**3. Surveillance studies for the assessment of resistance rates and the detection of MDR-TB**

MDR-TB poses a therapeutic challenge and is associated with increased mortality. Surveillance studies for the assessment of resistance rates and the detection of MDRTB are therefore crucial in order to optimize empiric drug therapy and to prevent the dissemination of resistant strains in a community [9]. The extent of the problem of MDR-TB has been examined by the WHO in cross-sectional surveys of drug resistance in either clinical series or whole-country cohorts [10]. Cross-sectional surveys almost certainly underestimate the burden and number of cases of MDR-TB because they do not take into account the numerical burden of TB in the high-burden countries [11]. When the exercise is repeated with a mathematical modeling design using drugresistance estimates and the number of cases of TB, a more accurate picture of the global MDR-TB burden is claimed [12].

### **3.1. Global project of drug resistance surveillance**

The WHO and the IUATLD (International Union against Tuberculosis and Lung Disease) have established a global project of drug resistance surveillance that is based on standard epide‐ miological methods and quality control through an extensive network of reference laborato‐ ries. The Global Project has served as a common platform for country, regional and global level evaluation of the magnitude and trends in anti-tuberculosis drug resistance quantified the growing global burden of MDR-TB and started to document the spread of XDR-TB. Since its launch in 1994, the Global Project has collected and analyzed data on drug resistance from surveys of sampled patients and from national surveillance systems from an ever increasing number of settings around the world [7].

The review of Cohn et al, 1997 represented a comprehensive description of worldwide drug resistance surveys performed during the 1990s. According to the study, resistance to multiple drugs varied by geographic region and was more common when resistance was acquired rather than primary. The rate of multidrug resistance (and occasionally other drugs) was low in most surveys of primary resistance, ranging from 0 to 10.8% (median rate, 0.5%); however, for acquired resistance, the rate of multidrug resistance ranged from 0 to 48.0% (median rate, 12.2%). For surveys that did not distinguish between primary and acquired resistance, the range was 0.5% to 14.3% (median rate, 2.3%). In terms of antituberculous drug resistance, they found a great deal of variability between different countries, and within some countries, differences between regions or cities [13].

*2.2.5. Cured*

*2.2.6. Failed*

**detection of MDR-TB**

TB burden is claimed [12].

**3.1. Global project of drug resistance surveillance**

number of settings around the world [7].

negative cultures taken at least 30 days apart.

186 Tuberculosis - Current Issues in Diagnosis and Management

A patient who has completed a course of anti-TB treatment according to programme protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive

Anti-TB treatment will be considered to have failed if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive. Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early because of poor clinical or radiological response or adverse events.

These latter failures can be indicated separately in order to do sub-analysis.

**3. Surveillance studies for the assessment of resistance rates and the**

MDR-TB poses a therapeutic challenge and is associated with increased mortality. Surveillance studies for the assessment of resistance rates and the detection of MDRTB are therefore crucial in order to optimize empiric drug therapy and to prevent the dissemination of resistant strains in a community [9]. The extent of the problem of MDR-TB has been examined by the WHO in cross-sectional surveys of drug resistance in either clinical series or whole-country cohorts [10]. Cross-sectional surveys almost certainly underestimate the burden and number of cases of MDR-TB because they do not take into account the numerical burden of TB in the high-burden countries [11]. When the exercise is repeated with a mathematical modeling design using drugresistance estimates and the number of cases of TB, a more accurate picture of the global MDR-

The WHO and the IUATLD (International Union against Tuberculosis and Lung Disease) have established a global project of drug resistance surveillance that is based on standard epide‐ miological methods and quality control through an extensive network of reference laborato‐ ries. The Global Project has served as a common platform for country, regional and global level evaluation of the magnitude and trends in anti-tuberculosis drug resistance quantified the growing global burden of MDR-TB and started to document the spread of XDR-TB. Since its launch in 1994, the Global Project has collected and analyzed data on drug resistance from surveys of sampled patients and from national surveillance systems from an ever increasing The review of Caminero et al of 2010 [14], broadly discuss the epidemiological data of the global report, issued in 2008. The report included drug susceptibility data from 90 726 patients in 83 countries and territories from year 2002 to 2007. The median prevalence of resistance in new cases of TB was 11.1% for any drug and 1.6% for MDR-TB. The prevalence of MDR-TB in new TB cases ranged from 0% in eight countries to 22.3% in Baku, Azerbaijan, and 19.4% in the Republic of Moldova. Of the 20 settings with the highest proportion of MDR-TB in new cases, 14 were located in countries of the former Soviet Union (between 6.8% and 22.3% in nine countries, including Moldovia and Azerbaijan) and four in China (7% in two provinces in China) [15, 16], A trend analysis of the 2008 report shows that between 1994 and 2007 the prevalence of MDR-TB in new cases (initial resistance) increased substantially in South Korea and two Russian Oblasts, Tomsk and Orel. By contrast, the prevalence remained stable in Estonia and Latvia, both of which have high rates of initial MDR-TB. The prevalence of MDR-TB in all TB cases decreased in Hong Kong and the United States [14].

Of 37 countries and territories that reported representative data on XDR-TB, five countries, all from the former Soviet Union, each reported 25 or more cases of XDR-TB, with MDR-TB prevalence ranging from 6.6% to 23.7% [15, 16], data from Eastern Mediterranean countries showed that the prevalence of initial MDR-TB was higher than previously estimated, with the exception of Morocco and Lebanon, with rates of respectively 0.5% and 1.1%. Initial MDR-TB rates in Jordan and Yemen were respectively 5.4% and 2.9%. The Americas, Central Europe and Africa reported the lowest rates of initial MDR-TB, with the notable exceptions of Peru, Rwanda and Guatemala, which reported rates of respectively 5.3%, 3.9% and 3.0%. [15, 16]. Data on previously treated cases from the WHO/ Union 2008 report were available for 66 countries and two regions of China [15]. Drug susceptibility testing (DST) results were available for 12 977 patients. Resistance to at least one anti-tuberculosis drug ranged from 0% in three European countries to 85.9% in Tashkent, Uzbekistan. The highest proportions of MDR-TB were reported in Tashkent (60.0%) and Baku, Azerbaijan (55.8%). data from Gujarat State, India, providing the first reliable descriptions of previously treated cases in India, showed 17.2% MDR-TB in this group [15].

The 2008 WHO/Union report also included a global estimation of the MDR-TB problem [14]. Based on drug resistance data from 114 countries and two regions of China reporting to this project, combined with nine other epidemiological factors, the proportion of MDR-TB among new, previously treated and combined cases was estimated for countries with no survey information available. The estimated proportion of MDR-TB for all countries was then applied to incident TB cases (also based on indirect estimates). It was calculated that 4 89 139 (95% confidence limits [95%CL] 455 093–614 215) cases emerged in 2006, and that the global proportion of MDR-TB among all cases was 4.8% (95%CL 4.6–6.0). India, China and the Russian Federation were estimated to have the highest number of MDR-TB cases: India and China have approximately 50% of the global burden and the Russian Federation a further 7%. Twenty seven countries accounted for 86% of the world's MDRTB burden [14].

**3.2. MDR-TB and immigration**

tance of continued surveillance in such a setup [9].

of multidrug resistance due to the immigration [19-21].

general populations [9].

**3.3. HIV and MDR-TB**

TB patients or an outbreak [7].

Gilad et al [9] assessed the incidence of TB in Southern Israel in the period between 1992 and 1997, and studied the prevalence of resistance to anti-TB drugs and its distribution among the various subpopulations inhabiting that region, with the intention of tailoring the empirical anti-TB treatment guidelines to those subpopulations. This study described the unique epidemiology of drug-resistant TB in Southern Israel, a region inhabited by both native and immigrant populations. Significant differences in age, gender, and resist‐ ance rates were found among the four distinct subpopulations inhabiting the Negev re‐ gion. They attributed the observed differences to immigration from countries of high prevalence of drug-resistant TB. According to an earlier 10-year survey (1978- 1987) of TB in the Negev, Ethiopian immigrants and Bedouin Arabs comprised 76% of TB cases and 33% of them were extrapulmonary TB [17]. However the study of Gilad et al [9], re‐ corded only 20% of isolates as extrapulmonary, and Ethiopian immigrants and Bedouin Arabs comprised only 40% of the cases. These differences demonstrate how dynamic this disease might be, tremendously influenced by immigration, and demonstrate the impor‐

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A worldwide survey of drug resistance rates by the WHO [18] demonstrated high rates of resistance among isolates in the former Soviet Union, with the highest rates detected in Latvia. The Resistance rates observed rom the study for the immigrants from the for‐ mer Soviet Union (IFSU) were much higher than those encountered in the Russian re‐ public for every drug or drug combination [9]. These rates were very similar to those found in Latvia, and were even higher overall (50% and 41.5%, respectively). In this cur‐ rent era, import of infectious diseases across international borders occurs much readily [9]. The studies done in Germany and Canada also had reported an increased incidence

These studies have shown the impact of immigration on the incidence and distribution of drugresistant TB in a particular country and the importance of continuous surveillance and immediate therapeutic decisions to prevent the dissemination of such resistant strains to their

The epidemiological impact of HIV on the epidemic of drug-resistant TB is not known and may depend on several factors. HIV-positive TB cases are more likely to be smear negative. In addition, delayed diagnosis of drug resistance and unavailability of treatment (particularly in previous years) have led to high death rates in people living with HIV. Both of these factors (smear negativity and short duration of disease due to mortality) may suggest a lower rate of general transmission. However, HIV-positive cases progress more rapidly to disease and in settings where MDR-TB is prevalent (either in the general population or in the local population such as a hospital or a district), this may lead to rapid development of a pool of drug-resistant

Caminero et al, divided the world into four large regions according to the influence of the three factors i.e., past and present management of TB and transmission of MDR-TB.


The fourth edition of WHO *Guidelines for surveillance of drug resistance in tuberculosis* is an updat‐ ed version of earlier editions published in 1994, 1997 and 2003. These guidelines incorporate the 2007 WHO *Interim recommendations for the surveillance of drug resistance in tuberculosis* and the conclusions of an Expert Committee Meeting on Anti-Tuberculosis Drug Resistance Surveys held in Geneva in September 2008. In addition experience gained from 15 years of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance is also included [7].

Given below are some of the updates and clarifications in surveillance methodology that have been incorporated into the 4th edition:


### **3.2. MDR-TB and immigration**

information available. The estimated proportion of MDR-TB for all countries was then applied to incident TB cases (also based on indirect estimates). It was calculated that 4 89 139 (95% confidence limits [95%CL] 455 093–614 215) cases emerged in 2006, and that the global proportion of MDR-TB among all cases was 4.8% (95%CL 4.6–6.0). India, China and the Russian Federation were estimated to have the highest number of MDR-TB cases: India and China have approximately 50% of the global burden and the Russian Federation a further 7%. Twenty

Caminero et al, divided the world into four large regions according to the influence of the three

The fourth edition of WHO *Guidelines for surveillance of drug resistance in tuberculosis* is an updat‐ ed version of earlier editions published in 1994, 1997 and 2003. These guidelines incorporate the 2007 WHO *Interim recommendations for the surveillance of drug resistance in tuberculosis* and the conclusions of an Expert Committee Meeting on Anti-Tuberculosis Drug Resistance Surveys held in Geneva in September 2008. In addition experience gained from 15 years of the Global

Given below are some of the updates and clarifications in surveillance methodology that have

**b.** If resistance is detected to rifampicin, then susceptibility to the fluoroquinolones and second- line injectable agents most often used in the setting have be tested. Testing for

**2.** Statistical and epidemiological methodology is a fundamental aspect of designing surveys that sample patients, and appropriate technical assistance should be received in the early stages of planning. In particular, for surveys that use cluster-based sampling methods, results should be adjusted to correct for biases introduced by these sampling techniques. Missing values should also be accounted for, e.g. using multiple imputation techniques

**3.** MDR-TB management is a component of the Stop TB Strategy and WHO Member States have committed themselves to achieve universal access to diagnosis and treatment by 2015. Therefore, all drug resistance surveillance activities should be linked to patient treatment and care. Planning a comprehensive treatment programme for patients identified during a survey as having drug-resistant TB should run in parallel to planning

**1.** At a minimum, surveillance should evaluate susceptibility to the following drugs:

susceptibility to the first-line drug ethambutol should also be considered.

seven countries accounted for 86% of the world's MDRTB burden [14].

**3.** Countries with low prevalence and incidence of MDR-TB and

factors i.e., past and present management of TB and transmission of MDR-TB. **1.** Countries with an epidemic: high prevalence and incidence of MDR-TB. **2.** Countries with high MDR-TB prevalence but low or decreasing incidence.

**4.** Countries with low prevalence but an increasing incidence of MDR-TB.

Project on Anti-Tuberculosis Drug Resistance Surveillance is also included [7].

been incorporated into the 4th edition:

188 Tuberculosis - Current Issues in Diagnosis and Management

**a.** Isoniazid and rifampicin;

when possible.

the survey itself.

Gilad et al [9] assessed the incidence of TB in Southern Israel in the period between 1992 and 1997, and studied the prevalence of resistance to anti-TB drugs and its distribution among the various subpopulations inhabiting that region, with the intention of tailoring the empirical anti-TB treatment guidelines to those subpopulations. This study described the unique epidemiology of drug-resistant TB in Southern Israel, a region inhabited by both native and immigrant populations. Significant differences in age, gender, and resist‐ ance rates were found among the four distinct subpopulations inhabiting the Negev re‐ gion. They attributed the observed differences to immigration from countries of high prevalence of drug-resistant TB. According to an earlier 10-year survey (1978- 1987) of TB in the Negev, Ethiopian immigrants and Bedouin Arabs comprised 76% of TB cases and 33% of them were extrapulmonary TB [17]. However the study of Gilad et al [9], re‐ corded only 20% of isolates as extrapulmonary, and Ethiopian immigrants and Bedouin Arabs comprised only 40% of the cases. These differences demonstrate how dynamic this disease might be, tremendously influenced by immigration, and demonstrate the impor‐ tance of continued surveillance in such a setup [9].

A worldwide survey of drug resistance rates by the WHO [18] demonstrated high rates of resistance among isolates in the former Soviet Union, with the highest rates detected in Latvia. The Resistance rates observed rom the study for the immigrants from the for‐ mer Soviet Union (IFSU) were much higher than those encountered in the Russian re‐ public for every drug or drug combination [9]. These rates were very similar to those found in Latvia, and were even higher overall (50% and 41.5%, respectively). In this cur‐ rent era, import of infectious diseases across international borders occurs much readily [9]. The studies done in Germany and Canada also had reported an increased incidence of multidrug resistance due to the immigration [19-21].

These studies have shown the impact of immigration on the incidence and distribution of drugresistant TB in a particular country and the importance of continuous surveillance and immediate therapeutic decisions to prevent the dissemination of such resistant strains to their general populations [9].

#### **3.3. HIV and MDR-TB**

The epidemiological impact of HIV on the epidemic of drug-resistant TB is not known and may depend on several factors. HIV-positive TB cases are more likely to be smear negative. In addition, delayed diagnosis of drug resistance and unavailability of treatment (particularly in previous years) have led to high death rates in people living with HIV. Both of these factors (smear negativity and short duration of disease due to mortality) may suggest a lower rate of general transmission. However, HIV-positive cases progress more rapidly to disease and in settings where MDR-TB is prevalent (either in the general population or in the local population such as a hospital or a district), this may lead to rapid development of a pool of drug-resistant TB patients or an outbreak [7].

According to Cohn et al, 1997 [13], though the association of MDR-TB with AIDS has been well documented during outbreaks [22-24], the role of HIV infection as a risk factor for the devel‐ opment of drug-resistant TB in other settings was not clear [25]. In Kenya, Malawi, Tanzania, COte d'Ivoire, and France, drug resistance was not associated with HIV infection [26-30]. In contrast, in a survey of eight metropolitan areas of the United States, HIV infection was associated with resistance to antituberculous drugs, both within and outside the New York City area [31]. The acquired MDR-TB also occurs in largely immunocompetent hosts, which was seen in India, Korea, Nepal, and Bolivia [32-35].

Molecular epidemiology makes use of the genetic diversity within strains of infectious organisms to track the transmission of these organisms in human populations and to evaluate

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Therefore molecular epidemiologic techniques can be incorporated into almost any epide‐

The molecular epidemiologic approach to studying tuberculosis epidemiology has identified several new observations that could not have been obtained by conventional epidemiologic or laboratory approaches [39]. Mycobacterial strain typing by means of molecular methods has become an important instrument for tuberculosis surveillance, control and prevention [40]. Among DNA fingerprinting methods which restriction fragment length polymorphism (RFLP) typing is the most common method used has permitted novel investigations of the epidemiology and pathogenesis of tuberculosis. The use of IS*6110*, an insertion sequence which is present in *Mycobacterium tuberculosis*, is generally considered to be the gold standard for tuberculosis molecular epidemiology studies [41], but other molecular typing techniques could

Spoligotyping is a technique based on the polymorphism of the direct repeat (DR) locus present in *M. tuberculosis* DNA. The DR sequences are composed of multiple 36bp copies, interspersed by short non repetitive sequences [43]. The direct-repeat locus in *M. tuberculosis* contains 10 to 50 copies of a 36-bp direct repeat, which are separated from one another by spacers that have different sequences. However, the spacer sequences between any two specific direct repeats are conserved among strains. Because strains differ in terms of the presence or absence of specific spacers, the pattern of spacers in a strain can be used for genotyping (spacer oligonu‐ cleotide typing, or "spoligotyping"). Spoligotyping has two advantages over IS*6110*-based genotyping. As small amounts of DNA are required, it can be performed on clinical samples or on strains of *M. tuberculosis* shortly after their inoculation into liquid culture. In addition the results of spoligotyping, which are expressed as positive or negative for each spacer, can be expressed in a digital format. However, spoligotyping has less power to discriminate among

Mycobacterial interspersed repeat units (MIRU) genotyping categorizes the number and size of the repeats in each of 12 independent MIRUs, with the use of a polymerase-chain-reaction (PCR) assay, followed by gel electrophoresis to categorize the number and size of repeats in 12 independent loci, each of which has a unique repeated sequence. Two to eight alleles are at each of the 12 loci, yielding approximately 20 million possible combinations of alleles. The discriminatory power of MIRU genotyping is almost as great as that of IS*6110*-based geno‐ typing. Unlike IS*6110*-based genotyping, MIRU analysis can be automated and can thus be used to evaluate large numbers of strains, yielding intrinsically digital results that can be easily

The PGRS, the DR and the GTG repeated sequences have mainly been used for sub typ‐ ing strains for which differentiation by IS*6110* finger printing appeared insufficient. This

the host and parasite -specific risk factors for disease spread.

**4.2. Molecular epidemiology of TB**

be used as adjuncts in selected circumstances [42].

*M. tuberculosis* strains than does IS*6110*-based genotyping.

catalogued on a computer data base.

miologic assessment to improve exposure and outcome measures

The studies by Borrell and Gagneux [36] pointed out that, from a scientific point of view, the actual evidence for primary transmission of MDR -TB in HIV-negative individ‐ uals that has been confirmed by molecular methods is very limited, and that more stud‐ ies including molecular data are needed to know the true extent of primary MDR-TB & XDR –TB in a general population.

#### **3.4. Inadequate treatment and development of MDR and XDR-TB**

Multidrug-resistant tuberculosis (MDR-TB) is a major challenge for TB control world‐ wide. Inadequate treatment of MDR-TB inevitably results in high mortality and the de‐ velopment of XDR-TB [37]. The study of Jeon et al, 2011 [38], shows how inadequate treatment has contributed to the high prevalence of MDR and XDR-TB in Korea. Accord‐ ing to Jeon et al, the three TB referral hospitals in the public sector are responsible for the management of MDR-TB in the public sector of Korea. This study showed poor out‐ come for patients with MDR-TB at the 3 TB hospitals in Korea: low treatment success rate (37.1%), high default rate (37.1%), and high all-cause mortality rate (31.2 %) during the 3-4 yr after treatment initiation. Since the National Tuberculosis Program (NTP) of Korea has focused on new cases, there have been limited nationwide data about the inci‐ dence and prevalence of MDR-TB and its treatment outcomes. Treatment success rate of their study was the lowest ever reported among MDR-TB cohorts in Korea [38].
