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

Abstract

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.

Molecular detection of mutations in rpoB gene involved in rifampin resistance in leprosy patients from Côte d'Ivoire

“…These same mutations were also reported in France by Chauffour and al. [13], according to these authors, the mutations correlated with resistance (numbering of the M. leprae TN genome) were as follows: Ser456Leu (2 cases) and Ser456Phe (1 case). The presence of mutations on the abovementioned codons of rpoB gene could explain the treatment failure in some of our patients to first-line drugs including rifampicin.…”

“…They are generally not reported to health authorities and are not investigated for rifampicin resistance. Systematic investigation of resistance in leprosy cases diagnosed in several endemic countries has revealed cases of secondary or primary resistance to rifampicin [13]. Although Côte d'Ivoire is not considered a high-risk country for leprosy, this may be a red herring.…”

A systematic review of Mycobacterium leprae DNA gyrase mutations and their impact on fluoroquinolone resistance

“…The line probe assay GenoType LepraeDR ® used in only two studies has also limitations. [37,39] Despite the fact that the line probe assay allows detection of the most important mutations in the three main genes involved in antibiotic resistance in M. leprae (i.e. rpoB, folP and gyrA), its weakness is that it focuses on the QRDR of only gyrA, and then on codon 91 directing the A91V substitution, while other mutations in this region require verification by PCR sequencing.…”

“…[13,25,26] The prior use of FQ was reported in 18 studies (Table 4). [13,[24][25][26]29,[32][33][34][35][36][37][38][39][40][41][42][43][44] Mutations in gyrA (Tables 1, 4) Among the 18 substitutions described in GyrA, nine were inside and seven outside the QRDR, and two were inside the intein (Table 1). The A91 substitution was the most prevalent.…”

Relapse in leprosy and drug resistance assessment in a tertiary hospital of the state of Espírito Santo, Brazil

“…However, some studies have indicated drug resistance to rifampicin, dapsone, and ofloxacin, also in cases of leprosy recurrence 12 - 14 , in addition to reporting mutations other than the traditional ones, such as nth (DNA repair), rpo , rpoC (rifampicin), gyrB (ofloxacin), and 23s rRNA (clarithromycin), but still having uncertain roles 13 . Reja et al 14 and Chauffour et al 15 affirmed that even cases of negative bacilloscopy can be targets of drug resistance, deserving even more attention during the follow-up period.…”