Pharmacokinetic Assessment of Staphylococcal Phage K Following Parenteral and Intra-articular Administration in Rabbits

Abstract

The therapeutic value of phage as an alternative to antibiotics for the treatment of bacterial infections is being considered in the wake of mounting antibiotic resistance. In this study, the pharmacokinetic properties of Staphylococcus aureus phage K following intravenous and intra-articular administration were investigated in a rabbit model. Using a traditional plaque assay and a novel quantitative PCR assay to measure phage levels in specimens over time, it was found that intra-articularly administered phage enters the systemic circulation; that phage may be detected in synovial fluid up to 24 h following the intra-articular, but not intravenous, administration; and that qPCR-based enumeration is generally more sensitive than plaque enumeration, with fair to moderate correlation between the two methods. Findings presented should inform the design of phage therapy experiments and therapeutic drug monitoring in preclinical and human phage studies.

Phage therapy in prosthetic joint infections caused by Staphylococcus aureus – A literature review

“…Totten et al. performed pharmacokinetic research in a single-dose, single-phage design with the phage K (ATCC 19685-B1) against S. aureus after IV and IA application in a rabbit model [ 43 ]. Their main finding was that phages were widely distributed within the course of 24 h independent of the administration route.…”

“…However, transvascular dissemination of inflammatory cells and papillary proliferation of bronchial epithelium were discovered in phage-treated rabbits, being otherwise healthy. The authors called for further studies dealing with the pharmacokinetic effects of iterated phage administration and declared demand for a better understanding of the production of neutralizing antibodies dependent on the administration route [ 43 ].…”

“…Additionally, considerable emergence of bacterial resistance to the applied phages was reported by none of the included publications. While, regardless of respective tissues or administration route, neither histopathological nor hematologic examinations revealed any evidence of host tissue impairment through low-endotoxin phages, investigated rabbits did exhibit inflammation-associated changes after exclusive application of phages in one study [ 43 ]. In contrast, the multiple times observed increase in liver transaminases following phage therapy in humans suffering from S. aureus -associated PJIs was particularly striking as it led in one also hepatomegaly involving case to phage therapy discontinuation [ 49 , 52 , 53 ].…”

“…Sensitivity testing for the purpose of individualized phage selection should be carried out beforehand [ 40 , 51 ], taking further into account, if relevant, secondary morphology colonies or bacterial cultures of different intrapatient origins [ 38 , 39 , 53 ]. As dose-dependency became evident [ 46 , 48 , 50 ], dosage requires careful consideration just like duration and other treatment parameters do [ 43 , 49 , 50 ]. Not only IA and IV administration led to therapeutic success [ 52 – 54 ], but also special use cases like a carrier hydrogel or a coated implant were associated with promising results [ 45 , 48 ].…”

Bacteriophage-derived endolysins as innovative antimicrobials against bovine mastitis-causing streptococci and staphylococci: a state-of-the-art review

“…PlyK, PlytrxSA-1 and PlyRODI were discovered in the virulent S. aureus phages K [85][86][87][88], IME-SA1 [89] and phiIPLA-RODI [90,91], respectively. These endolysins consist of an N-terminal CHAP, a middle amidase_2 and a C-terminal SH3_5.…”