Exploring synergistic and antagonistic interactions in phage-antibiotic combinations against ESKAPE pathogens.

Autor: Kunz Coyne AJ; Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA., Eshaya M; Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA., Bleick C; Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA., Vader S; Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA., Biswas B; Naval Medical Research Center-Fort Detrick, Frederick, Maryland, USA., Wilson M; Naval Medical Research Center-Fort Detrick, Frederick, Maryland, USA.; Leidos, Reston, Virginia, USA., Deschenes MV; Naval Medical Research Center-Fort Detrick, Frederick, Maryland, USA.; Leidos, Reston, Virginia, USA., Alexander J; Department of Microbiology, Virology and Immunology, AdventHealth Central Florida, Orlando, Florida, USA., Lehman SM; Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA., Rybak MJ; Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.; Division of Infectious Diseases, Department of Medicine, School of Medicine, Wayne State University, Detroit, Michigan, USA.; Department of Pharmacy, Detroit Medical Center, Detroit, Michigan, USA.
Jazyk: angličtina
Zdroj: Microbiology spectrum [Microbiol Spectr] 2024 Oct 03; Vol. 12 (10), pp. e0042724. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1128/spectrum.00427-24
Abstrakt: In the era of antimicrobial resistance, phage-antibiotic combinations offer a promising therapeutic option, yet research on their synergy and antagonism is limited. This study aims to assess these interactions, focusing on protein synthesis inhibitors and cell envelope-active agents against multidrug-resistant bacterial strains. We evaluated synergistic and antagonistic interactions in multidrug-resistant Staphylococcus aureus , Enterococcus faecium , and Pseudomonas aeruginosa strains. Phages were combined with protein synthesis inhibitors [linezolid (LZD), minocycline (MIN), gentamicin (GEN), and azithromycin (AZM)] or cell envelope-active agents [daptomycin (DAP), ceftaroline (CPT), and cefepime (FEP)]. Modified checkerboard minimum inhibitory concentration assays and 24-h time-kill analyses were conducted, alongside one-step growth curves to analyze phage growth kinetics. Statistical comparisons used one-way analysis of variance (ANOVA) and the Tukey test ( P < 0.05). In the checkerboard and 24-h time-kill analyses (TKA) of S. aureus and E. faecium , phage-LZD and phage-MIN combinations were antagonistic (FIC > 4) while phage-DAP and phage-CPT were synergistic (FIC 0.5) (ANOVA range of mean differences 0.52-2.59 log 10 CFU/mL; P < 0.001). For P. aeruginosa , phage-AZM was antagonistic (FIC > 4), phage-GEN was additive (FIC = 1), and phage-FEP was synergistic (ANOVA range of mean differences 1.04-1.95 log 10 CFU/mL; P < 0.001). Phage growth kinetics were altered in the presence of LZD and MIN against S. aureus and in the presence of LZD against a single E. faecium strain (HOU503). Our findings indicate that select protein synthesis inhibitors may induce phage-antibiotic antagonism. However, this antagonism may not solely stem from changes in phage growth kinetics, warranting further investigation into the complex interplay among strains, phage attributes, and antibiotic mechanisms affecting bacterial inhibition.IMPORTANCEIn the face of escalating antimicrobial resistance, combining phages with antibiotics offers a promising avenue for treating infections unresponsive to traditional antibiotics. However, while studies have explored synergistic interactions, less attention has been given to potential antagonism and its impact on phage growth kinetics. This research evaluates the interplay between phages and antibiotics, revealing both synergistic and antagonistic patterns across various bacterial strains and shedding light on the complex dynamics that influence treatment efficacy. Understanding these interactions is crucial for optimizing combination therapies and advancing phage therapy as a viable solution for combating antimicrobial resistance.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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