J Antimicrob Chemother 2013; 68: 1910 – 1916 doi:10.1093/jac/dkt103 Advance Access publication 10 April 2013

Decline in rates of acquired multidrug-resistant tuberculosis after implementation of the directly observed therapy, short course (DOTS) and DOTS-Plus programmes in Taiwan Jung-Yien Chien1,2, Chih-Cheng Lai3, Che-Kim Tan4, Shun-Tien Chien1, Chong-Jen Yu2 and Po-Ren Hsueh2,5* 1

Chest Hospital, Department of Health, Executive Yuan, Tainan, Taiwan; 2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Intensive Care Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan; 4Department of Intensive Care Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 5Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan *Corresponding author. Tel: +886-2-23123456 ext. 65355; Fax: +886-2-23224263; E-mail: [email protected]

Received 3 December 2012; returned 8 January 2013; revised 4 February 2013; accepted 26 February 2013 Objectives: To investigate the impact of the directly observed therapy, short course (DOTS) and DOTS-Plus strategies on changes in resistance profiles among Mycobacterium tuberculosis (MTB). Methods: We performed a retrospective analysis of resistance profiles among isolates of MTB obtained from 2160 consecutive patients with culture-confirmed pulmonary tuberculosis (TB) between 2005 and 2011 at a referral centre in southern Taiwan. Results: Of the 2160 patients, 70 (3.2%) had primary multidrug-resistant (MDR)-TB, 178 (8.2%) had acquired MDR-TB, 10 (0.5%) had primary extensively drug-resistant (XDR)-TB, 23 (1.1%) had acquired XDR-TB and 5 (0.2%) had totally drug-resistant (TDR)-TB. Trend analysis revealed that the rates of acquired MDR-TB were significantly lower after implementation of the DOTS and DOTS-Plus programmes (P,0.01). There was a significant negative correlation between the coverage rates of the DOTS and DOTS-Plus programmes and the rates of acquired MDR-TB (r¼ 20.84, P ¼0.02 and r¼ 20.92, P ¼0.03, respectively). The rates of resistance to rifampicin, isoniazid, ofloxacin, moxifloxacin, levofloxacin and para-aminosalicylic acid also decreased significantly during the study period. However, the rates of primary MDR-TB remained stable (P ¼0.11). Multivariate logistic regression analysis showed that age ranging from 45 to 64 years, positive acid-fast stain results at the initiation of treatment and treatment without DOTS were independent risk factors associated with acquired MDR-TB. In addition, previous treatment for TB (100% versus 19% for TDR-TB and non-TDR-TB, P,0.01) and treatment without DOTS (80% versus 44% for TDR-TB and non-TDR-TB, P ¼0.18) were risk factors for TDR-TB. Conclusions: DOTS and DOTS-Plus are both effective at preventing the acquisition of MDR-TB in Taiwan. Keywords: acquired resistance, MDR-TB, XDR-TB, totally drug-resistant tuberculosis

Introduction Tuberculosis (TB), especially drug-resistant TB, remains one of the most serious challenges to public health in spite of global control efforts. In 2010, there were an estimated 7– 8 million new cases of the disease and an estimated 1.3–1.6 million TB-related deaths.1 TB control has also been hampered by the emergence of Mycobacterium tuberculosis (MTB) strains that cannot be cured by standard anti-TB drug regimens. In 2011, the incidence rate of multidrug-resistant (MDR)-TB, defined as resistance of MTB to at least two of the most effective anti-TB drugs, namely isoniazid and rifampicin, was estimated by the WHO to be 650 000 cases per year.1 The emergence of extensively

drug-resistant (XDR) MTB and totally drug-resistant (TDR) MTB strains further complicates patient care. XDR-MTB is defined as an MDR strain that is resistant to rifampicin, isoniazid, a secondline injectable drug (capreomycin, kanamycin or amikacin), and all fluoroquinolones;2 – 4 TDR-MTB is defined as an MDR strain that is resistant to all second-line drug classes, including aminoglycosides, cyclic polypeptides, fluoroquinolones, thioamides, serine analogues and salicylic acid derivatives.5 Although the epidemiology of XDR-TB in Taiwan has been reported in recent studies,4,6,7 little is known about the epidemiology of TDR-TB. Treatment of patients with drug-resistant TB, including MDR-, XDR- and TDR-TB, requires prolonged and expensive chemotherapy comprising second-line drugs.8 The directly observed

# The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

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therapy, short course (DOTS) programme was launched in Taiwan in April 2006, and in May 2007 the Taiwan Multidrug-resistant Tuberculosis Consortium (TMTC) was established by the Taiwan Centers for Disease Control (Taiwan CDC) to manage and care for patients with MDR-TB. In the same year the Taiwan CDC mandated that each hospital that cares for patients with MDR-TB utilize the DOTS-Plus programme. According to the protocol, patients with MDR-TB are required to: (i) receive individualized treatment regimens, including at least four likely effective anti-TB drugs (including a later-generation fluoroquinolone and an injectable second-line drug); (ii) continue medication for 18 months after conversion of sputum cultures from positive to negative; and (iii) be monitored for adherence and adverse events twice per day during the course of treatment. However, the impact of the DOTS and DOTS-Plus programmes on resistance patterns of MTB is not well understood. The goal of this study was therefore to investigate the clinical characteristics of patients with TDR-TB in Taiwan and to evaluate the association between the implementation of the DOTS and DOTS-Plus programmes and resistance patterns of MTB.

Methods

Definitions Primary resistant TB was diagnosed in patients who had never received treatment for TB but who demonstrated evidence of an MTB strain that was resistant to anti-TB drugs. Acquired resistant TB was diagnosed in patients with a drug-susceptible strain of MTB that became drug resistant during treatment or relapse.10 Treatment failure was defined in patients whose sputum cultures were positive for MTB ≥5 months after initiation of treatment.11 Treatment default was defined as treatment that had been interrupted for two or more consecutive months.11 Good adherence to treatment was defined as the use of at least 80% of the prescribed anti-TB drugs during the treatment course by review of TB registry database.

Statistical analysis Categorical variables were compared using the x2 test or Fisher’s exact test as appropriate. Drug resistance trends over time were analysed using the Cochran–Armitage trend test. Pearson’s correlation was used to evaluate the association between the coverage rates of the DOTS/ DOTS-Plus programmes and drug resistance patterns of MTB. Multivariate logistic regression analysis was used to determine independent variables that are predictive of acquired MDR-TB and XDR-TB. A P value of ,0.05 was considered to indicate statistical significance; all tests were twotailed. All statistical analyses were performed on a personal computer with the statistical package Stata for Windows (Version 11, College Station, TX, USA).

Patients and setting Patients who had culture-confirmed pulmonary TB between 2005 and 2011 were selected from a TB database maintained by the mycobacterial laboratories of the Chest Hospital, a tertiary TB referral hospital in southern Taiwan. According to Taiwanese guidelines all TB patients are required to be entered in the national TB registry database established by the Taiwan CDC since 1996 and are required to submit sputum samples for mycobacterial culture and drug susceptibility testing at initiation of treatment and during the second and fifth month of treatment. Sputum samples were decontaminated and liquefied using NaOH and concentrated by centrifugation. If sputum sample smears were positive for acidfast bacilli, treatment was started as soon as possible. Since 2010 a rapid test for the detection of rifampicin and isoniazid resistance in the MTB isolates from patients with a previous treatment history for TB has been performed by the national referral laboratory of Taiwan CDC and treatment regimens adjusted accordingly. Processed samples were inoculated into Lowenstein –Jensen medium. All the clinical isolates of MTB were identified to the species level using conventional biochemical methods. Susceptibility of the isolates to anti-TB drugs was tested using modified proportional disc elution methods as described previously in all isolates.4,9 First-line drugs tested included isoniazid (0.2 mg/L), rifampicin (1 mg/L) and ethambutol (5 mg/L), and second-line drugs included streptomycin (2 mg/L), capreomycin (10 mg/L), kanamycin (6 mg/L), ofloxacin (2 mg/L), levofloxacin (1.0 mg/L), moxifloxacin (1.0 mg/L), ethionamide (10 mg/L) and para-aminosalicylic acid (PAS; 8 mg/L) For inpatients with multiple isolates, only the first isolate was subjected to trend analysis of drug susceptibility. The medical records of patients were reviewed and data collected on age, sex and status of acid-fast smears, as well as radiographic findings and status of participating in the DOTS/DOTS-Plus programme during treatment. We ascertained the treatment histories of the patients by questioning the patients about their previous treatment and cross-checking the TB registry database. Antibodies to HIV (anti-HIV) (Abbott AxSYMw HIV Assay, Abbott Laboratories, Abbott Park, IL, USA) were assayed in all patients. This study was approved by the Institutional Review Board of the National Cheng Kung University Hospital.

Results Between 2005 and 2011, 2178 patients with culture-confirmed TB were found in our hospital; 18 patients infected with HIV were excluded and 2160 patients without HIV infection were included in the study. Among 1201 patients treated under DOTS, 1069 (89%) had good adherence; however, among 959 patients treated without DOTS fewer patients had good adherence to treatment [720 (75%), P,0.01]. Among all patients, 1372 (63.5%) and 1650 (76.4%) were successfully treated within 12 and 18 months, respectively, and 168 (7.8%) patients died during treatment. Among all patients, 19 (0.9%), 7 (0.3%) and 1 (0.05%) had acquired monoresistance to isoniazid, rifampicin and ethambutol, respectively. Meanwhile, 6 (0.3%) patients had acquired multiresistance to both isoniazid and ethambutol and 1 (0.05%) patient had acquired multiresistance to rifampicin and ethambutol. MDR strains were isolated in 248 (11.5%) patients. Among patients with MDR-TB, 70 (28.2%) had primary MDR-TB and 178 (71.8%) had acquired MDR-TB (treatment failure in 140, treatment default in 5 and relapse in 33 patients). Among patients with acquired MDR-TB, 89 (50%) and 25 (14%) had acquired MDR from previous monoresistance to isoniazid or rifampicin, respectively. Ten (0.5%) patients had primary XDR-TB, 23 (1.1%) had acquired XDR-TB and 5 (0.2%) patients had TDR-TB. Among patients with acquired MDR-TB there was a significantly higher proportion of male patients (P ¼ 0.04), a significantly higher proportion of patients ranging in age from 45 to 64 years (P,0.01), a greater number of patients with pulmonary cavitary lesions (P ¼ 0.01), a greater number of patients with positive acid-fast stain results at the initiation of treatment (P,0.01), and a greater number of patients who did not participate in the DOTS programme (P,0.01) than among patients with either primary MDR-TB or non-MDR-TB (Table 1).

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Table 1. Demographic characteristics and radiographic and laboratory findings among patients with MDR-TB or XDR-TB MDR-TB

XDR-TB

none (n¼1912)

primary (n¼70)

acquired (n¼178)

500 (26.2) 1412 (73.8)

25 (35.7) 45 (64.3)

36 (20.2) 142 (79.8)

82 (4.3) 369 (19.3) 685 (35.8) 677 (35.4) 99 (5.2)

3 (4.3) 19 (27.1) 30 (42.9) 16 (22.9) 2 (2.9)

3 (1.7) 31 (17.4) 99 (55.6) 41 (23.0) 4 (2.2)

Cavitation no yes

1153 (60.3) 688 (36.0)

39 (55.7) 27 (38.6)

66 (37.1) 67 (37.6)

Acid-fast stain negative positive

772 (40.4) 1118 (58.5)

27 (38.6) 43 (61.2)

50 (28.1) 125 (70.2)

Treatment with DOTS no yes

768 (40.2) 1144 (59.8)

67 (95.7) 3 (4.3)

124 (69.7) 54 (30.3)

Sex female male Age (years) ,24 25 to ,45 45 to ,65 65 to ,85 ≥85

P value

none (n¼2127)

primary (n ¼10)

acquired (n ¼23)

551 (25.9) 1576 (74.1)

6 (60) 4 (40)

4 (17.4) 19 (82.6)

87 (4.1) 412 (19.4) 797 (37.5) 726 (34.1) 105 (4.9)

1 (10) 3 (30) 4 (40) 2 (20) 0 (0)

0 (0) 4 (17.4) 13 (56.5) 6 (26.1) 0 (0)

1244 (58.5) 773 (36.3)

9 (90) 1 (10)

5 (21.7) 8 (34.8)

840 (39.5) 1262 (59.3)

3 (30) 7 (70)

6 (26.1) 17 (73.9)

893 (42.0) 1234 (58.0)

10 (100) 0 (0.0)

18 (78.3) 5 (21.7)

0.04

0.04

0.57

,0.01

0.01

0.04

,0.01

,0.01

,0.01

Treatment with DOTS-Plus no yes

P value

,0.01

0.01 109 (5.1) 106 (5.0)

6 (60.0) 4 (40.0)

19 (82.6) 4 (17.4)

Data are n (%) unless otherwise stated.

Among patients with acquired XDR-TB there was a significantly higher proportion of male patients (P ¼ 0.04), a greater number of patients with pulmonary cavitary lesions (P ¼0.04), a greater number of patients with positive acid-fast stain results at the initiation of treatment (P,0.01), and a greater number of patients who did not participate in either the DOTS (P,0.01) or DOTS-Plus programmes (P ¼0.01) than among patients without acquired XDR-TB. The clinical manifestations of five patients with TDR-TB are summarized in Table 2. Four (80%) of these were male; diabetes mellitus (80%) was the most common underlying disease. Pulmonary cavitary lesions were noted in four (80%) patients. Compared with non-TDR-TB, the precipitating risk factors included previous treatment for TB (100% versus 19% for TDR-TB and non-TDR-TB, P,0.01) and treatment without DOTS (80% versus 44% for TDR-TB and non-TDR-TB, P ¼ 0.18). All had received multiple anti-TB drugs before acquisition of TDR-TB. For treating the current episode of TDR-TB all tolerable firstand second-line anti-TB drugs were given, including one of the new generation of fluoroquinolones (levofloxacin or moxifloxacin), one of the injectable anti-TB drugs (kanamycin or capreomycin) as well as protionamide, PAS, cycloserine and clofazimine. Treatment was successful in two (40%) patients after 24 and 36 months, but three (60%) were declared treatment failures and chronic TB excretors.

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Trend analysis revealed that with the increase in coverage rates of the DOTS programme and the DOTS-Plus programme there was a significant decrease (P, 0.01) in the rates of acquired MDR-TB (Table 3 and Figure 1) and a borderline decrease in the rates of XDR-TB (P ¼ 0.07) over the period studied. There was a significant negative correlation between the coverage rates of the DOTS and the DOTS-Plus programme and the rates of acquired MDR-TB (r ¼ 20.84, P ¼ 0.02 and r¼ 20.92, P ¼ 0.03, respectively). However, the rates of primary MDR-TB, primary XDR-TB and secondary XDR-TB (P ¼ 0.11, P ¼ 0.37 and P ¼ 0.12, respectively) remained stable and did not significantly correlate with the coverage rates of the DOTS/DOTS-Plus programmes. Of the 2160 MTB isolates, 276 (12.8%) were resistant to rifampicin, 445 (20.6%) were resistant to isoniazid, 116 (5.4%) were resistant to ethambutol and 255 (11.8%) were resistant to streptomycin. In addition, 54 (2.5%) isolates were resistant to kanamycin, 100 (4.6%) were resistant to ofloxacin, 49 (2.3%) were resistant to ethionamide and 85 (3.9%) were resistant to PAS. A total of 1968 clinical isolates were available for moxifloxacin and levofloxacin susceptibility testing. Of these, 72 (3.7%) were resistant to moxifloxacin and 96 (4.9%) were resistant to levofloxacin. Of 248 MDR-MTB isolates, 95 (38.3%) were resistant to ethambutol, 114 (46.0%) were resistant to streptomycin, 43 (17.3%) were resistant to kanamycin, 82

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Table 2. Clinical characteristics of five patients with TDR-TB

Patient

Year

Age (years)/ sex

Underlying medical conditions

Acid-fast stain result

Pulmonary cavitary lesions

Previous history of TB

Treatment with DOTS

Treatment with DOTS-Plus

Treatment with anti-TB drugs before acquisition of TDR-TB

1

2006

45/M

smoking

positive

yes

previous treatment failure

no

no

HERZ, streptomycin, moxifloxacin, protionamide, PAS HERZ, streptomycin, kanamycin, moxifloxacin, protionamide, cycloserine HERZ, streptomycin, capreomycin, ciprofloxacin, levofloxacin, moxifloxacin, cycloserine HERZ, kanamycin, moxifloxacin, protionamide, PAS, cycloserine, clofazimine, amoxicillin/clavulanate, clarithromycin HERZ, kanamycin, levofloxacin, moxifloxacin, protionamide, PAS, cycloserine

2

2007

51/M

DM, smoking

positive

no

previous treatment failure

no

no

3

2008

66/M

DM, COPD

positive

yes

previous treatment failure

no

no

4

2009

51/M

DM, COPD

positive

yes

previous treatment failure

yes

yes

5

2009

53/F

DM

positive

yes

relapse

no

yes

COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; F, female; M, male; HERZ, isoniazid, ethambutol, rifampicin, pyrazinamide.

(33.1%) were resistant to ofloxacin, 38 (15.3%) were resistant to ethionamide and 47 (19.0%) were resistant to PAS. Susceptibility testing against capreomycin, moxifloxacin and levofloxacin revealed resistance rates of 9.8% (10/102), 26.0% (60/231) and 35.5% (82/231), respectively. As shown in Table 3, the rates of resistance to rifampicin, isoniazid, ofloxacin, moxifloxacin, levofloxacin and PAS significantly decreased during the study period. We also found that there was a negative correlation between the coverage rates of DOTS and rates of resistance to isoniazid, moxifloxacin, levofloxacin and PAS as well as a negative correlation between the coverage rates of the DOTS-Plus programme and rates of resistance to isoniazid, kanamycin and PAS. Multivariate logistic regression analysis revealed that patient age ranging from 45 to 64 years (OR ¼ 2.07, CI ¼1.44 –2.99, P,0.01), positive acid-fast stain results at the initiation of treatment (OR¼ 2.09, CI ¼ 1.36–3.22, P,0.01) and treatment without DOTS (OR ¼2.94, CI ¼ 2.00–4.31, P,0.01) were independent risk factors associated with acquired MDR-TB (Table 4). In addition, treatment without DOTS-Plus was an independent risk factor associated with acquired XDR-TB (OR¼ 9.05, CI ¼ 1.82–44.94, P ¼0.01).

Discussion In this study, the overall prevalence of TDR-TB was 0.2%. Consistent with findings from a study in Iran,5 all of the patients with TDR-TB had a previous history of TB, including four patients with

treatment failure and one patient with disease relapse. Among these patients four had diabetes mellitus and four had radiographic evidence of pulmonary cavitary lesions. All five patients had received multiple anti-TB medications before acquisition of TDR-TB and most of them had not participated in the DOTS/DOTSPlus programmes. In the 2 years since full coverage of the DOTS/ DOTS-Plus programmes there have been no new cases of TDR-TB. Although the number of patients with TDR-TB in this study is small, our findings still provide useful epidemiological information about the emergence of TDR-TB in Taiwan. Trends in anti-TB drug resistance have been proposed as an indicator of programme performance.12,13 After the introduction of the DOTS/DOTS-Plus programme, we found the rates of resistance to isoniazid and rifampicin decreased significantly. This finding is consistent with findings reported in previous studies in Taiwan and other countries.14 – 18 In addition, the number of cases of MDR-TB decreased during the study period. A similar trend has been documented in other studies.19,20 Furthermore, we found that the decrease in the number of cases of MDR-TB was most likely related to the decrease in the number of cases of acquired MDR-TB because the rates of primary MDR-TB remained stable during the study period. Since the introduction of the DOTS programme in 2006 and the DOTS-Plus programme in 2007 at our hospital the coverage rate of DOTS has significantly increased from 6% to 94% while that of DOTS-Plus has increased from 63% to 95%. We found that there was a negative association between the implementation of the DOTS/DOTS-Plus

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Table 3. Trend analysis of drug resistance rates of MTB and correlation with coverage rates of DOTS/DOTS-Plus Correlation with DOTS coverage rate

Resistance rate in each year (%) 2005 No. of isolates

472

2006 371

2007 260

2008 277

2009 287

2010 252

2011

Test for trend P

r

P value

Correlation with DOTS-Plus coverage rate r

P value

241

MDR-MTB all primary acquired

13.56 2.75 10.81

13.75 1.62 12.13

14.62 4.23 10.38

10.11 3.61 6.50

9.06 4.18 4.88

7.54 2.38 5.16

9.13 4.98 4.15

,0.01* 0.11 ,0.01*

20.74 0.58 20.84

0.05 0.17 0.02*

20.73 0.34 20.92

0.16 0.58 0.03*

XDR-MTB all primary acquired

1.91 0.42 1.48

1.35 0.00 1.35

3.85 2.31 1.54

0.72 0.00 0.72

1.39 0.70 0.70

0.40 0.00 0.40

0.83 0.00 0.83

0.07 0.37 0.12

20.30 20.02 20.75

0.51 0.97 0.05

20.68 20.69 20.60

0.21 0.20 0.29

15.25 25.21 5.72 9.75 2.54

14.02 23.45 5.39 12.13 2.96

7.20 5.11 8.11 2.54 7.42

5.93 5.66 6.47 2.96 4.04

16.92 22.31 6.54 14.62 4.62 1.33 8.08 5.00 8.08 2.31 4.62

11.19 19.49 6.14 13.36 2.17 0.36 3.25 2.89 3.25 2.17 2.89

11.15 16.72 5.23 13.24 1.74 1.39 1.74 1.39 2.09 1.39 1.74

8.40 16.27 3.20 9.60 2.01 1.51 1.51 1.51 1.51 3.02 2.51

10.00 15.77 4.98 11.20 1.66 0.83 2.49 2.49 2.49 1.66 2.07

,0.01* ,0.01* 0.30 0.79 0.20 0.73 ,0.01* ,0.01* ,0.01* 0.38 ,0.01*

20.66 20.91 20.34 0.26 20.29 0.01 20.71 20.79 20.78 20.44 20.88

0.10 ,0.01* 0.46 0.57 0.53 0.99 0.08 0.03* 0.04* 0.33 0.01*

20.70 20.87 20.37 20.43 20.89 20.15 20.80 20.76 20.79 20.62 20.94

0.19 0.05 0.53 0.47 0.04* 0.81 0.10 0.14 0.11 0.26 0.02*

Drugs rifampicin isoniazid ethambutol streptomycin kanamycin capreomycin ofloxacin moxifloxacin levofloxacin ethionamide PAS *P, 0.05.

programmes and the rates of acquired MDR-TB. Moreover, the results of the multivariate logistic regression analysis also revealed that not participating in the DOTS/DOTS-Plus programme during anti-TB treatment was an independent risk factor for acquired MDR-TB and XDR-TB. Therefore, we suggest that the decrease in the number of cases of acquired MDR-TB and XDR-TB is due to, at least in part, the implementation of the DOTS and DOTS-Plus programmes. The rates of acquisition of primary MDR-TB and XDR-TB remained stable during the study period. Strains of MDR/XDR-TB can spread rapidly from one person to another. Therefore, the early establishment of a diagnosis and determination of drug susceptibility using rapid molecular drug susceptibility testing methods are of primary importance in preventing disease transmission.21,22 Previous studies have revealed that patients within the middle age group are less likely to adhere to treatment.23 We also found that among patients aged from 45 to 64 years old there were a greater number of patients with poor adherence to treatment (16.2% versus 13.4%, P ¼0.08) as well as a concomitantly higher proportion of patients with a previous treatment history (23.7% versus 16.0%, P,0.01) than in other age groups. Given that poor adherence to therapy is known to be associated with

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the development of drug-resistant TB,12,13 it could be said that being aged between 45 and 64 years is a significant risk factor for acquired MDR-TB. Fluoroquinolones have broad-spectrum antimicrobial activity and play useful roles in treatment for patients with proven MDR-TB and empirical treatment of TB disease in settings with high rates of MDR-MTB.24 – 26 In this study, we found that the rates of resistance to fluoroquinolones, including ofloxacin, levofloxacin and moxifloxacin, decreased over time and were negatively correlated with the coverage rates of the DOTS/DOTS-Plus programmes. There are three major limitations in this study. First, we did not perform molecular studies for each of the MTB isolates. Second, the number of patients with XDR/TDR-TB was small, which limited the power of our analysis. Finally, our hospital was set up by the Taiwanese government to manage patients with TB in southern Taiwan. The results of this study, therefore, cannot be generalized to the population as a whole. In conclusion, the DOTS and DOTS-Plus programmes are both effective at preventing MDR-TB. Continuous surveillance of clinical isolates of MTB is needed to identify TDR-TB, and effective TB intervention must continue to further decrease anti-TB drug resistance.

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Coverage rates of DOTS

Coverage rates of DOTS-Plus

Rates of primary MDR-TB

Rates of acquired MDR-TB

Rates of primary XDR-TB

Rates of acquired XDR-TB

Rates of TDR-TB 14

12 76.2

% of tuberculosis

10

78.6

78.0

93.8 95.5 89.7

100 90

78.9

80

68.1

70 63.2 60

8

50 6

40 31.0 30

4

% of DOTS, DOTS-plus coverage

92.3

20 2 10

6.6

0

0 2005

2006

2007

2008

2009

2010

2011

Year Figure 1. Coverage of DOTS and DOTS-Plus programmes and rates of primary and acquired MDR-TB and XDR-TB and of TDR-TB from 2005 to 2011.

Table 4. Predictors of acquired MDR- and XDR-TB by multivariate analysis Acquired MDR-TB OR Male Age 45–64 years Pulmonary cavitary lesion Positive acid-fast stain Without DOTS Without DOTS-Plus for MDR

95% CI

References 1 World Health Organization. Global Tuberculosis Control: WHO report 2011. http://www.who.int/tb/publications/global_report/2011/gtbr11_ full.pdf (11 January 2013, date last assessed).

Acquired XDR-TB P value

OR

95% CI

P value

1.19 0.77– 1.85 0.44 0.90 0.21 –3.9 2.07 1.44– 2.99 ,0.01 2.29 0.64 –8.21 1.24 0.85– 1.82 0.26 1.47 0.42 –5.18

0.89 0.20 0.55

2.09 1.36– 3.22 ,0.01 2.08 0.5– 8.6

0.31

2.94 2.00– 4.31 ,0.01 0.77 0.17 –3.51 9.05 1.82 –44.94

0.73 0.01

Funding This study was carried out as part of our routine work.

2 Zignol M, Hosseini MS, Wright A et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006; 194: 479– 85. 3 Centers for Disease Control and Prevention. Notice to readers: revised definition of extensively drug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2006; 55: 1176. 4 Lai CC, Tan CK, Huang YT et al. Extensively drug-resistant Mycobacterium tuberculosis during a trend of decreasing drug resistance from 2000 through 2006 at a Medical Center in Taiwan. Clin Infect Dis 2008; 47: e57– 63. 5 Velayati AA, Masjedi MR, Farnia P et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drugresistant tuberculosis or totally drug-resistant strains in Iran. Chest 2009; 136: 420–5. 6 Lai CC, Tan CK, Lin SH et al. Clinical and genotypic characteristics of extensively drug-resistant and multidrug-resistant tuberculosis. Eur J Clin Microbiol Infect Dis 2010; 29: 597– 600. 7 Yu MC, Wu MH, Jou R. Extensively drug-resistant tuberculosis, Taiwan. Emerg Infect Dis 2008; 14: 849– 50. 8 Mitnick CD, Shin SS, Seung KJ et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.

Transparency declarations None to declare.

9 Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and other aerobic Actinomycetes—Second Edition: Approved Standard M24-A2. CLSI, Wayne, PA, USA, 2011.

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18 Liu Y, Jiang G, Zhao L et al. [Drug resistance of Mycobacterium tuberculosis in a nationwide epidemiological survey in China in the year of 2000]. Zhonghua Jie He He Hu Xi Za Zhi 2002; 25: 224–7.

11 World Health Organization, Stop TB Initiative. Treatment of Tuberculosis: Guidelines. 4th edn. Geneva: World Health Organization, 2010.

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