Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model.
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ABSTRACT:
SUBMITTER: Kang AD
PROVIDER: S-EPMC5913965 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model.
Kang Anthony D AD Smith Kenneth P KP Berg Anders H AH Truelson Katherine A KA Eliopoulos George M GM McCoy Christopher C Kirby James E JE
Antimicrobial agents and chemotherapy 20180327 4
Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against <i>Acinetobacter baumannii</i> In a neutropenic murine thigh infection model, treatment-associated <i>A. baumannii</i> CFU reductions of >4 log<sub>10</sub> per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum (<i>C</i><sub>max</sub>)/MIC was ≈10 or higher. Based on these findings, we suggest that apramycin deserves further preclinica ...[more]
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Project description:Acinetobacter baumannii is a priority bacterial pathogen and leading cause of nosocomial infections, particularly in intensive care units (ICUs). The average incidence of carbapenem-resistant A. baumannii infections in ICUs is 41.7 cases/1,000 patients, highlighting the urgent need for more effective alternative therapies to replace carbapenems. Thus, this study aimed to investigate for the first time the antibacterial activity of curcumin in combination with the novel phage vB_AbaSI_1 to combat multidrug-resistant (MDR) A. baumannii in vitro. Phage vB_AbaSI_1 (capsid diameter 91 nm, contractile tail 94/20 nm) was isolated from sewage and infects ~ 29% of the 131 bacterial isolates examined. The 52,783 kb phage genome has 75 ORFs, encodes an integrase, lacks tRNAs/virulence genes, and belongs to the Caudoviricetes. Commercially sourced curcumin (400 µg/mL), combined with phage vB_AbaSI_1 (MOI 100) reduced MDR A. baumannii 131 to undetectable levels 1 h post-treatment at 37 °C, and this efficacy was further extended for 5 h in double-dosed phage/curcumin-treated cultures. In contrast, treatment with just phage vB_AbaSI_1 reduced bacterial growth but rebounded within 3 h, while curcumin-only treated cultures showed only 1-log bacterial reduction compared to untreated control. The phage/curcumin synergy occurred exclusively with phage-susceptible strains pre-curcumin exposure. This suggests the potential disruption of bacterial cell membrane during phage infection allowing curcumin entry, as no synergy was observed with phage-resistant strains. This innovative strategy of combining phage and curcumin showed great efficacy at controlling MDR A. baumannii and has a potential for therapeutic deployment. Future work will focus on engineering the phage to make it therapeutically acceptable.
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