Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.
J Antimicrob Chemother
; 79(5): 1069-1080, 2024 May 02.
Article
en En
| MEDLINE
| ID: mdl-38526879
ABSTRACT
OBJECTIVES:
The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics.METHODS:
To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC.RESULTS:
The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations.CONCLUSIONS:
Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Bacterianas
/
Beta-Lactamasas
/
Infecciones por Klebsiella
/
Pruebas de Sensibilidad Microbiana
/
Ceftazidima
/
Modelos Animales de Enfermedad
/
Combinación de Medicamentos
/
Sinergismo Farmacológico
/
Compuestos de Azabiciclo
/
Meropenem
Límite:
Animals
Idioma:
En
Año:
2024
Tipo del documento:
Article