Pharmacokinetics and Pharmacodynamics of a Novel Virulent Klebsiella Phage Kp_Pokalde_002 in a Mouse Model

Abstract

Phage therapy is one of the most promising alternatives to antibiotics as we face global antibiotic resistance crisis. However, the pharmacokinetics (PK) and pharmacodynamics (PD) of phage therapy are largely unknown. In the present study, we aimed to evaluate the PK/PD of a locally isolated virulent novel øKp_Pokalde_002 (Podoviridae, C1 morphotype) that infects carbapenem-resistant Klebsiella pneumoniae (Kp56) using oral and intraperitoneal (IP) route in a mouse model. The result showed that the øKp_Pokalde_002 rapidly distributed into the systemic circulation within an hour via both oral and IP routes. A higher concentration of phage in plasma was found after 4 h (2.3 x 105 PFU/ml) and 8 h (7.3 x 104 PFU/ml) of administration through IP and oral route, respectively. The phage titer significantly decreased in the blood and other tissues, liver, kidneys, and spleen after 24 h and completely cleared after 72 h of administration. In the Kp56 infection model, the bacterial count significantly decreased in the blood and other organs by 4–7 log10 CFU/ml after 24 h of øKp_Pokalde_002 administration. Elimination half-life of øKp_Pokalde_002 was relatively shorter in the presence of host-bacteria Kp56 compared to phage only, suggesting rapid clearance of phage in the presence of susceptible host. Further, administration of the øKp_Pokalde_002 alone in healthy mice (via IP or oral) did not stimulate pro-inflammatory cytokines (TNF-α and IL-6). Also, treatment with øKp_Pokalde_002 resulted in a significant reduction of pro-inflammatory cytokines (TNF-α and IL-6) caused by bacterial infection, thereby reducing the tissue inflammation. In conclusion, the øKp_Pokalde_002 possess good PK/PD properties and can be considered as a potent therapeutic candidate for future phage therapy in carbapenem-resistant K. pneumoniae infections.

Isolation of Klebsiella pneumoniae Phage vB_KpnS_MK54 and Pathological Assessment of Endolysin in the Treatment of Pneumonia Mice Model

“…To more clearly show that LPKP is inhibited and lysed by endolysin in mice, we counted the bacterial load in the lungs of mice. The assay results showed that LysCA and LysG24 can effectively inhibit the growth of the host bacteria LPKP in vivo and relieve inflammation in the lung tissue, similar to the results of several previous in vivo studies of endolysin therapy ( Peng et al, 2019 ; Dhungana et al, 2021 ). As expected, based on both the clinical signs and the bacterial load in the lungs of mice, LysCA showed a better therapeutic effect.…”

Characteristics of a Bacteriophage, vB_Kox_ZX8, Isolated From Clinical Klebsiella oxytoca and Its Therapeutic Effect on Mice Bacteremia

“…Many studies have reported that phage preparation does not cause changes in inflammatory factors in animals. For example, phage D29 administered via the endotracheal route did not cause significant changes in leukocytes, neutrophils, lymphocytes, and TNF-α levels in the lungs of healthy mice 24 h after treatment ( Liu et al, 2016 ); phage BcepIL02 administered via IP injection did not cause significant changes in TNF-α levels in the lungs of healthy mice 24 h after treatment ( Carmody et al, 2010 ); and phage Kp_Pokalde_002 administered via IP injection did not cause significant changes in TNF-α and IL-6 levels in the plasma of healthy mice 24 h after treatment ( Dhungana et al, 2021 ). In this study, administration of high-dose phage vB_Kox_ZX8 caused slight changes in TNF-α, IL-6, and IL-10 in the serum, liver, and spleen of mice after 24 h of treatment, but did not induce discomfort in mice.…”

“…In other studies of the Podoviridae phage, Klebsiella phage Kp_Pokalde_002 and Pseudomonas phage PEV20 had a longer residence time in mouse blood. The titer of Kp_Pokalde_002 in the blood measured via IP injection of 10 8 PFU reached the maximum at the fourth hour, gradually decreased, and cleared at 48 h ( Dhungana et al, 2021 ). The titer of PEV20 in rat blood measured via intravenous injection of 10 8 PFU reached the maximum within 1 h, gradually decreased, and cleared at 48 h ( Lin et al, 2020 ).…”

Genome report of three novel bacteriophages targeting different multidrug resistant clinical isolates (Escherichia, Klebsiella and Salmonella) from Enterobacteriaceae family

“…Furthermore, the use of genomics and phenotyping of phages and their host could improve the efficacy of phage therapy in the future in regard to the choice of phage for the pathogen of interest. In line with the aim of expanding phage research, previously, we reported phages exhibiting lytic activity against multidrug resistant Pseudomonas and Klebsiella [10] and also studied pharmacokinetics and pharmacodynamics of our Klebsiella phage Kp_Pokalde_002 in a mouse model [11]. Here, we report the isolation, genome analysis and taxonomic position of three newly isolated phages targeting MDR human pathogens: Escherichia coli, Klebsiella pneumoniae and Salmonella spp.…”