Evaluation of bacteriophage cocktail on urinary tract infection caused by colistin-resistant Klebsiella pneumoniae in mice model

Abstract

• This preclinical study evaluates the efficacy of a bacteriophage cocktail using different routes and dosages (in quantity and frequency) to eradicate the carbapenem-colistin-resistant Klebsiella pneumoniae (KpnBHU09) associated urinary tract infection in mice model. • The bacteriophage cocktail comprising three lytic phages of Autographiviridae family against the KpnBHU09 and evaluated the efficacy and safety of phage cocktail in treating UTI in mice model with different delivery routes. • In this preclinical study, two doses of phage cocktail of 1 × 105 Plaque-Forming Unit/mouse (PFU/mouse) and one dose of 1 × 109 PFU/mouse per urethra could eradicate the KpnBHU09. • The present study suggests that transurethral and gastrointestinal (oral and rectal) routes are satisfactory for the therapy. However, if gastrointestinal routes are selected, higher doses of both quantity and frequency of bacteriophage cocktails will be required. • In this study, no significant difference was observed in IL-6, TNFα, and endotoxin levels in mice blood with or without phage intervention in the UTI caused by K. pneumoniae . The colistin-resistant Klebsiella pneumoniae causes complicated urinary tract infections (UTIs). Of them, 73% of strains of K. pneumoniae formed moderate to strong biofilm. Multidrug-resistant (MDR)/Pandrug-resistant (PDR) bacteria causing UTIs are very challenging to conventional antibiotic therapy. However, bacteriophages may be a promising alternative as they easily disrupt the biofilm and act on receptors unrelated to antibiotic resistance mechanisms. This preclinical study evaluated the efficacy of a phage cocktail with different routes and dosages (in quantity and frequency) to eradicate the K. pneumoniae -associated UTI in the mice model. The three lytic phages with the broadest spectrum activity (ΦKpnBHU1, ΦKpnBHU2 and ΦKpnBHU3) were meticulously characterized using SEM and sequencing. The cocktails were administered to mice through urethral, rectal, subcutaneous and oral routes after establishing the UTI with 1 × 10 8 colony-forming unit/mouse (CFU/mouse) of K. pneumoniae (KpnBHU09) resistant to both the drugs carbapenem and colistin. The efficacy of different routes with varying dosages and frequency of administration was thoroughly optimized. We observed that two doses of a phage cocktail containing 1 × 10 5 Plaque-Forming Unit (PFU/mouse) and a single dose of 1 × 10 9 PFU/mouse per urethra could eradicate KpnBHU09. Intriguingly, the non-invasive administration through oral and rectal routes required higher concentration and many dosages of phages to eliminate KpnBHU09 at any stage of acute UTI. The subcutaneous route was found unsatisfactory in curing the infection. Bacteriophage cocktails administered through transurethral, oral and rectal routes may cure UTIs.

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