Artículo de revisión
Drug resistance and molecular epidemiology of Mycobacterium tuberculosis in Mexico: a systematic review
Farmacorresistencia y epidemiología molecular de Mycobacterium tuberculosis en México: una revisión sistemática
Samantha Flores-Treviño, MC,(1) Soraya Mendoza-Olazarán, MC,(2) Elvira Garza-González, D en C.(2)
(1) Departamento de Microbiología, Facultad de Medicina, Universidad Autónoma de Nuevo León. Nuevo León, México.
(2) Servicio de Gastroenterología y Departamento de Patología Clínica, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León. Nuevo León, México.
Objective. To compare drug resistance (DR) rates and genetic diversity of Mycobacterium tuberculosis strains from different states of Mexico.
Materials and methods. A systematic review of English and Spanish-language articles using MEDLINE and Google Scholar. Search terms included Mycobacterium tuberculosis, Mexico, resistance, mutation and epidemiology.
Results. Fifteen studies for phenotypic DR rates (n=2 694), twelve studies for genotypic DR (n=748) and eleven studies for genetic diversity (n=2 044) met our inclusion criteria. Mean DR and multidrug resistance (MDR) rates were 37.5% and 20.6%, respectively. The most frequent mutations were rpoB531 (53.1%), katG315 (50.6%), embB306 (32.1%), rpsL43 (14.6%) and pncA359 (16.7%) in DR strains. Novel mutations were found. Predominant shared types were SIT53 (T1, n=188, 3.9%), SIT119 (X1, n=125, 6.9%), SIT19 (EAI2-Manila, n=80, 6.3%) and SIT42 (LAM9, n=77, 3.0%). SIT1 Beijing genotype has been reported in six states from Mexico.
Conclusions. DR and MDR rates continue to increase. Genetic diversity of M. tuberculosis strains in Mexico is high. Reports of Beijing strains are increasing.
Key words: Mycobacterium tuberculosis; molecular epidemiology; drug resistance; mutation; Mexico.
Objetivo. Comparar los niveles de farmacorresistencia (FR) y la diversidad genética de cepas de Mycobacterium tuberculosis de diferentes estados de México.
Material y métodos. Una revisión sistemática de artículos en inglés y español usando MEDLINE y Google Scholar. Los términos de búsqueda incluyeron Mycobacterium tuberculosis, México, resistencia, mutación y epidemiología.
Resultados. Quince estudios de niveles de FR fenotípica (n=2 694), doce estudios de FR genotípica (n=748) y once estudios de diversidad genética (n=2 044) concordaron con nuestros criterios de inclusión. El promedio de los niveles de FR y multifarmacorresistencia (MFR) fue 37.5 y 20.6%, respectivamente. Las mutaciones más frecuentes fueron rpoB531 (53.1%), katG315 (50.6%), embB306 (32.1%), rpsL43 (14.6%) y pncA359 (16.7%) en cepas FR. Se encontraron nuevas mutaciones. Los tipos compartidos predominantes fueron SIT53 (T1, n=188, 3.9%), SIT119 (X1, n=125, 6.9%), SIT19 (EAI2-Manila, n=80, 6.3%) y SIT42 (LAM9, n=77, 3.0%). El genotipo Beijing SIT1 se ha reportado en seis estados de México.
Conclusiones. Las tasas de FR y MFR siguen incrementando. La diversidad genética de las cepas de M. tuberculosis es alta. Los reportes de cepas Beijing están aumentando.
Palabras clave: Mycobacterium tuberculosis; epidemiología molecular; resistencia a medicamentos; mutación; Mexico.
Almost one third of the global population is infected with Mycobacterium tuberculosis.1 The TB rate in Mexico is 16.8 per 100 000 population in 2010. Every year, more than two thousand people die from tuberculosis (TB) in this country.2 One of the most alarming trends worldwide concerning TB is the emergence of drug-resistant (DR) and multidrug-resistant strains of M. tuberculosis (MDR-TB). MDR strains are defined as those resistant to at least isoniazid (INH) and rifampicin (RIF). In M. tuberculosis, acquired drug resistance is caused mainly by spontaneous mutations in chromosomal genes, producing the selection of resistant strains during sub-optimal drug therapy.3, 4
Molecular typing of M. tuberculosis strains has been used to understand the transmission dynamics of TB.5 One genotyping technique is restriction fragment length polymorphism (RFLP) analysis, where the distribution and number of copies of an insertion sequence, IS6110, in a chromosome is monitored, with this event varying among different strains. However, PCR-based techniques have gradually been replacing RFLP analysis over the last decade. Spoligotyping detects polymorphisms present in a direct repeat locus, while molecular typing using mycobacterial interspersed repetitive unitsvariable number of DNA tandem repeats (MIRUVNTRs) is also used.6
DR and MDR strains have been steadily increasing over the past years, making treatment of TB difficult. Thus, it is important to identify resistant strains as soon as possible in order to adjust treatment strategies and minimize disease transmission. However, determining the DR rate in the country has proven difficult. Several reports are available and yet, some use different drug susceptility testing (DST). A systematic review of phenotypic and genotypic data of DR in M. tuberculosis strains, as well as an analysis of current genotypes has not been performed before.
To analyze the circulating M. tuberculosis strains from Mexico, we reviewed studies that assessed DR using specific DST, evaluated DR-associated mutation frequency and/or determined genetic diversity of M. tuberculosis strains in patients with either pulmonary or extrapulmonary TB from different states of Mexico.
Materials and methods
Analysis methods were performed based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement (http://www.prisma-statement.org/).
Studies were identified by searching the electronic Databases MEDLINE and Google Scholar.
No limits were applied for language and foreign papers were translated. The last search was run on July 8, 2013. Search terms included Mycobacterium tuberculosis, Mexico, resistance, mutation, molecular epidemiology, spoligotyping, RFLP-IS6110, MIRU-VNTR.
Articles were screened on the basis of title, abstract and manuscript review, when available. Data extraction from included studies was performed by one reviewer and inserted in a data sheet. Studies of phenotypic DR rate evaluation of first line drugs were included. To minimize risk of bias across studies, studies evaluating DR with a DST method other than the proportion or radiometric method were excluded from the review. Data of genotypic DR was included exclusively from DR strains from the selected studies. As such, we excluded the frequency of mutations in drug susceptible strains, and the mean mutation rate was modified accordingly. As well, genotype frequency comparison among states was performed only when the same genotyping method was used.
The information extracted from each included study was: 1) type of study (including articles studying phenotypic DR, genotypic DR or genetic diversity. No language, publication date, or publication status restrictions were imposed); 2) type of participants (including M. tuberculosis strains from patients either with pulmonary or extrapulmonar TB from any Mexican state); 3) characteristics of phenotypic and/or genotypic DR rates and/or genetic diversity (including state, year, number of strains and population), and the article's inclusion and exclusion criteria; 4) type of intervention (including drug susceptibility testing (DST) method, drugs evaluated (isoniazid (INH) and/or rifampicin (RIF), including or not ethambutol (EMB), streptomycin (STR) and pyrazinamide (PZA)), DR-associated mutation frequency (in genes associated to either aforementioned drug: rpoB, katG, inhA, oxyR-ahpC, embB, rss, rpsL and pncA), specific site mutation and genotyping method (spoligotyping, RFLP-IS6110 fingerprinting, MIRU-VNTR; 5) type of outcome measure (including the mean of phenotypic DR and MDR for each state, DR-associated genes mutation frequency, specific site (codon or nucleotide) mutation frequency, local sample total mutation rate, clustering rate, shared types, lineages and frequency of novel genotypes).
We performed three different analyses in our study. First, we compared DR and MDR levels, as well as resistance of each drug to M. tuberculosis strains among Mexican states. The mean rate was also obtained. Secondly, we compared the frequency of each site mutation associated to DR and obtained the most frequent. Thirdly, we obtained the frequency of shared types found in each study and compared it among Mexican states. Clustering rates were also determined (clustered shared type, representing two or more identical shared type found within study/state; unique, representing a single shared type found within study/state). As well, we searched specifically for strains belonging to the Beijing genotype.
Additional data not included in the studies, such as spoligotype description and frequency and geographical distribution of DR associated mutations, was supplemented with the multimarker database for M. tuberculosis (SITVITWEB)6 and the TB Drug Resistance Mutation Database (TBDReaMDB).7
Because the study designs, participants, interventions, and reported outcome measures varied markedly, we focused on describing the studies, their results, their applicability, and their limitations and on qualitative synthesis rather than meta-analysis. Thirty studies selected for the review were published in English and three in Spanish (figure 1). The included studies involved 3 969 M. tuberculosis strains from TB patients. The main inclusion criteria entailed strains from Mexico with phenotypic DR and/or MDR rate evaluation, genotypic DR and/or genetic diversity analysis (supplemental table I).
Phenotypic data was available for seven studies using the proportion method (n=800), seven using the radiometric (BACTEC) method (n=1 591) and one using both methods (n=303). In table I, phenotypic DR reports published between 1995 and 2013 are listed, and these represent a total of 2 694 isolates analyzed from 22 Mexican states.8-22 The overall mean DR and MDR rates were 37.5% and 20.6%, respectively. The states with the highest DR rates were Chiapas (72.2%),9 the Distrito Federal and the State of Mexico (68.3%),12 and Nuevo Leon (53.5%).14 As well, the highest MDR rates were reported in Chiapas (66.7%),10 Chiapas (53%)9 and Nuevo Leon (33.3%).15 Moreover, the lowest DR rates were reported in Baja California, Oaxaca and Sinaloa (21%),21 Tamaulipas (19.8%)19 and San Luis Potosi (9.7%).17 The lowest MDR rates were reported in Coahuila (4.5%),11 San Luis Potosi (4.2%)7 and Tamaulipas (2.1%).19
Genotypic DR data were available for twelve studies (n=748). Table II lists the gene mutations currently associated with DR strains of M. tuberculosis reported in Mexico.15, 19, 23-33 The most frequent mutations were rpoB531 (53.1%), rpoB526 (36.3%) and rpoB516 (19.5%) in RIF-resistant strains; katG315 (50.6%), position -15 of inhA (14.8%) and position -32 of ahpC (9.4%) in INH-resistant strains; embB306 (32.1%) and embB406 (8.1%) in ethambutol (EMB) resistant strains; rpsL43 (14.6%) and rrs513 (8.8%) in STR (streptomycin) resistant strains and pncA359 (16.7%) in pyrazinamide (PZA) resistant strains. In addition, a high number of previously unreported mutations in rpoB,24, 26, 27, 29, 30katG,26, 29rrs26, 32 and pncA33 were found, many of which are not included in the TBDReaMDB.
Genetic diversity data were available for ten studies. Three of them used RFLP analysis (n=807), and high clustering rates were discovered in Veracruz (36%)20 and Nuevo Leon (39%)13 for drug susceptible isolates. In contrast, the Mexican states of Tamaulipas and Chihuahua had a high clustering rate (46%) for MDR isolates.34 Two of them reported an analysis of the genetic diversity of mycobacterial strains using MIRU-VNTR. One analysis included strains isolated exclusively from HIV-infected patients from the Distrito Federal,30 and the other included only MDR strains from 23 different states.35 A wide variability in the M. tuberculosis strains was observed in both studies, with most of the genotypes being unique.30, 35
Eight studies used spoligotyping for genetic diversity analysis (n=1 237). In table III, a description of the M. tuberculosis shared types reported in Mexico so far are listed, and 26 states of Mexico and the Distrito Federal were included.15, 17, 22, 30, 34-37 The most predominant clades identified to date include the Haarlem (H) clade, the Latin American-Mediterranean (LAM) clade, the X clade, and the T clade, which were detected in almost all of the states analyzed (table III, supplemental figure S1). The associated sublineages include T1, LAM9, H3, and H1. Specifically, the most predominant shared types were SIT53 (T1, n=188, 3.9%), SIT119 (X1, n=125, 6.9%), SIT19 (EAI2-Manila, n=80, 6.3%) and SIT42 (LAM9, n=77, 3.0%). As well, clustering of spoligotypes is frequent. SIT1 Beijing genotype has been reported in Puebla,36 Jalisco,22 Baja California, Sinaloa, Veracruz35 and San Luis Potosi.17 A high number of spoligotypes previously unreported in the global database were detected (58% in Guerrero,37 34% in Distrito Federal30), which were not included in our results.
Some acceptable evidence from comparison of DR and MDR levels of M. tuberculosis strains from Mexico indicated higher rates than those presented in a nationally representative survey conducted during 2008-2009 in nine states (DR=7.8% and MDR=2.8%).38 This indicates that the prevalence of DR and MDR is a remaining issue.
The evidence regarding genotypic DR analysis is weak. Currently, only seven states (Nuevo Leon, Veracruz, Distrito Federal, Sonora, Tamaulipas, Puebla, and Durango) in Mexico have been studied to detect mutations associated with DR-TB strains. As such, the assessment of the actual mutation frequency in the country is difficult.
The evidence regarding genetic diversity is acceptable enough only for spoligotyping, given that few studies using RFLP and MIRU-VNTR analysis were found. The detection of high clustering rates for spoligotypes suggests that a high transmission rate of M. tuberculosis clones exists in the country. As well, the detection of a high number of spoligotypes previously unreported in the global database, highlights the need for further spoligotyping analyses to be conducted in Mexico.
Beijing M. tuberculosis strains have been reported to have an increased ability to spread and cause disease, and accordingly, are considered hypervirulent strains. In addition, although these strains are highly prevalent throughout Asia, they have also been detected worldwide.39 The SIT1 genotype, which belongs to the Beijing genotype of East-Asian lineage, has been reported in several states in Mexico.
Understanding the nature and frequency of mutations associated with DR-TB, as well as the distinct M. tuberculosis genotypes that are responsible for TB in different settings, are important for control of this disease. However, our study has several limitations. The quality, the methodology and population of the studies varied. Five of the studies did not explicitly state that evaluation of phenotypic DR data included quality control, which could lead to overestimation of actual DR levels in these studies. As well, nine studies did not include DR data for all five drugs, thus actual mean DR rate for these drugs may vary. As well, different methodologies used in the studies can difficult DR rate levels comparison. Consequently, this resulted in high degrees of variability between resistance levels found among different settings, as reported before.40
This represents the first systematic review of phenotypic and genotypic DR, and genetic diversity of M. tuberculosis strains from Mexico. DR-TB still remains in Mexico, and might still be increasing in some settings. The alarming lack of genotyping information available for clinical isolates of M. tuberculosis from Mexico, specifically MIRU-VNTR data, as well as the detection of a high number of spoligotypes previously unreported in the global database, highlights the need for additional analyses to be conducted in Mexico. Importantly, further information regarding the current genotypes that exist is needed. For example, the status of Beijing TB strains in Mexico also needs to be monitored, particularly to determine whether they are expanding. Some Beijing genotypes have been associated with MDR and the incidence rate of MDR strains and their associated mutations have not been decreasing over the past few years. Thus, additional emphasis must be placed on the search for these genotypes. Furthermore, considering that a meaningful decrease in the incidence rate of TB in Mexico has not been observed in recent years, additional studies are needed to better evaluate the transmission dynamics of TB and DR-TB.
We thank Sergio Lozano-Rodríguez, M.D., from Hospital Universitario for his review of the manuscript.
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Received on: July 22, 2013
Accepted on: July 26, 2013
Av. Madero s/n, col. Mitras Centro.
64460 Monterrey, Nuevo León, México.