In Vitro 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 in vitro activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus 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 S. aureus 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. S. aureus isolates were 33.7% levofloxacin nonsusceptible (LVX-NS). The delafloxacin MIC90 values against levofloxacin-nonsusceptible S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-susceptible S. aureus 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). S. aureus 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 S. aureus 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 S. aureus isolates with the S84L mutation in gyrA and the S80Y mutation in parC, 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 S. aureus 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.)

Efficacy of Delafloxacin versus Moxifloxacin against Bacterial Respiratory Pathogens in Adults with Community-Acquired Bacterial Pneumonia (CABP): Microbiology Results from the Delafloxacin Phase 3 CABP Trial

“…Despite these QRDR mutations, the microbiological outcome was eradicated/presumed eradicated for this isolate. This finding corroborates previously observed data for S. aureus isolates in the delafloxacin ABSSSI trial (5). For H. influenzae, favorable outcomes were prevalent across all MIC values except for a single isolate with an MIC value of 0.5 g/ml.…”

“…Delafloxacin is a novel fluoroquinolone antibiotic that possesses activity against Gram-positive, Gram-negative, and atypical pathogens, including activity against fluoroquinolone-nonsusceptible MRSA isolates (5). It is FDA approved for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) (6).…”

Identification of DNA gyrase Subunit a Mutations Associated with Ciprofloxacin Resistance in Staphylococcus aureus Isolated from Nasal Infection in Kurdistan-Iran

“…point mutations were: Asp73-> Gly, Ser84->Leu, Ilu(silence), Glu88-> Lys, and double mutations were Ser84->Leu and Asp73->Gly, Ser83->Leu and Ser 85-> Pro, Ser84->Leu and Ile(silent), Ser84->Leu and Glu88-> Lys (Wang et al, 1998). In the study of McCurdy gyrA mutations in Staphylococcus aureus 10 point mutations observed that 7 of them were Ser84->Leu and other were Glu88->Lys, S85->P (McCurdy, 2017). In the study of Cheng the results showd 10 point mutation in S84->Leu, four doual mutations in Ser84->Leu with Glu88->Val, one Ser84->Leu with Glu409->Lys, one Ser84->Leu with Ser85->Pro, One Ser 84->Leu with Glu88->Lys (Cheng et al, 2007).…”

New Bugs and New Drugs: Updates in Clinical Microbiology

“…The global emergence and spread of extensively resistant bacteria is a high-priority concern. However, it is encouraging that, in recent years, a number of new anti-infective agents with activity against multidrug-resistant bacteria have been approved for clinical use (69,71,72,78,81,(85)(86)(87)(88)90).…”

“…Delafloxacin (trade name, Baxdela ® ) is a fluoroquinolone antibiotic that has broad-spectrum activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus; gramnegative bacteria; atypical organisms, including Mycoplasma species, Chlamydophila pneumoniae, and Legionella; and anaerobic bacteria (85)(86)(87)(88).…”