Drug resistance in leprosy: An update following 70years of chemotherapy.

Leprosy is one of the oldest infectious diseases, reported for more than 2000years. Leprosy elimination goal as a public health problem set by the World Health Organization, aiming for a global prevalence rate<1 patient in a population of 10,000, was achieved in 2000 mainly thanks to the worldwide use of leprosy drugs starting in the 1980s and their access at no cost for patients since 1995. However, around 200,000 new cases are still reported each year, particularly in India, Brazil, and Indonesia. As with other bacteria of medical interest, antimicrobial resistance is observed in Mycobacterium leprae strains in several parts of the world, despite multidrug therapy being the recommended standard leprosy treatment to avoid resistance selection since 1982. Therefore, identifying and monitoring resistance is necessary. We provide an overview of the historical facts that led to the current drug resistance situation, the antibiotics effective against M. leprae, their mechanisms of action and resistance, and resistance detection methods. We also discuss therapeutic management of the resistant cases, new genes with potential roles in drug resistance and bacterial adaptation, new drugs under investigation, and the risk for resistance selection with the chemoprophylaxis measures.

Drug resistance in leprosy: an update following 70 years of chemotherapy

Leprosy is one of the oldest infectious diseases, reported for more than 2000 years. Leprosy elimination goal as a public health problem set by the World Health Organization, aiming for a global prevalence rate < 1 patient in a population of 10,000, was achieved in 2000 mainly thanks to the worldwide use of leprosy drugs starting in the 1980s and their access at no cost for patients since 1995. However, around 200,000 new cases are still reported each year, particularly in India, Brazil, and Indonesia. As with other bacteria of medical interest, antimicrobial resistance is observed in Mycobacterium leprae strains in several parts of the world, despite multidrug therapy being the recommended standard leprosy treatment to avoid resistance selection since 1982. Therefore, identifying and monitoring resistance is necessary. We provide an overview of the historical facts that led to the current drug resistance situation, the antibiotics effective against M. leprae, their mechanisms of action and resistance, and resistance detection methods. We also discuss therapeutic management of the resistant cases, new genes with potential roles in drug resistance and bacterial adaptation, new drugs under investigation, and the risk for resistance selection with the chemoprophylaxis measures.

Prospective study on antimicrobial resistance in leprosy cases diagnosed in France from 2001 to 2015.

Antimicrobial resistance (AMR) in leprosy is mostly unknown because Mycobacterium leprae does not grow in vitro and bacteriologic investigations have been abandoned. However, molecular detection of resistance can be applied to multibacillary cases. Patients living in France mainland or in the French territories and diagnosed with leprosy from 2001 to 2015 were prospectively studied for AMR by detecting mutations in rpoB for rifampicin resistance, in folP1 for dapsone and in gyrA for ofloxacin. Single nucleotide polymorphism (SNP) genotypes 1-4 were determined for resistant strains. Of 334 skin biopsy samples received for suspicion of leprosy, 184 (55.1%) were positive for M. leprae (acid-fast bacilli and M. leprae-specific repetitive element PCR) corresponding to 160 multibacillary cases. AMR was detected in 18 cases (11.3%): 13 cases (8.1%) of dapsone resistance, three (1.9%) rifampicin and two (1.3%) ofloxacin. There were no strains with multidrug resistance. The mutations (numbering system of M. leprae TN strain genome) found were P55L (n = 7), T53I (n = 5), T53A (n = 1) in folP1; S456L (n = 2) and S456F (n = 1) in rpoB; and A91V (n = 2) in gyrA. Resistance proportion differ significantly between new and relapse cases (9/127, 7.0%, vs. 9/33, 25.7%, p 0.003). The frequency distribution of SNP1-4 types of resistant strains was two, one, 12 and three with five SNP3 cases from New Caledonia harbouring the same T53I FolP1 substitution. This is the first report of AMR surveillance for new and relapse cases of leprosy in Europe. Detection of resistance helped in individual treatment as well as in epidemiologic investigations.

Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis.

In previous studies, the diarylquinoline R207910 (also known as TMC207) was demonstrated to have high bactericidal activity when combined with first- or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log(10) CFU). Two months of treatment with the combinations R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, or R207910-PZA-MXF resulted in culture-negative lung homogenates in 70 to 100% of the mice, while mice treated with INH-RIF-PZA (the reference regimen) or RIF-MXF-PZA remained culture positive. Combinations including R207910 but not PZA (e.g., R207910-INH-RIF and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two drugs and INH, RIF, or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including periods of relapse.

Efficient intermittent rifapentine-moxifloxacin-containing short-course regimen for treatment of tuberculosis in mice.

Long-half-life drugs raise the hope of once-a-week administration of antituberculous treatment. In a previous study with the murine model of tuberculosis, the most active intermittent regimen which contained rifapentine (RFP), isoniazid (INH), and moxifloxacin (MXF) given once a week during 5.5 months, preceded by 2 weeks of daily treatment with INH, rifampin (RIF), pyrazinamide (PZA), and MXF, was less active than the standard 6-month daily RIF-INH-PZA regimen. We evaluated with the same model similar regimens in which we increased the dosing of rifapentine from 10 to 15 mg/kg of body weight and of moxifloxacin from 100 to 400 mg/kg. Mice infected intravenously by 6.2 x10(6) CFU of Mycobacterium tuberculosis H37Rv were treated 2 weeks later when infection was established. After 6 months of treatment, all mice had negative lung culture. After 3 months of follow-up, no relapse occurred in the two groups that received moxifloxacin at 400 mg/kg, whatever the dosage of RFP, and in the group receiving the standard RIF-INH-PZA control regimen. In contrast, in the two groups receiving moxifloxacin at a lower dosage, the relapse rate was significantly higher (13% in mice receiving RFP at 15 mg/kg and 27% in those receiving RFP at 10 mg/kg). Finally, the fully intermittent once-a-week regimen (26 drug ingestions) of INH, RFP (15 mg/kg), and MXF (400 mg/kg) led to a relapse rate of 11%. In conclusion, when used at high dosage, rifapentine and moxifloxacin are very efficient when combined with isoniazid in a once-a-week treatment in mouse tuberculosis.