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. 2018 Nov 15;551(1-2):158-165.
doi: 10.1016/j.ijpharm.2018.09.024. Epub 2018 Sep 14.

Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa

Yu Lin  1 , Rachel Yoon Kyung Chang  1 , Warwick J Britton  2 , Sandra Morales  3 , Elizabeth Kutter  4 , Hak-Kim Chan  5
Affiliations

Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa

Yu Lin et al. Int J Pharm. .

Abstract

Nebulization is currently used for delivery of antibiotics for respiratory infections. Bacteriophages (or phages) are effective predators of pathogens including Pseudomonas aeruginosa commonly found in the lungs of patients with cystic fibrosis (CF). It is known that phages and antibiotics can potentially show synergistic antimicrobial effect on bacterial killing. In the present study, we investigated synergistic antimicrobial effect of phage PEV20 with five different antibiotics against three P. aeruginosa strains isolated from sputum of CF patients. The antibiotics included ciprofloxacin, tobramycin, colistin, aztreonam and amikacin, which are approved by U.S Food and Drug Administration (FDA) for inhaled administration. Phage and antibiotic synergy was determined by assessing bacterial killing performing time-kill studies. Among the different phage-antibiotic combinations, PEV20 and ciprofloxacin exhibited the most synergistic effect. Two phage-ciprofloxacin combinations, containing 1/4 and 1/2 of the minimum inhibitory concentration (MIC) of ciprofloxacin against P. aeruginosa strains FADD1-PA001 (A) and JIP865, respectively were aerosolized using both air-jet and vibrating mesh nebulizers and the synergistic antibacterial activity was maintained after nebulization. Air-jet nebulizer generated droplets with smaller volume median diameters (3.6-3.7 µm) and slightly larger span (2.3-2.4) than vibrating mesh nebulizers (5.1-5.3 µm; 2.1-2.2), achieving a higher fine particle fraction (FPF) of 70%. In conclusion, nebulized phage PEV20 and ciprofloxacin combination shows promising antimicrobial and aerosol characteristics for potential treatment of respiratory tract infections caused by drug-resistant P. aeruginosa.

Keywords: Antibiotics; Bacteriophage; Ciprofloxacin; Cystic fibrosis; Inhalation; Nebulizer; Phage therapy; Pseudomonas aeruginosa; Respiratory tract infection.

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Figures

Figure 1.
Figure 1.
Antibacterial activities of phage PEV20 (MOI=0.1) against P. aeruginosa FADD1-PA001 in the presence of 1/4 MIC of ciprofloxacin (CIP), amikacin (AMI), colistin (COL), tobramycin (TOB), and aztreonam (AZT).(n=5)
Figure 2.
Figure 2.
Antibacterial activities of phage PEV20 (MOI=100) against P. aeruginosa JIP865 in the presence of 1/2 MIC of ciprofloxacin (CIP), amikacin (AMI), colistin (COL), tobramycin (TOB), and aztreonam (AZT) (n=5).
Figure 3.
Figure 3.
Antibacterial activities of phage PEV20 (MOI=1000) against P. aeruginosa 20844n/m(s) in the presence of 1/2 MIC of ciprofloxacin (CIP), amikacin (AMI), colistin (COL), tobramycin (TOB), and aztreonam (AZT) (n=5).
Figure 4.
Figure 4.
Antibacterial activities of phage PEV20, ciprofloxacin and their combination against P. aeruginosa FADD1-PA001 (A) and P. aeruginosa JIP865 (B) before and after nebulisation using vibrating mesh nebulizer (n=5).
Figure 5.
Figure 5.
Antibacterial activities of phage PEV20, ciprofloxacin and their combination against strains FADD1-PA001 (A) and JIP865 (B) before and after nebulization using air-jet nebulizer (n=5).
Figure 6.
Figure 6.
FPF of the nebulized phage-ciprofloxacin combinations using the Pari air-jet nebulizer and eFlow vibrating mesh nebulizer (n=3).
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