**7. Regimens used in treating patients with drug-resistant tuberculosis**

**6. Radiological features in patients with MDR/XDR-TB**

248 Tuberculosis - Current Issues in Diagnosis and Management

A recent study in South Korea showed 100% of lung nodules, 60% of lung consolidation, and 47% of lung cavities that were mainly located in the upper and middle lung zones in XDR-TB patients whereas less frequent lung nodules and ground-glass opacity lesions were found in XDR-TB patients compared to the patients with anti-TB drug-susceptible pulmonary TB [50]. More frequent multiple lung cavities, lung nodules, and bronchial di‐ latation were found in both MDR-TB and XDR-TB patients compared to the patients with anti-TB drug-susceptible pulmonary TB [50]. There was no different radiological findings between MDR-TB and XDR-TB patients [50]. Another recent study in South Ko‐ rea revealed that micronodules and tree-in-bud appearance were found in 100% of the pulmonary XDR-TB patients whereas lung consolidations, lung cavities, bronchiectasis, lobar consolidations were found in 85%, 85%, 80%, and 70%, respectively [51]. This study showed a significantly larger extent of tree-in-bud appearance and lung consolidations compared to the MDR-TB patients [51]. In childhood patients, chest radiological features at the time of diagnosis demonstrates lobar opacification, intrathoracic lymphadenopathy, particular hilar lymph nodes, and airway narrowing [52]. Chest radiological features of three patients with MDR-TB who attended the 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, Thailand are shown in the Figure 4 (A,B,C) which demonstrated a single cavity at the upper lung zone in two patients and no lung cavity in another one. These three patients possibly attended the 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, Thailand at the earlier stages compared to the above study results.

A B C

**Figure 4.** First-attendance chest radiological features of the three patients (A,B,C) with MDR-TB at the 10th Zonal Tu‐ berculosis and Chest Disease Centre, Chiang Mai, Thailand A : Showing bilaterally diffuse lung infiltration with a cavity in the left upper lung zone, B : Showing fibrotic infiltration with surrounding new infiltration at the right upper lung zone with bilaterally diffuse emphysematous lung changes, C : Showing bilaterally diffuse infiltration with a cavity in

the right upper lung zone with left pleural effusion.

A recent study on MDR-TB treatment revealed that use of later generation quinolones (moxifloxacin, gatifloxacin, sparfloxacin, levofloxacin), ofloxacin or ethionamide/prothiona‐ mide, use of four or more likely effective drugs in the initial intensive phase, and three or more likely effective drugs in the continuation phase was associated with the treatment success compared to the treatment failure or relapse [53]. The duration of initial phase up to 7.1-8.5 months and the total duration of treatment up to 18.6-21.5 months increased the chances of treatment success [53]. In 2011, the WHO recommended the regimens containing a fluoroqui‐ nolone, pyrazinamide, ethionamide (or prothionamide), para-aminosalicylic acid (or cyclo‐ serine), and a second-line injectable drug with more than 20 months of treatment duration [54]. Five MDR-TB control projects with used DST results and previous treatment history were conducted among 1,047 MDR-TB patients in 5 resource-limited settings with well-established DOTS programmes (Manila, Estonia, Latvia, Lima, and Tomsk) in 1999 for Lima and Manila, 2000 for Tomsk and Latvia, and 2001 for Estonia [55]. At least 4 drug (ethambutol, pyrazina‐ mide, cycloserine, clofazimine, para-aminosalicylic acid, ethionamide, or prothionamide, augmentin, clarithromycin or thiacetazone) including an injectable drug (kanamycin, amika‐ cin, capreomycin, or streptomycin) and a fluoroquinolone (ofloxacin, ciprofloxacin, or levofloxacin) were administered for the duration of treatment (18-24 months) except for the injectable drug, which was administered for a specified interval after the patient' s specimens were culture-negative [55]. Monthly sputum-AFB smear and culture were monitored [55]. Every 6-months (Manila and Lima) and 3-months chest radiographs (Tomsk, Latvia, and Estonia) were performed [55]. The treatment outcomes among new and previously treated MDR-TB patients revealed 74.8% and 68.3% cured patients, 2.5% and 0.3% completed treat‐ ment patients, 4.2% and 7.0% failed treatment patients, 3.4% and 14.2% dead patients, and 77.3% and 66.6% treatment success rates (cure rate + completed treatment rate), respectively [55]. The results showed worsen outcomes among previously treated patients. Report from the 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, Thailand, in 2011 which had been collected from the data of laboratory-confirmed 254 MDR-TB patients (72.8% of all probable MDR-TB cases) among 349 totally suspected-MDR-TB cases with 15.8% of HIV coinfection in northern Thailand between 2005-2010 gradually increased from 62.2% of probable MDR-TB cases in 2005 to 78.3% in 2010 and revealed 3.2% treatment-denial patients, 75.2% treatment-registered patients, 30.2% died before starting the second-line drug treatment regimens (pyrazinamide, ethambutol, ofloxacin, para-aminosalicylic acid administered for 18-24 months and one injectable drug (kanamycin, or amikacin) administered 5 days per week for the initial 6-month phase), 25.4% default-treatment patients (continuous interruption of treatment more than 2 months), 54.8% treatment success rate, and 22.2% unavailable-data patients [7]. Among 19 cases with pre-treatment death, 10 cases (52.63%) demonstrated HIV co-infection. Extra-pulmonary cases accounted for 2.4% of the laboratory-confirmed cases which was lower than percentage of susceptible extra-pulmonary TB cases in the same area [56]. Four cases with laboratory-confirmed MDR-TB emerged as XDR-TB during treatment [7]. A previous study on outcomes of a daily supervised-MDR-TB treatment regimen which consisted of initial phase of 6-9 months with kanamycin, ofloxacin, cycloserine, ethionamide,

ethabutol, and pyrazinamide demonstrated that in cases of persistent culture positive at fourth month, the initial phase was extended for additional 3 months. Then ofloxacin, cycloserine, ethionamide, and ethambutol were continued for 18 months [57]. The results of the study revealed that 82% of cases demonstrated time to culture conversion at the second month or before. The culture conversion rates at third month and sixth month were 84% and 87%, respectively. The cure rate was 66%. At 24 months, 79% of the patients remained culture negative for more than 18 months. Adverse drug reactions were reported among 58% of cases and 2 failure cases emerged as XDR-TB during treatment [57]. A recent study on comparison between traditional hospital-based treatment-model of MDR-TB patient care and communitybased model in rural areas of South Africa revealed that median times to starting the treatment and sputum smear conversion were shorter for community-based model (84 days versus 106.5 days and 59 days versus 92 days, respectively) [58]. Lack of sputum culture conversion at month 9 was a predictor of pulmonary MDR-TB treatment failure with 84% of sensitivity and 94% of specificity [59]. A recent study by Dheda K *et al*. demonstrated that the number of XDR-TB deaths was not significantly different compared between patients with and without HIV co-infection [60] whereas Well CD recently reported that lower cure rates and higher death rates were found in MDR-TB patients with HIV co-infection compared to the patients without HIV co-infection [61]. Survival of XDR-TB patients with HIV co-infection was associated with absence of biomarkers indicative of multiorgan dysfunction, less advanced stage of both diseases at time of diagnosis, and antiretrovirals provision [62]. Previous culture-proven MDR-TB, number of drug used in a MDR-TB treatment regimen, and treatment with moxifloxacin were independent predictors of death [60] while some previous reports showed that treatment success rates were poor (30-50%) in XDR-TB patients with HIV co-infection [63] and the MDR/ XDR-TB prevalence was substantially precipitated by the HIV epidemic [64, 65]. In children with MDR-TB, the treatment guidelines are the same principles, using the same drugs as in adult patients with strict and prolonged supervision by expert pediatricians [66]. HIV coinfection are particular challenges and requires early starting of antiretroviral therapy with careful monitoring for drug-adverse side-effects [66]. Children with close contact with MDR-TB patients should be tested with tuberculin skin testing or interferon-gamma release assays, direct AFB-smear examinations, cultures, and DST and taking the chest radiological exami‐ nations [24]. Cases with close contact should be at least 2-year followed up [24]. If they are diagnosed MDR-TB, they must be treated with the empirical MDR-TB regimen [24]. Empirical MDR-TB treatment regimen is not recommended for MDR-TB chemoprophylaxis [24]. MDR-TB chemoprophylaxis for children with at least 2 second-line drugs for 6-12 months and reflecting the susceptibility profile of the source case' s isolate with daily supervision should be considered [52, 67]. The knowledge of mechanisms of the second-line drugs for children is necessary for ensuring the treatment adherence and long-term control of the disease.

amikacin + ethionamide + capreomycin 2.5% [68]. Currently, the data of the second-line drug

Drug-Resistant Tuberculosis – Diagnosis, Treatment, Management and Control: The Experience in Thailand

The Thailand' s 2012 National Tuberculosis Management Guidelines [24] recommends the guidelines for both pulmonary and extra-pulmonary MDR-TB treatment as the following flow

diagram : 15

Probable/Suspected MDR-TB If dramatic response to the regimen

If previous treatment outcome showed failure to the regimen 2HRZE/4HR, prescribe the empirical MDR-

During waiting for the DST results and previous treatment outcome showed relapse TB, prescribe

(Note : 2 months of streptomycin (S), isoniazid (H), rifampicin (R), pyrazinamide, and ethambutol (E), followed by 1 month of H, R, Z, and E, and followed by 5 months of H, R, and E)

the regimen 2SHRZE/1HRZE/5HRE

**Figure 5.** Flow Diagram of Management of Patient with Probable/Suspected MDR-TB

Currently, in Thailand, patients with persistent AFB-smear and/or culture positive after completeness of MDR-TB treatment will be prescribed isoniazid alone for lifelong while no

8K5-7(PAS)(Eth)(Lfx)(Cs)/12(PAS)(Eth)(Lfx)(Cs) (Note : 8 months of kanamycin (K, 5-7 doses per week), para-aminosalicylic acid (PAS), ethionamide (Eth), levofloxacin ((Lfx), cycloserine (Cs), and followed by 12 months of PAS, Eth, Lfx, and Cs)

TB treatment regimen

2HRZE/6HR, continue 2HRZE/4HR (2 months of rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E), followed by 4 months of R and H)

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251

Performing DST for R, H, Z, E, S for exclusion of Non-TB mycobacteria (very few centres in Thailand can perform the DST for pyrazinamide)

If know DST results, the treatment regimen used depends on clinical responses, AFBsmear examination results, and DST results

resistance are not available [9].

 

A previous study on the second-line drug susceptibility among 40 MDR-TB strains in Turkey revealed mono-resistant to ethionamide 25%, amikacin 10.0%, kanamycin 2.5%, ofloxacin 2.5%, amikacin 0%, and clofazimine 0%, any resistant to ethionamide 37.5%, capreomycin 25.0%, kanamycin 5.0%, ofloxacin 5.0%, amikacin 5.0%, and clofazimine 2.5%, resistant to both ethionamide + capreomycin 5.0%, both capreomycin + clofazimine 2.5%, ofloxacin + ethiona‐ mide + capreomycin 2.5%, amikacin + ethionamide + capreomycin 2.5%, and kanamycin + amikacin + ethionamide + capreomycin 2.5% [68]. Currently, the data of the second-line drug resistance are not available [9].

ethabutol, and pyrazinamide demonstrated that in cases of persistent culture positive at fourth month, the initial phase was extended for additional 3 months. Then ofloxacin, cycloserine, ethionamide, and ethambutol were continued for 18 months [57]. The results of the study revealed that 82% of cases demonstrated time to culture conversion at the second month or before. The culture conversion rates at third month and sixth month were 84% and 87%, respectively. The cure rate was 66%. At 24 months, 79% of the patients remained culture negative for more than 18 months. Adverse drug reactions were reported among 58% of cases and 2 failure cases emerged as XDR-TB during treatment [57]. A recent study on comparison between traditional hospital-based treatment-model of MDR-TB patient care and communitybased model in rural areas of South Africa revealed that median times to starting the treatment and sputum smear conversion were shorter for community-based model (84 days versus 106.5 days and 59 days versus 92 days, respectively) [58]. Lack of sputum culture conversion at month 9 was a predictor of pulmonary MDR-TB treatment failure with 84% of sensitivity and 94% of specificity [59]. A recent study by Dheda K *et al*. demonstrated that the number of XDR-TB deaths was not significantly different compared between patients with and without HIV co-infection [60] whereas Well CD recently reported that lower cure rates and higher death rates were found in MDR-TB patients with HIV co-infection compared to the patients without HIV co-infection [61]. Survival of XDR-TB patients with HIV co-infection was associated with absence of biomarkers indicative of multiorgan dysfunction, less advanced stage of both diseases at time of diagnosis, and antiretrovirals provision [62]. Previous culture-proven MDR-TB, number of drug used in a MDR-TB treatment regimen, and treatment with moxifloxacin were independent predictors of death [60] while some previous reports showed that treatment success rates were poor (30-50%) in XDR-TB patients with HIV co-infection [63] and the MDR/ XDR-TB prevalence was substantially precipitated by the HIV epidemic [64, 65]. In children with MDR-TB, the treatment guidelines are the same principles, using the same drugs as in adult patients with strict and prolonged supervision by expert pediatricians [66]. HIV coinfection are particular challenges and requires early starting of antiretroviral therapy with careful monitoring for drug-adverse side-effects [66]. Children with close contact with MDR-TB patients should be tested with tuberculin skin testing or interferon-gamma release assays, direct AFB-smear examinations, cultures, and DST and taking the chest radiological exami‐ nations [24]. Cases with close contact should be at least 2-year followed up [24]. If they are diagnosed MDR-TB, they must be treated with the empirical MDR-TB regimen [24]. Empirical MDR-TB treatment regimen is not recommended for MDR-TB chemoprophylaxis [24]. MDR-TB chemoprophylaxis for children with at least 2 second-line drugs for 6-12 months and reflecting the susceptibility profile of the source case' s isolate with daily supervision should be considered [52, 67]. The knowledge of mechanisms of the second-line drugs for children is

250 Tuberculosis - Current Issues in Diagnosis and Management

necessary for ensuring the treatment adherence and long-term control of the disease.

A previous study on the second-line drug susceptibility among 40 MDR-TB strains in Turkey revealed mono-resistant to ethionamide 25%, amikacin 10.0%, kanamycin 2.5%, ofloxacin 2.5%, amikacin 0%, and clofazimine 0%, any resistant to ethionamide 37.5%, capreomycin 25.0%, kanamycin 5.0%, ofloxacin 5.0%, amikacin 5.0%, and clofazimine 2.5%, resistant to both ethionamide + capreomycin 5.0%, both capreomycin + clofazimine 2.5%, ofloxacin + ethiona‐ mide + capreomycin 2.5%, amikacin + ethionamide + capreomycin 2.5%, and kanamycin + The Thailand' s 2012 National Tuberculosis Management Guidelines [24] recommends the guidelines for both pulmonary and extra-pulmonary MDR-TB treatment as the following flow diagram : 15

**Figure 5.** Flow Diagram of Management of Patient with Probable/Suspected MDR-TB

Currently, in Thailand, patients with persistent AFB-smear and/or culture positive after completeness of MDR-TB treatment will be prescribed isoniazid alone for lifelong while no standardized treatment is recommended yet. Types of patients with MDR-TB, patient moni‐ toring during MDR-TB treatment and assessment of sputum conversion, and classification of treatment outcomes are shown in the Table 1, 2, and 3, respectively [24].

then every 6 months for 18 months. Chest radiological examinations are preformed when

Drug-Resistant Tuberculosis – Diagnosis, Treatment, Management and Control: The Experience in Thailand

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253

patient who treated with MDR-TB treatment regimen following the Thailand' s 2012 National Tuberculosis Control Management (or NTP) Guidelines with consecutively 5- negative results of the 30 day-interval AFB smear examinations and cultures of the last 12 months of treatment duration

patient with completeness of the MDR-TB treatment following the Thailand' s 2012 NTP Guidelines but no consecutively AFB-smear examination and culture results during the last 12 month treatment duration

Guidelines

patient treated with MDR-TB regimen following the Thailand' s 2012 NTP Guidelines with 2 positive results of the 5 consecutive AFB-smear examinations and cultures during the last 12 months of treatment duration or patient with 1 positive-culture result of the last 3 consecutive cultures or patient with physician' s decision to stop the MDR-TB treatment due to clinical unresponsiveness or various adverse-drug reactions

Guidelines

setting with unknown treatment outcomes will be registered as " Transfer out "

**Died** patient with any cause of death during MDR-TB treatment following the Thailand' s 2012 NTP

**Default** patient with continuous interruption of the MDR-TB treatment following the Thailand' s 2012 NTP

**Transfer out** partially MDR-TB treated patient with referring from (Transferring out) one setting to another

**9. MDR-TB management and treatment outcomes in Thailand between**

The prevalence of laboratory-confirmed MDR-TB was 0.08%. Highest prevalence (0.21%) was found in the central part of Thailand. MDR-TB was mostly diagnosed and treated at the secondary care settings or general hospitals (31.5% and 31.14%), 24.3% and 25.08% of cases were diagnosed at the tertiary care settings and only 6.9% and 6.7% of the patients were diagnosed at the university hospitals, respectively [9]. The majority of the patients (63.82%) were registered as " after failure of the first-TB treatment " [9]. In Thailand, numbers of the secondary care settings or general hospitals are more than that of the tertiary care hospitals, this may reflex the above figures. Only 33.5% of cases were referred to the well-facilitated setting for directly observed treatment (DOT) [9]. Only 60.6% of MDR-TB cases were prescri‐ bed 4 oral second-line drugs and an injectable aminoglycoside drug [9] which recommended by the Thailand' s 2012 National Tuberculosis Management Guidelines while the rests were prescribed various treatment regimens [24]. Only 57.5% of cases had completed treatment adherence [9]. Low DOT implementation can contribute to high default rates, high treatment failure rates, high death rates, and low cured rates. There was 24.2 % of patients with com‐

indicated.

**Cured**

**Treatment completed**

**Failed**

**2007-2009**

**Table 3.** Classification of treatment outcomes [24]


**Table 1.** Registration of the patients with MDR-TB [24]


**Table 2.** Patient monitoring during MDR-TB treatment and Assessment of sputum conversion [24]
