Estudio de resistencia a la rifampicina y la dapsona en tres pacientes con recurrencia de lepra

Hernández, Elkin; Cardona-Castro, Nora; Rodríguez, Gerzaín; Villegas, Sonia L.; Beltrán, Camilo; Kimura, Miyako; Vissa, Varalakshmi; Gómez, Yenny

doi:10.1590/s1020-49892008000200001

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…In this regard, four gene targets were amplified by single and/or multiplex PCR- rpoB, folP1, gyrB and gyrA regions involved in resistance to rifampicin, dapsone and ofloxacin respectively (Figure 2A) and sequenced (Hernandez et al, 2008, WHO 2010). During the course of these investigations, we noted that NHDP63, an armadillo-derived human isolate of M. leprae DNA that was routinely used as positive DNA control for PCR was found to have a nucleotide change in codon 99; CGT instead of the CGC seen in the sequenced TN strain (genolist.pasteur.fr/Leproma/), resulting in a silent mutation (Arg to Arg).…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium leprae in Colombia described by SNP7614 in gyrA, two minisatellites and geography

Cardona-Castro

Beltrán-Alzate

Romero-Montoya

et al. 2013

Infection, Genetics and Evolution

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New cases of leprosy are still being detected in Colombia after the country declared achievement of the WHO defined ‘elimination’ status. To study the ecology of leprosy in endemic regions, a combination of geographic and molecular tools were applied for a group of 201 multibacillary patients including six multi-case families from eleven departments. The location (latitude and longitude) of patient residences were mapped. Slit skin smears and/or skin biopsies were collected and DNA was extracted. Standard agarose gel electrophoresis following a multiplex PCR-was developed for rapid and inexpensive strain typing of M. leprae based on copy numbers of two VNTR minisatellite loci 27-5 and 12-5. A SNP (C/T) in gyrA (SNP7614) was mapped by introducing a novel PCR-RFLP into an ongoing drug resistance surveillance effort. Multiple genotypes were detected combining the three molecular markers. The two frequent genotypes in Colombia were SNP7614(C)/27-5(5)/12-5(4) [C54] predominantly distributed in the Atlantic departments and SNP7614 (T)/27-5(4)/12-5(5) [T45] associated with the Andean departments. A novel genotype SNP7614 (C)/27-5(6)/12-5(4) [C64] was detected in cities along the Magdalena river which separates the Andean from Atlantic departments; a subset was further characterized showing association with a rare allele of minisatellite 23-3 and the SNP type 1 of M. leprae. The genotypes within intra-family cases were conserved. Overall, this is the first large scale study that utilized simple and rapid assay formats for identification of major strain types and their distribution in Colombia. It provides the framework for further strain type discrimination and geographic information systems as tools for tracing transmission of leprosy.

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Section: Resultsmentioning

confidence: 99%

Mycobacterium leprae in Colombia described by SNP7614 in gyrA, two minisatellites and geography

Cardona-Castro

Beltrán-Alzate

Romero-Montoya

et al. 2013

Infection, Genetics and Evolution

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“…The study utilized a patient group assembled over a ten-year period. While the threshold for alarm over drug resistance to MDT, locally and globally, has not been well defined, we demonstrate that single and multi-drug resistant strains are detectable in Colombia, albeit at low frequencies [ 10 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, the duration of treatment for PB patients may be extended for one year, and in the case of MB the treatment, up to 2 years, if lesions persist and the Bacillary index (BI) is positive [ 7 , 9 ]. Leprosy resistance in Colombia has been associated with relapses, especially in patients undergoing dapsone monotherapy [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country

et al. 2016

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An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively.

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“…Therefore, relapse has not been considered a problem, and organization of studies of this disease characteristic was somewhat neglected, leading to the recent WHO initiative to organize a resistance surveillance project for relapse cases, 26 years after having started MDT. This was possible due to the development and standardization of molecular genotyping procedures of genes associated with drug resistance (5,16,23,24,38,39). After the introduction of relapse surveillance by the WHO, many of the countries of endemicity reported leprosy relapses.…”

Section: Discussionmentioning

confidence: 99%

Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

et al. 2012

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h Skin biopsy samples from 145 relapse leprosy cases and from five different regions in Brazil were submitted for sequence analysis of part of the genes associated with Mycobacterium leprae drug resistance. Single nucleotide polymorphisms (SNPs) in these genes were observed in M. leprae from 4 out of 92 cases with positive amplification (4.3%) and included a case with a mutation in rpoB only, another sample with SNPs in both folP1 and rpoB, and two cases showing mutations in folP1, rpoB, and gyrA, suggesting the existence of multidrug resistance (MDR). The nature of the mutations was as reported in earlier studies, being CCC to CGC in codon 55 in folP (Pro to Arg), while in the case of rpoB, all mutations occurred at codon 531, with two being a transition of TCG to ATG (Ser to Met), one TCG to TTC (Ser to Phe), and one TCG to TTG (Ser to Leu). The two cases with mutations in gyrA changed from GCA to GTA (Ala to Val) in codon 91. The median time from cure to relapse diagnosis was 9.45 years but was significantly shorter in patients with mutations (3.26 years; P ‫؍‬ 0.0038). More than 70% of the relapses were multibacillary, including three of the mutation-carrying cases; one MDR relapse patient was paucibacillary. There is no doubt about the efficiency of the currently used multidrug therapy (MDT) scheme for treatment of leprosy, as demonstrated by the strong decrease in disease prevalence since its implementation and the low number of reported relapse cases (18). However, there has been a scarcity of in-depth studies of relapse occurrences in recent decades (27). As is known, differentiating diagnosis of relapse and reactional states poses some difficulties in the field, being responsible for under-or overdiagnosis of both disease stages. This is important because undiagnosed relapse cases could contribute to continuing disease transmission. In addition, hardly any data on the contribution of emergence of drug-resistant strains of Mycobacterium leprae to leprosy relapses exist.Diaminodiphenylsulfone (DDS), also called dapsone, was the first drug to be effective against leprosy worldwide, and the first cases of resistance to dapsone were detected in 1964 and involved two single nucleotide polymorphisms (SNPs) in the gene folP1, located in codons 53 and 55 (8, 9, 14, 29). Rifampin is the key component of the standard multidrug regimen used for treatment of leprosy, and it has been shown that PCR-based DNA sequence analysis of the rpoB gene of M. leprae was in full concordance with rifampin susceptibility testing in the mouse footpad system (17, 30). In addition to dapsone and rifampin, ofloxacin is also used for leprosy treatment and is a quinolone with an action mechanism based on interaction with DNA gyrase (2); SNPs in gyrA and gyrB confer resistance or hypersensitivity to quinolones (15). Although there is not yet an official definition of multidrug resistance (MDR) in leprosy, in parallel with tuberculosis, we adopt this terminology when we encounter resistance to rifampin and one other drug of the standard M...

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Estudio de resistencia a la rifampicina y la dapsona en tres pacientes con recurrencia de lepra

Abstract: The mutation identified showed strains of rifampin-resistant M. leprae in two of the three patients with recurring leprosy. Mutations that indicate dapsone-resistance were not detected in any of the three patients.

Cited by 9 publications

References 22 publications

Mycobacterium leprae in Colombia described by SNP7614 in gyrA, two minisatellites and geography

Mycobacterium leprae in Colombia described by SNP7614 in gyrA, two minisatellites and geography

Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country

Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

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