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1.
Antimicrob Agents Chemother ; 68(3): e0149723, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38358266

RESUMO

Bacillus anthracis is a Gram-positive Centers for Disease Control and Prevention category "A" biothreat pathogen. Without early treatment, inhalation of anthrax spores with progression to inhalational anthrax disease is associated with high fatality rates. Gepotidacin is a novel first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is being evaluated for use against biothreat and conventional pathogens. Gepotidacin selectively inhibits bacterial DNA replication via a unique binding mode and has in vitro activity against a collection of B. anthracis isolates including antibacterial-resistant strains, with the MIC90 ranging from 0.5 to 1 µg/mL. In vivo activity of gepotidacin was also evaluated in the New Zealand White rabbit model of inhalational anthrax. The primary endpoint was survival, with survival duration and bacterial clearance as secondary endpoints. The trigger for treatment was the presence of anthrax protective antigen in serum. New Zealand White rabbits were dosed intravenously for 5 days with saline or gepotidacin at 114 mg/kg/d to simulate a dosing regimen of 1,000 mg intravenous (i.v.) three times a day (TID) in humans. Gepotidacin provided a survival benefit compared to saline control, with 91% survival (P-value: 0.0001). All control animals succumbed to anthrax and were found to be blood- and organ culture-positive for B. anthracis. The novel mode of action, in vitro microbiology, preclinical safety, and animal model efficacy data, which were generated in line with Food and Drug Administration Animal Rule, support gepotidacin as a potential treatment for anthrax in an emergency biothreat situation.


Assuntos
Acenaftenos , Vacinas contra Antraz , Antraz , Bacillus anthracis , Compostos Heterocíclicos com 3 Anéis , Infecções Respiratórias , Coelhos , Humanos , Animais , Antraz/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Vacinas contra Antraz/uso terapêutico
2.
Infect Dis Ther ; 12(9): 2307-2320, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37751016

RESUMO

INTRODUCTION: Gonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class, bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea. METHODS: This phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12 years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000 mg 10-12 h apart) or ceftriaxone (500 mg, intramuscular) plus azithromycin (1 g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit. PLANNED OUTCOMES: This trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04010539.

3.
Antimicrob Agents Chemother ; 67(5): e0138122, 2023 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-37097147

RESUMO

Francisella tularensis (F. tularensis) is a Centers for Disease Control (CDC) category "A" Gram-negative biothreat pathogen. Inhalation of F. tularensis can cause pneumonia and respiratory failure and is associated with high mortality rates without early treatment. Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action. Gepotidacin selectively inhibits bacterial DNA replication via a unique binding mode, has activity against multidrug-resistant target pathogens, and has demonstrated in vitro activity against diverse collections of F. tularensis isolates (MIC90 of 0.5 to 1 µg/mL). Gepotidacin was evaluated in the cynomolgus macaque model of inhalational tularemia, using the SCHU S4 strain, with treatment initiated after exposure and sustained fever. Macaques were dosed via intravenous (i.v.) infusion with saline or gepotidacin at 72 mg/kg/day to support a human i.v. infusion dosing regimen of 1,000 mg three times daily. The primary study endpoint was survival, with survival duration and bacterial clearance as secondary endpoints. Gepotidacin treatment resulted in 100% survival compared to 12.5% in the saline-treated control group (P < 0.0001) at Day 43 postinhalational challenge. All gepotidacin-treated animals were blood and organ culture negative for F. tularensis at the end of the study. In contrast, none of the saline control animals were blood and organ culture negative. Gepotoidacin's novel mechanism of action and the efficacy data reported here (aligned with the Food and Drug Administration Animal Rule) support gepotidacin as a potential treatment for pneumonic tularemia in an emergency biothreat situation.


Assuntos
Francisella tularensis , Tularemia , Animais , Humanos , Tularemia/microbiologia , Modelos Animais de Doenças , Macaca fascicularis , Vacinas Bacterianas
4.
Sci Transl Med ; 14(647): eabg1787, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35648812

RESUMO

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode and has the potential to treat a number of bacterial diseases. Development of this new agent to treat pneumonic plague caused by Yersinia pestis depends on the U.S. Food and Drug Administration Animal Rule testing pathway, as testing in humans is not feasible. Here, preclinical studies were conducted in the African green monkey (AGM) inhalational model of pneumonic plague to test the efficacy of gepotidacin. AGMs infected with Y. pestis were dosed intravenously with gepotidacin (48, 36, or 28 milligrams/kilogram per day) for 10 days to provide a plasma concentration that would support a rationale for a 1000 mg twice or thrice daily intravenous dose in humans or saline as a control. The primary end point was AGM survival with predefined euthanasia criteria. Secondary end points included survival duration and bacterial clearance. Gepotidacin showed activity in vitro against diverse Y. pestis isolates including antibiotic-resistant strains. All control animals in the inhalational plague studies succumbed to plague and were blood culture and organ culture positive for Y. pestis. Gepotidacin provided a 75 to 100% survival benefit with all dose regimens. All surviving animals were blood culture and organ culture negative for Y. pestis. Our randomized, controlled efficacy trials in the AGM pneumonic plague nonhuman primate model together with the in vitro Y. pestis susceptibility data support the use of gepotidacin as a treatment for pneumonic plague caused by Y. pestis.


Assuntos
Peste , Yersinia pestis , Acenaftenos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Chlorocebus aethiops , Compostos Heterocíclicos com 3 Anéis , Peste/tratamento farmacológico , Primatas , Estados Unidos , Yersinia pestis/genética
5.
Antimicrob Agents Chemother ; 59(1): 289-98, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25348524

RESUMO

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.).


Assuntos
Compostos de Boro/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Leucina-tRNA Ligase/antagonistas & inibidores , Infecções Urinárias/tratamento farmacológico , Antibacterianos/farmacologia , Anti-Infecciosos Urinários/farmacologia , Compostos de Boro/uso terapêutico , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Escherichia coli/patogenicidade , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Genoma Bacteriano , Humanos , Mutação , Filogenia , Infecções Urinárias/microbiologia
6.
Int J Infect Dis ; 8(6): 362-73, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15494258

RESUMO

OBJECTIVES: A new, pharmacokinetically enhanced, oral formulation of amoxicillin/clavulanic acid has been developed to overcome resistance in the major bacterial respiratory pathogen Streptococcus pneumoniae, while maintaining excellent activity against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase producing strains. This study was conducted to provide in vitro susceptibility data for amoxicillin/clavulanic acid and 16 comparator agents against the key respiratory tract pathogens. METHODS: Susceptibility testing was performed on 9172 isolates collected from 95 centers in North America, Europe, Australia, and Hong Kong by broth microdilution MIC determination, according to NCCLS methods, using amoxicillin/clavulanic acid and 16 comparator antimicrobial agents. Results were interpreted according to NCCLS breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints based on oral dosing regimens. RESULTS: Overall, 93.5% of Streptococcus pneumoniae isolates were susceptible to amoxicillin/clavulanic acid at the current susceptible breakpoint of < or =2 microg/mL and 97.3% at the PK/PD susceptible breakpoint of < or =4 microg/mL for the extended release formulation. Proportions of isolates that were penicillin intermediate and resistant were 13% and 16.5%, respectively, while 25% were macrolide resistant and 21.8% trimethoprim/sulfamethoxazole resistant. 21.9% of Haemophilus influenzae were beta-lactamase producers and 16.8% trimethoprim/sulfamethoxazole resistant, >99% of isolates were susceptible to amoxicillin/clavulanic acid, cefixime, ciprofloxacin and levofloxacin at NCCLS breakpoints. The most active agents against Moraxella catarrhalis were amoxicillin/clavulanic acid, macrolides, cefixime, fluoroquinolones, and doxycycline. Overall, 13% of Streptococcus pyogenes were resistant to macrolides. CONCLUSION: The extended release formulation of amoxicillin/clavulanic acid has potential for empiric use against many respiratory tract infections worldwide due to its activity against species resistant to many agents currently in use.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Moraxella catarrhalis/efeitos dos fármacos , Vigilância da População , Infecções Respiratórias/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Administração Oral , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Austrália , Farmacorresistência Bacteriana , Europa (Continente) , Haemophilus influenzae/isolamento & purificação , Hong Kong , Humanos , Testes de Sensibilidade Microbiana , Moraxella catarrhalis/isolamento & purificação , América do Norte , Streptococcus pneumoniae/isolamento & purificação
7.
Int J Antimicrob Agents ; 24(2): 144-9, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15288313

RESUMO

The purpose of this study was to determine effect of repeated exposure to sub-inhibitory concentrations of amoxicillin/clavulanic acid on the development of resistance in Streptococcus pneumoniae. Other agents, azithromycin, cefaclor and levofloxacin, were also tested. Twenty S. pneumoniae were passaged for 9 days in the presence of sub-inhibitory concentrations of each antimicrobial agent and MICs determined by NCCLS macro-dilution method. There was a four-fold increase in amoxicillin/clavulanic acid MICs for 2 of 20 isolates. Three of 9 tested against cefaclor, 11 of 13 tested against azithromycin and 9 of 20 tested against levofloxacin showed > or =4-fold increase. Amoxicillin/clavulanic acid was the most stable of the agents tested. Cefaclor MICs were also fairly stable. Azithromycin and levofloxacin MICs were most affected.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Azitromicina/farmacologia , Cefaclor/farmacologia , Farmacorresistência Bacteriana Múltipla , Levofloxacino , Ofloxacino/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Meios de Cultura , Quimioterapia Combinada , Humanos , Testes de Sensibilidade Microbiana , Streptococcus pneumoniae/crescimento & desenvolvimento
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