Dataset Information

In Vitro Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

ABSTRACT: Gepotidacin (formerly GSK2140944) is a first-in-class triazaacenaphthylene antibacterial currently in phase III clinical trials. When tested against Gram-negative (n = 333) and Gram-positive (n = 225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates at concentrations of 4 and 2 μg/mL, respectively. Given gepotidacin's in vitro activity against the anaerobic isolates tested, further study is warranted to better understand the utility of gepotidacin in the treatment of infections caused by clinically relevant anaerobic organisms.

SUBMITTER: Hackel MA

PROVIDER: S-EPMC8846401 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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In Vitro Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

Hackel Meredith A MA Karlowsky James A JA Canino Michele A MA Sahm Daniel F DF Scangarella-Oman Nicole E NE

Antimicrobial agents and chemotherapy 20211220 2

Gepotidacin (formerly GSK2140944) is a first-in-class triazaacenaphthylene antibacterial currently in phase III clinical trials. When tested against Gram-negative (n = 333) and Gram-positive (n = 225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates at concentrations of 4 and 2 μg/mL, respectively. Given gepotidacin's in vitro activity against the anaerobic isolates tested, further study is warranted to better understand the utility of gepotidacin in the tre ...[more]

PMID: 34930028

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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

In Vitro Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

Publications

<i>In Vitro</i> Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

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