Nicole Scangarella-Oman

In vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, Against a Broad Spectrum of Bacterial Pathogens

ABSTRACT Gepotidacin inhibits bacterial DNA replication through a mode different from that of fluoroquinolones. Gepotidacin and comparators were tested by broth and agar dilution against clinical isolates. The in vitro activities of gepotidacin were comparable against methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) isolates (MIC90, 0.5 μg/ml). The gepotidacin MIC90s were as follows (in micrograms per milliliter) for the indicated bacteria: Streptococcus pyogenes, 0.25; Escherichia coli, 2; Moraxella catarrhalis, ≤0.06; Streptococcus pneumoniae (0.25), Haemophilus influenzae, 1; Clostridium perfringens, 0.5; and Shigella spp., 1, including levofloxacin-resistant subsets. Gepotidacin warrants further investigation for clinical development.

Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

ABSTRACT GSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coli isolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coli isolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.)

Microbiological profile of a new topical antibacterial: retapamulin ointment 1%

Retapamulin is a new topical pleuromutilin antibiotic for the treatment of skin and skin-structure infections, including impetigo. In vitro studies indicate that retapamulin has a unique mode of action that minimizes the potential for target-specific cross-resistance with other antibacterials and a limited potential for resistance development. Its spectrum of activity includes the most likely causative pathogens Staphylococcus aureus and Streptococcus pyogenes. In the Global Surveillance Program, retapamulin was highly active in vitro, including against strains of S. aureus resistant to methicillin, mupirocin or fusidic acid. In clinical studies, retapamulin was noninferior to fusidic acid and oral cefalexin, achieving per-pathogen success rates of 86–99%. Topical retapamulin has a good safety profile and is associated with high patient compliance.

Determination of Disk Diffusion and MIC Quality Control Guidelines for GSK2140944, a Novel Bacterial Type II Topoisomerase Inhibitor Antimicrobial Agent

ABSTRACT GSK2140944 is a novel bacterial type II topoisomerase inhibitor in development for the treatment of conventional and biothreat pathogens, including Gram-positive pathogens and methicillin-resistant Staphylococcus aureus. This quality control study was performed to establish ranges for selected control strains: S. aureus ATCC 29213 and ATCC 25923, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, and Streptococcus pneumoniae ATCC 49619. The control ranges will be crucial for the accurate evaluation of GSK2140944 potency as it progresses through clinical trial development.

Determination of Disk Diffusion and MIC Quality Control Ranges for GSK1322322, a Novel Peptide Deformylase Inhibitor

ABSTRACT GSK1322322 is a novel peptide deformylase inhibitor in the early phase of development for treatment of complicated bacterial skin and skin structure infection and hospitalized community-acquired pneumonia. This quality control (QC) study was performed to establish broth microdilution and disk diffusion QC ranges for strains Staphylococcus aureus ATCC 29213 (MIC range, 1 to 4 μg/ml), Haemophilus influenzae ATCC 49247 (MIC and disk diffusion zone diameter ranges, 0.5 to 4 μg/ml and 20 to 28 mm, respectively), Streptococcus pneumoniae ATCC 49619 (MIC and disk diffusion zone diameter ranges, 0.12 to 0.5 μg/ml and 23 to 30 mm, respectively), and S. aureus ATCC 25923 (disk diffusion zone diameter range, 18 to 26 mm). These ranges are crucial for evaluating GSK1322322 potency as it progresses through clinical trials.

In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae

ABSTRACT Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated in vitro activity against Neisseria gonorrhoeae, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25 N. gonorrhoeae strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three N. gonorrhoeae strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three N. gonorrhoeae strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two N. gonorrhoeae strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC50 and MIC90 for gepotidacin against the 25 N. gonorrhoeae isolates tested were 0.12 and 0.25 μg/ml, respectively. The MBC50 and MBC90 for gepotidacin were 0.25 and 0.5 μg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by in vitro time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These in vitro data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by N. gonorrhoeae.

Multicenter Investigation of Gepotidacin (GSK2140944) Agar Dilution Quality Control Determinations for Neisseria gonorrhoeae ATCC 49226

ABSTRACT Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae. To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.8% of gepotidacin MIC results at the 0.5 μg/ml mode).

Determination of disk diffusion and MIC quality control guidelines for GSK2251052: a novel boron-containing antibacterial☆

GSK2251052 is a boron-containing antimicrobial agent in clinical development for the treatment of serious Gram-negative bacterial infections. These GSK2251052 quality control (QC) studies were performed to establish ranges for control strains (broth microdilution [BMD] MIC and disk diffusion zones) as follows: Pseudomonas aeruginosa ATCC 27853 (2-8 μg/mL and 15-24 mm), Escherichia coli ATCC 25922 (0.5-2 μg/mL and 23-30 mm), Haemophilus influenzae ATCC 49247 (0.25-1 μg/mL and 22-31 mm), Streptococcus pneumoniae ATCC 49619 (0.25-1 μg/mL and 19-28 mm), Bacteroides fragilis ATCC 25285 (1-4 μg/mL [BMD] and 1-4 μg/mL [agar dilution]), and Bacteroides thetaiotaomicron ATCC 29741 (1-8 μg/mL [BMD] and 2-8 μg/mL [agar dilution]). These ranges, approved by Clinical and Laboratory Standards Institute, will be crucial in accurately evaluating GSK2251052 in vitro potency.

The safety and efficacy of topical retapamulin ointment versus placebo ointment in the treatment of secondarily infected traumatic lesions: a randomized, double-blind superiority study.

OBJECTIVE: To evaluate whether retapamulin 1% is clinically superior to a placebo in the treatment of patients with secondarily infected traumatic lesions. DESIGN: The study was a double-blind, placebo-controlled, parallel-group, phase 3 study. SETTING: Patients were recruited from 5 countries. PATIENTS: The aforementioned patients were all 2 months or older and diagnosed with secondarily infected traumatic lesions. INTERVENTIONS: Study medication was applied twice daily for 5 days. MAIN OUTCOME MEASURES: Primary end point: clinical response (success/failure) at follow-up. Secondary efficacy end points included clinical and microbiological outcomes at end of therapy (on days 7–9); microbiological and therapeutic responses at follow-up. MAIN RESULTS: A total of 508 patients were recruited for the study; 359 patients were included in the primary efficacy analysis population (246 received retapamulin; 113 received the placebo). Secondarily infected abrasions were the most common secondarily infected traumatic lesions present (56.3%), Staphylococcus aureus being the most frequently isolated pathogen at baseline (60.1%); 15.1% infections were methicillin-resistant. At follow-up, patients receiving retapamulin had higher clinical success rates than those receiving the placebo (74.8% vs 66.4%, respectively) in the primary efficacy analysis population; however, the treatment difference was not statistically significant (8.4%; 95% confidence interval, −1.6 to 18.4). The proportion of patients experiencing adverse events, which were typically mild or moderate in severity, was similar between the retapamulin (5.6%, 19/342) and placebo groups (4.8%, 8/165). CONCLUSION: Clinical success rates were higher with retapamulin versus placebo in the treatment of patients with secondarily infected traumatic lesions, but the difference between treatment groups was not significant. Retapamulin was well tolerated.

Topical retapamulin in the management of infected traumatic skin lesions.

Retapamulin is a novel semisynthetic pleuromutilin antibiotic specifically designed for use as a topical agent. The unique mode of action by which retapamulin selectively inhibits bacterial protein synthesis differentiates it from other nonpleuromutilin antibacterial agents that target the ribosome or ribosomal factors, minimizing the potential for target-specific cross-resistance with other antibacterial classes in current use. In vitro studies show that retapamulin has high potency against the Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes, and coagulase-negative staphylococci) commonly found in skin and skin-structure infections (SSSIs), including S. aureus strains with resistance to agents such as macrolides, fusidic acid, or mupirocin, and other less common organisms associated with SSSIs, anaerobes, and common respiratory tract pathogens. Clinical studies have shown that twice-daily topical retapamulin for 5 days is comparable to 10 days of oral cephalexin in the treatment of secondarily infected traumatic lesions. A 1% concentration of retapamulin ointment has been approved for clinical use as an easily applied treatment with a short, convenient dosing regimen for impetigo. Given the novel mode of action, low potential for cross-resistance with established antibacterial agents, and high in vitro potency against many bacterial pathogens commonly recovered from SSSIs, retapamulin is a valuable enhancement over existing therapeutic options.