PII-021 - VIRAL VANGUARD: TURNING THE TIDE AGAINST SUPERBUGS

T. Nguyen¹, J. Sanborn¹, A. Frymoyer², G. Suh³, P. Bollyky^4,5, D. Roach⁶, N. Smith¹; ¹Division of Clinical and Translational Therapeutics, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA, ²Neonatal and Developmental Medicine, Department of Pediatrics, Department of Medicine, Stanford University, Stanford, California, USA, ³Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA, ⁴Department of Infectious Diseases, School of Medicine, Stanford University, Stanford, California, USA, ⁵Department of Microbiology, School of Medicine, Stanford University, Stanford, California, USA, ⁶Department of Biology, San Diego State University, San Diego, California, USA.

Background: Bacteriophages (phages) have re-emerged as a promising therapy for drug-resistant bacteria, however the pharmacokinetics/pharmacodynamics (PK/PD) of phages remain under characterized. The objectives of this study were to (1) quantify the time-course of killing of a clinical KPC-5-producing Pseudomonas aeruginosa (KPC-PA) strain after treatment with mono and dual phage therapy, and (2) use a previously published mechanism-based model to compare infectivity parameters for KPC-PA with the reference P. aeruginosa, PAO1.

Methods: Phages LUZ19, PYO2, and E215 were studied against a clinical KPC-PA strain using the Hollow Fiber Infection Model (HFIM) over 7 d at an initial inoculum of 107 CFU/mL. The system half-life was fixed to 2h to simulate in vivo PK. HFIM regimens included monotherapy bolus (Cmax = 107 PFU/mL) of LUZ19, PYO2, or E215, and combination bolus regimens (LUZ19 + PYO2 or LUZ19 + E215). Bacterial and phage samples were serial diluted, plated on Mueller-Hinton agar, and incubated for 8-24 h at 37°C prior to enumeration. Bacterial and phage data were simultaneously fit to a previously published model of LUZ19, PYO2, and E215 to quantify changes in infectivity parameters compared to the reference bacterial strain, PAO1.

Results: Monotherapy PYO2 resulted in a bacterial log reduction of 6.82 log10CFU/mL with undetectable counts at 4-28h. Similarly, combination therapy LUZ19 + PYO2 resulted in a bacterial log reduction of 6.81 log10CFU/mL with undetectable counts at 12h. In contrast, monotherapy LUZ19 or E215 along with combination LUZ19 + E215 resulted in a bacterial reduction of < 2 log10 CFU/mL. E215 was estimated to have a larger burst size (168 PFU/CFU) and a longer latent period (31.7 min) against the reference isolate compared to PYO2 (73.8 PFU/CFU, 20.4 min) and LUZ19 (83.0 PFU/CFU, 27.9 min). Against the clinical isolate, E215 had a burst size of 160 PFU/CFU and a latent period of 31.5 min, while PYO2 and LUZ19 showed burst sizes of 69 and 77 PFU/CFU, with latent periods of 32.7 and 57.3 min, respectively.

Conclusion: PYO2 as a monotherapy and in combination with LUZ19 exhibited significant bactericidal activity against a clinical KPC-5-producing P. aeruginosa. The HFIM was well suited to characterize phage infection kinetics and can provide significant opportunities to characterize this re-emerging class of antibacterials for human use.