ABSTRACT
BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.
Subject(s)
Anti-Bacterial Agents , Gonorrhea , Neisseria gonorrhoeae/drug effects , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Disease Models, Animal , Drug Development , Gonorrhea/drug therapy , Gonorrhea/microbiology , Humans , MiceABSTRACT
Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid-buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid-buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids-buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid-buffered formulation.
Subject(s)
Anti-Bacterial Agents/chemistry , Macrolides/chemistry , Solubility/drug effects , Triazoles/chemistry , Administration, Intravenous/methods , Amino Acids/chemistry , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Chemistry, Pharmaceutical/methods , Clinical Trials, Phase I as Topic , Community-Acquired Infections/drug therapy , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Macrolides/administration & dosage , Macrolides/adverse effects , Tartrates/chemistry , Triazoles/administration & dosage , Triazoles/adverse effectsABSTRACT
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.
