Bithionol is ineffective in a mouse model of S. aureus implant-associated osteomyelitis despite potent in vitro activity

Abstract

Abstract Implant-associated osteomyelitis (IAOM) is a severe complication of the usage of orthopaedic implants. IAOM is difficult to treat and infection relapse is often due to insufficient treatment of bacterial persister cells. The anthelmintic drug bithionol is promising in combating persister cells - including Staphylococcus aureus persister cells. We investigated bithionol alone and in combination with antibiotics both in vitro and in vivo, using a murine IAOM model. In vitro experiments confirmed bithionol’s anti-persister activity against S. aureus, demonstrating significant CFU reductions in combination with daptomycin and moxifloxacin. In the murine IAOM model, moxifloxacin led to a small but significant reduction in bacterial load in bone of approx. log 0.5 CFU/ml. However, combining bithionol with antibiotics did not further reduce bacterial load in either bone or on implants. We subsequently demonstrated dramatically reduced activity of bithionol in the presence of albumin, suggesting low bioavailability in vivo. Despite promising in vitro results, bithionol’s efficacy against persister cells did not translate into improving treatment outcome the IAOM model. The study highlights the challenges in translating in vitro findings to in vivo outcomes, and future research into application of bithionol to treat bacterial infections must first address its bioavailability or investigate local delivery options.