**1. Introduction**

Although major progress has been made to reduce global incidence of drug-susceptible tuberculosis (TB), the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB over the past decade presents an unprecedented public health challenge to which countries of concern are responding far too slowly. Indeed, a recent WHO TB surveillance report indicates the highest global level of drug-resistance ever recorded, which affected disproportionately developing countries with an estimated 440,000 MDR-TB cases worldwide resulting in 150,000 deaths in 2009 [1]. Even more troubling is being the recent emergence of new strains of totally drug-resistant *M. tuberculosis* (Mtb), currently occurring in densely populated cities such as Teheran (Iran) [2] and Mumbai (India) [3]. Given that an untreated TB patient can infect up to 15 contacts in a year in overcrowded areas [4], it is highly likely that totally drug-resistant TB will continues spreading and one would worry that TB will again become an incurable disease.

While part of the increase in drug resistance can be attributed to difficulty in treating patients who are double infected with HIV, which represent about 13% of total TB cases [5], detailed field studies revealed that the emergence drug-resistant TB is clearly a direct consequence of misdiagnosis and mismanagement of drug susceptible TB, which result in only a fraction of TB patients getting correct diagnosis and appropriate therapy ([6,7] and Fig.1). In other words, "Resistance is man-made, caused by exposure to the wrong treatment, the wrong regimen, the wrong treatment duration" says TB expert Giovanni Miglio [8]. Therefore, a comprehensive approach to ensure rapid detection, proper treatment and public health measures needs to be applied globally to cure TB patients and prevent further transmission of the disease. This chapter discusses various challenges facing the management of drug resistant TB and presents the efforts of WHO and its partners for the development of strategies and guidelines for optimal TB control.

© 2013 Hmama; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

months to 6 months because it kills the persistent Mtb population in the lung [15]. EMB is active against growing Mtb but has no effect on dormant bacilli. The combination of drugs acting at different stages of the Mtb life cycle during SSC therapy has been successful in TB treatment in most endemic countries when patients adhere to a fairly strict daily regimen. SSC therapy causes minor or no side effects and is affordable, costing less than \$40 for a full course of treatment. Side effects, if they occur, are manageable and usually do not result in the

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 205

Aproximately 90% of people infected with Mtb develop an efficient immune response that successfully contains the infection but unfortunately without killing all the bacteria. Surviving bacteria persist in the lung as non-replicative (i.e. dormant) organisms [16]. In this stage of latent TB infection (LTBI), people do not exhibit TB symptoms and cannot pass the infection on to other individuals. However, in weakened immune system conditions (old age, HIV infection or therapeutic immunosupression), dormant bacteria revert into dividing organisms

LTBI is highly suspected in individuals previously exposed to those with known active TB, which would include people in hospitals, homeless shelters and prisons, or people having recently traveled to countries where TB is highly endemic. The stage of clinical latency is of surpassing importance for TB control as most cases of active TB arise from the vast reservoir of the latently infected population [17]. In fact, it estimated that the infection reactivates and

Purified protein derivative (PPD) skin test (also known as the Mantoux test) is the major diagnostic tool used to identify LTBI patients. A positive skin reaction to the PPD test reflects a local cellular immune response, which is interpreted as recent or remote exposure to the TB bacterium. However, despite its usefulness and simplicity, the PPD test have a low predictive value since false-positive reactions can occur as a result of previous BCG vaccination or sensitization to environmental mycobacteria [19,20,21]. In fact, the skin test uses a crude mix of Mtb antigens shared among many mycobacterial species. As a replacement for the PPD test, new interferon-gamma release assays (IGRAs) have been recently developed and shown to be more accurate for LTB diagnosis [22]. IGRAs measure *ex-vivo* production of IFN-gamma by circulating T cells in whole blood in response to more specific Mtb antigens such as ESAT6,

Although LTBI is symptom-free and non contagious, many countries have adopted its treatment in order to reduce the risk of infection progression to active TB and the spread of the disease to the general population. Six to 9 month treatment with INH alone was proven to be effective and safe [10]. Unfortunately, if LTBI results from exposure to a person with MDRor TB XDR-TB, preventive treatment options are very limited or may not be possible. In both active and latent TB cases, it is crucial that health care providers make every effort to ensure that infected persons complete the entire course of treatment. They must explain clearly the benefit of the treatment and also possible side effects (or drug interactions). Additionally, They should identify potential barriers to the course of treatment, which will help to establish an

cause active TB in approximately 5 to 10% of latently infected persons [18].

interruption of the treatment.

leading to TB reactivation [16].

CFP10 and TB7.7.

efficient plan to ensure adherence.

**Figure 1.** Misdiagnosis and mismanagement can result in only fraction of TB patients getting correct diagnosis, appro‐ priate therapy, and positive outcomes. Reprinted from Ref. 9 with permission from Dr. Madhukar Pai.
