Archives of Medical Research - (2015) 1 2 3 ORIGINAL ARTICLE 4 5 6 7 8 9 Alejandro G omez-G omez,a,b,c Martin Maga~ na-Aquino,a,b,c Salvador L opez-Meza,d 10 Q2 e f 11 Marcelo Aranda-Alvarez, Dora E. Dıaz-Ornelas, Marıa Guadalupe Hernandez-Segura,g 12 Miguel Angel Salazar-Lezama,h Martın Castellanos-Joya,i and Daniel E. Noyolaj 13 a 14 Division de Medicina Interna, Hospital Central ‘‘Dr. Ignacio Morones Prieto’’, San Luis Potosı, Mexico b 15 Departamento de Medicina Interna, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico c 16 Comite Estatal de Tuberculosis Farmacorresistente, dPrograma de Atencion al Adulto Mayor, eDireccion de Polıticas y Calidad en Salud, f 17 Programa de Micobacteriosis Servicios de Salud del Estado de San Luis Potosı, San Luis Potosı, Mexico g 18 Servicio de Medicina Preventiva, Hospital Central ‘‘Dr. Ignacio Morones Prieto’’, San Luis Potosı, Mexico h 19 Asesor Nacional en Tuberculosis Farmacorresistente, Instituto Nacional de Enfermedades Respiratorias, Mexico, D.F., Mexico i 20 Direccion Programa Nacional de Tuberculosis, Secretarıa de Salud, Mexico, D.F., Mexico j 21 Departmento de Microbiologıa, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico 22 Received for publication August 22, 2014; accepted January 29, 2015 (ARCMED-D-14-00474). 23 24 25 26 Background and Aims. Multidrug resistant tuberculosis (MDR-TB) poses problems in 27 treatment, costs and treatment outcomes. It is not known if classically described risk fac28 tors for MDR-TB in other countries are the same in Mexico and the frequency of the as29 sociation between diabetes mellitus (DM) and MDR-TB in our country is not clear. We 30 undertook this study to analyze risk factors associated with the development of MDR-TB, 31 with emphasis on DM. 32 33 Methods. A case-control study in the state of San Luis Potosi (SLP), Mexico Was carried 34 out. All pulmonary MDR-TB patients diagnosed in the state of SLP between 1998 and 35 2013 (36 cases) evaluated at a state pharmacoresistant tuberculosis (TB) clinic and com36 mittee; 139 controls were randomly selected from all pulmonary non-multidrug-resistant 37 tuberculosis (non-MDR-TB) cases identified between 2003 and 2008. Cases and controls 38 were diagnosed and treated under programmatic conditions. 39 40 Results. Age, gender, malnutrition, being a health-care worker, HIV/AIDS status, and 41 drug abuse were not significantly different between MDR-TB and non-MDR-TB patients. 42 Significant differences between MDR-TB and non-MDR-TB patients were DM (47.2 vs. 43 28.1%; p 5 0.028); previous anti-TB treatments (3 vs. 0, respectively; p ! 0.001), and 44 duration of first anti-TB treatment (8 vs. 6 months, respectively; p ! 0.001). 45 Conclusions. MDR-TB and DM are associated in 47.2% of MDR TB cases (17/36) in 46 47 this study. Other recognized factors were not found to be significantly different in 48 MDR-TB compared to non-MDR-TB in this study. Cost-feasible strategies must be im49 plemented in the treatment of DM-TB in order to prevent the selection of MDR50 TB. Ó 2015 IMSS. Published by Elsevier Inc. 51 Key Words: MDR-TB, Diabetes, Latin America. 52 53 54 55 56 57 Introduction 58 59 Tuberculosis (TB) remains a global public health problem Address reprint request to: Alejandro Gomez-Gomez, Dr., Internal 60 (1,2). Multidrug-resistant TB (MDR-TB) is defined as a Medicine Division, Hospital Central ‘‘Dr. Ignacio Morones Prieto’’, Ave61 Mycobacterium tuberculosis strain that shows resistance nida Venustiano Carranza 2395, San Luis Potosı 78210, Mexico; Phone: 62 to two or more drugs, at least simultaneously to rifampin ---; FAX: ---; E-mail: [email protected]
Diabetes and Other Risk Factors for Multi-drug Resistant Tuberculosis in a Mexican Population with Pulmonary Tuberculosis: Case Control Study
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(R) and isoniazid (H). Pulmonary infections caused by these strains are much more difficult and expensive to treat, with cure rates between 48 and 54% compared to 96% success in drug-susceptible pulmonary tuberculosis (DS-TB) (1e4). The World Health Organization (WHO) has estimated 630,000 cases of MDR-TB worldwide (range 460,000e790,000) (1). WHO estimates that 3.7% of new TB cases and 20% of re-treatment cases are MDR-TB (1). According to the National Program for Tuberculosis Control and Prevention in Mexico, there were 18,848 new cases of tuberculosis in 2010 and 629 MDR-TB cases between the years 2010 and 2012 (5,6). Many risk factors for the development of MDR-TB have been described but a history of multiple drug treatments is the most frequent factor (2,7e11). In Mexico, factors that have been reported in association with this condition include administration of monotherapy, treatment dropouts, long-term evolution of the disease, and multiple previous treatments (12,13). Other risk factors frequently reported in many countries (2,7e11) such as drug use, imprisonment, psychological disorders, HIV infection, and being a health-care worker have rarely been described in Mexican MDR-TB patients (6,12,13). The lack of Directly Observed Therapy Strategy (DOTS) is another risk factor in these studies; in Mexico DOTS is applied to 85e90% of DS TB patients (5). Mexico recommends a standardized treatment for all first anti-TB treatment recommended by WHO (14,15). Diabetes mellitus (DM) has been clearly associated as a risk factor for TB; however, the prevalence of DM among TB patients varies widely (1.9e30%) in different studies. DM has also been shown to increase the risk of treatment failure (16e24). In the U.S. the frequency of DM among TB patients is higher in the Hispanic population (Mexican-Americans) than in other populations (17). The association of DM and MDR-TB is less clear and different studies have shown conflicting results with some reporting a significant association (25,26), whereas others have failed to do so (27,28); nevertheless, as DM has been associated with the number of cavities observed on chest films, delayed sputum conversion, and treatment failure (16,20,22), it is inferred to be a risk factor for MDR-TB. DM is present in 50% MDR-TB patients in Mexico (observational unpublished national data of MDR-TB patients between years 2010 and 2012; http://www.who.int/tb/mexico_ tb.pdf), the highest frequency for this association described in the world. Because of the elevated frequency of DM in Mexico compared to other countries (9.2% prevalence in the general population and 9.4e26.3% in persons between ages 40 and 69 years old (29), its impact on MDR-TB may be higher compared to other countries. Due to the elevated economic cost of treatment and high transmission risk of MDR-TB it is important to define the role of DM as a risk factor for this condition because this may lead to specific
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policies for the follow-up of DM-TB patients in Mexico. The objective of this study was to describe risk factors associated with pulmonary MDR-TB with emphasis in DM in a Mexican cohort of pulmonary non-MDR-TB and MDR-TB patients under programmatic conditions.
Materials and Methods As of 1998, all patients with suspected MDR-TB in the state of San Luis Potosı (SLP) (total population 2,585,518 inhabitants according to the 2010 census) are referred to a multidisciplinary group for assessment, treatment, and follow-up (State Committee for MDR-TB). For this study, data from all cases $18 years of age with confirmed pulmonary MDR-TB evaluated from 1998e2013 by this committee was analyzed (n 5 36). Patient assessment included a careful past treatment history obtained by a standardized protocol, sputum culture for mycobacteria, polymerase chain reaction (PCR) assay for Mycobacterium tuberculosis complex, and drug susceptibility test for first line antituberculosis drugs. HIV and general laboratory tests are performed in all MDR-TB cases as part of the initial evaluation. Drug susceptibility testing was done by the proportion method. All strains were tested at the Laboratorio Estatal de Salud Publica, a regional certified laboratory, for susceptibility to four first-line drugs as a policy of the Mexican Ministry of Health: the medium used was modified Middle-Brook 7H9e7H10-BACTECÔ MGITÔ 960 (30,31) and tests performed were for isoniazid (0.2 mg/ mL), rifampin (2.0 mg/mL), streptomycin (4.0 mg/mL) and ethambutol (5.0 mg/mL). Resistance was defined as the growth of O1% of the colonies in drug-containing media compared with the growth in a drug-free (control) medium. All patients classified as MDR-TB had a positive culture and positive PCR test for M. tuberculosis as well as resistance to at least isoniazid and rifampin. In addition, 60% of samples from MDR-TB cases were also processed at the Instituto de Diagnostico y Referencia Epidemiologicos (InDRE), a supranational laboratory for quality control that used Middlebrook 7H10- BACTECÔ MGITÔ 960 (30,31). As a comparison group, we included information from patients treated in SLP for pulmonary TB during a 6-year period under programmatic conditions. For this group, 139 patients were randomly selected from all patients reported to the TB program in SLP between years 2003 and 2008 with sputum samples in which acid-fast bacilli were identified by Ziehl-Neelsen staining, with clinicalradiographic data compatible with the diagnosis of pulmonary TB and in whom resistance to rifampin and MDR-TB were excluded (non-MDR-TB). In Mexico it is not a standard practice to perform culture and drug susceptibility tests to all recently diagnosed cases of TB. The control population was selected from patients treated from 2003e2008
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290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 Results 308 309 Between 1999 and 2012 there were 4,293 cases of pulmo310 nary TB diagnosed in San Luis Potosı. Among these, 1053 311 had drug susceptibility testing carried out between 2003 312 and 2008. Altogether, there were 36 patients with MDR313 TB identified during this period. A total of 174 patients 314 were analyzed in this study: the 36 cases of pulmonary 315 MDR-TB and 139 controls of pulmonary non MDR-TB 316 (non MDR-TB); the control group was randomly selected 317 from the 1053 pulmonary tuberculosis cases who had drug 318 susceptibility testing prior to initiation of therapy (3.8 con319 trols per case). The frequency of resistance to anti-TB med320 ications in the control group were the following: isoniazid, 321 5.75%; rifampicin, 0%: ethambutol, 2.2%, streptomycin, 322 3.6%. The demographic characteristics and comorbidities 323 registered in the study subjects are presented in Table 1. 324 There were two prisoners in the case population (one 325 former and one current at the time of MDR-TB evaluation 326 and treatment); in addition, two MDR-TB patients had 327 COPD. There was no patient with HIV infection among 328 329 Table 1. Demographic characteristics and comorbidities in MDR-TB and non-MDR-TB patients 330 331 MDR-TB (n [ 36) Non MDR-TB (n [ 139) Or 95% CI 332 Sociodemographic features 333 Male 28 (77.8%) 96 (69.1%) 1.57 0.66e3.72 334 Age (years, mean, 47.5 (35e60) 50 (35e63) 1.01 0.99e1.03 335 IQR) 1.16 0.43e3.14 Low income 29 (80.6%) 57/73 (78.1)a 336 Comorbiditiesa 337 Malnutrition 11 (30.6%) 52 (37.4%) 0.74 0.33e1.62 338 Chronic alcohol abuse 10 (27.8%) 29 (20.9%) 1.46 0.63e3.37 339 Smoking 9 (25%) 19 (13.7%) 2.1 0.86e5.16 340 Diabetes mellitus 17 (47.2%) 39 (28.1%) 2.29 1.08e4.86 Others 0 9 (6.5%) 0.19 0.01e3.31 341 342 IQR, interquartile range; DOTS, directly observed therapy strategy. b Some patients had more than one comorbidity. Q1 343 a 344 Data available for 73 patients.
because during this time period all pulmonary TB cases from SLP had drug susceptibility testing performed prior to first treatment as part of a project to determine primary MDR-TB frequency. All control subjects had sputum samples collected and M. tuberculosis was confirmed by culture and PCR; all controls were treated and followed according to WHO and Mexican guidelines (14,15). All clinical, laboratory, and treatment outcomes were obtained from patient files and the state TB database (former EPI-TB, since 2007 Plataforma Unica de Informaci on), which has been used since 1995 in the National Program for Tuberculosis Control in Mexico. Definitions of outcomes including death were according to WHO (32), except default for which the definition of Norma Oficial Mexicana was used (15). Data from MDR-TB cases as well as the comparison group were collected in standard forms including demographic, socioeconomic, clinical, and TB treatment-related variables. For all patients, DM cases were confirmed by two fasting serum glucose determinations (O126 mg/dL/O70 mmol/ L) and/or at least two abnormal glycosylated hemoglobin measurements (O7%); these data were supported by confirmation of the diagnosis of DM by the patient during follow-up and/or regular oral intake of a sulfonylurea. In the MDR-TB group, patients with DM were treated and followed-up by endocrinology specialists. To determine death rates in both groups, the national death certificate database of the Ministry of Health was consulted. Results were updated until October 2013. Initially we aimed to include four controls per subject (1:4 case/control ratio). Taking into account the observation of a high DM prevalence in MDR-TB patients from a preliminary analysis (40%) and the reported prevalence of DM in the Mexican population (9.2%), this would provide O95% power to detect a significant difference between both study groups with 95% confidence (29,33,34). In a subsequent analysis, taking into account the actual DM prevalence in the final study population, we obtained a 58.6% power to detect
differences with 95% confidence. Patients’ characteristics between pulmonary non-MDR-TB and pulmonary MDRTB subjects were analyzed. Continuous variables were compared using Student t test or Mann-Whitney U test according to data distribution. Categorical variables were compared using the c2 or Fisher’s exact test as appropriate. Odds ratios and 95% confidence intervals were calculated. Multivariate analysis was performed using logistic regression analysis. Statistical analyses were carried out using SPSS for Windows, version 14.0 and OpenEpi (35). A p value !0.05 was considered as significant. This study consisted of the review of existing databases and did not include any intervention. The study was approved by the Research and Ethics Committee at Servicios de Salud del Estado de San Luis Potosı.
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MDR-TB cases. There were no statistically significant differences in the history of smoking, alcohol abuse, or malnutrition between MDR-TB and non-MDR-TB patients (Table 1). However, the frequency of DM was significantly higher in patients with MDR-TB (47.2%, 17/36) compared to the non-MDR-TB group (28.1%, 39/139; OR 2.29, 95% CI 1.08e4.86). Because the prevalence of DM varies with age, and because smoking history differed between subjects with MDR-TB and non-MDR-TB (albeit not statistically significant), we decided to carry out a multivariate analysis to assess if the association between diabetes and MDR-TB was independent of other underlying conditions. In addition to age, sex, smoking history and DM, we included the presence of malnutrition, chronic alcohol abuse, and other underlying illnesses in the regression model. Multivariate logistic regression analysis indicated that the association between DM and MDR-TB was independent of other variables (adjusted OR 2.51; 95% CI 1.11e5.67). Because DM prevalence increases with age, we analyzed the frequency of this disorder in different age groups. We also compared the frequency of DM in the study patients with the prevalence of this disorder in the Mexican population. The frequency of DM in both the MDR-TB (47.2%) and non-MDR-TB (28.1%) patients was much higher than the prevalence reported in adults in Mexico (9.2%) (29). The period of time since diabetes diagnosis ranged between 3 and 10 years before the first diagnosis of pulmonary TB among MDR cases. Most non-MDR-TB patients (84.9%, 118/139) had never been treated previously for TB; in contrast, only one patient with MDR-TB had not been treated previously for TB (range 0e5 treatments; OR 14.99, 95% CI 6.1e36.82 when both groups were compared). When we compared the data from the first treatment that MDR-TB cases had ever received with the treatment received by the control patients, we found that patients with drug-resistant infections received treatment for longer periods of time (median
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8 months vs. 6 months, OR 1.65, 95% CI 1.31e2.08) (Table 2). Of note, MDR-TB patients showed low clinical/bacteriological cure rates during their first treatment; 2.8% (1/36) had documented bacteriological cure. In 75%, treatment failure was documented, whereas in 19.4% (7/36) treatment outcome data were not available from the records). In contrast, control subjects had combined clinical/bacteriological cure rates of 89% (125/139). Directly observed treatment strategy (DOTS) during first anti-TB treatment was significantly lower among MDRTB patients (Table 2). Death occurred in 15/36 patients (42%) of MDR-TB group by October 2013, all due to TB. Nine deaths occurred in the control group (6.4%), eight during the study period and one more by the year 2013. Three were directly due to tuberculosis and six were non-TB related (two AIDS, two complications of DM, two due to malnutrition and other additional non-pulmonary bacterial infections).
Discussion This study compares pulmonary MDR-TB cases and pulmonary TB patients without MDR under programmatic conditions in a Mexican population. The characteristics of TB patients in this study are consistent with national data in terms of age, gender and other demographic features, prevalence of underlying disorders (including malnutrition, alcohol and other drug abuse, HIV/AIDS status, diabetes, among others), and cure rates (83.2%) as shown in national TB registries and large Mexican cohorts (5,16). As reported in other national studies (12,13), in this report the number of previous anti-TB treatments (3 vs. 1), and the duration (8 vs. 6 months) and rate of failure (75 vs. 1.4%) to first anti-TB treatment were significantly higher among MDR-TB patients compared to non MDRTB cases, respectively. Application of DOTS during the
Table 2. Comparison of treatment characteristics between MDR-TB and non-MDR-TB groupsa MDR-TB (n [ 36) Number of previous treatments (median, IQR) Duration of treatment (months, median, IQR) DOTS Bacteriological cure Treatment completed Lost to follow-up Not recorded Treatment failure Death by October 2013 TB-related death Non-TB related death
3 8 15 1
(2e3.75) (6e12)b (53%)c (2.8%) 0 1 (2.8%) 7 (19.4%) 27 (75%) 15 (42%) 0
Non-MDR-TB (n [ 139) 0 6 120 104 21 2 10 2
(0e0) (6e6). (86%) (74%) (15%) (1.4%) (7.1%) (1.4%)
3 (2.1%) 6 (4.3%)
a
Or
95% CI
14.99 1.65 0.18 0.009 0.07 1.96 3.11 205.5
6.1e36.82 1.31e2.08 0.07e0.44 0.001e0.073 0.004e1.28 0.17e22.21 1.09e8.87 42.04e1004.51
32.38 0.28
8.63e121.46 0.01e5.11
For MDR-TB cases, data (except the number of previous treatments) corresponds to the first TB treatment that the patient ever received; for non MDR-TB subjects, data corresponds to the treatment prescribed during the study episode. b Data available for 35 patients. c Data available for 28 patients.
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first anti-TB treatment was significantly lower among MDR-TB patients compared to non-MDR-TB cases (53 vs. 86%), respectively. It is noteable that risk factors for MDR-TB frequently reported in other countries (drug abuse, health care workers, HIV) were not significantly different between cases and control groups in this study (2,7e11) and this is supported by national data described previously in this report. Other known risk factors for MDR-TB such as low income, malnutrition, and alcohol were not significantly different between non-MDR-TB and MDR-TB groups. The important finding in this study is the association between pulmonary MDR-TB and DM, present in 47.2% (17/36) of cases and these results are consistent with national data. In a national pulmonary MDR-TB cohort of Servicios de Salud de Mexico involving all cases diagnosed with MDR-TB between years 2000 and 2012 (total 5 629 cases), 50% had the association of MDR-TB and DM (6). The trend in frequency of this association has remained with little variation during this period of time at state (San Luis Potosı) and national levels, 42e48% and 45e50% respectively. Regarding the association of non-MDR-TB and DM, data from this study are consistent with national data as well as being demonstrated in two large cohorts. In a national cohort of Servicios de Salud de Mexico including 19,491 cases (5), this association was present in 21% of all TB cases. In a recent study published by Jimenez-Corona and Ponce-de-Leon et al., frequency of DM in a cohort of 1,262 tuberculosis patients in Mexico was 29.6%. These figures are similar to the 28.1% found in non-MDR-TB patients in our study. Although the association between DM and TB is widely known, this is the first study to show that Mexico could have the highest frequency of DM among MDR-TB patients, but a national study is necessary to confirm this. This could be explained by a higher prevalence of DM in Mexico compared to other countries (29). Previous analyses of a smaller case series lead us to suspect this high association in Mexico (33,34). The frequency of the association of DM and MDR-TB is diverse in different regions. In a study in a mixed AmericanMexican population near the Texas-Mexico border, FisherHoch et al. found DM as a risk factor for MDR-TB, with a DM prevalence of 27.8% among MDR-TB cases (26). This association is considerably lower in other countries like China and India (14.5% and 5e8 to 11%, respectively) (36,37). The association of DM and MDR-TB in Mexico can impact on the economic burden of treatment and the risk of MDR-TB transmission. In addition, it could have an impact on the generation of XDR-TB. Therefore, additional studies are warranted in our country to explore the potential causes for MDR-TB development among DM-TB patients. Possible explanations for the increased frequency of MDR-TB among DM-TB patients include the following: a) switching to the maintenance phase of anti-TB treatment (isoniazid and rifampin) in smear positive patients at the second month (16,36,38); b) a higher mycobacterial burden in DM-TB patients. In the same study by Jimenez-Corona
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et al., DM was associated with a higher frequency of cavities in chest x-rays, 45% among diabetics vs. 35% in non-diabetic patients ( p ! 0.001) (16); c) lower treatment adherence in DM-TB patients compared to those without DM although this has not been shown in other studies (16,21,37); in this report, 47% of MDR-TB patients were not treated under DOTS strategy; d) obesity and glycemic control during anti-TB treatment with consequent alterations in immunity (39,40); e) a higher primary resistance to isoniazid among DM-TB patients although this has not been demonstrated in our country (12,16); and f) altered pharmacokinetic of anti-TB drugs and pharmacological interactions between anti-TB medications and sulphonylureas, mainly with rifampin where altered pharmacokinetics have been demonstrated (41,42). Simple measures should be reinforced in patients with DM and pulmonary TB such as strengthening education to primary care physicians in charge of treatment of TB patients, apply DOTS strategy to all patients treated for TB, change to second phase treatment with two drugs only when sputum conversion has been achieved and demonstrated; diagnose MDR-TB at the end of the second or at most at the fourth month of first anti-TB treatment, if rapid test or culture/drug-susceptibility tests are used, respectively; and refer patients to the state TB clinic after MDR has been demonstrated or patient remains with smear positive after the second month and culture has been performed. There are other interventions that could be evaluated in DM-TB patients such as the use of rapid molecular tests. GeneXpertÒ, a test for rifampin resistance detection, has demonstrated an earlier diagnosis of MDR-TB and is cost-effective according to WHO recommendations (3). This measure seems already needed in Mexico given the high frequency of persistent smear positive at the end of the second month of four drug anti-TB treatment (46% in DM-TB and 37% in non-DM-TB patients) (16). It would be desirable to detect not only MDR-TB when it is already established, but also primary isoniazid resistance in patients with DM and first pulmonary TB diagnosis in order to offer appropriate treatment to decrease the probability to select multi-drug resistant strains during a standardized first anti-TB treatment. This can be achieved with the use of tests like GenotypeÒ MTBDRplus. Although more expensive, it has demonstrated to be cost effective as well (3,43). There are some potential changes in the treatment of DM-TB patients that could be evaluated in further studies such as increase in the dose of rifampin, controlling DM with insulin instead of oral drugs if uncontrolled DM is detected after the first month, select and appropriate treatment for patients with DM and TB and primary resistance to isoniazid. These measures could be evaluated in future studies in DM-TB patients. The limitations of the study are the reduced number of cases, which may not be representative of all Mexican MDR-TB patients. Also, controls and cases were not
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recruited during the same period of time. Although according to the National Survey on Health and Nutrition there has been an increase in the prevalence of DM between 2000 and 2012 (29), the frequency of DM among MDRTB cases in our cohort has remained very similar throughout the study period. Of note, our results are supported by similar rates of DM in both non-MDR-TB and MDR-TB in national data gathered during a long period of time. In conclusion, DM is associated with MDR-TB in our region. Our study population appears to be consistent with national data for Mexican MDR-TB patients. Due to the high frequency of DM in Mexican MDR-TB patients and the high prevalence of DM in this country, future studies in this population must be conducted and development of specific recommendations for the treatment and follow-up of diabetic patients with TB may reduce the number of MDR-TB cases.
Conflict of Interest The authors report no conflict of interest.
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12. Garcıa-Garcıa ML, Ponce-de-Leon A, Jimenez-Corona ME, et al. Clinical consequences and transmissibility of drug-resistant tuberculosis in southern Mexico. Arch Intern Med 2000;160:630e636. 13. Alvarez-Gordillo GC, Halperin-Frisch D, Blancarte-Melendres L, et al. Factores de riesgo para resistencia a drogas antifımicas en Chiapas, Mexico. Salud Publica Mex 1995;37:408e416. 14. World Health Organization. Guidelines for the treatment of tuberculosis. Geneva: World Health Organization; 2010. 15. Secretaria de Salud. Modifiacion a la Norma Oficial Mexicana NOM006-SSA2-1993, para la prevencion y control de la tuberculosis en la atencion primaria a la salud. Diario Oficial, September 2005. 16. Jimenez-Corona ME, Cruz-Hervert LP, Garcıa-Garcıa L, et al. Association of diabetes and tuberculosis: impact on treatment and posttreatment outcomes. Thorax 2013;68:214e220. 17. Pablos-Mendez A, Blustein J, Knirsch C. The role of diabetes mellitus in the higher prevalence of tuberculosis among Hispanics. Am J Public Health 1997;87:574e579. 18. Bacakoglu F, Basoglu OK, Cok G, et al. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595e600. 19. Ponce-De-Leon A, Garcia-Garcia Md Mde L, Garcia-Sancho MC, et al. Tuberculosis and diabetes in southern Mexico. Diabetes Care 2004;27:1584e1590. 20. Wang CS, Chen HC, Yang CJ, et al. Impact of type 2 diabetes on manifestations and treatment outcome of pulmonary tuberculosis. Epidemiol Infect 2009;137:203e210. 21. Singla R, Khan N, Al-Sharif N, et al. Influence of diabetes on manifestations and treatment outcome of pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2006;10:74e79. 22. Alisjahbana B, van Crevel R, Sahiratmadja E, et al. Diabetes mellitus is strongly associated with tuberculosis in Indonesia. Int J Tuberc Lung Dis 2006;10:696e700. 23. Ruslami R, Aarnoutse RE, Alisjahbana B, et al. Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health 2010;15:1289e1299. 24. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 2009;9:737e746. 25. Bashar M, Alcabes P, Rom WN, et al. Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997. Chest 2001;120:1514e1549. 26. Fisher-Hoch SP, Whitney E, McCormick JB, et al. Type 2 diabetes and multidrug-resistant tuberculosis. Scand J Infect Dis 2008;40:888e893. 27. Subhash HS, Ashwin I, Mukundan U, et al. Drug resistant tuberculosis in diabetes mellitus: a retrospective study from south India. Trop Doct 2003;33:154e156. 28. Garcıa-Garcıa ML, Sifuentes-Osornio J, Jimenez-Corona ME, et al. Resistencia de Mycobacterium tuberculosis a los antimicrobianos en Orizaba, Veracruz. Implicaciones para el Programa de Prevencion y Control de la Tuberculosis. Rev Invest Clin 2001;53:315e323. 29. Instituto Nacional de Salud Publica. Encuesta Nacional de Salud y Nutricion 2012. Cuernavaca, Mexico: INSP; 2012. Available from: http://ensanut.insp.mx/informes/ENSANUT2012. ResultadosNacionales.pdf. Accessed July 26, 2013. 30. Clinical and Laboratory Standards Institute (CLSI). Susceptibility testing of Mycobacteria, Nocardia and other aerobic actinomycetes; approved standard-second edition M24-A2. Wayne, PA: CLSI; 2011. p. 31. 31. Kr€u€uner A, Yates MD, Drobniewski FA, et al. Evaluation of MGIT 960-based antimicrobial susceptibility testing and determination of critical concentrations of first and second-line antimicrobial drugs with clinical-drug resistant strains of mycobacterium tuberculosis. J Clin Microbiol 2006;44:811e818. 32. World Health Organization. Definitions and reporting framework for tuberculosis—2013 revision. Geneva: World Health Organization; 2013.
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33. G omez-G omez A, Gonzalez-Rubio MV, Maga~na-Aquino M, et al. Factores de riesgo asociados a multi-resistencia en una cohorte de pacientes con tuberculosis pulmonar multi-drogoresistente (TB-MDR). Neumol Cir Torax 2004;63:21e22. 34. G omez-G omez A, Maga~na-Aquino M, Villeda-Sanchez E, et al. Frecuencia incrementada de respuesta tardıa y recaıda a tratamiento anti-tuberculosis en una cohorte de pacientes con tuberculosis pulmonar y diabetes mellitus. Neumol Cirugıa Torax 2005;64(Suppl):S70. 35. Dean AG, Sullivan KM, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health (www.OpenEpi.com). 36. Yuan X, Zhang T, Kawakami K, et al. Genotyping and clinical characteristics of multidrug and extensively drug-resistant tuberculosis in a tertiary care tuberculosis hospital in China. BMC Infect Dis 2013; 13:315e324. 37. Porwal C, Kaushik A, Makkar N, et al. Incidence and risk factors for extensively drug-resistant tuberculosis in Delhi region. Plos One 2013; 8:e55299.
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38. Restrepo BI, Fisher-Hoch SP, Smith B, et al. Mycobacterial clearance from sputum is delayed during the first phase of treatment in patients with diabetes. Am J Trop Med Hyg 2008;79:541e544. 39. Restrepo BI, Fisher-Hoch SP, Pino PA, et al. Tuberculosis in poorly controlled type 2 diabetes: altered cytokine expression in peripheral white blood cells. Clin Infect Dis 2008;47:634e641. 40. Stalenhoef JE, Alisjahbana B, Nelwan EJ, et al. The role of interferongamma in the increased tuberculosis risk in type 2 diabetes mellitus. Eur J Clin Microbiol Infect Dis 2008;27:97e103. 41. Nijland HMJ, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006;43:848e854. 42. Milan-Segovia RC, Domınguez-Ramırez AM, Jung-Cook H, et al. Relative bioavailability of rifampicin in a three-drug fixed-dose combination formulation. Int J Tuberc Lung Dis 2010;14:1454e1460. 43. Oxlade O, Falzon D, Menzies D. The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis. Eur Respir J 2012;39:626e634.
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Diabetes and Other Risk Factors for Multi-drug Resistant Tuberculosis in a Mexican Population with Pulmonary Tuberculosis: Case Control Study
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(R) and isoniazid (H). Pulmonary infections caused by these strains are much more difficult and expensive to treat, with cure rates between 48 and 54% compared to 96% success in drug-susceptible pulmonary tuberculosis (DS-TB) (1e4). The World Health Organization (WHO) has estimated 630,000 cases of MDR-TB worldwide (range 460,000e790,000) (1). WHO estimates that 3.7% of new TB cases and 20% of re-treatment cases are MDR-TB (1). According to the National Program for Tuberculosis Control and Prevention in Mexico, there were 18,848 new cases of tuberculosis in 2010 and 629 MDR-TB cases between the years 2010 and 2012 (5,6). Many risk factors for the development of MDR-TB have been described but a history of multiple drug treatments is the most frequent factor (2,7e11). In Mexico, factors that have been reported in association with this condition include administration of monotherapy, treatment dropouts, long-term evolution of the disease, and multiple previous treatments (12,13). Other risk factors frequently reported in many countries (2,7e11) such as drug use, imprisonment, psychological disorders, HIV infection, and being a health-care worker have rarely been described in Mexican MDR-TB patients (6,12,13). The lack of Directly Observed Therapy Strategy (DOTS) is another risk factor in these studies; in Mexico DOTS is applied to 85e90% of DS TB patients (5). Mexico recommends a standardized treatment for all first anti-TB treatment recommended by WHO (14,15). Diabetes mellitus (DM) has been clearly associated as a risk factor for TB; however, the prevalence of DM among TB patients varies widely (1.9e30%) in different studies. DM has also been shown to increase the risk of treatment failure (16e24). In the U.S. the frequency of DM among TB patients is higher in the Hispanic population (Mexican-Americans) than in other populations (17). The association of DM and MDR-TB is less clear and different studies have shown conflicting results with some reporting a significant association (25,26), whereas others have failed to do so (27,28); nevertheless, as DM has been associated with the number of cavities observed on chest films, delayed sputum conversion, and treatment failure (16,20,22), it is inferred to be a risk factor for MDR-TB. DM is present in 50% MDR-TB patients in Mexico (observational unpublished national data of MDR-TB patients between years 2010 and 2012; http://www.who.int/tb/mexico_ tb.pdf), the highest frequency for this association described in the world. Because of the elevated frequency of DM in Mexico compared to other countries (9.2% prevalence in the general population and 9.4e26.3% in persons between ages 40 and 69 years old (29), its impact on MDR-TB may be higher compared to other countries. Due to the elevated economic cost of treatment and high transmission risk of MDR-TB it is important to define the role of DM as a risk factor for this condition because this may lead to specific
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policies for the follow-up of DM-TB patients in Mexico. The objective of this study was to describe risk factors associated with pulmonary MDR-TB with emphasis in DM in a Mexican cohort of pulmonary non-MDR-TB and MDR-TB patients under programmatic conditions.
Materials and Methods As of 1998, all patients with suspected MDR-TB in the state of San Luis Potosı (SLP) (total population 2,585,518 inhabitants according to the 2010 census) are referred to a multidisciplinary group for assessment, treatment, and follow-up (State Committee for MDR-TB). For this study, data from all cases $18 years of age with confirmed pulmonary MDR-TB evaluated from 1998e2013 by this committee was analyzed (n 5 36). Patient assessment included a careful past treatment history obtained by a standardized protocol, sputum culture for mycobacteria, polymerase chain reaction (PCR) assay for Mycobacterium tuberculosis complex, and drug susceptibility test for first line antituberculosis drugs. HIV and general laboratory tests are performed in all MDR-TB cases as part of the initial evaluation. Drug susceptibility testing was done by the proportion method. All strains were tested at the Laboratorio Estatal de Salud Publica, a regional certified laboratory, for susceptibility to four first-line drugs as a policy of the Mexican Ministry of Health: the medium used was modified Middle-Brook 7H9e7H10-BACTECÔ MGITÔ 960 (30,31) and tests performed were for isoniazid (0.2 mg/ mL), rifampin (2.0 mg/mL), streptomycin (4.0 mg/mL) and ethambutol (5.0 mg/mL). Resistance was defined as the growth of O1% of the colonies in drug-containing media compared with the growth in a drug-free (control) medium. All patients classified as MDR-TB had a positive culture and positive PCR test for M. tuberculosis as well as resistance to at least isoniazid and rifampin. In addition, 60% of samples from MDR-TB cases were also processed at the Instituto de Diagnostico y Referencia Epidemiologicos (InDRE), a supranational laboratory for quality control that used Middlebrook 7H10- BACTECÔ MGITÔ 960 (30,31). As a comparison group, we included information from patients treated in SLP for pulmonary TB during a 6-year period under programmatic conditions. For this group, 139 patients were randomly selected from all patients reported to the TB program in SLP between years 2003 and 2008 with sputum samples in which acid-fast bacilli were identified by Ziehl-Neelsen staining, with clinicalradiographic data compatible with the diagnosis of pulmonary TB and in whom resistance to rifampin and MDR-TB were excluded (non-MDR-TB). In Mexico it is not a standard practice to perform culture and drug susceptibility tests to all recently diagnosed cases of TB. The control population was selected from patients treated from 2003e2008
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290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 Results 308 309 Between 1999 and 2012 there were 4,293 cases of pulmo310 nary TB diagnosed in San Luis Potosı. Among these, 1053 311 had drug susceptibility testing carried out between 2003 312 and 2008. Altogether, there were 36 patients with MDR313 TB identified during this period. A total of 174 patients 314 were analyzed in this study: the 36 cases of pulmonary 315 MDR-TB and 139 controls of pulmonary non MDR-TB 316 (non MDR-TB); the control group was randomly selected 317 from the 1053 pulmonary tuberculosis cases who had drug 318 susceptibility testing prior to initiation of therapy (3.8 con319 trols per case). The frequency of resistance to anti-TB med320 ications in the control group were the following: isoniazid, 321 5.75%; rifampicin, 0%: ethambutol, 2.2%, streptomycin, 322 3.6%. The demographic characteristics and comorbidities 323 registered in the study subjects are presented in Table 1. 324 There were two prisoners in the case population (one 325 former and one current at the time of MDR-TB evaluation 326 and treatment); in addition, two MDR-TB patients had 327 COPD. There was no patient with HIV infection among 328 329 Table 1. Demographic characteristics and comorbidities in MDR-TB and non-MDR-TB patients 330 331 MDR-TB (n [ 36) Non MDR-TB (n [ 139) Or 95% CI 332 Sociodemographic features 333 Male 28 (77.8%) 96 (69.1%) 1.57 0.66e3.72 334 Age (years, mean, 47.5 (35e60) 50 (35e63) 1.01 0.99e1.03 335 IQR) 1.16 0.43e3.14 Low income 29 (80.6%) 57/73 (78.1)a 336 Comorbiditiesa 337 Malnutrition 11 (30.6%) 52 (37.4%) 0.74 0.33e1.62 338 Chronic alcohol abuse 10 (27.8%) 29 (20.9%) 1.46 0.63e3.37 339 Smoking 9 (25%) 19 (13.7%) 2.1 0.86e5.16 340 Diabetes mellitus 17 (47.2%) 39 (28.1%) 2.29 1.08e4.86 Others 0 9 (6.5%) 0.19 0.01e3.31 341 342 IQR, interquartile range; DOTS, directly observed therapy strategy. b Some patients had more than one comorbidity. Q1 343 a 344 Data available for 73 patients.
because during this time period all pulmonary TB cases from SLP had drug susceptibility testing performed prior to first treatment as part of a project to determine primary MDR-TB frequency. All control subjects had sputum samples collected and M. tuberculosis was confirmed by culture and PCR; all controls were treated and followed according to WHO and Mexican guidelines (14,15). All clinical, laboratory, and treatment outcomes were obtained from patient files and the state TB database (former EPI-TB, since 2007 Plataforma Unica de Informaci on), which has been used since 1995 in the National Program for Tuberculosis Control in Mexico. Definitions of outcomes including death were according to WHO (32), except default for which the definition of Norma Oficial Mexicana was used (15). Data from MDR-TB cases as well as the comparison group were collected in standard forms including demographic, socioeconomic, clinical, and TB treatment-related variables. For all patients, DM cases were confirmed by two fasting serum glucose determinations (O126 mg/dL/O70 mmol/ L) and/or at least two abnormal glycosylated hemoglobin measurements (O7%); these data were supported by confirmation of the diagnosis of DM by the patient during follow-up and/or regular oral intake of a sulfonylurea. In the MDR-TB group, patients with DM were treated and followed-up by endocrinology specialists. To determine death rates in both groups, the national death certificate database of the Ministry of Health was consulted. Results were updated until October 2013. Initially we aimed to include four controls per subject (1:4 case/control ratio). Taking into account the observation of a high DM prevalence in MDR-TB patients from a preliminary analysis (40%) and the reported prevalence of DM in the Mexican population (9.2%), this would provide O95% power to detect a significant difference between both study groups with 95% confidence (29,33,34). In a subsequent analysis, taking into account the actual DM prevalence in the final study population, we obtained a 58.6% power to detect
differences with 95% confidence. Patients’ characteristics between pulmonary non-MDR-TB and pulmonary MDRTB subjects were analyzed. Continuous variables were compared using Student t test or Mann-Whitney U test according to data distribution. Categorical variables were compared using the c2 or Fisher’s exact test as appropriate. Odds ratios and 95% confidence intervals were calculated. Multivariate analysis was performed using logistic regression analysis. Statistical analyses were carried out using SPSS for Windows, version 14.0 and OpenEpi (35). A p value !0.05 was considered as significant. This study consisted of the review of existing databases and did not include any intervention. The study was approved by the Research and Ethics Committee at Servicios de Salud del Estado de San Luis Potosı.
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MDR-TB cases. There were no statistically significant differences in the history of smoking, alcohol abuse, or malnutrition between MDR-TB and non-MDR-TB patients (Table 1). However, the frequency of DM was significantly higher in patients with MDR-TB (47.2%, 17/36) compared to the non-MDR-TB group (28.1%, 39/139; OR 2.29, 95% CI 1.08e4.86). Because the prevalence of DM varies with age, and because smoking history differed between subjects with MDR-TB and non-MDR-TB (albeit not statistically significant), we decided to carry out a multivariate analysis to assess if the association between diabetes and MDR-TB was independent of other underlying conditions. In addition to age, sex, smoking history and DM, we included the presence of malnutrition, chronic alcohol abuse, and other underlying illnesses in the regression model. Multivariate logistic regression analysis indicated that the association between DM and MDR-TB was independent of other variables (adjusted OR 2.51; 95% CI 1.11e5.67). Because DM prevalence increases with age, we analyzed the frequency of this disorder in different age groups. We also compared the frequency of DM in the study patients with the prevalence of this disorder in the Mexican population. The frequency of DM in both the MDR-TB (47.2%) and non-MDR-TB (28.1%) patients was much higher than the prevalence reported in adults in Mexico (9.2%) (29). The period of time since diabetes diagnosis ranged between 3 and 10 years before the first diagnosis of pulmonary TB among MDR cases. Most non-MDR-TB patients (84.9%, 118/139) had never been treated previously for TB; in contrast, only one patient with MDR-TB had not been treated previously for TB (range 0e5 treatments; OR 14.99, 95% CI 6.1e36.82 when both groups were compared). When we compared the data from the first treatment that MDR-TB cases had ever received with the treatment received by the control patients, we found that patients with drug-resistant infections received treatment for longer periods of time (median
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8 months vs. 6 months, OR 1.65, 95% CI 1.31e2.08) (Table 2). Of note, MDR-TB patients showed low clinical/bacteriological cure rates during their first treatment; 2.8% (1/36) had documented bacteriological cure. In 75%, treatment failure was documented, whereas in 19.4% (7/36) treatment outcome data were not available from the records). In contrast, control subjects had combined clinical/bacteriological cure rates of 89% (125/139). Directly observed treatment strategy (DOTS) during first anti-TB treatment was significantly lower among MDRTB patients (Table 2). Death occurred in 15/36 patients (42%) of MDR-TB group by October 2013, all due to TB. Nine deaths occurred in the control group (6.4%), eight during the study period and one more by the year 2013. Three were directly due to tuberculosis and six were non-TB related (two AIDS, two complications of DM, two due to malnutrition and other additional non-pulmonary bacterial infections).
Discussion This study compares pulmonary MDR-TB cases and pulmonary TB patients without MDR under programmatic conditions in a Mexican population. The characteristics of TB patients in this study are consistent with national data in terms of age, gender and other demographic features, prevalence of underlying disorders (including malnutrition, alcohol and other drug abuse, HIV/AIDS status, diabetes, among others), and cure rates (83.2%) as shown in national TB registries and large Mexican cohorts (5,16). As reported in other national studies (12,13), in this report the number of previous anti-TB treatments (3 vs. 1), and the duration (8 vs. 6 months) and rate of failure (75 vs. 1.4%) to first anti-TB treatment were significantly higher among MDR-TB patients compared to non MDRTB cases, respectively. Application of DOTS during the
Table 2. Comparison of treatment characteristics between MDR-TB and non-MDR-TB groupsa MDR-TB (n [ 36) Number of previous treatments (median, IQR) Duration of treatment (months, median, IQR) DOTS Bacteriological cure Treatment completed Lost to follow-up Not recorded Treatment failure Death by October 2013 TB-related death Non-TB related death
3 8 15 1
(2e3.75) (6e12)b (53%)c (2.8%) 0 1 (2.8%) 7 (19.4%) 27 (75%) 15 (42%) 0
Non-MDR-TB (n [ 139) 0 6 120 104 21 2 10 2
(0e0) (6e6). (86%) (74%) (15%) (1.4%) (7.1%) (1.4%)
3 (2.1%) 6 (4.3%)
a
Or
95% CI
14.99 1.65 0.18 0.009 0.07 1.96 3.11 205.5
6.1e36.82 1.31e2.08 0.07e0.44 0.001e0.073 0.004e1.28 0.17e22.21 1.09e8.87 42.04e1004.51
32.38 0.28
8.63e121.46 0.01e5.11
For MDR-TB cases, data (except the number of previous treatments) corresponds to the first TB treatment that the patient ever received; for non MDR-TB subjects, data corresponds to the treatment prescribed during the study episode. b Data available for 35 patients. c Data available for 28 patients.
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first anti-TB treatment was significantly lower among MDR-TB patients compared to non-MDR-TB cases (53 vs. 86%), respectively. It is noteable that risk factors for MDR-TB frequently reported in other countries (drug abuse, health care workers, HIV) were not significantly different between cases and control groups in this study (2,7e11) and this is supported by national data described previously in this report. Other known risk factors for MDR-TB such as low income, malnutrition, and alcohol were not significantly different between non-MDR-TB and MDR-TB groups. The important finding in this study is the association between pulmonary MDR-TB and DM, present in 47.2% (17/36) of cases and these results are consistent with national data. In a national pulmonary MDR-TB cohort of Servicios de Salud de Mexico involving all cases diagnosed with MDR-TB between years 2000 and 2012 (total 5 629 cases), 50% had the association of MDR-TB and DM (6). The trend in frequency of this association has remained with little variation during this period of time at state (San Luis Potosı) and national levels, 42e48% and 45e50% respectively. Regarding the association of non-MDR-TB and DM, data from this study are consistent with national data as well as being demonstrated in two large cohorts. In a national cohort of Servicios de Salud de Mexico including 19,491 cases (5), this association was present in 21% of all TB cases. In a recent study published by Jimenez-Corona and Ponce-de-Leon et al., frequency of DM in a cohort of 1,262 tuberculosis patients in Mexico was 29.6%. These figures are similar to the 28.1% found in non-MDR-TB patients in our study. Although the association between DM and TB is widely known, this is the first study to show that Mexico could have the highest frequency of DM among MDR-TB patients, but a national study is necessary to confirm this. This could be explained by a higher prevalence of DM in Mexico compared to other countries (29). Previous analyses of a smaller case series lead us to suspect this high association in Mexico (33,34). The frequency of the association of DM and MDR-TB is diverse in different regions. In a study in a mixed AmericanMexican population near the Texas-Mexico border, FisherHoch et al. found DM as a risk factor for MDR-TB, with a DM prevalence of 27.8% among MDR-TB cases (26). This association is considerably lower in other countries like China and India (14.5% and 5e8 to 11%, respectively) (36,37). The association of DM and MDR-TB in Mexico can impact on the economic burden of treatment and the risk of MDR-TB transmission. In addition, it could have an impact on the generation of XDR-TB. Therefore, additional studies are warranted in our country to explore the potential causes for MDR-TB development among DM-TB patients. Possible explanations for the increased frequency of MDR-TB among DM-TB patients include the following: a) switching to the maintenance phase of anti-TB treatment (isoniazid and rifampin) in smear positive patients at the second month (16,36,38); b) a higher mycobacterial burden in DM-TB patients. In the same study by Jimenez-Corona
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et al., DM was associated with a higher frequency of cavities in chest x-rays, 45% among diabetics vs. 35% in non-diabetic patients ( p ! 0.001) (16); c) lower treatment adherence in DM-TB patients compared to those without DM although this has not been shown in other studies (16,21,37); in this report, 47% of MDR-TB patients were not treated under DOTS strategy; d) obesity and glycemic control during anti-TB treatment with consequent alterations in immunity (39,40); e) a higher primary resistance to isoniazid among DM-TB patients although this has not been demonstrated in our country (12,16); and f) altered pharmacokinetic of anti-TB drugs and pharmacological interactions between anti-TB medications and sulphonylureas, mainly with rifampin where altered pharmacokinetics have been demonstrated (41,42). Simple measures should be reinforced in patients with DM and pulmonary TB such as strengthening education to primary care physicians in charge of treatment of TB patients, apply DOTS strategy to all patients treated for TB, change to second phase treatment with two drugs only when sputum conversion has been achieved and demonstrated; diagnose MDR-TB at the end of the second or at most at the fourth month of first anti-TB treatment, if rapid test or culture/drug-susceptibility tests are used, respectively; and refer patients to the state TB clinic after MDR has been demonstrated or patient remains with smear positive after the second month and culture has been performed. There are other interventions that could be evaluated in DM-TB patients such as the use of rapid molecular tests. GeneXpertÒ, a test for rifampin resistance detection, has demonstrated an earlier diagnosis of MDR-TB and is cost-effective according to WHO recommendations (3). This measure seems already needed in Mexico given the high frequency of persistent smear positive at the end of the second month of four drug anti-TB treatment (46% in DM-TB and 37% in non-DM-TB patients) (16). It would be desirable to detect not only MDR-TB when it is already established, but also primary isoniazid resistance in patients with DM and first pulmonary TB diagnosis in order to offer appropriate treatment to decrease the probability to select multi-drug resistant strains during a standardized first anti-TB treatment. This can be achieved with the use of tests like GenotypeÒ MTBDRplus. Although more expensive, it has demonstrated to be cost effective as well (3,43). There are some potential changes in the treatment of DM-TB patients that could be evaluated in further studies such as increase in the dose of rifampin, controlling DM with insulin instead of oral drugs if uncontrolled DM is detected after the first month, select and appropriate treatment for patients with DM and TB and primary resistance to isoniazid. These measures could be evaluated in future studies in DM-TB patients. The limitations of the study are the reduced number of cases, which may not be representative of all Mexican MDR-TB patients. Also, controls and cases were not
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recruited during the same period of time. Although according to the National Survey on Health and Nutrition there has been an increase in the prevalence of DM between 2000 and 2012 (29), the frequency of DM among MDRTB cases in our cohort has remained very similar throughout the study period. Of note, our results are supported by similar rates of DM in both non-MDR-TB and MDR-TB in national data gathered during a long period of time. In conclusion, DM is associated with MDR-TB in our region. Our study population appears to be consistent with national data for Mexican MDR-TB patients. Due to the high frequency of DM in Mexican MDR-TB patients and the high prevalence of DM in this country, future studies in this population must be conducted and development of specific recommendations for the treatment and follow-up of diabetic patients with TB may reduce the number of MDR-TB cases.
Conflict of Interest The authors report no conflict of interest.
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