A pharmacometric model assessing the in vitro synergistic effect of a bacteriophage-polymyxin B combination in a clinical multidrug-resistant K. pneumoniae isolate.

Abstract

Background: Klebsiella pneumoniae represents one of the most critical pathogens globally and bacteriophage (phage) therapy offers a promising alternative for treatment. Phage therapy poses challenges due to its high specificity and fast resistance development in bacteria. One promising option to overcome these challenges is combining phages with conventional antibiotics.

Objective: This study investigates phage kinetics and pharmacodynamic interactions between novel phage pK8 and polymyxin B against a clinical multidrug-resistant K. pneumoniae.

Methods: Time-kill assays with time-dissolved sampling of phages and bacteria were coupled with pharmacometric modelling to describe phage-bacteria kinetics and killing dynamics. Additionally, different interaction models were investigated to assess the observed synergy between phage pK8 and polymyxin B.

Results: Key findings reveal that while polymyxin B alone showed no effect and phage pK8 alone was not efficacious enough to prevent the regrowth of K. pneumoniae II-503, their combined application resulted in notable bactericidal effects up to complete eradication. This was particularly notable in scenarios with higher phage doses. The developed pharmacokinetic/pharmacodynamic model describes synergy as bacterial resensitization to polymyxin B when combined with phage pK8.

Conclusions: The study shows that phage pK8 and polymyxin B combination effectively combats a clinical polymyxin-resistant K. pneumoniae strain. These promising results pave the way for further in vivo studies to validate and refine treatment strategies for tackling multidrug-resistant infections.