PET-based Modeling and High-dose Rifampin for S. aureus Implant Infections

Oren Gordon ¹ Donald E. Lee ² Bessie Liu ^1,3 Brooke Langevin ² Alvaro A. Ordonez ¹ Dustin A. Dikeman ⁴ Babar Shafiq ⁵ John M. Thompson ⁵ Paul D. Sponseller ⁵ Kelly Flavahan ¹ Martin A. Lodge ⁶ Steven P. Rowe ⁶ Robert F. Dannals ⁶ Camilo A. Ruiz-Bedoya ¹ Timothy D. Read ⁷ Charles A. Peloquin ⁸ Nathan K. Archer ⁴ Lloyd S. Miller ⁴ Kimberly M. Davis ³ Jogarao V. S. Gobburu ² Sanjay K. Jain ¹

¹Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA, USA
²Center for Translational Medicine, University of Maryland School of Pharmacy, USA
³W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, USA
⁴Department of Dermatology, Johns Hopkins University
⁵Department of Orthopedic Surgery, Department of Dermatology, Johns Hopkins University School of Medicine,, USA
⁶Division of Nuclear Medicine and Molecular Imaging, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, USA
⁷Division of Infectious Diseases, Department of Medicine, Emory University, USA
⁸Infectious Disease Pharmacokinetics Laboratory, Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, USA

Staphylococcus aureus orthopedic implant-associated infection is a devastating surgical complication. Current antibiotic regimens include combination with rifampin (10-15 mg/kg/day) which has dose-dependent bactericidal activity. However, treatment regimens have not been optimized owing to lack of data on bacterial dynamics and antibiotic pharmacokinetics at the site of infection. We employed a non-invasive holistic approach using dynamic 11C-rifampin positron emission tomography (PET) to image patients with S. aureus bone infection (n=3) or controls (n=12). The area under the concentration-curve bone to plasma ratio was 0.14, indicating lower bone penetration than previously thought. PET-based pharmacokinetic modeling predicted rifampin bone concentrations and facilitated studies in mice. High-dose rifampin (equipotent to human 35 mg/kg/day) was required to achieve adequate bone concentrations, enhanced bacterial killing and shortened the duration of therapy from 6 to 4 weeks without increasing treatment failure rates. High-dose rifampin ameliorated antibiotic resistance (0% vs. 38%; P=0.04), mitigated bone remodeling (P<0.01) and reduced selection of mutations in genes related to bacterial resistance and persistence. High-dose rifampin has optimal bone exposure that results in favorable bacterial dynamics and improve treatment for S. aureus orthopedic implant infection.