Bacteriophage‐antibiotic combination therapy for multidrug‐resistant Pseudomonas aeruginosa: In vitro synergy testing

Aims Here, we investigate the impact of phage‐antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug‐resistant (MDR) P. aeruginosa. Methods and Results After screening 10 well‐characterized MDR P. aeruginosa strains against...

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Veröffentlicht in:Journal of applied microbiology Jg. 133; H. 3; S. 1636 - 1649
Hauptverfasser: Holger, Dana J., Lev, Katherine L., Kebriaei, Razieh, Morrisette, Taylor, Shah, Rahi, Alexander, Jose, Lehman, Susan M., Rybak, Michael J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Oxford University Press 01.09.2022
Schlagworte:
Antibiotic resistance
Antibiotics
Bacteria
bacteriophages
Ciprofloxacin
Colistin
Combination therapy
Drug resistance
Host range
In vivo methods and tests
Meropenem
Minimum inhibitory concentration
Multidrug resistant organisms
multiple drug resistance
Parameter identification
Phages
Pharmacodynamics
Pharmacokinetics
Pharmacology
Pseudomonas aeruginosa
Reduction
Strains (organisms)
synergism
therapeutics
ISSN:1364-5072, 1365-2672, 1365-2672
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Zusammenfassung:Aims Here, we investigate the impact of phage‐antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug‐resistant (MDR) P. aeruginosa. Methods and Results After screening 10 well‐characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage‐antibiotic combinations (PAC) against MDR P. aeruginosa, time‐kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage‐meropenem‐colistin and phage‐ciprofloxacin‐colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml−1) and R10266 (4.50 log10 CFU ml−1) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. Conclusions These findings support the potential of phage‐antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. Significance and Impact of Study This study identifies novel bactericidal phage‐antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage‐mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1364-5072
1365-2672
1365-2672
DOI:10.1111/jam.15647