**5. Treatment of drug-resistant TB**

The emergence of MDR- and XDR-TB has shattered the initial optimism that DOTS based programmes would progressively eliminate TB. MDR TB is defined as resistance to at least the two most potent first-line TB drugs—ie, INH and RMP [46,47]. XDR TB strains are resistant to INH or RMP, any fluoroquinolone, and at least one of three second-line injectable drugs—ie, capreomycin, kanamycin, and amikacin [46,47]. In order to control the spread of drug resist‐ ant TB, the WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called"DOTS-Plus")[48].ImplementationofDOTS-Plus requires the capacitytoperformdrugsusceptibility testing and the availability of second-line agents, in addition to all the require‐ ments for DOTS. Clinical pilot experiences from the past few years showed that high cure rates of drug resistant TB are achieved in settings where DOTS-Plus has been established [49-51].

Resistance to INH is the most common form of TB drug resistance reported, either in isolation or in combination with other drugs [13]. INH monoresistant TB is relatively easy to treat with SCC treatment. Up to 98% cure and less than 5% relapse can be achieved when all four drugs INH, RMP, PZA and EMB are used during the 6-month treatment period [52]. RMP-resistant TB often carries a much more ominous prognosis, as the outcome of SCC treatment is poor in terms of both disease status at the end of the treatment and relapse [13]. Moreover, RMP monoresistance in Mtb is rare and usually reflects resistance to INH as well, i.e., MDR-TB [53]. In fact, SCC cures less than 60% of MDR-TB, with a recurrence rate of about 28% among patient with apparent success [38,54].

rings of MTT, which produces a violet-purple color [44]. Many of these assays gave excellent detection of MDR-TB, within a significantly shorter time frame when compared to conven‐

The effective implementation of these rapid diagnostic tests for TB and drug resistance will increase the proportion of patients promptly placed on appropriate therapy, and therefore will improve substantially management and control of TB disease globally. However a major limitation to the use of these rapid tests is their affordability and the availability of equipped laboratories in resource-constrained countries, which unfortunately tend to have the highest burden of MDR-TB cases. Thus, global initiatives are needed to make new diagnostics

MTBDRplus MODS NRA AB Resazurin MTT MGIT 960 LJPM

2 7 7 8 8 8 9 30

100 90 77 87 87 74 42 -

100 100 100 100 97 87 81 -

MODS = microscopic observation drug susceptibility; NRA = nitrate reductase assay; AB =Alamar Bbue ; MTT = 3-[4,5 dimethyl- thiazol-2-yl)-2,5-diphenyltetrazolium bromide; MGIT = Mycobacterium Growth Indicator Tube; LJPM =

The emergence of MDR- and XDR-TB has shattered the initial optimism that DOTS based programmes would progressively eliminate TB. MDR TB is defined as resistance to at least the two most potent first-line TB drugs—ie, INH and RMP [46,47]. XDR TB strains are resistant to INH or RMP, any fluoroquinolone, and at least one of three second-line injectable drugs—ie, capreomycin, kanamycin, and amikacin [46,47]. In order to control the spread of drug resist‐ ant TB, the WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called"DOTS-Plus")[48].ImplementationofDOTS-Plus requires the capacitytoperformdrugsusceptibility testing and the availability of second-line agents, in addition to all the require‐ ments for DOTS. Clinical pilot experiences from the past few years showed that high cure rates of drug resistant TB are achieved in settings where DOTS-Plus has been established [49-51].

Resistance to INH is the most common form of TB drug resistance reported, either in isolation or in combination with other drugs [13]. INH monoresistant TB is relatively easy to treat with SCC treatment. Up to 98% cure and less than 5% relapse can be achieved when all four drugs

**Table 1.** Time to results and percentage of results obtained within 8 and 10 days. Reprinted from Ref. 45 with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union.

tional culturing methods (Table 1).

208 Tuberculosis - Current Issues in Diagnosis and Management

accessible to low-income countries.

Löwenstein-Jensen proportion method.

**5. Treatment of drug-resistant TB**

Average time to results, days

Results within 8 days, %

Results within 10 days, %

The current recommendation for individualized treatment regimens is a combination of at least four drugs to which the Mtb isolate is likely to be susceptible [55]. Drugs are chosen with a stepwise selection process through 5 groups of TB drugs (Table 2) on the basis of efficacy and safety [55]. More than 5 drugs can be used if the sensitivity to a given drug is unclear or if the regimen contains few bactericidal drugs. The duration of the intensive phase of treatment (when an injectable drug is given) should be at least 6 months (or 4 months after culture conversion). The continuation phase (without the injectable drug) should last until 18 months after culture conversion [55].

Although the effectiveness and feasibility of MDR-TB management in resource-limited settings have been demonstrated, less than 2% of all estimated MDR-TB patients currently receive appropriate treatment [5]. Thus, the growing MDR-TB epidemic globally requires moving beyond the pilot project stage in order to scale up DOTS-plus based TB management as a routine component of national TB control programmes. However, there are potential difficulties with implementing DOTS-Plus in low-income countries as it can absorb a large part of resources dedicated to existing DOTS programmes, and subsequently decrease the overall standard of care [56]. Note that the emergence of drug resistant TB in these countries is actually the result of limited resources to implement the simple DOTS programme.

A major barrier to the management of drug resistant TB in low-income countries is the prohibi‐ tive price of second-line drugs. Therefore in an attempt to address this issue, in 2000, the WHO and its partners established the Green Light Committee (GLC) initiative to facilitate access to quality-assured second-line TB drugs at reduced prices [57,58]. Evaluation of the first GLCendorsed pilot projects of MDR-TB management in five resource-limited countries showed treatment success rates of 59%–83% [59]. During 2012, the number of patients with MDR-TB approved for treatment by the GLC Committee was only 42,033 with 13,000 actually starting treatment.Itisclearthatthesenumbersremainsmallcomparedtotheestimatedannualincidence (440,000 cases) of MDR-TB [1]. Therefore, substantial funding through public-private partner‐ ships is desperately needed to scale up the availability of second line drugs.

Other than the price of second-line drugs, frequent adverse events and the long duration of the regimen further compromise adherence to TB treatment, even in the most advanced industrialized countries. These drawbacks have resulted in resurgence in research efforts during last decade to develop new TB drugs. In recent years, a number of new drug candidates with novel modes of action and excellent activity against Mtb have entered clinical trials [60]. OPC-67683 (nitro-dihydro-imidazooxazole) and diarylquinoline TMC207 are the most promising of these new drugs since both are highly active against drug-resistant and suscep‐ tible Mtb strains and possess excellent sterilizing activity [61]. These and other drugs under


outcome and patient compliance, leading to acquisition of more resistance and spread of drugresistant strains. Initial evidence of the prevalence of adverse events associated with the use of second-line drugs was deducted from observation of patients enrolled in five DOTS-Plus sites: Estonia, Latvia, Peru, the Philippines and the Russian Federation. The data collected from these sites showed that among 818 patients enrolled on MDR-TB 30% required removal of

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 211

Adverse events can be distinguished as major or minor and may not be consistently found among all patients treated for MDR-TB [39]. The major adverse events associated with second

Ototoxicity causes damage to the outer hair cells in the cochlea and vestibular labyrinth leading to permanent hearing loss. Ototoxic hearing loss is common in patients treated with amino‐ glycosides (Streptomycin, Kanamycin and Amikacin). A prospective cohort study of the incidence of ototoxicity in MDR-TB individuals (with normal hearing) showed that 57% of aminoglycoside-treated patients developed high-frequency of hearing loss [64]. The same study showed that HIV-positive patients (70%) were more likely to develop hearing loss than HIV-negative patients (42%). Susceptibility to hearing loss increases further in patients bearing mutations in mitochondrial genes [65]. Numerous mutations linked to susceptibility to ototoxicity have been identified in the mitochondrial MT-RNR1 gene that encodes the human 12S rRNA ribosomal subunit. In particular, the A1555G mutation causes increased binding of aminoglycosides to the 12S rRNA ribosomal subunit [66], which results in the disruption of mitochondrial protein synthesis and death of the cell. In this regard, a recent study in South Africa detected A1555G mutation in a significant proportion of the population (0.9% of Black and 1.1% of Afrikaner), indicative of high proportion of individuals genetically predisposed to developing aminoglycoside-induced hearing loss. It is unfortunate that the widespread and poorly controlled use of aminoglycosides will lead to many individuals suffering from permanent deafness. Auditory monitoring should be an integral part of the care programme of MDR-TB patients, particularly in countries where aminoglycosides are still commonly used. In addition, identification of patients who are genetically predisposed will significantly reduce

Patients with neurologic side effects (depression, psychosis and suicidal tendencies) have less favorable outcome and increased risk of death. Cycloserine is the most significant TB drug associated with central nervous system (CNS) toxicity. Cycloserine is used as second line drug in TB treatment based of its structural analogy to D-alanine. Cycloserine competitively inhibits two necessary enzymes (alanine racemase and alanine ligase) that incorporate alanine into an alanyl-alanine dipeptide, an essential component of the mycobacterial cell wall [67]. Early studies revealed that neurological and psychiatric manifestations are present in as many as 33% of patients treated with cycloserine [68]. The principal side effects associated with cycloserine therapy are convulsions, exacerbations of bipolar states and multiple neurological symptoms including excitation, dizziness, headaches, insomnia and anxiety [69]. Cycloserinemediated neurologic side effects are exacerbated even more when used in combination with isoniazid [70]. These variable psychotropic responses are related to cycloserine action as an

suspected drugs from the regimen due to adverse events [62] and Table 3.

the risk of developing ototoxicity.

line drugs include auditory toxicity (ototoxicity) and neurologic side effects [63].

**Table 2.** Categories of TB drugs. Reprinted from Ref. 55 with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union.

development give hope that a safe and effective TB regimen of shorter duration will be available within the next few years.
