Richard Pushkin1, Maria D Iglesias-Ussel1,2, Kara Keedy1, Chris MacLauchlin1, Diane R Mould3, Richard Berkowitz4, Stephan Kreuzer5, Rabih Darouiche6, David Oldach1, Prabha Fernandes1. 1. Cempra Inc. 2. University of North Carolina, Chapel Hill. 3. Projections Research Inc, Phoenixville, Pennsylvania. 4. Phoenix Clinical Research, Tamarac, Florida. 5. Memorial Bone and Joint Clinic and University of Texas Health Science Center at Houston. 6. Departments of Medicine, Surgery, and Physical Medicine and Rehabilitation, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas.
Abstract
BACKGROUND:Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described. METHODS: In a phase 2 open-label randomized study, we evaluated oral FA/RIF vs standard-of-care (SOC) intravenous antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at reimplantation (week 12) for subjects with 2-stage exchange, and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively. RESULTS:Fourteen subjects were randomized 1:1 to FA/RIF or SOC. Pharmacokinetic profiles were obtained for 6 subjects randomized to FA/RIF. FA concentrations were lower than anticipated in all subjects during the first week of therapy, and at weeks 4 and 6, blood levels continued to decline. By week 6, FA exposures were 40%-45% lower than expected. CONCLUSIONS: The sponsor elected to terminate this study due to a clearly illustrated drug-drug interaction between FA and RIF, which lowered FA levels to a degree that could influence subject outcomes. Optimization of FA exposure if used in combination with RIF should be a topic of future research. CLINICAL TRIALS REGISTRATION: NCT01756924.
RCT Entities:
BACKGROUND:Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described. METHODS: In a phase 2 open-label randomized study, we evaluated oral FA/RIF vs standard-of-care (SOC) intravenous antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at reimplantation (week 12) for subjects with 2-stage exchange, and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively. RESULTS: Fourteen subjects were randomized 1:1 to FA/RIF or SOC. Pharmacokinetic profiles were obtained for 6 subjects randomized to FA/RIF. FA concentrations were lower than anticipated in all subjects during the first week of therapy, and at weeks 4 and 6, blood levels continued to decline. By week 6, FA exposures were 40%-45% lower than expected. CONCLUSIONS: The sponsor elected to terminate this study due to a clearly illustrated drug-drug interaction between FA and RIF, which lowered FA levels to a degree that could influence subject outcomes. Optimization of FA exposure if used in combination with RIF should be a topic of future research. CLINICAL TRIALS REGISTRATION: NCT01756924.
Authors: L Morata; J Cobo; M Fernández-Sampedro; P Guisado Vasco; E Ruano; J Lora-Tamayo; M Sánchez Somolinos; P González Ruano; A Rico Nieto; A Arnaiz; M Estébanez Muñoz; M E Jiménez-Mejías; A B Lozano Serrano; E Múñez; D Rodriguez-Pardo; R Argelich; A Arroyo; J M Barbero; F Cuadra; A Del Arco; M D Del Toro; L Guio; D Jimenez-Beatty; N Lois; O Martin; R M Martínez Alvarez; F J Martinez-Marcos; L Porras; M Ramírez; J Vergas García; A Soriano Journal: Antimicrob Agents Chemother Date: 2019-04-25 Impact factor: 5.191
Authors: Borg Leijtens; Joris B W Elbers; Patrick D Sturm; Bart Jan Kullberg; Berend W Schreurs Journal: BMC Infect Dis Date: 2017-05-02 Impact factor: 3.090