methicillin-resistant Staphylococcus aureus. To address this medical need as well as the ongoing threat of increasing resistance, new antibiotics are being developed. Clinical trials involving patients with complicated ABSSSI are being implemented to understand the efficacy and safety of these new antibiotic agents. Because antibiotics clearly have an effect on the resolution of the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies. However, to conduct noninferiority trials a noninferiority margin must be determined on the basis of the effect size of the comparator antibiotic. The lack of modern-day placebo-controlled studies of ABSSSI makes determining effect size/noninferiority margin--and as a result, trial design--challenging. The US Food and Drug Administration (FDA) in collaboration with the Foundation for the National Institutes of Health (FNIH) have been working hard to resolve these issues and develop a new guidance to aid investigators in the conduct of these trials. In this article, we first review the 1998 guidance and its shortcomings. Next, we address the ongoing discussion of the new 2010 guidance as we understand it, along with its perceived strengths and weaknesses. Throughout this process, we wish to emphasize that the continued development of antibiotics is essential. Thus, we hope that as the FDA and FNIH move forward they will strike a balance between "The Perfect" statistical solution and "The Good" practical clinical realities.
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ABSTRACT: Objective: To measure the incidence of treatment failure and associated costs in patients with methicillin-resistant Staphylococcus aureus skin and soft tissue infections (SSTIs). This was a prospective, observational study in 13 primary care clinics. Primary care providers collected clinical data, wound swabs, and 90-day follow-up information. Patients were considered to have "moderate or complicated" SSTIs if they had a lesion ≥5 cm in diameter or diabetes mellitus. Treatment failure was evaluated within 90 days of the initial visit. Cost estimates were obtained from federal sources. Overall, treatment failure occurred in 21% of patients (21 of 98) at a mean additional cost of $1,933.71 per patient. In a subgroup analysis of patients who received incision and drainage, those with moderate or complicated SSTIs had higher rates of treatment failure than those with mild or uncomplicated SSTIs (36% vs. 10%; P=.04). One in 5 patients presenting to a primary care clinic for a methicillin-resistant S. aureus SSTI will likely require additional interventions at an associated cost of almost $2,000 per patient. Baseline risk stratification and new treatment approaches are needed to reduce treatment failures and costs in the primary care setting.The Journal of the American Board of Family Medicine 09/2013; 26(5):508-517. DOI:10.3122/jabfm.2013.05.120247 · 1.85 Impact Factor
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ABSTRACT: JNJ-Q2 is a fluoroquinolone with broad coverage including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind, multicenter, phase II noninferiority study treated 161 patients for 7 to 14 days, testing the efficacy of JNJ-Q2 (250 mg, twice a day [BID]) versus linezolid (600 mg, BID) in patients with acute bacterial skin and skin structure infections (ABSSSI). The prespecified criterion for noninferiority was 15%. Primary intent-to-treat analysis was unable to declare noninferiority, as the risk difference lower bound of the 95% confidence interval between treatments was 19% at 36 to 84 h postrandomization for the composite end point of lesion assessment and temperature. Prespecified clinical cure rates 2 to 14 days after completion of therapy were similar (83.1% for JNJ-Q2 versus 82.1% for linezolid). Post hoc analyses revealed that JNJ-Q2 was statistically noninferior to linezolid (61.4% versus 57.7%, respectively; P = 0.024) based on the 2010 FDA guidance, which defines treatment success as lack of lesion spread and afebrile status within 48 to 72 h postrandomization. Despite evidence of systemic disease, <5% of patients presented with fever, suggesting fever is not a compelling surrogate measure of systemic disease resolution for this indication. Nausea and vomiting were the most common adverse events. Of the patients, 86% (104/121) had S. aureus isolated from the infection site; 63% of these were MRSA. The results suggest JNJ-Q2 shows promise as an effective treatment for ABSSSI, demonstrating (i) efficacy for early clinical response (i.e., lack of spread of lesions and absence of fever at 48 to 72 h), and (ii) cure rates for ABSSSI pathogens (especially MRSA) consistent with the historical literature.Antimicrobial Agents and Chemotherapy 09/2011; 55(12):5790-7. DOI:10.1128/AAC.05044-11 · 4.45 Impact Factor
- Clinical Infectious Diseases 12/2011; 53(12):1308-9; author reply 1309-10. DOI:10.1093/cid/cir741 · 9.42 Impact Factor