Factors Associated with Multidrugresistant Tuberculosis: Comparison of Patients Born Inside and Outside of the Czech Republic

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1 The Journal of International Medical Research 2010; 38: [first published online as 38(3) 26] Factors Associated with Multidrugresistant Tuberculosis: Comparison of Patients Born Inside and Outside of the Czech Republic V BARTU 1, E KOPECKA 2 AND M HAVELKOVA 3 1 Department of Respiratory Diseases, Medicon, Prague, Czech Republic; 2 Central Unit for MDR-TB, Department of Respiratory Diseases, 1st Medical School, Faculty Thomayer Hospital, Prague, Czech Republic; 3 Mycobacteriology Unit and National Reference Laboratory for Mycobacteria NIPH, WHO/IUATLD Supranational Reference Laboratory for Mycobacteria, Prague, Czech Republic Multidrug-resistant tuberculosis (MDR- TB) is defined as resistance of Mycobacterium tuberculosis complex (MTB) to at least isoniazid and rifampicin. The aim of this study was to evaluate and compare a cohort of 50 patients with MDR-TB according to birthplace, resistance type, clinical outcome, length of bacteriological positivity of sputum and length of hospitalization. Thirty-three of the patients were born in the Czech Republic (group A) and 17 were immigrants to the Czech Republic (group B). Patients in group B were significantly younger (mean [range] age 33 [19 56] years) than those in group A (mean [range] age 48 [33 80] years). Primary resistance was present in 16 (48%) cases in group A and in 13 (76%) cases in group B. There were 36 (72%) cured patients, five (10%) remained on treatment and nine (18%) died; no patients failed or transferred out of the study. The mean length of bacteriological positivity of sputum samples was 5.9 months and the mean length of hospitalization was 8.2 months. Resistance to capreomycin was an important predictor of poor outcome. KEY WORDS: MULTIDRUG-RESISTANT TUBERCULOSIS; RISK FACTORS; IMMIGRANTS; CZECH REPUBLIC; CLINICAL OUTCOME Introduction Tuberculosis (TB) remains one of the leading global infectious diseases. Multidrugresistant TB (MDR-TB) is characterized by resistance to the most potent anti-tb drugs, isoniazid and rifampicin, and contributes to rising morbidity and mortality rates for people with TB. 1 The most recent data, from 2006, show that the number of new cases of MDR-TB per annum is approaching half a million. 2 One of the priorities of TB management is monitoring the trends in drug resistance, in particular its impact on the incidence of MDR-TB. 3 In global terms, although there are some geographical differences, immigrants make up a substantial (and increasing) proportion of TB cases in the Western world. On average 1156

2 across western Europe, for example, 30% of the cases of TB occur in immigrants, although this figure is as high as 70% of cases in Norway, Sweden and The Netherlands; conversely, for southern Europe, immigrants make up only 15% of all TB cases. 4,5 The Czech Republic is a country with a favourable TB epidemiological situation: in 2008, 871 cases of TB were recorded, with an incidence of 8.4 per inhabitants; 153 of the cases (17.6%) were male immigrants. MDR-TB accounts for 2% of the overall TB prevalence and the number of cases has been stable in recent years. 6 The Czech Republic now represents a natural transit point for patients from eastern Europe or Asia who are aiming to live in a central or western European country. Consequently, authorities in the Czech Republic now pay much more attention to TB diagnosis and treatment in immigrants in order to prevent the further spread of TB, particularly its drug-resistant forms. The management of MDR-TB is complicated and the choice of an optimal therapeutic regimen may be controversial since few directly comparable published protocols exist. 7 In addition to first-line anti- TB therapies, MDR-TB requires sensitive second-line drugs (e.g. aminoglycosides, capreomycin, fluoroquinolones, ethionamid and para-aminosalicyclic acid [PAS]), which show lower efficacy and higher toxicity compared with first-line agents. 8 MDR-TB management should involve at least four sensitive drugs, 9 which are used over a long treatment period that varies between 18 and 24 months. 10 The aim of the present study was to evaluate and compare cohorts of patients with MDR-TB, born inside and outside of the Czech Republic, who were treated at the specialist unit for MDR-TB in Prague that serves the entire country. The study focused on demographic, clinical and epidemiological patient data. Patients and methods PATIENTS Patients with MDR-TB, who were treated at the Central Unit for MDR-TB, Department of Respiratory Diseases, 1st Medical School, Faculty Thomayer Hospital, Prague, Czech Republic, between 1 January 2001 and 30 June 2009, were enrolled sequentially into this retrospective study. Patients were monitored for between 6 and 24 months after completing treatment and were divided into two groups according to their birthplace: group A comprised patients born in the Czech Republic; and group B comprised immigrants to the Czech Republic. Each case of MDR-TB was identified according to World Health Organization (WHO) criteria for the management of resistant TB. 11 These criteria were also used to define resistance, record and evaluate treatment, and monitor outcome. An MDR-TB case was defined as a patient with disease where infectious Mycobacterium tuberculosis complex (MTB) isolates were resistant in vitro to at least isoniazid and rifampicin. Written informed consent was obtained for the initiation of MDR-TB treatment from all patients. The protocol was approved by the Ethics Review Committee of Faculty Thomayer Hospital. EPIDEMIOLOGICAL CLINICAL AND LABORATORY EVALUATIONS Epidemiological and clinical aspects of patients disease were evaluated. For each patient, the treating physician took anamnesis data and carried out a routine chest X-ray. TB resistance types and extent of MTB resistance, including its impact on the use of treatments classified as first- and 1157

3 second-line anti-tb drugs was assessed. Microbiological tests included repeated microscopic and culture examinations of sputum samples, the length of time to bacteriological conversion of sputum, identification of MTB isolates, and drug susceptibility testing. The results of susceptibility testing for firstline (isoniazid, ethambutol, streptomycin, pyrazinamide and rifampicin) and secondline (capreomycin, amikacin, kanamycin, ethionamid, ofloxacin, ciprofloxacin, cycloserine, clofazimin and PAS) anti-tb drugs were evaluated. All tests were confirmed with data for mycobacteria from the National Reference Laboratory for Mycobacteria (NRLM), and susceptibility testing was performed in accordance with recommended standard methods in microbiology for mycobacterial infections (National Health Institute NRLM, Prague, 1998) by Canetti s proportion method 12 (firstline anti-tb, kanamycin, ethionamid, cycloserine and PAS). For amikacin, rifabutin, ofloxacin, ciprofloxacin, clofazimin and capreomycin, a microdilution method was used to determine their minimum inhibition concentrations (mg/l). From 2004, the GenoType MTBDR test (Hain Lifescience, Nehren, Germany) confirmed that MTB with so-called marginal susceptibility to rifampicin or isoniazid was resistant to these drugs. In the entire cohort, the number of resistant first-line anti-tb drugs was evaluated in relation to microscopic and culture positivity of sputum. Clinical outcome and length of hospitalization were monitored; outcome was defined according to WHO definitions as cured, died, on treatment, failed and transferred out. Human immunodeficiency virus (HIV) serological testing was performed in all cases. TREATMENT PROCESS AND MONITORING All patients received individualized treatment regimens in accordance with WHO recommendations. 11 These regimens were based on the results of susceptibility testing conducted for the first- and secondline anti-tb treatments. Daily drug dosages were administered in accordance with the WHO recommendations. After sputum samples became negative, repeat testing was performed monthly and patients were considered cured after 18 months consecutive negative cultures. At this point, treatment ceased and they were discharged from care. Direct monitoring continued from the initial treatment phase, through hospitalization, and until the achievement of repeated bacteriological conversion of sputum. Routine laboratory monitoring including ions, liver function, urea and creatinine testing was performed monthly. After transferring patients to out-patient treatment regimens, direct therapeutic monitoring was not ensured in all people. During this period, patients were evaluated monthly with the focus on tolerance and undesirable treatment effects. STATISTICAL ANALYSIS Normally distributed data were analysed by analysis of variance and differences among groups were detected using the Tuke Kramer test. The Kruskal Wallis test and Kruskal Wallis Z-test were used in cases of nonnormal data distribution. A P value 0.05 was considered to be statistically significant. Results A total of 50 patients with MDR-TB, treated at the Central Unit for MDR-TB in Prague, Czech Republic, between 1 January 2001 and 30 June 2009, were enrolled into this 1158

4 retrospective study; 33 patients were born in the Czech Republic (group A) and 17 were immigrants to the Czech Republic (group B). Patients in group B originated from the Ukraine (n = 8), Russia (n = 3), Belarus (n = 2), Moldova (n = 1), Vietnam (n = 1), Korea (n = 1) and Croatia (n = 1). Table 1 shows the key demographic and clinical characteristics. A total of 37 patients (74%) had epidemiologically defined serious TB, with microscopic- and culture-positive sputum. All patients had pulmonary MDR-TB; none was diagnosed with non-pulmonary TB and none was HIV positive. The patients in group B were significantly younger than the patients in group A (P = ) (Table 1). Seventeen patients (52%) in group A, and four (24%) in group B, had anamnesis of previous TB treatments and had previously used anti-tb drugs for > 1 month, which corresponded to the resistance data obtained. Resistance to four of the five first-line anti-tb drugs (isoniazid, rifampicin, ethambutol, streptomycin) and possibly also to pyrazinamide was commonly found. In the whole cohort, such resistance was identified in 26 (52%) patients: 18 (55%) from group A and eight (47%) from group B. Resistance to three drugs was diagnosed in 13 (26%) patients: eight (24%) from group A and five (29%) from group B. Resistance to isoniazid and rifampicin was proven in only 11 (22%) of the whole cohort of patients; seven (21%) from group A and four (24%) from group B. Levels of resistance to second-line anti-tb drugs across the entire cohort are shown in Table 2; the four patients with capreomycinresistant disease died of MDR-TB. In addition, fluoroquinolone resistance was identified in 15 (30%) of the patients, of whom five (29%) were from group B. The number of drugs used in individual regimens was dependent on the results of in vitro drug susceptibility testing. Usually, aminoglycoside or capreomycin, fluoroquinolone, ethionamid, cycloserine or PAS were administered; the number of drugs used in combination are listed in Table 3. Treatment outcomes for patients in both study groups, according to WHO definitions, are listed in Table 4. In total, 36 (72%) of the patients were cured, five (10%) remained on treatment and nine (18%) patients died (all in group A). None of the patients required surgery during the study period. It was not necessary to interrupt therapy due to drug toxicity in any of the patients, although dyspeptic difficulties (nausea and loss of appetite) were present in two (4%) patients; there were no similarities in the treatment regimens for these two patients which might TABLE 1: Demographic and clinical characteristics of Czech Republic-born or immigrant patients (n = 50) with multidrug-resistant tuberculosis treated in Prague, Czech Republic Czech Republic-born Immigrants Demographic or characteristic (group A) (group B) Patients, n (%) 33 (66) 17 (34) Age, mean years (range) 48 (33 80) 33 (19 56) a Male sex, n (%) 28 (85) 13 (76) Primary resistance, n (%) 16 (48) 13 (76) Acquired resistance, n (%) 17 (52) 4 (24) Smear and culture positive, n (%) 23 (70) 14 (82) Only culture positive, n (%) 10 (30) 3 (18) a P = versus Czech Republic-born patients (Tuke Kramer test). 1159

5 TABLE 2: Resistance levels to second-line antituberculosis drugs in the cohort of patients (n = 50) with multidrug-resistant tuberculosis treated in Prague, Czech Republic Drug resistant combinations n (%) AMK 2 (4) AMK + CPX 4 (8) AMK + CPX + PAS 4 (8) AMK + CPX + PAS + CS 7 (14) AMK + CS + CL 5 (10) AMK + PAS + CL 7 (14) CM 4 (8) AMK, amikacin; CPX, ciprofloxacin; PAS, paraaminosalicylic acid; CS, cycloserin; CL, clofazimin, CM, capreomycin. TABLE 3: Number of antituberculosis drugs used in combination in the treatment of patients (n = 50) with multidrug-resistant tuberculosis treated in Prague, Czech Republic Drug combination n (%) Four drugs 13 (26) Five drugs 31 (62) Six drugs 6 (12) have accounted for the dyspeptic difficulties. Nine patients died, all males born in the Czech Republic (mean age [range] 52 [40 80] years), eight of whom had both microscopic- and culture-positive MDR-TB. Secondary resistance was proven in seven of the nine cases and seven of the deceased patients had resistance to four anti-tb drugs. All the deceased patients were smokers with concomitant medical problems: chronic obstructive pulmonary disease (COPD, n = 6), cardiovascular disease (n = 3), diabetes mellitus (n = 3), or hepatopathy (n = 4). In comparison with patients who were cured, those who died were significantly older (P = 0.05) and also resistant to more anti-tb drugs (although the difference in resistance did not reach statistical significance in this study [P = ]). The mean ± SD length of hospitalization was 8.2 ± 5.7 months, being slightly longer for group A (9.1 ± 5.9 months) and shorter for group B (6.5 ± 3.4 months); this difference was not statistically significant. The mean ± SD length of time that sputum remained microscopic- and culture-positive was 5.9 ± 5.2 months for the whole cohort (6.7 ± 3.6 months for group A and 4.5 ± 2.3 months for group B; not statistically significant). After sputum samples became negative, monthly testing was performed and patients were considered cured after 18 months consecutive negative cultures, whereupon treatment ceased and they were discharged. TABLE 4: Treatment outcomes, according to World Health Organization definitions, 11 for the Czech Republic-born or immigrant patients (n = 50) with multidrug-resistant tuberculosis treated in Prague, Czech Republic Czech Republic-born Immigrants Outcome (group A) (n = 33) (group B) (n = 17) Cured, n (%) 21 (64) 15 (88) On treatment, n (%) 3 (9) 2 (12) Died, n (%) 9 (27) 0 (0) Failed, n (%) 0 (0) 0 (0) Transferred out, n (%) 0 (0) 0 (0) No statistically significant between-group differences. 1160

6 Discussion Drug resistance in the treatment of TB is generally a man-made problem caused by unsuitable drug administration and poor patient adherence to treatment. These problems have led to an increase in the number of people with MDR-TB, which now comprises 5.3% of all TB cases. 13,14 In many countries, the number of immigrants who have TB is increasing. In the present study, 17 of the 50 patients (34%) with MDR-TB were from eastern Europe and Asia, which supports this international trend. It is unsurprising that people migrate from these countries to the Czech Republic as it has strong connections with both western and eastern Europe. Significant differences in clinical and epidemiological data were observed between patients born in the Czech Republic compared with those who were immigrants; e.g. immigrants with MDR-TB were significantly younger than patients born in the Czech Republic. Immigrants often come to the Czech Republic for employment opportunities and to enjoy the improved socioeconomic culture and are, therefore, likely to be younger. Similar to findings reported from Spain, 4 primary resistance to anti-tb drugs was higher among immigrants than among Czech Republic-born patients, although this did not reach statistical significance in the present study. The high incidence of drug resistance found among people who had previously received > 1 month s anti-tb treatment confirms systematic failures in the detection, treatment and isolation of people with resistant MTB. Such failures can easily contribute to the spread of TB and are key reasons for the ever-increasing global incidence in MDR-TB cases through the migration of infected people from countries with high epidemiological risk of drugresistant disease. 3 Aminoglycosides and fluoroquinolones play key roles in the success of treatment for MDR-TB. The most important predictor of resistance to a particular drug is its prior use as anti-tb therapy for > 1 month. 9 Resistance to capreomycin alone, but not to either kanamycin or amikacin alone, appears to be an indicator of poor prognosis. 19 In the four cases that were capreomycin-resistant in the present study, the patients all had further risk factors for unsuccessful clinical outcomes and all died of MDR-TB. Multidrug resistance to first-line anti-tb drugs decreases the number of suitable and efficient drugs for combination therapy. According to the latest recommendations, there should be at least four efficacious drugs. 9,11 One of the risk factors that can contribute to the development of secondary resistance is the uncontrolled and unsubstantiated prescribing of drugs that are not among those recommended for anti-tb therapy. This narrows the spectrum of the few sensitive drugs that are designed for the treatment of MDR-TB, in particular endangering the fluoroquinolones, which are in the third group of anti-tb drugs. Their prescription and use against Gram-positive and Gramnegative organisms is very common. In cases of undiagnosed TB, treatment with fluoroquinolones can lead to monoresistance, 8 and resistance to them develops very quickly. 20 In the cohort from the present study, fluoroquinolone resistance was identified in 15 (30%) of the patients, of whom five were immigrants. For the susceptibility testing of MTB isolates to firstand second-line anti-tb drugs, we observed the WHO recommendations and used at least four drugs in the treatment regimens with respect to their division into the five efficacy classes. 11 Although this involves a long-term therapeutic strategy and carries a 1161

7 risk of undesirable effects, treatment was not interrupted due to drug toxicity in any patient, which is similar to the study by Shin et al. 21 In the present cohort, MDR-TB was cured in 36 patients and five remained on treatment. More favourable results were found in the immigrants with MDR-TB, where 15 (88%) patients were cured compared with 21 (64%) in the Czech Republic-born group (no statistically significant difference). A strong connection between TB-related deaths and smoking was noted among Czech-born patients compared with those who were immigrants. Smoking is one of the risk factors for TB observed by Pai et al. 22 and is also a cause of significant comorbidity, in particular COPD and cardiovascular diseases, with the incidence of both increasing with age. The patients who died of MDR-TB were all Czech Republic-born males, all of whom were smokers. Other risk factors for death included older age, increased incidence of comorbidities and resistance to anti-tb drugs, particularly capreomycin where all four resistant patients died. Similar conclusions have been drawn by others. 23,24 The mean time to bacteriological conversion of sputum was 5.9 months, which corresponded to the seriousness of the disease and to the necessity of letting the initial treatment phase run for a 6-month period, as in the WHO recommendations. 9,11 The mean hospitalization time of 8.2 months corresponded with the period during which bacteriological conversion of sputum was confirmed and the patient continued with out-patient treatment. There were certain limitations to the present study, including a limited sample size. It is planned to evaluate a larger cohort in the future. Despite this, it was possible to show significant clinical and epidemiological differences between the immigrants and patients born in the Czech Republic, as shown in a previous study. 4 These findings may help in the implementation of programmes for TB screening and routine drug-susceptibility testing in immigrants, emphasizing the subsequent need for strict monitoring of their ongoing treatment. The rapid identification of patients with MDR-TB, their isolation for the period of infectiousness and the use of efficacious treatments can help to reduce the risk of the spread of this disease in the population. In conclusion, this study compared Czech Republic-born and immigrant patients with MDR-TB. The data reflected issues observed with MDR-TB as a worldwide health problem. The high prevalence of TB, including MDR-TB, in countries such as the former Soviet Union poses a high risk of primary resistance. Younger individuals infected with TB are likely to migrate from these eastern European countries to the Czech Republic in search of employment, where they subsequently receive treatment. Sociobehavioural factors are likely to be important in the development of MDR-TB and should be investigated in depth. To prevent further spread of TB and increases in cases of MDR-TB, it is necessary to undertake direct observations of treatment in all patients in order to ensure better treatment adherence. Acknowledgements Part of this study was carried out with the support of a EC 102 grant within the EEA Financial Mechanism and Norwegian Financial Mechanism. We thank the donors for their financial support. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. 1162

8 Received for publication 20 January 2010 Accepted subject to revision 25 January 2010 Revised accepted 15 April 2010 Copyright 2010 Field House Publishing LLP References 1 Masjedi MR, Tabarsi P, Chitsaz E, et al: Outcome of treatment of MDR-TB patients with standardised regimens, Iran, Int J Tuberc Lung Dis 2008; 12: Zignol M, Hosseini MS, Wright A, et al: Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006; 194: Cohen T, Colijn C, Wright A, et al: Challenges in estimating the total burden of drug-resistant tuberculosis. Am J Respir Crit Care 2008; 177: Diz S, López-Vélez R, Moreno A, et al: Epidemiology and clinical features of tuberculosis in immigrants at an infectious diseases department in Madrid. Int J Tuberc Lung Dis 2007; 11: Kan B, Berggren I, Ghebremichael S, et al: Extensive transmission of an isoniazid-resistant strain of Mycobacterium tuberculosis in Sweden. Int J Tuberc Lung Dis 2008; 12: Institution of Public Health Protection: The TB Registry: Tuberculosis and Respiratory Diseases. Prague: Institute of Health Information and Statistics of the Czech Republic, Caminero JA: Management of multidrugresistant tuberculosis and patients in retreatment. Eur Respir J 2005; 25: Jugheli L, Rigouts L, Shamputa IC, et al: High levels of resistance to second-line antituberculosis drugs among prisoners with pulmonary tuberculosis in Georgia. Int J Tuberc Lung Dis 2008; 12: Caminero JA: Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Dis 2006; 10: Shin S, Furin J, Alcántara F, et al: Hypokalemia among patients receiving treatments for multidrug-resistant tuberculosis. Chest 2004; 3: World Health Organization (WHO): Guidelines for the Programmatic Management of Drugresistant Tuberculosis. WHO/HTM/TB Geneva: WHO, Canetti G, Fox W, Khomenko A, et al: Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests in tuberculosis control programmes. Bull World Health Organ 1969; 41: Reichman LB: Tuberculosis drug resistance comes full circle. Lancet 2008; 371: The WHO/IUATLD Global Project on Antituberculosis Drug Resistance Surveillance: Antituberculosis Drug Resistance in the World: Report No 4. Geneva: WHO, 2008 (available at: eport4_26feb08.pdf). 15 Schwartzman K: Them and us : the two worlds of tuberculosis? Am J Respir Crit Care Med 2007; 176: Yew WY, Leung CHCH: Update in tuberculosis Am J Respir Crit Care Med 2008; 177: Zevallos M, Justman JE: Tuberculosis in the elderly. Clin Geriatr Med 2003; 19: Schachter EN: Tuberculosis: a global problem at our doorstep. Chest 2004; 126: Migliori GB, Lange C, Centis R, et al for the TBNET Study Group:. Resistance to second-line injectables and treatment outcome in multidrug-resistant and extensively drugresistant tuberculosis cases. Eur Respir J 2008; 31: Ginsburg AS, Woolwine SC, Hooper N, et al: The rapid development of fluoroquinolone resistance in M. tuberculosis. N Engl J Med 2003; 349: Shin SS, Pasechnikov AD, Gelmanova IY, et al: Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. Int J Tuberc Lung Dis 2007; 11: Pai M, Mohan A, Dheda K, et al: Lethal interaction: the colliding epidemics of tobacco and tuberculosis. Expert Rev Anti Infect Ther 2007; 5: Lefebvre N, Falzon D: Risk factors for death among tuberculosis cases: analysis of European surveillance data. Eur Respir J 2008; 31: Espinal MA, Laszlo A, Simonsen L, et al: Global trends in resistance to antituberculosis drugs. N Engl J Med 2001; 344: Author s address for correspondence Dr Vaclava Bartu Department of Respiratory Diseases, Medicon, Antala Staska 1670/80, Prague, Czech Republic. vaclava.bartu@mediconas.cz 1163