RESUMO
The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.
Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Klebsiella pneumoniae/isolamento & purificação , Klebsiella pneumoniae/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Pielonefrite/microbiologia , Infecções Urinárias/microbiologia , beta-Lactamases/metabolismoRESUMO
This study examines the alteration in Staphylococcus aureus gene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN-1252 did not alter virulence mRNA levels in a saeR deletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabH mRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivo was determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC(0-48)]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabH mRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabH and virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria.
