bThis open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n ؍ 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a >20% decrease in the area of erythema, and 77.9% of patients had a >20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n ؍ 37 patients with methicillin-resistant S. aureus W idespread overuse of broad-spectrum antibiotics over the past 20 years has been associated with significant rates of antibiotic resistance, with multidrug resistance prevalent among a broad range of bacterial pathogens (1), including Staphylococcus aureus. Many experts have advocated the development of speciestargeted agents which reduce off-target selection pressures on the human microbiome and could potentially decrease such conditions as antibiotic-induced colitis and candidiasis (2). Antiinfectives that specifically target Staphylococcus spp. may be less likely to lead to the development of resistant enterococcal, pneumococcal or other common bacterial pathogens.FabI catalyzes the last step in the essential bacterial fatty acid biosynthetic pathway and is the sole form of enoyl-acyl carrier protein (ACP) reductase present in S. aureus, Staphylococcus epidermidis, and other staphylococci (3, 4, 5, 6). Other enoyl-ACP reductase enzymes are present in many bacterial species, but these are sufficiently different to enable species-specific selectivity (7). AFN-1252, a FabI inhibitor, is the result of a program tasked with finding a new antimicrobial agent specifically active against Staphylococcus spp., including methicillin-resistant S. aureus (MRSA) (8).The objective of the current proof-of-concept study was to investigate the efficacy and safety of orally administered AFN-1252 in patients with acute bacterial skin and skin structure infection (ABSSSI) due to staphylococci. The study design followed recent FDA guidance (9) on the development of drugs for the treatment of ABSSSI. The inclusion criteria were designed to identify patients with a high likelihood of having a proven staphylococcal infection to ensure a high number of microbiologically evaluable patients.
MATERIALS AND METHODSAntibacterial agent. AFN-1252 (free base, AFN-12520000) was formulated as immediate-release (IR) tablets.Study design. This noncontrolled, open-label, phase II trial was designed as a proof-of-concept study to evaluate the s...