Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections, and in the clinic it is often used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial metabolic activities that can be required by phages. Explicit testing of antibiotic antagonism of phage infection activities, though, is not a common feature of phage therapy studies. Here we use optical density-based ‘lysis-profile’ assays to assess the impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new-virion-production activities of three Pseudomonas aeruginosa phages. Though phages and antibiotics in combination are more potent in killing P. aeruginosa than either acting alone, colistin nevertheless substantially interferes with phage bacteriolytic and virion-production activities even at its minimum inhibitory concentration (1× MIC). Ciprofloxacin, by contrast, has little anti-phage impact at 1× or 3× MIC. We corroborate these results with more traditional measures, particularly colony-forming units, plaque-forming units, and one-step growth experiments. Our results suggest that ciprofloxacin could be useful as a concurrent phage therapy co-treatment especially when phage replication is required for treatment success. Lysis-profile assays also appear to be useful, fast, and high-throughput means of assessing antibiotic antagonism of phage infection activities.
Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections. In the clinic, phage therapy often is used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial activities, such as DNA and protein synthesis, which also are required for phage infection processes. Resulting antagonistic impacts of antibiotics on phages nevertheless are not commonly determined in association with phage therapy studies using standard, planktonic approaches. Here we assess the antagonistic impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new virion production activities of Pseudomonas aeruginosa podovirus PEV2, using a broth culture, optical density-based lysis profile assay. Though phage-antibiotic combinations were more potent in reducing cell viability than phages or antibiotics alone, colistin substantially interfered with phage PEV2 bacteriolytic and virion-production activities at minimum inhibitory concentration (MIC). Ciprofloxacin, by contrast, had no such impact at 1x MIC or 3x MIC. At higher but still clinically relevant concentrations (9x MIC) burst sizes were still significant (~30 phages/infected bacterium). We corroborated these lysis profile results by more traditional measurements (colony forming units, plaque forming units, one-step growth experiments) and two other P. aeruginosa phages. To our knowledge this is the first study in which detailed antibiotic impact on P. aeruginosa phage infection activities has been determined under conditions similar to those used to determine antibiotic MICs and could point especially to ciprofloxacin as a minimally antagonistic phage therapy co-treatment of P. aeruginosa infections.
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