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Volume 14
Issue 3
10.3390/ph14030184
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Article

Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment

by
Emily Engeman
1,2,
Helen R. Freyberger
1,3,
Brendan W. Corey
4,
Amanda M. Ward
1,3,
Yunxiu He
1,3,
Mikeljon P. Nikolich
1,
Andrey A. Filippov
1,3,*,
Stuart D. Tyner
1 and
Anna C. Jacobs
1,3
1
Center for Infectious Diseases Research, Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
2
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN 37831, USA
3
ICON plc, Ellicott City, MD 21043, USA
4
Multidrug-Resistant Organism Repository and Surveillance Network, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(3), 184; https://doi.org/10.3390/ph14030184
Submission received: 23 January 2021 / Revised: 16 February 2021 / Accepted: 22 February 2021 / Published: 25 February 2021
(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)
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Abstract

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections pose a serious health threat. Bacteriophage–antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage P. aeruginosa cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic activity. Combination treatment in vitro resulted in a significant increase in susceptibility of MDR strains to antibiotics. Treatment with ceftazidime (CAZ), meropenem, gentamicin, or ciprofloxacin in the presence of the phage increased the number of P. aeruginosa strains susceptible to these antibiotics by 63%, 56%, 31%, and 81%, respectively. Additionally, in a mouse dorsal wound model, seven of eight mice treated with a combination of CAZ and PAM2H for three days had no detectable bacteria remaining in their wounds on day 4, while all mice treated with CAZ or PAM2H alone had ~107 colony forming units (CFU) remaining in their wounds. P. aeruginosa recovered from mouse wounds post-treatment showed decreased virulence in a wax worm model, and DNA sequencing indicated that the combination treatment prevented mutations in genes encoding known phage receptors. Treatment with PAM2H in combination with antibiotics resulted in the re-sensitization of P. aeruginosa to antibiotics in vitro and a synergistic reduction in bacterial burden in vivo.
Keywords: Pseudomonas aeruginosa; phage therapy; phage–antibiotic synergy; antimicrobial resistance; re-sensitization Pseudomonas aeruginosa; phage therapy; phage–antibiotic synergy; antimicrobial resistance; re-sensitization

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MDPI and ACS Style

Engeman, E.; Freyberger, H.R.; Corey, B.W.; Ward, A.M.; He, Y.; Nikolich, M.P.; Filippov, A.A.; Tyner, S.D.; Jacobs, A.C. Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment. Pharmaceuticals 2021, 14, 184. https://doi.org/10.3390/ph14030184

AMA Style

Engeman E, Freyberger HR, Corey BW, Ward AM, He Y, Nikolich MP, Filippov AA, Tyner SD, Jacobs AC. Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment. Pharmaceuticals. 2021; 14(3):184. https://doi.org/10.3390/ph14030184

Chicago/Turabian Style

Engeman, Emily, Helen R. Freyberger, Brendan W. Corey, Amanda M. Ward, Yunxiu He, Mikeljon P. Nikolich, Andrey A. Filippov, Stuart D. Tyner, and Anna C. Jacobs. 2021. "Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment" Pharmaceuticals 14, no. 3: 184. https://doi.org/10.3390/ph14030184

APA Style

Engeman, E., Freyberger, H. R., Corey, B. W., Ward, A. M., He, Y., Nikolich, M. P., Filippov, A. A., Tyner, S. D., & Jacobs, A. C. (2021). Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment. Pharmaceuticals, 14(3), 184. https://doi.org/10.3390/ph14030184

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