Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens

• DOI: 10.1371/journal.pcbi.1010823
• Publication Date: 2023-06-15T18:18:25Z
• Authors: Maral Budak; Joseph M. Cicchese; Pauline Maiello; H. Jacob Borish; Alexander G. White; Harris B. Chishti; Jaime Tomko; L. James Frye; Daniel Fillmore; Kara Kracinovsky; Jennifer Sakal; Charles A. Scanga; Philana Ling Lin; Véronique Dartois; Jennifer J. Linde...; JoAnne L. Flynn; Denise E. Kirschner
• Keywords: Regimen; Rifapentine; Bedaquiline; Pharmacodynamics

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims reduce TB-related 2035 by 95%. Recent research goals have focused on discovering more effective and patient-friendly antibiotic drug regimens increase patient compliance decrease emergence resistant TB. Moxifloxacin is promising may improve current standard regimen shortening treatment time. Clinical trials vivo mouse studies suggest containing moxifloxacin better bactericidal activity. However, testing possible combination with either or clinically not feasible due experimental clinical limitations. To identify systematically, we simulated pharmacokinetics/pharmacodynamics various (with without moxifloxacin) evaluate efficacies, then compared our predictions both nonhuman primate performed herein. We used GranSim, well-established hybrid agent-based model simulates granuloma formation treatment, for this task. In addition, established a multiple-objective optimization pipeline using GranSim discover optimized based objectives interest, i.e., minimizing total dosage lowering time needed sterilize granulomas. Our approach can efficiently test many successfully optimal inform pre-clinical ultimately accelerate discovery process.