Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing klebsiella pneumoniae
Int. j. antimicrob. agents
; 59(4)Apr.2022. graf, tab
Artigo
em Inglês
| CONASS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP
| ID: biblio-1362633
Biblioteca responsável:
BR79.1
ABSTRACT
Abstract Determining the role of the immune response in preventing antimicrobial resistance and optimizing antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae (KPC) is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamics and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B_MIC 0.5-64 mg/L; Fosfomycin MIC 16-128 mg/L) to evaluate the pharmacodynamics of mono- and combination therapies in static time-kill studies. A mechanism based model was used to characterize the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared to monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect which resulted in an increase in fosfomycin's ability to reach its target site. The mechanism based model described the data well across all six strains with R2 values ranging from 0.705 to 0.935. The combination reduced K. pneumoniae-induced IL-6 and IL-8 but not TNF-α expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone, and combinations showed significantly greater reductions compared to monotherapies. Our findings suggest that further research is needed to understand immune-mediated killing to identify a strategy which harnesses the power of the immune response against these hard to treat bacteria in an in vivo system.
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Coleções:
Bases de dados nacionais
/
Brasil
Contexto em Saúde:
Doenças Negligenciadas
Problema de saúde:
Doenças Negligenciadas
/
Zoonoses
Base de dados:
CONASS
/
Sec. Est. Saúde SP
/
SESSP-IDPCPROD
Assunto principal:
Fosfomicina
/
Klebsiella pneumoniae
Tipo de estudo:
Estudo prognóstico
Idioma:
Inglês
Revista:
Int. j. antimicrob. agents
Ano de publicação:
2022
Tipo de documento:
Artigo
Instituição/País de afiliação:
Instituto Dante Pazzanese de Cardiologia/BR
/
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo/US
/
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill/US
/
University of North Carolina at Chapel Hill/US
/
Zavante Therapeutics, Inc/US