A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination With Oral Rifampin Compared With Standard-of-Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction.
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.


BACKGROUND
NCT01756924.
Cempra Inc.
Richard
R
Pushkin
Cempra Inc.|University of North Carolina, Chapel Hill.
Maria D
MD
Iglesias-Ussel
Cempra Inc.
Kara
K
Keedy
Cempra Inc.
Chris
C
MacLauchlin
Projections Research Inc, Phoenixville, Pennsylvania.
Diane R
DR
Mould
Phoenix Clinical Research, Tamarac, Florida.
Richard
R
Berkowitz
Memorial Bone and Joint Clinic and University of Texas Health Science Center at Houston.
Stephan
S
Kreuzer
Departments of Medicine, Surgery, and Physical Medicine and Rehabilitation, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas.
Rabih
R
Darouiche
Cempra Inc.
David
D
Oldach
Cempra Inc.
Prabha
P
Fernandes
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005672:Fusidic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D016459:Prosthesis-Related Infections / Q000188:drug therapy*; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D005672:Fusidic Acid; D012293:Rifampin
arthroplasty; fusidic acid; prosthetic joint infection; rifampin