Analysis of Drug-Resistant Strains of Mycobacterium leprae in an Endemic Area of Vietnam

Kai, Masahiro; Phuc, Nhu Ha Nguyen; Nguyen, Hoang An; Pham, Thi Hoang Bich Diu; Nguyen, Khanh; Miyamoto, Yuji; Maeda, Yosuke; Fukutomi, Yoshiki; Nakata, Noboru; Matsuoka, Masao; Makino, Masahiko; Nguyen, Thanh T.

doi:10.1093/cid/ciq217

Cited by 40 publications

(32 citation statements)

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“…Antimicrobial drug-resistant M. leprae has been documented mostly with the use of dapsone in some areas of endemicity where dapsone has been used as monotherapy (61,62). Fortunately, there have been only a limited number of multidrug-resistant cases identified through representative mutations in more than two genes reported in the literature (62,63).…”

Section: Management Of Hdmentioning

confidence: 99%

Leprosy in the 21st Century

2015

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SUMMARY Despite significant improvements in leprosy (Hansen's disease) treatment and outlook for patients since the introduction of multidrug therapy (MDT) 3 decades ago, the global incidence remains high, and patients often have long-term complications associated with the disease. In this article, we discuss recent findings related to genetics, susceptibility, and disease reservoirs and the implications of these findings for Hansen's disease control and health outcomes for patients. We describe the continued difficulties associated with treatment of inflammatory episodes known as “leprosy reactions,” which cause much of the disability associated with the disease and can affect people for many years after MDT is complete. We also discuss some of the contemporary challenges for physicians and patients, including international and internal migration of people affected by the disease. We suggest some important areas of focus for future Hansen's disease research.

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Section: Management Of Hdmentioning

confidence: 99%

Leprosy in the 21st Century

2015

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“…These changes are determined by mutations in the drug resistance-determining region (DRDR) in the folP1, rpoβ, and gyrA genes which have demonstrated to confer resistance to dapsone, rifampicin, and ofloxacin, respectively. By defining resistance mechanisms it is possible to use DNAbased assays, namely PCR-direct DNA sequencing or reverse hybridization to examine susceptibility to these drugs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

¿Es la resistencia de Mycobacterium leprae a los medicamentos un verdadero motivo de preocupación? Primera aproximación a la vigilancia molecular de pacientes colombianos multibacilares con tratamiento previo para lepra y sin él

et al. 2013

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Introduction:There is no information in Colombia on Mycobacterium leprae primary and secondary drug resistance in regards to the WHO-multidrug therapy regime. On the other hand, public health authorities around the world have issued various recommendations, one of which prompts for the immediate organization of resistance surveillance through simple molecular methods. Objective: To determine the prevalence of Mycobacterium leprae drug resistance to rifampicin, ofloxacin and dapsone in untreated and previously treated patients at the Centro Dermatológico Federico Lleras Acosta during the 1985-2004 period. Materials and methods: We conducted a retrospective study which included multibacillary patient biopsies through elective sampling: 381 of them from new patients and 560 from previously treated patients. Using a microtome, we obtained six slides from each skin biopsy preserved in paraffin, and we extracted M. leprae DNA. We amplified three molecular targets through PCR and obtained the patterns of drug resistance to dapsone, rifampicin and ofloxacin by reverse hybridization. Finally, we collected epidemiological, clinical and demographical data for analyses. Results: From 941 samples under study, 4.14% of them were resistant to one or more drugs, and 5.77 and 3.04% had resistant genotypes in new and previously treated patients, respectively. Total resistance for each drug was 0.43% for dapsone, 3.19% for rifampicin and 1.17% for ofloxacin. We found statistically significant differences for rifampicin and for the total population when comparing the results from untreated versus previously treated patients. Two thirds of the resistant samples were resistant to rifampicin alone or combined. Conclusions:The standard multidrug therapy schemes continue being effective for leprosy cases; however, it is necessary to guarantee adherence and regularity. Surveillance to drug resistance in new and previously treated leprosy cases should be established.

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“…For this reason, in 1982, the World Health Organization (WHO) formally recommended multidrug therapy (MDT) which includes dapsone, rifampin, and clofazimine for the treatment and control of multibacillary (MB) leprosy (43). Sporadic reports of clinical resistance to dapsone and rifampin started appearing in several countries such as Vietnam, Mexico, India, and Philippines (1,8,13,19,24,25,26). Noncompliance and inadequate therapy may be the causes of the clinical resistance, particularly for MB leprosy.…”

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confidence: 99%

Real-Time PCR and High-Resolution Melt Analysis for Rapid Detection of Mycobacterium leprae Drug Resistance Mutations and Strain Types

Matsuoka

Kai

et al. 2012

J Clin Microbiol

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c Drug resistance surveillance and strain typing of Mycobacterium leprae are necessary to investigate ongoing transmission of leprosy in regions of endemicity. To enable wider implementation of these molecular analyses, novel real-time PCR-highresolution melt (RT-PCR-HRM) assays without allele-specific primers or probes and post-PCR sample handling were developed. For the detection of mutations within drug resistance-determining regions (DRDRs) of folP1, rpoB, and gyrA, targets for dapsone, rifampin, and fluoroquinolones, real-time PCR-HRM assays were developed. Wild-type and drug-resistant mouse footpadderived strains that included three folP1, two rpoB, and one gyrA mutation types in a reference panel were tested. RT-PCR-HRM correctly distinguished the wild type from the mutant strains. In addition, RT-PCR-HRM analyses aided in recognizing samples with mixed or minor alleles and also a mislabeled sample. When tested in 121 sequence-characterized clinical strains, HRM identified all the folP1 mutants representing two mutation types, including one not within the reference panel. The false positives (<5%) could be attributed to low DNA concentration or PCR inhibition. A second set of RT-PCR-HRM assays for identification of three previously reported single nucleotide polymorphisms (SNPs) that have been used for strain typing were developed and validated in 22 reference and 25 clinical strains. Real-time PCR-HRM is a sensitive, simple, rapid, and high-throughput tool for routine screening known DRDR mutants in new and relapsed cases, SNP typing, and detection of minor mutant alleles in the wild-type background at lower costs than current methods and with the potential for quality control in leprosy investigations. Leprosy is an infectious disease of skin and nerves caused by Mycobacterium leprae. The disease remains endemic in many parts of the world and is now listed as a neglected tropical disease (27) by the World Health Organization. The drug dapsone was introduced in 1950 and was administered in the form of long-term monotherapy for treatment of leprosy; unfortunately, drug resistance emerged during the 1960s and 1970s (4). For this reason, in 1982, the World Health Organization (WHO) formally recommended multidrug therapy (MDT) which includes dapsone, rifampin, and clofazimine for the treatment and control of multibacillary (MB) leprosy (43). Sporadic reports of clinical resistance to dapsone and rifampin started appearing in several countries such as Vietnam, Mexico, India, and Philippines (1,8,13,19,24,25,26). Noncompliance and inadequate therapy may be the causes of the clinical resistance, particularly for MB leprosy. The drug targets and the mutations in the coding genes folP1, rpoB, and gyrA that lead to clinical resistance to dapsone, rifampin, and the fluoroquinolones (used in an alternative leprosy drug regimen), respectively, have been identified and characterized (5,10,14,39). The in vivo drug susceptibility or resistance phenotypes of various mutations seen in clinical strains in patient skin biop...

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Analysis of Drug-Resistant Strains of Mycobacterium leprae in an Endemic Area of Vietnam

Cited by 40 publications

References 13 publications

Leprosy in the 21st Century

Leprosy in the 21st Century

¿Es la resistencia de Mycobacterium leprae a los medicamentos un verdadero motivo de preocupación? Primera aproximación a la vigilancia molecular de pacientes colombianos multibacilares con tratamiento previo para lepra y sin él

Real-Time PCR and High-Resolution Melt Analysis for Rapid Detection of Mycobacterium leprae Drug Resistance Mutations and Strain Types

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