Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy

• Published in: PLoS neglected tropical diseases Vol. 14; no. 9; p. e0008583
• Main Authors: Lenz, Shannon M, Collins, Jaymes H, Ray, Nashone A, Hagge, Deanna A, Lahiri, Ramanuj, Adams, Linda B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2020; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Antibiotics; Asymptomatic Infections - therapy; Bacilli; Bacterial Load - drug effects; Biology and Life Sciences; Clarithromycin; Clarithromycin - therapeutic use; Clinical trials; Combination drug therapy; Deoxyribonucleic acid; Disease prophylaxis; Disease transmission; DNA; Drug Combinations; Drug dosages; Drug efficacy; Drugs; Engineering and Technology; Exposure; Funding; Growth; Health services; Infections; Inoculation; Inoculum; Laboratory animals; Leprostatic Agents - therapeutic use; Leprosy; Leprosy - drug therapy; Leprosy - transmission; Medical research; Medicine and Health Sciences; Methods; Mice; Mice, Nude; Minocycline; Minocycline - therapeutic use; Moxifloxacin; Moxifloxacin - therapeutic use; Mycobacterium leprae - drug effects; Mycobacterium leprae - growth & development; Nucleotide sequence; Ofloxacin; Patient outcomes; PCR; Post-Exposure Prophylaxis - methods; Prevention; Prophylaxis; Regression analysis; Research and Analysis Methods; Rifampin; Rifampin - analogs & derivatives; Rifampin - therapeutic use; Subclinical infection; Transmission; Tropical diseases; United States; Louisiana; Baton Rouge Louisiana; United States > US; Nepal
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0008583

Subclinical infection with Mycobacterium leprae is one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials. Athymic nude mice were inoculated in the footpad (FP) with 6 x 103 viable M. leprae and treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, and M. leprae were enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurable M. leprae growth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation. The delay in discernable M. leprae growth post-treatment was an excellent indicator of drug efficacy for both early (3-4 months) and late (8-9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission.