INT J TUBERC LUNG DIS 12(7):750–755 © 2008 The Union
Outcome of treatment of MDR-TB patients with standardised regimens, Iran, 2002–2006 M. R. Masjedi, P. Tabarsi, E. Chitsaz, P. Baghaei, M. Mirsaeidi, M. V. Amiri, P. Farnia, P. Javanmard, D. Mansouri, A. A. Velayati Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran SUMMARY BACKGROUND:
Multidrug-resistant tuberculosis (MDRTB) imposes a formidable burden on national health systems. There is still no consensus on the subject, with controversies regarding treatment protocols, treatment outcomes and the various treatment regimens. M E T H O D S : The present study describes Iran’s second national cohort for treatment of MDR-TB. The study comprised all documented MDR-TB cases in Iran referred to our centre during the period 2002–2006. All patients received a standardised second-line regimen consisting of ofloxacin, cycloserine, prothionamide and amikacin. Based on drug susceptibility testing results, ethambutol and pyrazinamide were added to the regimen. R E S U LT S : Forty-three patients diagnosed with MDR-TB, with a mean age of 44.38 ± 19.05 years, received treat-
ment; of these, 27 (62.8%) were male. Twenty-three were (53.5%) Iranians and the remainder were Afghans. All patients were acquired MDR-TB cases. Of the 43 cases, 25 (58.1%) experienced severe clinically significant adverse effects; 29 (67.5%) had a successful outcome and 14 (32.5%) had a poor outcome (treatment failure in six [14%] and death in eight [18.6%]). Mortality was higher in Iranians (P = 0.039) and in patients whose initial regimen was changed due to adverse drug reactions (P = 0.01). C O N C L U S I O N : Compared with previous studies, our study was able to obtain more favourable outcomes of MDR-TB treatment using a standardised regimen. K E Y W O R D S : MDR-TB; standardised regimen; treatment outcome; Iran
OVER THE PAST FEW DECADES, tuberculosis (TB) has become a major global health concern, and it is currently the leading cause of death among curable infections. World Health Organization (WHO) data show that approximately one third of the world’s population is infected with TB. Approximately 8 million people become infected annually, resulting in more than 2 million deaths each year.1,2 The emergence of multidrugresistant tuberculosis (MDR-TB), defined as resistance to both isoniazid (INH) and rifampicin (RMP), has made the problem more pronounced, and its increasing incidence has turned it into a global threat.1,3–5 The emergence of drug resistance was first noticed soon after chemotherapy for TB was started in 1944.6 It should be noted that drug resistance occurs as a result of the selection of pre-existing resistant mutants, particularly by the administration of monotherapy.4–8 According to various reports, primary MDR-TB (in new cases) comprises only 3– 4% of all MDR-TB cases, with patients who have received previous anti-tuberculosis treatment accounting for the rest (acquired MDR-TB). Therefore, treatment relapse, failure or retreatment cases comprise the majority of MDR-TB cases.9 A variety of methods have been suggested to treat
MDR-TB. Consensus on the subject is still lacking due to the disparities between centres providing treatment with regard to settings, facilities, access to therapeutic and diagnostic measures, as well as the lack of integrated and holistic statistical data.1,9 Since 2002, second-line anti-tuberculosis agents have been regularly available in Iran for the treatment of MDR-TB.10 In this study, which describes the second national cohort for the treatment of MDR-TB, attempts were made to assess treatment efficacy and successful outcomes using a standardised regimen—of particular importance in countries where drug susceptibility testing (DST) facilities are not easily accessible. We also studied the outcome of MDR-TB treatment where the treatment process is integrated into the national health care system.
MATERIALS AND METHODS Settings This study describes Iran’s second national cohort for the treatment of MDR-TB. It was conducted at the National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, the
Correspondence to: Payam Tabarsi, Masih Daneshvari Hospital, Niavaran St, Darabad, Tehran, Iran 1955841452. Tel: (+98) 21 2010 5050. Fax: (+98) 21 2010 9484. e-mail:
[email protected] Article submitted 28 September 2007. Final version accepted 26 February 2008.
Outcome of MDR-TB treatment
WHO collaborating centre for the Middle East, and where the sole national referral centre for tuberculosis, the National Mycobateriological Reference Laboratory (NRL), is based. The NRL is under the technical supervision of the Supranational Reference Laboratories of the Swedish Institute for Infectious Disease Control (Solna, Sweden) and the Research Institute of Tuberculosis of the Japan Anti-Tuberculosis Association (Tokyo, Japan). The study consisted of all documented MDR-TB cases in Iran referred to the NRITLD during the period 2002–2006. Under Iran’s National TB Programme (NTP), all treatment costs are supported by the Ministry of Health and are therefore delivered to all patients free of charge. Iran’s health care system is designed as a tree-like network, whereby the rural health units are governed by the district health offices, which are in turn covered by the provincial health units, supervised by the Ministry of Health. In 2002, MDR-TB treatment was integrated into the national health system. Under the NTP, all patients are referred to the peripheral health centres responsible for providing DOTS after the patient has been discharged for the continuation phase of treatment. In addition to routine MDR-TB treatment, psychological help was provided to patients regarding the difficulties of the disease and its long-term treatment to ensure greater patient adherence. We also sought to detect and treat psychological adverse effects resulting from TB medication. Nutritional assessments and dietary advice were also provided for all patients. Case recruitment According to Iran’s NTP treatment protocol, all new TB patients receive the WHO Category I regimen or, in case of relapse or failure, the Category II regimen.11 If Category II treatment fails, patients are referred to the NRITLD for evaluation and treatment of MDR-TB. Data were gathered on the patients’ age, sex, nationality, history of smoking, history of imprisonment and radiological findings. For all patients classified as treatment failures, DST against first-line drugs was performed. DST for INH, RMP, streptomycin and ethambutol (EMB) was performed by the proportion method on LöwensteinJensen media at concentrations of 0.2, 40, 4.0 and 2.0 mg/ml, respectively. Susceptibility to pyrazinamide (PZA; 900 and 1200 mg/ml) was tested using a 2phase medium where the strain was reported to be resistant to PZA if, on day 21, the proportion of drugresistant colonies was higher than the defined critical proportion. The above-mentioned methods are discussed elsewhere in greater detail.10 Treatment Patients diagnosed with MDR-TB based on DST results received a standardised second-line regimen consisting of ofloxacin (OFX), cycloserine (CS), pro-
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Table 1 Anti-tuberculosis drugs used in the treatment of MDR-TB and their dosages Drug
Dose
EMB PZA AMK
15–25 mg/kg/day 20–30 mg/kg/day 15 mg/kg/day (5 days/week, maximum 1 g/day) 2– 4 g daily 1000 mg/day 750–1000 mg/day 750–1000 mg/day 400–800 mg/day
Amoxicillin-clavulanate Clarithromycin PTH CS OFX
MDR-TB = multidrug-resistant tuberculosis; EMB = ethambutol; PZA = pyrazinamide; AMK = amikacin; PTH = prothionamide; CS = cycloserine; OFX = ofloxacin.
thionamide (PTH) and amikacin (AMK; Table 1). EMB and PZA were also added to the regimen based on DST results. As no TB cases in Iran receive second-line drugs, MDR-TB patients are assumed to be susceptible to second-line agents, which are considered active. All patients received at least 6 months of an injectable aminoglycoside (e.g., AMK), which was continued for at least 4 months after the culture turned negative or the patient developed adverse effects to the drug. Patients referred to our centre first underwent an intermediate regimen comprising four second-line drugs OFX, CS, PTH and AMK, until the results of DST were available. The regimen was then modified on the basis of DST so that all first-line drugs to which they were susceptible were included in combination with at least four active second-line drugs. If major adverse effects occurred, the suspected agent was replaced by other drugs, such as clarithromycin or amoxicillinclavulanate, which may be of unproven efficacy but are recommended as the fifth group of anti-tuberculosis agents by the WHO for the management of MDR-TB when other agents are not available or cannot be used. None of the patients underwent surgery during the study period. All patients remained hospitalised until negative sputum smear results had been obtained on two consecutive occasions 15 days apart. During the continuation phase, treatment continued until the 24month course was completed. Monitoring and follow-up After discharge from hospital, treatment was continued at the peripheral centres of the national health care system. Patients were also visited and re-evaluated every 6 months at our referral centre. Patients were monitored at the hospital by monthly sputum smears and cultures until the first negative smear was obtained. Thereafter, smears were taken monthly and cultures performed every 3 months. Adverse drug reactions were monitored on clinical symptoms and signs. Blood urea nitrogen and creatinine values and liver function tests were performed every 15 days in the hospital and monthly thereafter.
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Definitions of treatment outcomes
Cure Patient has completed treatment and is consistently culturenegative, with at least five negative results in the last 12 months of treatment OR no clinical deterioration with at most one positive culture followed by three negative cultures 30 days apart in the final 12 months Treatment completed Patient completed treatment but cannot be categorised as cure or treatment failure due to lack of adequate mycobacteriological evidence Treatment failure Two or more positive cultures among the five cultures in the final 12 months of treatment OR any positive culture in the last three cultures OR premature treatment termination due to poor response or adverse effects Death Death for any reason during the course of treatment
Otolaryngological examinations and audiometry were performed for those who had been receiving AMK, in case of hearing loss or tinnitus. For patients who received PTH, thyroid function tests were performed every 2 months. Treatment outcomes were categorised into two groups: successful outcome (cure, treatment completed) and poor outcome (treatment failure, death; Table 2).12 Statistical analysis Statistical analysis of the collected data was performed using SAS 8e (Statistical Analysis Software Institute, Cary, NC, USA). The χ2 test was used for nominal variables, and whenever necessary the Fisher’s exact test was utilised. We also used Student’s t-test and the Mann-Whitney U-test for variables with normal distribution and non-normal distributed data, respectively. A P value 6 months (P = 0.75). Likewise, a total of 35 (81.4%) patients received PZA and 14 (32.6%) received EMB based on their DST results. Nevertheless, treatment outcomes did not indicate any significant difference between those who had received either PZA and/or EMB vs. those cases who received neither of these two drugs. Data were also analysed for mortality. Of the 43 patients, 35 (81.4%) survived (22 males and 13 females) and 8 (18.6%) died of the disease or from its complications (five males and three females). There were no defaulters. The mean age of the patients was 43 and 50 years, respectively. There was no difference in mortality rate for men and women. It is, however, of note that seven of the eight mortalities were among patients of Iranian nationality (87%), indicating that mortality was higher and statistically more significant (to a certain extent) in Iranians than in Afghans (P = 0.039). Another noteworthy result was that a significant association existed between mortality rates and any
Table 3 Adverse effects of major second-line anti-tuberculosis drugs
Adverse effect
Affected patients n (%)
Suspected drug
Hearing loss Hepatitis Psychosis/suicide attempt
20 (46) 4 (9.2) 3 (6.9)
AMK PTH CS
AMK = amikacin; PTH = prothionamide; CS = cycloserine.
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Table 4
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Demographic characteristics and treatment outcomes Successful outcome Cure n (%)
Treatment completed n (%)
43
10 (23.3)
19 (44.2)
27 (62.8) 16 (37.2)
Patients n (%) Total Sex Male Female Nationality Iranian Afghan Regimen change Yes No Total
Poor outcome Treatment failure n (%)
Death n (%)
6 (14)
8 (18.6)
18 (66.7) 11 (68.8)
9 (33.3) 5 (31.3)
5 (18.5 ) 3 (18.8 )
23 (53.5) 20 (46.5)
13 (56.5) 16 (80)
10 (43.5) 4 (20)
7 (30.4) 1 (5.3)
20 (46.5) 23 (53.5) 43
11 (55) 18 (78.3) 29 (67.5)
9 (45) 5 (21.7) 14 (32.5)
7 (35) 1 (4.3) 8 (18.6)
P value 0.98
0.039
0.01
modification in the initial regimen. Only 13 (65%) of the 20 cases who had developed adverse effects and hence had their initial regimen modified survived in comparison to 22 (95.7%) of 23 patients who did not have their regimens changed (P = 0.01; Table 4).
DISCUSSION The treatment of MDR-TB has caused a major problem in TB treatment.6 Although no randomised clinical trial has yet been performed to assess treatment of MDR-TB, the current evidence recommends using regimens consisting of second-line anti-tuberculosis agents.14–17 Studies on MDR-TB treatment report varying success rates, ranging from 38% to 100%.17,18 An important factor that is said to be partly responsible for this variation is the number of new individuals with MDRTB (primary MDR-TB):19–22 more successful outcomes were reported by studies with a higher number of primary MDR-TB cases. In the present study, the successful outcome of MDR-TB treatment was 67.5%. All patients involved in our study had acquired MDRTB, with a high rate of resistance to other first-line anti-tuberculosis drugs. Our study has therefore shown remarkable success in treating MDR-TB patients. However, the mortality rate of eight patients (18.6%) in our study was slightly higher than that reported by other studies.20,21 A notable point is that the mortality rate was substantially higher in Iranian patients (seven cases) than in patients of Afghan ethnicity (one case). Moreover, mortality was significantly higher in those patients whose treatment regimens were changed due to major adverse effects. This indicates that the modification of treatment regimens gives worse outcomes because of the limited number of available anti-MDRTB agents, which are much less potent. The impact of major adverse effects on mortality cannot be overlooked. However, we were not able to determine the cause of the increased mortality rate among Iranians in comparison to Afghans, and further studies focused
on this subject are required to explain this observation and shed light on its clinical importance. Our findings also show a substantial number of treatment failures. All of our patients were closely observed and followed up during treatment by peripheral health care centres as well as our referral centre, with none lost to followup. However, due to a lack of access to routine DST for second-line drugs, extensively drug-resistant TB (XDRTB) cases could not be detected at the time of treatment. Undiagnosed XDR-TB may therefore be the cause of mortality or treatment failure in some of our patients. Some studies have demonstrated that individualised treatment yields more favourable outcomes than standard regimens,21,23,24 while in other studies appropriate treatment results are achieved using standardised regimens.25 However, it has been clearly demonstrated that individualised treatment is highly expensive and difficult to implement in the majority of middle- and low-income countries, which bear the highest burden of MDR-TB. Also, as many countries have employed very few second-line drugs in recent years, the microorganisms would be expected to be more susceptible to these than would be assumed from the often unreliable DST results. Therefore, the use of standardised treatment regimens for MDR-TB patients who have only received first-line agents facilitates their management, reduces the number of health care facilities needed and lowers the overall cost of treatment by five to ten times.26 Our study attests that even with acquired MDR-TB cases who showed high rates of resistance to first-line anti-tuberculosis drugs, a standardised regimen has obtained an acceptable success rate. This finding does not, however, disprove the efficacy of individualised treatment. Nevertheless, because the number of second-line agents accessible in Iran is limited, and DST for second-line anti-tuberculosis drugs is not routinely available in Iran, treating MDR-TB with individualised regimens is not feasible at present. However, it should be kept in mind that unlike DST for INH and RMP, in vitro resistance detected during DST for other anti-tuberculosis agents does not nec-
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essarily correspond to their inefficacy in vivo or even in a new drug regimen.26 The majority of studies on the treatment of MDRTB have been performed in referral centres. In our study, the treatment was initiated in our national referral centre and continued in peripheral health centres, along with follow-up. Given that a favourable treatment outcome was achieved in our study, it can be assumed that the treatment protocol for MDR-TB can be properly integrated into the national health care system. However, it can be effective only if regular supplies of second-line anti-tuberculosis agents are available and a good surveillance system is maintained.23 In our study, eight Afghan immigrants were transferred to Afghanistan while on treatment and were excluded from the study, as the data on their treatment results and follow-up were not available. This may indicate the need for further cooperation between neighbouring countries, possibly by establishing crossborder stations leading to a better surveillance system for following up MDR-TB treatment and outcome. Finally, we suggest that access to more second-line anti-tuberculosis drugs would be an important measure in better treatment of MDR-TB. Furthermore, DST for second-line agents such as injectables and fluoroquinolones, rather than other, relatively unreliable DSTs against other second-line drugs,26 would result in improvements in treatment outcome.
CONCLUSION MDR-TB treatment using a standard regimen gave favourable outcomes in our study. Depending on the availability of second-line drugs and an efficient surveillance system, an MDR-TB treatment protocol can be integrated into the national health care system. Acknowledgement The authors are highly indebted to Dr J H Grosset for his careful review and precious comments on this manuscript.
References 1 Aziz M A, Wright A, Laszlo A, et al. WHO/International Union Against Tuberculosis And Lung Disease Global Project on Anti-tuberculosis Drug Resistance Surveillance. Epidemiology of anti-tuberculosis drug resistance (the Global Project on Antituberculosis Drug Resistance Surveillance): an updated analysis. Lancet 2006; 368: 2142–2154. 2 Dye C. Global epidemiology of tuberculosis. Lancet 2006; 367: 938–939. 3 Zignol M, Hosseini M, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006; 194: 479– 485. 4 Pablos-Mendez A, Gowda D, Frieden T. Controlling multidrugresistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 2002; 80: 489–500. 5 Ginsburg A, Grosset J, Bishai W. Fluoroquinolones, tuberculosis and resistance. Lancet Infect Dis 2003; 3: 432–442.
6 Dorman S, Chaisson R. From magic bullets back to the Magic Mountain: the rise of extensively drug-resistant tuberculosis. Nat Med 2007; 13: 295–298. 7 Robert J, Trystram D, Truffot-Pernot C, Jarlier V. Multidrugresistant tuberculosis: eight years of surveillance in France. Eur Respir J 2003; 22: 833–837. 8 Espinal M A, Laszlo A, Simonsen L, et al. Global trends in resistance to anti-tuberculosis drugs. World Health Organization– International Union Against Tuberculosis and Lung Disease Working Group on Anti-tuberculosis Drug Resistance Surveillance. N Engl J Med 2001; 344: 1294–1303. 9 Burgos M, Gonzalez L, Paz E, et al. Treatment of multidrugresistant tuberculosis in San Francisco: an outpatient-based approach. Clin Infect Dis 2005; 40: 968–975. 10 Mirsaeidi M, Tabarsi P, Khoshnood K, et al. Treatment of multiple drug-resistant tuberculosis (MDR-TB) in Iran. Int J Infect Dis 2005; 9: 317–322. 11 World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/ 2006.361. Geneva, Switzerland: WHO, 2006. 12 Laserson K F, Thorpe L E, Leimane V, et al. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2005; 9: 640–645. 13 Tabarsi P, Nooraki A, Mirsaeidi M, et al. Representative drug susceptibility patterns for guiding design of re-treatment regimens for multidrug-resistant tuberculosis in Iran. Respirology 2008; 13: 108–111. 14 Ti T, Lwin T, Mar T T, et al. National anti-tuberculosis drug resistance survey, 2002, in Myanmar. Int J Tuberc Lung Dis 2006; 10: 1111–1116. 15 Ormerod L P. Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. Br Med Bull 2005; 73: 17–24. 16 Espinal M A. The global situation of MDR-TB. Tuberculosis [Edinb] 2003; 83: 44–51. 17 Raviglione M C, Gupta R, Dye C M, Espinal M A. The burden of drug-resistant tuberculosis and mechanisms for its control. Ann NY Acad Sci 2001; 953: 88–97. 18 Mukherjee J S, Rich M L, Socci A R, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004; 363: 474– 481. 19 Escudero E, Pena J M , Alvarez-Sala R, Vazquez J J, Ortega A. Multidrug-resistant tuberculosis without HIV infection: success with individualised therapy. Int J Tuberc Lung Dis 2006; 10: 409–414. 20 Tahaoglu K, Torun T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001; 345: 170–174. 21 Leimane V, Riekstina V, Holtz T, et al. Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet 2005; 65: 318–326. 22 Nathanson E, Lambregts-van Weezenbeek C, Rich M L, et al. Multidrug-resistant tuberculosis management in resourcelimited settings. Emerg Infect Dis 2006; 12: 1389–1397. 23 Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348: 119–128. 24 Suarez P G, Floyd K, Portocarrero J, et al. Feasibility and costeffectiveness of standardized second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359: 1980–1989. 25 Van Deun A, Salim M A, Das A P, Bastian I, Portaels F. Results of a standardized regimen for multidrug-resistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis 2004; 8: 560–567. 26 Caminero J A. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006; 10: 829–837.
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RÉSUMÉ C O N T E X T E : La tuberculose multirésistante (TB-MDR) représente un fardeau effroyable pour les systèmes nationaux de santé. Aucun consensus n’existe encore sur le sujet et des controverses persistent concernant les protocoles de traitement, les résultats du traitement et les divers régimes. M É T H O D E S : Cette étude rapporte les résultats du traitement de la TB-MDR dans la deuxième cohorte nationale d’Iran. Cette étude implique tous les cas documentés de TB-MDR en Iran et référés vers notre centre au cours de la période 2002–2006. Tous les patients ont reçu un régime standardisé de deuxième ligne qui a consisté uniformément en ofloxacine, cyclosérine, prothionamide et amikacine. L’éthambutol et le pyrazinamide ont été ajoutés au régime en se basant sur les tests de sensibilité aux médicaments. R É S U LTAT S : Au total, 43 patients atteints de TB-MDR
ont été inclus dans le traitement. Parmi eux, 27 (62,8%) étaient des hommes ; l’âge moyen était de 44,38 ± 19,05 ans. Vingt-trois d’entre eux (53,5%) étaient Iraniens et les autres Afghans. Tous les patients étaient des cas de TB-MDR secondaire. Sur le total de 43 cas, 25 (58,1%) ont souffert d’effets indésirables majeurs et de signification clinique. Vingt-neuf (67,5%) ont eu un résultat couronné de succès. A l’inverse, au total 14 (32,5%) ont eu un résultat médiocre (échec du traitement chez six [14%] et décès chez huit [18,6%]). La mortalité a été plus élevée chez les Iraniens (P = 0,039) et chez les patients dont le régime initial a dû être modifié par suite de réactions indésirables à l’égard des médicaments (P = 0,01). C O N C L U S I O N : Dans notre etude, les résultats du traitement de la TB-MDR par un régime standardisé ont été favorables par comparaison avec ceux des études antérieures. RESUMEN
La tuberculosis multidrogoresistente (TB-MDR) impone una carga de morbilidad considerable a los sistemas nacionales de salud. No existe aun unanimidad con respecto a esta enfermedad ; persisten controversias sobre los protocolos de tratamiento, los desenlaces terapéuticos y concurren diversas pautas terapéuticas. M É T O D O S : El presente estudio representa la segunda cohorte nacional de tratamiento de la TB-MDR en Irán. Se incluyeron todos los casos de TB-MDR confirmados en Irán y remitidos al Instituto Nacional de Investigación en Tuberculosis y Enfermedades Respiratorias entre 2002 y 2006. Todos los pacientes recibieron un tratamiento estandarizado uniforme de segunda línea que comprendía ofloxacino, cicloserina, protionamida y amikacina. Según los resultados de las pruebas de sensibilidad a los medicamentos se añadieron etambutol y pirazinamida. R E S U LTA D O S : Se registró un total de 43 pacientes con MARCO DE REFERENCIA :
diagnóstico de TB-MDR para tratamiento, de los cuales 27 (62,8%) fueron hombres. El promedio de la edad fue 44,38 ± 19,05. Veintitrés de ellos (53,5%) eran de origen iraní y el resto afgano. Todos los pacientes correspondieron a casos de TB-MDR secundaria. De los 43 pacientes, 25 (58,1%) presentaron reacciones adversas mayores de relevancia clínica ; 29 (67,5%) alcanzaron desenlaces exitosos. Al contrario, 14 pacientes (32,5%) presentaron un desenlace desfavorable (seis [14%] fracasos terapéuticos y ocho [18,6%] defunciones). La mortalidad fue más alta en los pacientes iraníes (P = 0,039) y en aquellos pacientes en quienes se modificó la pauta inicial debido a reacciones adversas a los medicamentos (P = 0,01). C O N C L U S I Ó N : En el presente estudio, con el uso de pautas estandarizadas en el tratamiento de la TB-MDR se alcanzaron desenlaces más favorables que los obtenidos en estudios previos.
