TB control and care. Curr Opin Pulm Med 16: ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins

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1 Emerging epidemic of drug-resistant tuberculosis in Europe, Russia, China, South America and Asia: current status and global perspectives Giovanni Battista Migliori a, Rosella Centis a, Chris Lange b, Morgan D Arcy Richardson c and Giovanni Sotgiu d a WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy, b Division of Clinical Infectious Diseases, Medical Clinic, Research Centre Borstel, Borstel, Germany, c HIV/TB Global Program, PATH, Seattle, Washington, USA and d Hygiene and Preventive Medicine Institute, University of Sassari, Sassari, Italy Correspondence to Giovanni Battista Migliori, MD, WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, TBNET (TuBerculosis Network European Trials group) Secretariat, via Roncaccio 16, Tradate, Italy Fax: ; giovannibattista.migliori@fsm.it Current Opinion in Pulmonary Medicine 2010, 16: Purpose of review Drug resistance, particularly through multidrug-resistant tuberculosis (TB) and extensively drug-resistant TB strains, poses a real threat to TB control worldwide. Recent reports from the WHO and the International Union Against Tuberculosis and Lung Disease demonstrate that the emerging epidemic of drug-resistant TB is a global problem, although emphasis has been placed on several hot spots because of lack of good global data. Recent findings The present article is aimed at reviewing the available information on drug-resistant TB with special focus on the features of the epidemic in Europe, Russia, Latin America, Asia and specifically China, and to discuss the global perspectives related to drug-resistant TB control and care. Summary Drug-resistant TB originates from different human errors, including misuse of anti-tb drugs and other reasons related to prescribers, patients and drug producers. Although there is an urgent need for new drugs, a sound public health approach is necessary for their introduction in clinical treatment settings to prevent/avoid creating additional resistance, as has already been observed for first and second-line anti-tb drugs in many settings. Keywords Asia, China, drug-resistant tuberculosis, Europe, extensively drug-resistant tuberculosis, Latin America, multidrug-resistant tuberculosis, Russia, tuberculosis Curr Opin Pulm Med 16: ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction The global tuberculosis (TB) epidemic has been complicated by the emergence of strains of Mycobacterium tuberculosis that are resistant to anti-tb drugs. Drugresistant TB originates from a range of human errors, including misuse of anti-tb drugs, poor adherence to treatment, poor-quality drugs and other reasons related to prescribers, patients and producers [1,2]. The spread of multidrug-resistant TB (MDR-TB) [3 6,7 ], and, more recently, of extensively drug-resistant TB (XDR-TB) [8 10] is considered as a real threat to achieve the global goal of TB control and elimination by The objectives of the present article are: to review the available information on drug-resistant TB; to discuss the features of the epidemic in Europe, Latin America and Asia; and to discuss global perspectives related to drug-resistant TB control and care. Methods and definitions The present review was based on a Medline search performed using the key words tuberculosis, drugresistant tuberculosis, MDR-TB and XDR-TB, covering the period up to September The articles identified were divided into the following sections: Europe (Russian Federation excluded), Russian Federation, China, South America and Asia (China excluded), and quoted in the review based on priority criteria. Pan-sensitive TB is defined as TB susceptible to all firstline agents (isoniazid, rifampicin, pyrazinamide and ethambutol). MDR-TB is caused by M. tuberculosis resistant to at least isoniazid and rifampicin (the two most potent first-line anti-tb drugs) [3 6,11]. XDR-TB is defined as TB caused by strains of M. tuberculosis that are resistant to at least isoniazid and rifampicin (i.e ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MCP.0b013e e

2 172 Infectious diseases MDR-TB), to any fluoroquinolone and to at least one of three injectable drugs used in anti-tb treatment: capreomycin, kanamycin, amikacin [8,10,12,13]. A European study [14] has recently demonstrated that the occurrence of XDR-TB, as currently defined, has both a clinical value (predicting poor outcome) and an operational significance (confirming the loss of first-line drugs coupled with key second-line ones). For the purposes of this review, the emerging epidemic of drug-resistant TB is described in Europe, Russia, South America, Asia and China with special attention given to known hot spots. The majority of the data from Europe reported here are derived from the WHO/International Union against Tuberculosis and Lung Disease Global Project on Drug-resistance Surveillance [5,7 ]. Additional data from Europe reported in this review are derived from the TBNET (Tuberculosis Network European Trials group) studies reporting epidemiological and clinical data for all culture-confirmed TB patients (n ¼ 4583) diagnosed consecutively by the TB clinical reference centres in Estonia, Germany, Italy and Russian Federation between 1999 and Standard WHO definitions for MDR- TB, XDR-TB and treatment outcome (treatment success, died, failure, default and transferred out) were used in all the TBNET studies [14,15,16 19,20,21 ]. Risk factors for multidrug-resistant tuberculosis Spontaneous chromosomal mutations at sites of key drug targets are the predominant mechanism of acquired resistance to antibiotic drugs by M. tuberculosis. Primary drug resistance the transmission of already resistant M. tuberculosis must be distinguished from secondary drug resistance resistance acquired in the host as a result of inadequate treatment. As the main risk factor for the development of M. tuberculosis drug resistance is previous treatment against TB, secondary drug resistance is responsible for the majority of these cases [3,22,23]. Espinal et al. [23] evaluated 9615 patients with TB, 8222 (85.5%) were new patients of TB and 1393 (14.5%) were previously treated patients. Compared with new patients, previously treated cases were significantly more likely to have resistance to one [odds ratio (OR) ¼ 2.5, P < 0.001], two (OR ¼ 4.6, P < 0.001), three (OR ¼ 11.5, P < 0.001) and four (OR ¼ 18.5, P < 0.001) drugs. An approximately linear increase in the likelihood of having MDR-TB was observed as the total time (measured in months) of prior anti-tb treatment increased (P < 0.001). In multivariate analysis, prior TB treatment for 6 11 months (OR ¼ 7.6, P < 0.001) and more than 12 months (OR ¼ 13.7, P < 0.001) was associated with MDR-TB [23]. Previous treatment against TB has been identified as the key covariate for M. tuberculosis drug resistance and the association becomes stronger as the level of M. tuberculosis drug resistance increases [15,22,24,25 27]. Recently, migration from high MDR-TB prevalence countries has been identified as the strongest risk factor for MDR-TB in Europe [28 ]. Infection with HIV per se is not likely to be an independent risk factor for MDR-TB [23]. However, because of the high prevalence of TB and HIV infection in prisons and the relationship of the transmission of resistant strains of M. tuberculosis to overcrowded conditions, there is a statistical association between MDR-TB and HIV infection in Europe (OR ¼ 3.52) [22]. Drug-resistant tuberculosis in Europe The fourth report on global anti-tb drug resistance [5,7 ] provides the latest data on the extent of drug-resistant TB between 2002 and This report [7 ] includes drug susceptibility test (DST) data for patients from 83 countries. Since 1994, 40 countries of the European region reported drug-resistance data from areas representing 35% of all TB patients in the region. The population-weighted mean of MDR-TB based on all countries reporting in Central and Western Europe is 0.9% among new patients, 7.7% among previously treated patients and 1.5% among combined patients, respectively. As expected, the proportion of MDR-TB was significantly higher in the Eastern European and Central Asian countries. Seventy-four countries provided data on the prevalence of any drug resistance among new patients of TB. The overall drug resistance ranged from 0% (Iceland), 1.4% in Bosnia and Herzegovina to 49.2% in Georgia, 51.2% in Tashkent, Uzbekistan and 56.3% in Baku City, Azerbaijan, respectively. Seven settings in Europe reported prevalence of resistance to any drug as 30% or higher (Table 1) [5,7 ]. Prevalence of any drug resistance among previously treated patients was available for 68 countries. No resistance was reported in Iceland and Norway, the number of previously treated patients being very small. In contrast, in Baku, Azerbaijan, and in Tashkent, Uzbekistan, the prevalence of any resistance was very high, at 84.4 and 85.9%, respectively [5]. In nine European settings, prevalence of any resistance was reported as 50% or higher (Table 1) [5,7 ]. Among new patients, prevalence of any resistance to isoniazid ranged from 0% in Malta and Iceland to 42.4% in Tashkent, Uzbekistan, and 40.8% in Baku City, Azerbaijan. Overall in Europe, nine settings reported a

3 Drug-resistant tuberculosis worldwide Migliori et al. 173 Table 1 Prevalence of drug resistance in new and previously treated tuberculosis patients in Europe in 2006 New TB patients Previously treated patients Country Any resistance % INH % RMP % MDR % Any resistance % INH % RMP % MDR % Andorra 11.1 ( ) 11.1 ( ) 0.0 ( ) 0.0 ( ) Armenia 37.5 ( ) 27.2 ( ) 10.9 ( ) 9.4 ( ) 74.4 ( ) 63.2 ( ) 47.1 ( ) 43.2 ( ) Austria 12.1 ( ) 9.5 ( ) 2.5 ( ) 1.9 ( ) 12.5 ( ) 12.5 ( ) 12.5 ( ) 12.5 ( ) Azerbaijan (Baku City) 56.3 ( ) 40.8 ( ) 22.7 ( ) 22.3 ( ) 84.4 ( ) 79.7 ( ) 56.0 ( ) 55.8 ( ) Belgium 5.8 ( ) 4.9 ( ) 1.5 ( ) 1.2 ( ) 9.8 ( ) 9.8 ( ) 7.3 ( ) 7.3 ( ) Bosnia and Herzegovina 1.4 ( ) 0.8 ( ) 0.7 ( ) 0.4 ( ) 24.5 ( ) 13.2 ( ) 13.2 ( ) 6.6 ( ) Croatia 2.9 ( ) 2.0 ( ) 1.0 ( ) 0.5 ( ) 8.2 ( ) 4.9 ( ) 4.9 ( ) 4.9 ( ) Czech Republic 7.7 ( ) 3.7 ( ) 1.4 ( ) 1.2 ( ( ) 35.0 ( ) 30.0 ( ) 30.0 ( ) Denmark 5.5 ( ) 4.9 ( ) 1.6 ( ) 1.6 ( ) 22.2 ( ) 16.7 ( ) 0.0 ( ) 0.0 ( ) Estonia 28.8 ( ) 20.6 ( ) 13.3 ( ) 13.3 ( ) 63.4 ( ) 60.6 ( ) 52.1 ( ) 52.1 ( ) Finland 4.0 ( ) 3.5 ( ) 1.0 ( ) 1.0 ( ) 4.5 ( ) 4.5 ( ) 4.5 ( ) 4.5 ( ) France 8.7 ( ) 5.5 ( ) 1.2 ( ) 1.1 ( ) 21.4 ( ) 14.3 ( ) 8.0 ( ) 7.1 ( ) Georgia 49.2 ( ) 23.4 ( ) 7.6 ( ) 6.8 ( ) 66.0 ( ) 47.2 ( ) 28.5 ( ) 27.4 ( ) Germany 11.0 ( ) 7.3 ( ) 2.2 ( ) 1.8 ( ) 25.1 ( ) 21.9 ( ) 12.7 ( ) 12.4 ( ) Iceland 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0% ( ) 0.0 ( ) Ireland 3.0 ( ) 3.0 ( ) 0.5 ( ) 0.5 ( ) 20.0 ( ) 20.0 ( ) 10.0 ( ) 10.0 ( ) Israel 21.8 ( ) 15.2 ( ) 5.7 ( ) 5.7 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) Italy (eight regions) 9.7 ( ) 6.2 ( ) 2.3 ( ) 1.6 ( ) 36.7 ( ) 30.4 ( ) 17.7 ( ) 17.7 ( ) Latvia 35.9 ( ) 30.9 ( ) 10.8 ( ) 10.8 ( ) 52.7 ( ) 49.5 ( ) 36.3 ( ) 36.3 ( ) Lithuania 24.2 ( ) 20.3 ( ) 9.9 ( ) 9.8 ( ) 60.0 ( ) 56.8 ( ) 48.2 ( ) 47.5 ( ) Luxembourg 11.1 ( ) 8.3 ( ) 0.0 ( ) 0.0 ( ) Malta 18.2 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) Moldova 42.9 ( ) 31.2 ( ) 20.7 ( ) 19.4 ( ) 70.5 ( ) 61.3 ( ) 53.9 ( ) 50.8 ( ) Netherlands 8.3 ( ) 6.5 ( ) 1.4 ( ) 0.7 ( ) 16.7 ( ) 10.0 ( ) 6.7 ( ) 3.3 ( ) Norway 22.3 ( ) 10.4 ( ) 1.6 ( ) 1.6 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) 0.0 ( ) Poland 5.6 ( ) 3.4 ( ) 0.6 ( ) 0.3 ( ) 18.0 ( ) 13.6 ( ) 9.8 ( ) 8.2 ( ) Portugual 14.4 ( ) 6.5 ( ) 1.0 ( ) 0.9 ( ) 20.3 ( ) 15.1 ( ) 11.0 ( ) 9.3 ( ) Romania 14.4 ( ) 8.4 ( ) 4.8 ( ) 2.8 ( ) 32.7 ( ) 28.3 ( ) 12.8 ( ) 11.0 ( ) Serbia 3.0 ( ) 0.8 ( ) 0.8 ( ) 0.4 ( ) 11.6 ( ) 5.8 ( ) 6.6 ( ) 4.1 ( ) Slovakia 7.3 ( ) 5.2 ( ) 2.8 ( ) 1.6 ( ) 17.9 ( ) 17.9 ( ) 7.1 ( ) 7.1 ( ) Slovenia 4.6 ( ) 3.2 ( ) 0.0 ( ) 0.0 ( ) 14.3 ( ) 10.7 ( ) 3.6 ( ) 3.6 ( ) Spain (Galicia) 6.5 ( ) 3.5 ( ) 0.2 ( ) 0.2 ( ) 13.2 ( ) 7.4 ( ) 1.5 ( ) 1.5 ( ) Spain (Aragon) 6.5 ( ) 5.5 ( ) 0.5 ( ) 0.0 ( ) 19.2 ( ) 19.2 ( ) 15.4 ( ) 15.4 ( ) Sweden 12.2 ( ) 9.9 ( ) 0.7 ( ) 0.5 ( ) 23.5 ( ) 23.5 ( ) 11.8 ( ) 11.8 ( ) Switzerland 4.6 ( ) 4.3 ( ) 0.9 ( ) 0.6 ( ) 6.7 ( ) 6.7 ( ) 6.7 ( ) 6.7 ( ) Ukraine (Donetsk Oblast) 39.8 ( ) 31.0 ( ) 17.9 ( ) 16.0 ( ) 70.2 ( ) 60.3 ( ) 48.8 ( ) 44.3 ( ) UK 7.1 ( ) 6.7 ( ) 1.0 ( ) 0.7 ( ) 9.2 ( ) 8.5 ( ) 3.3 ( ) 2.6 ( ) Uzbekistan (Tashkent) 51.2 ( ) 42.4 ( ) 15.8 ( ) 14.8 ( ) 85.9 ( ) 81.2 ( ) 60.0 ( ) 60.0 ( ) CI, confidence interval; INH, isoniazid; MDR, multidrug-resistant; RMP, rifampicin; TB, tuberculosis. Data from [5,7 ].

4 174 Infectious diseases prevalence of isoniazid resistance 20% or higher among new patients (Table 1) [5,7 ]. The prevalence of isoniazid resistance in previously treated patients ranged from 0% in Iceland and Norway and 4.5% in Finland to 79.7% in Baku City, Azerbaijan, and 81.2% in Tashkent, Uzbekistan. Seven settings in Europe reported a prevalence of isoniazid resistance 30% or higher among previously treated patients (Table 1) [5,7 ]. The median prevalence of MDR-TB in new TB patients was 1.6%, ranging from 0% in eight countries with low TB prevalence to 19.4% in Moldova and 22.3% in Baku, Azerbaijan [7 ]. The prevalence of MDR-TB in new TB patients was more than 6% in 15 settings; two of these settings were provinces in China and 12 were in 10 countries of the former Soviet Union (FSU: Azerbaijan, Moldova, Ukraine, Russian Federation, Uzbekistan, Estonia, Latvia, Lithuania, Armenia and Georgia) [5]. The median prevalence of MDR-TB in previously treated TB patients was 11.7% [7 ]. Six countries reported no patients with MDR-TB, whereas 55.8% of retreatment patients in Baku (Azerbaijan) and 60% in Tashkent (Uzbekistan) had MDR-TB. Among the 17 settings reporting a prevalence of MDR-TB more than 25% in retreatment patients, nine were in FSU countries [5]. In summary, although the prevalence of drug resistance (as well as that of MDR-TB and XDR-TB) is in general low in Central and Western Europe (the hot spots being localized in Eastern Europe), some pitfalls have been described in the region. Among them, the need for improved coordination of the laboratory networks at national level and their links with the surveillance system need to be emphasized. These elements of the TB control programme are necessary to ensure that all M. tuberculosis strains that are MDR or XDR are collected and tested for second-line drugs in national reference laboratories, allowing a precise quantification of their number and characteristics as well as of the quality of their clinical management [1,2,15 ]. Drug-resistant tuberculosis in China A summary of the data available in China is reported in Table 2. According to the WHO report [5] published in 2008, China accounts for an estimated 25% of MDR-TB patients worldwide and has the second highest MDR-TB prevalence after FSU countries such as Azerbaijan, Georgia, Kazakhstan and Uzbekistan. There are several possible explanations for the high prevalence of drug-resistant TB in China, including inadequate use of TB medications in public hospitals, insufficient treatment supervision, ineffective drug management, a lack of infection control measures in hospitals and the availability of anti-tb drugs without a prescription in some geographic areas [5,7,29]. Table 2 Prevalence of multidrug resistance in new and previously treated tuberculosis patients in Asian countries in 2006 New TB patients Previously treated patients Country No. of new TB patients No. of MDR-TB patients (95% CIs) MDR-TB (%) No. of previously treated TB patients No. of MDR-TB patients (95% CIs) MDR-TB (%) Bangladesh ( ) ( ) 19.3 Bhutan (3 108) (2 25) 19.9 Brunei Darussalam (1 44) (1 12) 19.5 Cambodia (0 332) (0 221) 3.1 China ( ) ( ) 25.6 China Hong Kong SAR (21 59) (19 75) 8.0 China Macao SAR (2 13) (0 10) 15.8 DPR Korea ( ) ( ) 22.4 India ( ) ( ) 17.2 Indonesia ( ) ( ) 18.9 Japan (99 328) (70 186) 9.8 Lao PDR ( ) (16 241) 19.4 Malaysia (0 96) (0 291) 0.0 Maldives (1 21) (0 4) 19.3 Mongolia (9 107) (13 204) 20.5 Myanmar ( ) ( ) 15.5 Nepal ( ) ( ) 11.7 Philippines ( ) ( ) 20.9 Republic of Korea ( ) ( ) 14.0 Singapore (0 7) (0 5) 1.0 Sri Lanka (0 75) (0 53) 0.0 Thailand ( ) ( ) 34.5 Timor-Leste ( ) (3 43) 18.8 Vietnam ( ) ( ) 19.3 CI, confidence interval; MDR, multidrug-resistant; TB, tuberculosis. Data from [5,7 ].

5 Drug-resistant tuberculosis worldwide Migliori et al. 175 Between 2002 and 2007, MDR-TB among new patients ranged from less than 1% in Hong Kong to 7.2 and 7.3% in Heilongjiang and the Inner Mongolia Autonomous region of China [7 ]. The proportion of MDR-TB among previously treated patients was 41.9% in Inner Mongolia Autonomous Region and 30.4% in Heilongjiang [7 ]. Interpretation of these results is difficult, as they may reflect the effect of treating large numbers of people outside the formal health sector [29,30 ]. The proportion of non-mdr rifampicin resistance among previously treated patients was substantial in several Chinese settings: 6.4% in Zhejiang Province, 5.7% in Heilongjiang Province, 5.2% in Inner Mongolia Autonomous Region, 3.5% in Liaoning Province and 3% in Henan Province [7 ]. Because rifampicin resistance unaccompanied by isoniazid resistance is rare, the quality of laboratory testing has been questioned. Possible factors associated to this phenomenon are suboptimal adherence and inadequate regimen prescription or use of the drug (in monotherapy) for purposes other than treating TB. This also includes the use of rifapentine in health facilities where national guidelines were not strictly followed. As rifapentine has a long half-life [31], irregular treatment of rifapentine, isoniazid, ethambutol and pyrazinamide may impose the risk of functional monotherapy of rifapentine, resulting in the emergence of non- MDR rifampicin resistance. These factors need to be investigated in China in settings with a high proportion of non-mdr rifampicin resistance. In summary, enormous improvement has been achieved to control TB in China. Although hot spots of MDR-TB have been described in some provinces, the commitment of the government coupled with the relevant investments in terms of technical assistance and financial support will hopefully achieve better and better results in the future [1,2,15 ]. The main priorities in the country are presently represented by improving TB case management, drug management and infection control [5,7,29]. Drug-resistant tuberculosis in Russia Although in the Russian Federation TB notification rates have been relatively stable since 1997 (81 per population) through 2006 (87 per population), data from selected administrative regions (named Oblasts), where TB control has been implemented according to the WHO recommendations, are showing some declines in TB rates. In Orel Oblast, for example, the TB notification rate has declined by over 3% per year for the past 6 years, whereas in Tomsk Oblast the decline over the same period was 1.3% [5]. In terms of trends, the same two Oblasts are providing data that are considered reliable, as culture and DST have been provided to % of the new TB patients over this time period, new and previously treated patients are adequately differentiated, and there is evidence of good laboratory performance over the period of data collection [5]. Unfortunately, the trends in drug resistance are increasing from an average 13.0% per year in Tomsk to 32.0% per year in Orel [5]. The absolute numbers of newly diagnosed MDR-TB patients are increasing as well. Discussion is ongoing to explain the reasons why this is happening in spite of the good quality of the MDR-TB management programmes in place. Among the possible reasons, while susceptible patients are being successfully treated, a sufficient reduction in MDR-TB patients has not been achieved, leaving drugresistant patients as an increasing reservoir of TB transmission. Information on place of origin, previous history of hospitalization or imprisonment is not sufficiently reliable to allow further deeper analysis. A report [32] jointly published in 2006 by the Russian Ministry of Health and WHO indicated an increase in MDR-TB both in proportion and absolute numbers of patients and highlighted the variation in proportions of resistance across oblasts, indicating that up to 20% of new TB patients in Samara Oblast may have MDR-TB. According to this report, approximately 40% of TB patients in the Russian Federation were categorized as chronic patients in the national surveillance system. This enormous pool is likely to constitute an important reservoir of transmission of MDR-TB. A summary of the prevalence proportions of drug resistance in Russia is reported in Table 3 [5,7 ]. In conclusion, Russia and the other FSU countries represent important hot spots of MDR-TB and XDR-TB. Although relevant efforts were done by the international community to improve TB control (to prevent new cases of drug resistance from emerging) and to improve case management of existing patients, more and more technical and financial support is necessary to control this emerging epidemic in the region [1,2,15 ]. Drug-resistant tuberculosis in South America A summary of the data available in South America is reported in Table 4. More than new cases of MDR-TB were estimated to occur in 2006 in Latin America, with Peru alone accounting for about one-third of these and Ecuador and Brazil for about an eighth each [5]. Peru was the first high-burden TB country to successfully implement Directly Observed Treatment Short course (DOTS), which resulted in a sharp decline in the incidence of TB patients from 1991 to 1999 [33]. Although Peru accounts for only 3% of the population of the Americas, it has 12% of the region s TB patients [5].

6 176 Infectious diseases Table 3 Prevalence of drug resistance in new and previously treated tuberculosis patients in Russia in 2006 New TB patients Previously treated patients Multidrug resistance % RMP % INH % Any resistance % MDR % RMP % INH % Any resistance % Russia Tomsk Oblast 35.3 ( ) 26.4 ( ) 16.7 ( ) 15.0 ( ) Orel Oblast 27.4 ( ) 20.2 ( ) 9.5 ( ) 8.8 ( ) 46.7 ( ) 46.7 ( ) 16.7 ( ) 16.7 ( ) Mary El Oblast 29.9 ( ) 26.0 ( ) 12.5 ( ) 12.5 ( ) CI, confidence interval; INH, isoniazid; MDR, multidrug-resistant; RMP, rifampicin; TB, tuberculosis. Data from [5,7 ]. By also pioneering new DOTS approaches to combat MDR-TB (XDR-TB patients have been diagnosed since the first month of 2007), the country has developed a highly capable specialized health research community [34,35]. The national surveillance system reported increases in any resistance, isoniazid resistance and MDR-TB among new patients, though only the increasing trend in any resistance and isoniazid resistance were significant. MDR-TB increased from 2.4% in 1996 to 5.3% in 2006 [5]. Peru showed a yearly decrease in the TB notification rate between 1994 and 2002 (4 6%); however, since 2003, it has slightly increased, at per The recent rise in the notification rate and the increase in drug resistance may be due to weakness in management of TB patients (both new and MDR-TB) in previous years and to weakness in the entire healthcare system [5,7,35]. In Brazil, there were an estimated 1056 patients of MDR- TB in 2007 (30% of whom received treatment), but as of March 2009, XDR-TB patients had also been found [30 ]. The proportion of drug-resistant TB is low in Argentina and Uruguay [5,30 ]. Argentina showed a slight, but not statistically significant, increase in MDR-TB among new patients from 1.8% in 1999 to 2.2% in 2005, and the TB notification rate has steadily decreased over the last decade. Uruguay showed an insignificant decrease in resistance to any drug. The prevalence of any resistance remains low in this country at 2.1% among new TB patients. In summary, although some hot spots of MDR-TB are emerging in Latin America, the experience of Peru demonstrates that it is possible to tackle the epidemic and achieve relatively high treatment success rates in these patients [1,2,15 ]. Drug-resistant tuberculosis in Asia It is important to note that, although in most countries of the region the proportion of MDR-TB patients among both new and retreatment patients is generally low, the total number of patients is quite high due to the overall burden of TB in the region. In Asia, the highest proportion of MDR-TB among new patients was reported from Myanmar (3.9%) and among previously treated patients from Thailand (34.5%). India, Sri Lanka and Thailand reported less than 2% MDR-TB among new patients (Table 2). Myanmar was the exception in the Asian scenario, reporting 3.9% MDR-TB among new and 15.5% among retreatment patients in Despite resource constraints, it is achieving the goal of implementing a national MDR-TB programme supervised by the local National TB programme [5,7 ].

7 Drug-resistant tuberculosis worldwide Migliori et al. 177 Table 4 Prevalence of multidrug-resistant tuberculosis in South America in 2006 Country No. of TB patients No. of MDR patients 95% CI % MDR-TB 95% CI New TB patients Argentina Bolivia Brazil Chile Colombia Ecuador Guyana Paraguay Peru Uruguay Venezuela Previously treated patients Argentina Bolivia Brazil Chile Colombia Ecuador Guyana Paraguay Peru Uruguay Venezuela All TB patients Argentina Bolivia Brazil Chile Colombia Ecuador Guyana Paraguay Peru Uruguay Venezuela CI, confidence interval; MDR, multidrug-resistant; TB, tuberculosis. Data from [5,7 ]. Although India has a very low proportion of new and retreatment patients with MDR-TB, the sheer size of the caseload makes it the second highest MDR-TB burden country in the world, after China. There are several important factors in the generation and transmission of MDR-TB and XDR-TB in India. First, there is a large private sector treating TB and MDR-TB, and many practitioners are not following international standards for TB treatment, nor is treatment support provided to ensure private patients complete treatment. Second, both first and second-line anti-tb medications are freely available without a prescription and are of variable quality. Third, the capacity to diagnose and, therefore, treat MDR-TB properly has lagged behind the creation of cases, allowing ongoing transmission to occur. In general, the TB control programme has achieved good results (e.g. case detection is 77% and treatment success is over 86%); however, a planned network of interregional laboratories, capable of culture and DST and of supporting MDR-TB management settings, is still in the process of implementation. Laboratory capacity is seen as the most important drawback in the Indian ability to respond to the rapid emergence of drug-resistant mycobacterial strains. There is a general consensus that the private health sector should be more involved, but formal linkages are taking time to establish [5,7,30 ]. The data from Mimika district of Papua province in Indonesia show moderate levels of resistance; however, the sample represented a small proportion of the population. Indonesia, like Myanmar and India, is facing issues related to the quality assurance of its laboratories [5]. The proportion of MDR-TB among new patients in Nepal has fluctuated from 1 to 3% in the surveys that have been conducted since 1996, making trends difficult to interpret; the current estimate is 2.9% among new patients and 11.7% among retreatment patients [5]. Nepal, after establishing its pilot MDR-TB control programme in the public sector with 75% success rate among MDR-TB patients, has developed a plan to expand its services to cover the whole country [5,30 ]. Stable trends in resistance have

8 178 Infectious diseases been described in Thailand, with MDR-TB prevalence less than 2% among new TB patients [5,30 ]. Unlike the countries previously described, Thailand has an extensive laboratory network. Owing to the decentralization of public laboratories and the large quantity of private laboratories, maintaining a high level of quality in laboratory performance is one of the major challenges. The Republic of Korea reports a considerable burden of MDR-TB. In this population, 3472 MDR-TB incident patients were estimated in 2006 or 6.8% of all patients [5,30 ]. The country has developed plans to improve the capacity of the reference laboratories to conduct culture and DST; however, the primary hindrance is the lack of sustainable funding for the development of the laboratory network. In summary, several MDR-TB hot spots do exist in Asia. Among the main public health priorities in the region, the strengthening of the laboratory network and the improved case management of TB patients (particularly within the private sector) deserve to be mentioned [1,2,15 ]. Conclusion With the development of several antibiotic drugs in the middle of the 20th century, treatment against TB made revolutionary progress. Only small progress was seen in the diagnosis of TB at that time. Now the tide has turned. For several decades, the advances that have been achieved in the diagnosis of TB have outweighed the inefficient progress of new drug development against TB by far. Although TB ranges among the leading causes of deaths worldwide and substantial progress has been made recently in the development of new drugs against other infectious diseases, for example, HIV infection or against the causative agents of viral hepatitis, the world has not observed the market launch of a single new drug for the treatment of TB in the past 40 years. In contrast to viruses and most other bacterial pathogens, the replication and mutation rates of M. tuberculosis are very slow. Nevertheless, under constant evolutionary pressure of treatment with the same drugs and man-made mistakes in the clinical and case management of patients with TB, emergence of M. tuberculosis drug resistance has become the greatest threat for the global efforts to combat TB in the 21th century. Although we now have the technology to rapidly identify patients with sputum smear-positive MDR-TB or XDR-TB in many places of the world, we are missing the drugs to treat these patients adequately. In contrast, treatment against MDR-TB and XDR-TB is becoming increasingly difficult and poses a substantial challenge to healthcare resources in many parts of the world. Global control of TB will only become possible when significant advances in the prevention and treatment of TB will also be achieved by better vaccines and better drugs than the ones that are currently available. A strong public health approach aimed at applying correctly the WHO-recommended strategy of TB control (known as Stop TB Strategy) is also necessary to prevent the burning of these new drugs in the treatment arena, as already observed for first and second-line anti-tb drugs in many settings [1,2,12]. Acknowledgements The authors gratefully acknowledge Lia D Ambrosio, WHO Collaborating Centre for TB and Lung Diseases, and Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy, for her contribution in revising the manuscript. There are no conflicts of interest. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Migliori GB, Richardson MD, Sotgiu G, Lange C. Multidrug-resistant and extensively drug-resistant tuberculosis in the West, Europe and United States: epidemiology, surveillance, and control. Clin Chest Med 2009; 30: A detailed and updated review of the MDR-TB/XDR-TB problem in the Western part of the world. 2 Matteelli A, Migliori GB, Cirillo D, et al. Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control. Expert Rev Anti Infect Ther 2007; 5: Pablos-Méndez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug-resistance, N Engl J Med 1998; 338: Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis 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: World Health Organization. The WHO/IUATLD Global Project on Anti- Tuberculosis Drug-resistance Surveillance Antituberculosis drug-resistance in the world. Report no. 4. World Health Organization Document 2008, WHO/HTM/TB/ ; pp Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrugresistant tuberculosis. J Infect Dis 2006; 194: Wright A, Zignol M, Van Deun A, et al., for the Global Project on Anti- Tuberculosis Drug-resistance Surveillance. Epidemiology of antituberculosis drug-resistance : an updated analysis of the Global Project on Anti- Tuberculosis Drug-resistance Surveillance. Lancet 2009; 373: An updated summary of the global situation on drug resistance. 8 Shah NS, Wright A, Drobniewski F, et al. Extreme drug-resistance in tuberculosis ( XDR-TB ): global survey of supranational reference laboratories for Mycobacterium tuberculosis with resistance to second-line drugs. Int J Tuberc Lung Dis 2005; 9 (Suppl 1):S77. 9 Holtz TH, Riekstina V, Zarovska E, et al. XDR-TB: extreme drug-resistance and treatment outcome under DOTS-Plus, Latvia, Int J Tuberc Lung Dis 2005; 9 (Suppl 1):S Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide. Morb Mortal Wkly Rep 2006; 55: Nathanson E, Lambregts-van Weezenbeek C, Rich ML, et al. Multidrugresistant tuberculosis management in resource-limited settings. Emerg Infect Dis 2006; 12:

9 Drug-resistant tuberculosis worldwide Migliori et al Migliori GB, Loddenkemper R, Blasi F, et al. 125 years after Robert Koch s discovery of the tubercle bacillus: the new XDR-TB threat. Is science enough to tackle the epidemic? Eur Respir J 2007; 29: Holtz TH, Cegielski JP. Origin of the term XDR-TB. Eur Respir J 2007; 30: Migliori GB, Besozzi G, Girardi E, et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J 2007; 30: Sotgiu G, Ferrara G, Matteelli A, et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009; 33: The first systematic review of the evidence available on MDR-TB and XDR-TB. The manuscript includes a comparative evaluation of the sputum smear and culture conversion rates achieved as well as of the treatment outcomes in XDR-TB patients. 16 Migliori GB, Ortmann J, Girardi E, et al. Extensively drug-resistant tuberculosis, Italy and Germany. Emerg Infect Dis 2007; 13: Migliori GB, Lange C, Centis R, et al. Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases. Eur Respir J 2008; 31: Migliori GB, Lange C, Girardi E, et al. Extensively drug-resistant tuberculosis is worse than multidrug-resistant tuberculosis: different methodology and settings, same results. Clin Infect Dis 2008; 46: Migliori GB, Lange C, Girardi E, et al. Fluoroquinolones: are they essential to treat multidrug-resistant tuberculosis? Eur Respir J 2008; 31: Migliori GB, Sotgiu G, Richardson MD, et al. Consensus not yet reached on key drugs for extensively drug-resistant tuberculosis treatment. Clin Infect Dis 2009; 49: The study discusses the issues related to rational use of drugs for the treatment of XDR-TB patients. 21 Migliori GB, Sotgiu G, Richardson MD, et al. MDR-TB and XDR-TB: drugresistance and treatment outcomes. Eur Respir J 2009; 34: The study investigates the relationship between drug resistance and treatment outcomes. 22 Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006; 61: Espinal MA, Laserson K, Camacho M, et al. Determinants of drug-resistant tuberculosis: analysis of 11 countries. Int J Tuberc Lung Dis 2001; 5: Kliiman K, Altraja A. Predictors of extensively drug-resistant pulmonary tuberculosis. Ann Intern Med 2009; 150: An excellent study demonstrating the predictors of XDR-TB in Estonia, a country with high prevalence of this difficult-to-treat disease. 25 Casal M, Vaquero M, Rinder H, et al. A case control study for multidrugresistant tuberculosis: risk factors in four European countries. Microb Drug Resist 2005; 11: Falzon D, Infuso A, Aït-Belghiti F. In the European Union, TB patients from former Soviet countries have a high risk of multidrug-resistance. Int J Tuberc Lung Dis 2006; 10: Granich RM, Oh P, Lewis B, et al. Multidrug-resistance among persons with tuberculosis in California, JAMA 2005; 293: Sotgiu G, Sorete Arbore A, Kliiman K, et al. Social determinants of MDR-TB in Europe: a multicenter TBNET study. Eur Respir J 2009; 34 (S53):4446. New data on social determinants of MDR-TB from the TBNET network. 29 He GX, Zhao YL, Jiang GL, et al. Prevalence of tuberculosis drug-resistance in 10 provinces of China. BMC Infect Dis 2008; 8: World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report World Health Organization Document 2009, WHO/HTM/TM/ ; pp The WHO report includes the updated figures from each region and country. An essential document for consultation. 31 Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999; 353: Tuberculosis in the Russian Federation, An analytical review of the main tuberculosis statistical indicators used in the Russian Federation, (Ministry of Health and Social Development of RF/FPHI/RIPP/CTRI/FSIN/WHO), Moscow; pp. 33 Global tuberculosis control: WHO report http// who.int/hq/2000/who_cds_tb_ ; Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing DOTS-plus. BMJ 1998; 317: Bonilla CA, Crossa A, Jave HO, et al. Management of extensively drugresistant tuberculosis in Peru: cure is possible. PLoS One 2008; 3:e2957.