Dataset Information

Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections.

ABSTRACT: Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind phase (part 1; intravenous [750 mg or 1,000 mg every 12 h {q12h}]) and an open-label phase (part 2; intravenous [750 mg q12h, 1,000 mg q12h, or 1,000 q8h]). The primary endpoint was a composite of efficacy and safety which consisted of the early cure rate and the withdrawal rate due to drug-related adverse events and utilized a clinical utility index for dose selection. At the early efficacy visit (48 to 72 h after the first dose), the 750-mg q12h and 1,000-mg q8h groups met prespecified success criteria for clinical utility in terms of efficacy and safety; however, the 1,000-mg q12h group did not meet these criteria due to observed lower efficacy rates. The most frequently reported adverse events were nausea (20%) and diarrhea (13%). These encouraging phase 2 results demonstrate the potential for gepotidacin to meet the medical need for novel antibacterial agents to treat ABSSSIs due to drug-resistant pathogens through a unique mechanism of action. (This study has been registered at ClinicalTrials.gov under registration no. NCT02045797.).

SUBMITTER: O'Riordan W

PROVIDER: S-EPMC5444153 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections.

O'Riordan William W Tiffany Courtney C Scangarella-Oman Nicole N Perry Caroline C Hossain Mohammad M Ashton Teri T Dumont Etienne E

Antimicrobial agents and chemotherapy 20170524 6

Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has <i>in vitro</i> activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind pha ...[more]

PMID: 28373199

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Project description:Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the MICs and minimum bactericidal concentrations (MBCs) of gepotidacin and comparator agents for Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli Gepotidacin in vitro activity was also evaluated by using time-kill kinetics and broth microdilution checkerboard methods for synergy testing and for postantibiotic and subinhibitory effects. The MIC90 of gepotidacin for 50 S. aureus (including methicillin-resistant S. aureus [MRSA]) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates was 0.5 μg/ml, and for E. coli (n = 25 isolates), it was 4 μg/ml. Gepotidacin was bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, 98, and 88% of the isolates tested, respectively. Time-kill curves indicated that the bactericidal activity of gepotidacin was observed at 4× or 10× MIC at 24 h for all of the isolates. S. aureus regrowth was observed in the presence of gepotidacin, and the resulting gepotidacin MICs were 2- to 128-fold higher than the baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index of >0.5 to ≤4; 82.7% for Gram-positive isolates and 82.6% for Gram-negative isolates). The postantibiotic effect (PAE) of gepotidacin was short when it was tested against S. aureus (≤0.6 h against MRSA and MSSA), and the PAE-sub-MIC effect (SME) was extended (>8 h; three isolates at 0.5× MIC). The PAE of levofloxacin was modest (0.0 to 2.4 h), and the PAE-SME observed varied from 1.2 to >9 h at 0.5× MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME against Gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.

Project description:Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log10 CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (Cmax) to the MIC (Cmax/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r2 = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

Dataset Information

Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections.

Publications

Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections.

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