**2. Epidemiology of MDR TB**

1

among countries.

Health Organization (WHO) has designated 22 countries of the world as high-burden countries for Tuberculosis (HBCTB) and 27 as high-burden countries for multidrug-resistant Tubercu‐ losis (HBC MDR TB), making a total of 36 countries in either of these categories [1]. The latter are countries where at least 4,000 cases of MDR TB are identified per year and/or at least 10%

Figures are based on the most recent year for which data have been reported, which variesamong countries.

Figures are based on the most recent year for which data have been reported, which varies

 **No data** 

**Figure 1.** Percentage of new TB cases with MDR-TB (Adapted from WHO Global TB Report, 2014)

**Figure 1 Percentage of new TB cases with MDR-TB** 

 **Percentage of cases** 

 **6-11.9 12-17.9 ≥18** 

 **Percentage** 

 **0-2.9 3-5.9 6-11.9 12-17.9 ≥18 No data** 

 **Subnational data only Not applicable** 

 **0-2.9 3-5.9** 

 **Not applicable Subnational data only** 

**(Adapted from WHO Global TB Report, 2014)** 

MDR TB and XDR TB epidemics are largely driven by transmission and are mainly found in new cases and patients with TB relapse [2]. Since 1994, WHO has been receiving and analyzing data on anti-TB drug resistance from countries via its Drug Resistance Surveillance Project, which depends on continuous data based on rapid molecular diagnostics and drug sensitivity testing (DST). However, neither is widely or routinely available due to prohibitive costs involved, especially in low- and middle-income economies that are also high-burden countries. In these low- and middle-income high TB burden countries, cases of MDR TB are identified mainly through special surveys rather than continuous surveillance reporting. In 2013, only 11 of the 36 HBCTB/HBC MDRTB had up-to-date data through these drug-resistance surveys. From these surveys it is clearly understood that the MDR TB burdens attributed to these countries are only estimates based on notification of cases which in most countries is incom‐

Despite these shortfalls in the determination of exact incidences, especially where TB burden is highest, there have been recent global efforts to bridge the gap between diagnosis and appropriate therapy with second- and third-line drugs. Treatment after diagnosis of MDR TB and follow-up of confirmed cases is however bedeviled with unavailability of human resour‐ ces, accessibility to second-line drugs in high MDR TB areas, and logistics. Global treatment

**Figure 2. Percentage of previously treated TB cases with MDR-TB (Adapted from WHO Global TB** 

plete and as such may only be the tip of the iceberg (Figures 1 & 2).

Percentages of previously treated TB cases with MDR-TB in Bahrain, Bonaire, Israel, Saint Eustatius and Saba, and Sao Tomé and Principe refer to only a small number of notified cases (range: 1-8 notified previously

 **of cases** 

of newly registered TB cases are MDR TB.

2 An Overview of Tropical Diseases

**.**

treated TB cases).

**Report, 2014)** 

among countries.

It is estimated that more than 90% of new TB cases and death occur in the high TB burden developing countries [3]. Multidrug anti-tuberculous therapy had been found effective when using the Directly Observed Therapy Short Course (DOTS) strategy to improve compliance to treatment of TB. With the emergence of MDR TB, the DOTS strategy was expanded to accommodate second-line drugs in the Directly Observed Therapy short course with MDR diagnosis, management, and treatment (DOTS PLUS) strategy. Treatment failure, however, can still occur leading to relapse and development of drug-resistant TB strains to second-line drugs which is the XDR TB [4].

Multidrug-resistant Tuberculosis (MDR TB) is defined as resistance to at least both Isoniazid and Rifampicin with or without resistance to other first-line drugs. [5]. A subset of this is Extensively Drug-Resistant Tuberculosis (XDR TB) where there is also resistance to fluoro‐ quinolones and at least one injectable second-line drug (such as Amikacin, Kanamycin, or Capreomycin) in addition [6]. XDR TB was first noted in the late 1980s and 1990s and reported by WHO and Center for Disease Control (CDC), USA, in 2004.

In a survey of some of their National Reference laboratories, it was observed that 20% of resistant strains tested were MDR TB, while 10% were XDR TB. Asia and Eastern Europe had the highest rates [7]. From recent reports, about 60% of the global burden of Multidrug-resistant TB is in China, India and Russia occurring in 3.7% of new TB cases (CI: 2.1-5.2%) and 20% of previously treated TB cases (CI:13-26%). In countries where there are data available, 9% of MDR–TB cases have XDR (CI: 6.7-11.2%) and 14.5% have fluoroquinolone resistance (CI: 11.6-17.4%) [8].

According to the WHO, Eastern Europe's rates of MDR TB are the highest and MDR TB makes up to 20% of all new TB cases, while in The Union State, it accounts for 28% of new TB cases. In Africa, reports of MDR TB based on continuous surveillance as in South Africa [9] show progressively increasing MDR rates despite overall decreasing numbers of TB cases. This is attributed to improved notification through laboratory surveillance. In developing countries with limited access to TB drug sensitivity tests, prevalence of MDR TB is dependent on special national surveys [1] and hospital-based clinical researches as in Nigeria [10-18]. Most of the hospital-based reports in Nigeria indicate that there is some level of MDR TB, which though not documented on a regular basis show progressive increase over time. This case scenario plays out in other developing countries where continuous surveillance or monitoring of MDR TB is not available. In Nigeria, as well as in other high-burden countries such as South Africa and India, it has been noted that the increasing TB prevalence may be driven by HIV coinfection [19]. Most of these reports are, however, based on testing of adult populations.

Pediatric MDR TB has been majorly underreported in continuous surveillance and special surveys. However, in some countries like South Africa, some modest efforts have been made to document and monitor progress of disease in these populations. A recent meta-analysis [20] of WHO data between 1994 and 2011, testing associations between MDR TB and age groups <15 years, and those >15 years, revealed that MDR TB was positively associated with age <15years in Germany, Namibia, South Africa, UK, and USA. The data also revealed that similar proportions of children and adults were diagnosed with MDR TB in many settings. HIV coinfection was found to be in close association with pediatric MDR TB in South Africa invariably due to the high prevalence of HIV in this area.

#### **2.1. Genesis of MDR TB**

Drug-resistant TB has microbial, clinical, and programmatic causes [21]. It manifests when there is a selective growth of resistant mutants among the actively multiplying bacillary population in the presence of drugs, thus making the drug ineffective against mutant bacilli. Microbiologically, the emergence of drug resistance depends upon the frequency of drugresistant mutants in the susceptible bacillary population, the size of the actively multiplying bacillary population in the lesions, and the antimicrobial quality of the drugs used [22]. The frequency of spontaneous mutations that can be developed to each drug are believed to be of the following magnitude: Streptomycin 1 in 106 , Isoniazid 1 in 106 , Rifampicin 1 in 108 , Ethambutol 1 in 107 , Pyrazinamide 1 in 106 , Fluoroquinolones 1 in 106-8 [23]. When these drugresistant mutants occur in large bacterial population, they have a tendency to further multiply depending on the corresponding clinical treatment regimen the patient receives. This varies from one program to the other and will depend on what drugs are available to a treatment program and the ease of access the patients have to these drugs.

Administered therapy may be inadequate in the following instances: monotherapy, poor adherence to treatment protocols, erratic or even interrupted treatment, or low drug quality. When there is inadequate treatment, resistance develops because bacilli with drug-resistant mutation proliferate and become the dominant strain in the infected individual. Inadequate treatment of susceptible TB can lead to drug resistance to first-line drugs (MDR TB), which is a marker of a failing susceptible TB treatment program. Likewise, inadequate treatment of MDR TB will lead to drug resistance to second-line drugs (XDR TB), which is a marker of failing MDR TB treatment programs.

Drug resistance of the Mycobacterium tuberculosis isolated from patients may be categorized based on length of previous anti-TB drug therapy they had received prior to the diagnosis of resistance. Acquired drug resistance is described in those who have been inadequately treated for 1 month or more; Relapse in cases previously completed treatment and reported cured; while that of patients who have never been treated previously or treated for less than 1 month is called Primary drug resistance or resistance in new case. The patients grouped as relapse or as new infections which are found to be drug resistant are grouped together as transmission cases; 82% of MDR TB are reported to be transmission cases. The other 18% are acquired cases, which are mostly adult populations. The acquired cases provoke and sustain MDR TB epidemics in both developed and undeveloped countries [24].

#### **2.2. Epidemics of MDR TB**

Extensively Drug-Resistant Tuberculosis (XDR TB) where there is also resistance to fluoro‐ quinolones and at least one injectable second-line drug (such as Amikacin, Kanamycin, or Capreomycin) in addition [6]. XDR TB was first noted in the late 1980s and 1990s and reported

In a survey of some of their National Reference laboratories, it was observed that 20% of resistant strains tested were MDR TB, while 10% were XDR TB. Asia and Eastern Europe had the highest rates [7]. From recent reports, about 60% of the global burden of Multidrug-resistant TB is in China, India and Russia occurring in 3.7% of new TB cases (CI: 2.1-5.2%) and 20% of previously treated TB cases (CI:13-26%). In countries where there are data available, 9% of MDR–TB cases have XDR (CI: 6.7-11.2%) and 14.5% have fluoroquinolone resistance (CI:

According to the WHO, Eastern Europe's rates of MDR TB are the highest and MDR TB makes up to 20% of all new TB cases, while in The Union State, it accounts for 28% of new TB cases. In Africa, reports of MDR TB based on continuous surveillance as in South Africa [9] show progressively increasing MDR rates despite overall decreasing numbers of TB cases. This is attributed to improved notification through laboratory surveillance. In developing countries with limited access to TB drug sensitivity tests, prevalence of MDR TB is dependent on special national surveys [1] and hospital-based clinical researches as in Nigeria [10-18]. Most of the hospital-based reports in Nigeria indicate that there is some level of MDR TB, which though not documented on a regular basis show progressive increase over time. This case scenario plays out in other developing countries where continuous surveillance or monitoring of MDR TB is not available. In Nigeria, as well as in other high-burden countries such as South Africa and India, it has been noted that the increasing TB prevalence may be driven by HIV coinfection

[19]. Most of these reports are, however, based on testing of adult populations.

invariably due to the high prevalence of HIV in this area.

**2.1. Genesis of MDR TB**

Pediatric MDR TB has been majorly underreported in continuous surveillance and special surveys. However, in some countries like South Africa, some modest efforts have been made to document and monitor progress of disease in these populations. A recent meta-analysis [20] of WHO data between 1994 and 2011, testing associations between MDR TB and age groups <15 years, and those >15 years, revealed that MDR TB was positively associated with age <15years in Germany, Namibia, South Africa, UK, and USA. The data also revealed that similar proportions of children and adults were diagnosed with MDR TB in many settings. HIV coinfection was found to be in close association with pediatric MDR TB in South Africa

Drug-resistant TB has microbial, clinical, and programmatic causes [21]. It manifests when there is a selective growth of resistant mutants among the actively multiplying bacillary population in the presence of drugs, thus making the drug ineffective against mutant bacilli. Microbiologically, the emergence of drug resistance depends upon the frequency of drugresistant mutants in the susceptible bacillary population, the size of the actively multiplying bacillary population in the lesions, and the antimicrobial quality of the drugs used [22]. The

by WHO and Center for Disease Control (CDC), USA, in 2004.

11.6-17.4%) [8].

4 An Overview of Tropical Diseases

During the late 1980s and early 1990s, epidemics of MDR TB occurred in North America and Europe killing about 80% of those who were infected. Today, the greatest number of cases is in India and China [25-26], although smaller epidemics have been described due to migrations [27]. The convergence of the following were believed to precipitate MDR TB epidemics especially that of XDR TB: High TB burden, high HIV prevalence, suboptimal TB control practices, and introduction of second-line TB drugs into low- and middle-income countries [28-29]. Among the pediatric age group, there is global paucity of data on MDR TB epidemics. Most data obtained have been reported from South Africa [30]. Some of the identical issues that were identified in all these epidemics were that there was delayed diagnosis of MDR TB cases for over 6 weeks to 6 months due in turn to delayed turnaround time for mycobacterial culture and DST. This invariably led to very high mortality rates which first called attention to the need for DST. In the XDR TB epidemic reported in South Africa [29], there was promi‐ nence of associated HIV coinfection in most patients who were transmission cases. Another feature was poor observance of infection control precautions such as: inadequate patient isolation and airflow regulation within wards, which made the wards conducive for trans‐ mission between patients in contact with MDR TB cases. There was also notable direct transmission from patients to health care workers, which was evident by Tuberculin Skin Test (TST) conversion as well as later linkage mappings that correlated the strains in the patients' samples with those of the health workers [29].

#### **2.3. Implications of transmission versus acquired cases**

In the high-burden countries, there are reportedly 20-35.2% of new cases and 54-62% of relapse cases that develop MDR TB, accounting for 82% of all incidences of MDR TB [1]. Thus, high burdens of MDRTB and XDR TB are eventually perpetuated from direct transmission within communities. In cases where TB–HIV coinfections are also prevalent, this significantly favors direct transmissibility [31]. Direct transmission is therefore the most common way drugresistant TB is spread and this must be stemmed to arrest the imminent global health threat from TB.
