**2. Epidemiology**

Development of anti-tuberculosis drug resistance can occur due to *Mycobacterium tuberculo‐ sis* genetic factor, previous anti-tuberculosis treatment-related factors and many other factors [11]. The mechanism of drug-resistance is shown in Figure 1. There is a constant rate of spontaneous mutation of 0.0033 mutations/deoxyribonucleic acid (DNA) replication that is unique for a diverse spectrum of prokaryotic organisms [12]. The average rates of spontaneous mutation for rifampicin, isoniazid, pyrazinamide, streptomycin, and ethambutol are 2.25 x 10-10, 2.56 x 10-8, 1 x 10-3, 2.95 x 10-8, and 1.0 x 10-7, respectively [13]. A previous study in India revealed 3.4% and 25% of primary and acquired MDR-TB, respectively [14] which were higher than the primary MDR-TB and acquired MDR-TB prevalence previously surveyed in Thailand [2,3,4]. Liu CH *et al*. reported their study in China which presented 19.4% of MDR-TB, 1.3% of XDR-TB, 19.8% of poly-resistant TB, and 47.1% of any anti-tuberculosis drug resistance [15]. A surveillance data in 2007 from the WHO demonstrated 4.8% of MDR-TB cases among new TB cases worldwide [16] compared to the study from MDR-TB surveillance in Thailand between 2007-2009 revealed the MDR-TB prevalence of 0-0.21% (average 0.08%) which was highest in the central part of Thailand [9]. The prevalence among patients with previously TB treatment from the same surveillance project was between 1.58-58.72% (average 8.49%, higher than the percentage of hotspot of MDR-TB prevalence set by the WHO (3%, an indicator for implementation of DOTS (Directly Observed Treatment, Short Course)-Plus programmes) which was also found highest in the central part of Thailand while the northern part of Thailand was the second [9]. This Thailand's serious MDR-TB situation needs urgently management such as implementation of DOTS-Plus programmes. In 2006, Gandhi NR *et al*. firstly reported of XDR-TB co-infected with HIV/AIDS which had been studied in Kwazulu Natal, South Africa (KZN) [11]. XDR-TB epidemic in South Africa appears to be the primary mechanism through the acquisition of 63-75% of XDR-TB cases [11] whereas the strain of *Mycobacterium tuberculo‐ sis* infected among a large number of XDR-TB cases in KZN was F15/LAM4/KZN [11]. Generally, individual who is infected with *Mycobacterium tuberculosis* has approximately 5-10% lifetime risk of developing TB disease, but in an individual with HIV-infection/AIDS the risk is 5-15% a year [11]. This can contribute HIV-infection/AIDS to facilitate the control of outbreaks of MDR-TB and XDR-TB, although it has contributed to outbreaks of drug-resistant TB [17]. The patients with MDR-TB and HIV/AIDS co-infection will have exceedingly high mortality [16]. Gandhi NR *et al*. recently reported their study on risk factors for mortality among MDR/XDR-TB patients with HIV/AIDS co-infection which revealed that 80% of XDR-TB patients died whereas 63% of MDR-TB patients were dead following the diagnosis [18]. The CD4-T cell count less than 50 cells/mm3 was the strongest independent factor for mortality among both patient groups [18]. History of TB treatment is the most significant predictor of development of MDR-TB [19]. High prevalence of HIV/AIDS co-infection and inadequate resources for case detection and management have contributed to the emergence of untreatable XDR-TB [20]. Unfortunately, the presence of XDR-TB in non—HIV-infected patients with MDR-TB is independent poor prognostic factors [11]. Prevalence of XDR-TB is globally accounted for approximately 5.4% of MDR-TB prevalence [21]. Drug-resistant TB and drugresistant gram-negative bacterial infection and disease are associated with the most serious health problems in developing countries [22]. Estimated 81,000 patients with MDR-TB (18.4% of the estimated MDR-TB patients worldwide in 2011) live in the 53 countries of the WHO European Region [23]. This European MDR-TB problem contributed to launching of a new WHO Regional Office for Europe Action Plan to fight MDR-TB to contain the spread of drugresistant TB in the region by the end of 2015 [23]. The new action plan set the targets to be achieved by the end of 2015, are : 1) decreasing 20% of the proportion of MDR-TB cases among previously treated patients 2) diagnosis of at least 85% of the estimated MDR-TB cases and 3) treating successfully at least 75% of notified MDR-TB cases [23]. If this plan is fully imple‐ mented and expected, by 2015, to successfully treat 127,000 MDR-TB cases, and to prevent the emergence of 250,000 new MDR-TB cases and 13,000 new XDR-TB cases [23]. This would interrupt the transmission of MDR-TB and save 120,000 lives in this region [23].

#### **3. Systematic management of MDR/XDR-TB**

Project on Anti-tuberculosis Drug Resistance Surveillance in Thailand (Situation of Multidrug-Resistant Tuberculosis in Thailand : Fiscal Year 2007-2009) that studied in 126 hospitals countrywide showed 877 patients with laboratory-confirmed MDR-TB and 64 patients with laboratory-confirmed XDR-TB while 21.5 % were dead and 12.74 % of these MDR/XDR-TB patients had human immunodeficiency virus (HIV) infection /acquired immunodeficiency syndrome (AIDS) compared to 21.57% of probable or presumptive MDR-TB patients coinfected with HIV/AIDS [9]. Only 18.2% of the studied data sources came from TB registered book for MDR-TB patients and most of them came from the hospital medical registry [9]. A previous study by Scano F *et al*. revealed 52 of the 53 patients with XDR-TB died [10]. The median survival time from collection of specimen to death of these patients was 16 days [10]. The prevalence of XDR-TB among all MDR-TB patient was as the following : 10.3% in Germany and 14.3% in Italy (1993-2004) ; 1.5% in Asia, 15.4% in Republic of Korea, 13.6% in Russia, 0.6% in Africa and Middle East, 6.5% in industrialized countries, and 6.6% overall worldwide (2000-2004); 12% in Hong Kong (2004); 10.9% in Iran (2006); 7.3% in India; and 4% in France (2006) [11]. The WHO notified that Thailand possibly underreported of MDR/XDR-TB prevalence due to delaying of transportation of the specimens for anti-tuberculosis drug susceptibility testing to the specialized centres and processes of unstandardized data collecting of the country [9]. More than 400,000 new MDR-TB cases globally occur each year while approximately half of a million cases occurred in 2007 and accounted for more than 5% of the annually global cases of TB disease. The emerging of drug-resistant TB is a global health problem, although emphasis has been placed on several " hotspots " (higher than 3% of its prevalence) worldwide because of lacking of good global data reported to the WHO. The

240 Tuberculosis - Current Issues in Diagnosis and Management

emergence of MDR-TB and XDR-TB is a real health threat to achieve TB elimination.

Development of anti-tuberculosis drug resistance can occur due to *Mycobacterium tuberculo‐ sis* genetic factor, previous anti-tuberculosis treatment-related factors and many other factors [11]. The mechanism of drug-resistance is shown in Figure 1. There is a constant rate of spontaneous mutation of 0.0033 mutations/deoxyribonucleic acid (DNA) replication that is unique for a diverse spectrum of prokaryotic organisms [12]. The average rates of spontaneous mutation for rifampicin, isoniazid, pyrazinamide, streptomycin, and ethambutol are 2.25 x 10-10, 2.56 x 10-8, 1 x 10-3, 2.95 x 10-8, and 1.0 x 10-7, respectively [13]. A previous study in India revealed 3.4% and 25% of primary and acquired MDR-TB, respectively [14] which were higher than the primary MDR-TB and acquired MDR-TB prevalence previously surveyed in Thailand [2,3,4]. Liu CH *et al*. reported their study in China which presented 19.4% of MDR-TB, 1.3% of XDR-TB, 19.8% of poly-resistant TB, and 47.1% of any anti-tuberculosis drug resistance [15]. A surveillance data in 2007 from the WHO demonstrated 4.8% of MDR-TB cases among new TB cases worldwide [16] compared to the study from MDR-TB surveillance in Thailand between 2007-2009 revealed the MDR-TB prevalence of 0-0.21% (average 0.08%) which was highest in the central part of Thailand [9]. The prevalence among patients with previously TB treatment from the same surveillance project was between 1.58-58.72% (average 8.49%, higher

**2. Epidemiology**

Diagnostic and treatment consultation networks for MDR/XDR-TB which set by the 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, 10th Office of Disease Prevention and Control, Department of Disease Control, Ministry of Public Health, Thailand beyond the year

treat 127,000 MDR-TB cases, and to prevent the emergence of 250,000 new MDR-TB cases and 13,000 new XDR-TB cases [23]. This would interrupt the

treatment is the most significant predictor of development of MDR-TB [19]. High prevalence of HIV/AIDS co-infection and inadequate resources for case detection and management have contributed to the emergence of untreatable XDR-TB [20]. Unfortunately, the presence of XDR-TB in non—HIV-infected patients with MDR-TB is independent poor prognostic factors [11]. Prevalence of XDR-TB is globally accounted for approximately 5.4% of MDR-TB prevalence [21]. Drug-resistant TB and drug-resistant gram-negative bacterial infection and disease are associated with the most serious health problems in developing countries [22]. Estimated 81,000 patients with MDR-TB (18.4% of the estimated MDR-TB patients worldwide in 2011) live in the 53 countries of the WHO European Region [23]. This European MDR-TB problem contributed to launching of a new WHO Regional Office for Europe Action Plan to fight MDR-TB to contain the spread of drug-resistant TB in the region by the end of 2015 [23]. The new action plan set the targets to be achieved by the end of 2015, are : 1) decreasing 20% of the proportion of MDR-TB cases among previously treated patients 2) diagnosis of at least 85% of the estimated MDR-

4

**5.** patients with evidence of HIV co-infection/AIDS before the 6-month short course chemo‐

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

http://dx.doi.org/10.5772/54852

243

**6.** general TB patients with history of MDR-TB patient exposure, including health or medical personnel with TB disease who have history of MDR-TB patient exposure, and

**7.** other high-risk patients of MDR-TB, such as general TB patient with huge lung cavity, diabetic patients, prisoners with TB disease, and TB patients who live in the cross-

Several plans have been announced for the WHO Stop TB Department to collaborate with the Foundation for Innovative New Diagnostics (FIND) to initiate and introduce rapid-culture technology and new rapid drug-resistant tests in the southern African countries and the world including the international standards for the second-line drug-susceptibility testing [11]. The Thailand' s 2012 National Tuberculosis Management Guidelines [24] set the laboratory investigations for MDR-TB which are direct acid-fast bacilli (AFB)-sputum smear examina‐ tions with sputum culture and drug susceptibility testing (DST). For reduction of the diagnosis time for unrecognized drug-resistant TB, new rapid diagnostic technologies for drug resistance from sputum smear or positive culture for smear-negative and extra-pulmonary TB must be prioritized [10]. All TB control programmes in moderate- and high-MDR TB prevalent settings should consider the promotion of culture and DST including implementation of use of algorithms for the diagnosis of pulmonary and extra-pulmonary TB [10]. Rapid DST is preferred to the conventional DST due to 1-2 days of resulting. Recently, the 2011 WHO Guidelines recommends " Xpert MTB/RIF® " and line-probe assay which are new molecular diagnostic technologies and can detect drug resistance to both isoniazid and rifampicin or only rifampicin [24], but their disadvantage is inability to detect the resistance to every drugs used in MDR-TB treatment for detecting probable XDR-TB, required expertise and expensive technologies/equipments which limit their wider uses [25]. The conventional DST takes 1-3 months of the results that take markedly longer than the new molecular methods and is laborintensive [24]. Other alternative phenotypic methods based on the *Mycobacterium tuberculosis* metabolism such as CO2 (carbon dioxide) production, oxygen uptake, ATP (adenosine triphosphate) bioluminescence, etc. have been experimented and demonstrated promising in overcoming this obstacle of longer time resulting [25]. These methods also have impressive sensitivity and specificity compared to the conventional DST [25]. Currently, molecular line probe assays and automated liquid culture systems are recommended by the WHO as the gold standard for the first-line and second-line DSTs. Liquid culture DST has been demonstrated to have relatively good reliability and reproducibility for aminoglycosides, fluoroquinolones, and polypeptides for detecting XDR-TB [26]. However, liquid culture DST for other secondline drugs such as para-aminosalisylic acid, linezolid, clarithromycin, amoxicillin-clavulanate, cycloserine, clofazimine, terizidone, ethionamide, and prothionamide is not recommended by the WHO [26]. A recent study reported the use of spoligotyping and sequence 6110 restriction

therapy starting,

borderline areas.

**5. Laboratory investigations for MDR-TB**

**Figure 1.** Mechanism of development of anti-tuberculosis drug resistance

2000 have been firstly initiated at tertiary care hospitals in northern Thailand. Data collecting on MDR/XDR-TB control has been tracked through the special project paper-based recording and reporting systems set by the 10th Zonal Tuberculosis and Chest Disease Centre which separated from the routine DOTS recording and reporting systems. Currently, a new computer programme has been developed by staff of this centre to efficiently record and report the MDR/ XDR-TB data in the area of northern Thailand and attempt to gradually extend the use of this computer programme throughout the country.

**Figure 1**. **Mechanism of development of anti-tuberculosis drug resistance** 
