<i>In Vitro</i> Activity of Delafloxacin and Microbiological Response against Fluoroquinolone-Susceptible and Nonsusceptible Staphylococcus aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections

Abstract

Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad-spectrum <i>in vitro</i> activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The <i>in vitro</i> activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible <i>Staphylococcus aureus</i> isolates were determined from two global phase 3 studies of delafloxacin versus vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients from 23 countries, predominately the United States but also Europe, South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 1,042 patients from which 685 <i>S. aureus</i> isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, North Liberty, IA). The comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Nonsusceptibility to these antibiotics was determined using CLSI breakpoints. <i>S. aureus</i> isolates were 33.7% levofloxacin nonsusceptible (LVX-NS). The delafloxacin MIC₉₀ values against levofloxacin-nonsusceptible <i>S. aureus</i>, methicillin-resistant <i>S. aureus</i> (MRSA), and methicillin-susceptible <i>S. aureus</i> isolates were all 0.25 μg/ml. Delafloxacin demonstrated high rates of microbiological response against LVX-NS isolates as well as isolates with documented mutations in the quinolone resistance-determining region (QRDR). <i>S. aureus</i> was eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin-treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin-nonsusceptible <i>S. aureus</i> isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). Microbiological response rates of 98.6% were observed with delafloxacin-treated subjects with <i>S. aureus</i> isolates with the S84L mutation in <i>gyrA</i> and the S80Y mutation in <i>parC</i>, the most commonly observed mutations in global phase 3 studies. The data suggest that delafloxacin could be a good option for the treatment of infections caused by <i>S. aureus</i> isolates causing ABSSSI, including MRSA isolates, where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed. (The phase 3 studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT01984684 and NCT01811732.).