Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa

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.

Quantitative Models of Phage-Antibiotic Combination Therapy

“…For example, one of our main results states that phage-antibiotic combined therapy has a greater antimicrobial effect than single-phage or antibiotic therapies; this is consistent with several in vitro settings that show a greater bacterial density reduction for combined rather than single therapies (25)(26)(27)(28). Moreover, additional studies explore the use of sublethal concentrations of antibiotics otherwise insufficient for controlling bacterial growth but efficient when combined with phage against diverse bacterial populations (25,26,28,29). These findings are consistent with our in silico outcomes where pathogen clearance is observed at sub-MIC antibiotic levels in the combined therapy framework.…”

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

“…Similarly, recent biofilm PAS studies noted that sequentially treating cells with phage and ciprofloxacin (noted synergism) instead of a simultaneous application (noted antagonism), may have allowed phage replication to occur first before ciprofloxacin's interruption (23,38). These results raise the possibility that the type of interactions in each phage-antibiotic combination is heavily dictated by the primary target of the antibiotic and the cellular processes required for phage replication (34,39,40). Lastly, since protein synthesis inhibitors most likely would interfere with phage production, the dominant synergistic effects seen in kanamycin was unexpected.…”

Investigation of different interactions between Staphylococcus aureus phages and pomegranate peel, grape seed, and black cumin extracts

“…In the last few years, studies involving the interaction of bacteriophages with various components have been frequently found in the literature. The majority of these studies are based on phage-antibiotic synergism and the elimination of biofilms (Chaudhry et al, 2017;Nouraldin et al, 2016) or bacteria such as Acinetobacter baumannii (Jansen et al, 2018), Money, 2017), Pseudomonas aeruginosa (Lin et al, 2018;Uchiyama et al, 2018), S. aureus (Jo, Kim, Ding, & Ahn, 2016). There are also studies examining the interaction of phages with different agents such as honey (Oliveira et al, 2017) or disinfectants (Agún et al, 2018).…”