**6. Adverse drug reactions to second line TB drugs**

The treatment of MDR-TB is a challenging issue due to the adverse events associated with long-term exposure (18 to 24 months) to second line drugs, all in great contrast to the short treatment period of drug sensitive TB. Adverse events significantly influence treatment 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 suspected drugs from the regimen due to adverse events [62] and Table 3.

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

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 the risk of developing ototoxicity.

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

development give hope that a safe and effective TB regimen of shorter duration will be

**Table 2.** Categories of TB drugs. Reprinted from Ref. 55 with permission of the International Union Against

**Group five:** less-effective drugs or drugs on which clinical data are sparse (use all necessary drugs if there are less ily

TB drug group Daily dose

5 mg/kg 10 mg/kg 15–25 mg/kg 30 mg/kg

15 mg/kg 15 mg/kg 7.5–10 mg/kg

15 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg

15 mg/kg 15 mg/kg 150 mg/kg

100 mg 875/125 mg 600 mg 500–1000 mg 500 mg 10–15 mg/kg 150 mg

The treatment of MDR-TB is a challenging issue due to the adverse events associated with long-term exposure (18 to 24 months) to second line drugs, all in great contrast to the short treatment period of drug sensitive TB. Adverse events significantly influence treatment

available within the next few years.

Tuberculosis and Lung Disease. Copyright © The Union.

**Group one**: first-line oral TB drugs (use all possible drugs)

210 Tuberculosis - Current Issues in Diagnosis and Management

**Group two**: fluoroquinolones (use only one, because they share genetic targets)

**Group four:** less-effective second-line TB drugs (use all possible drugs if necessary)

**Group three**: injectable TB drugs (use only one, because they share very similar genetic targets)

Isoniazid Rifampicin Ethambutol Pyrazinamide

Ofloxacin Levofloxacin Moxifloxacin

Streptomycin Kanamycin Amikacin Capreomycin

Clofazimine

Linezolid

Imipenem (every 6 h) Clarithromycin (every 12 h) High-dose isoniazid Thioacetazone

Ethionamide/Prothionamide Cycloserine/Terizidone P-aminosalicylic acid (acid salt)

than four from the other groups)

Amoxicillin with clavulanate (every 12 h)

**6. Adverse drug reactions to second line TB drugs**


main adverse effects of anti-TB drugs occur during the first two to three weeks of treatment. If they are recognized in time and managed properly, high rates of treatment completion and cure can be achieved. Proper monitoring should include patient education, clinical examina‐ tion and appropriate laboratory tests. Special training for staff on the various adverse events associated with second line drugs is essential for successful management. In particular, staff should consider altering dosages when appropriate, supplementary drugs to treat adverse

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 213

MDR-TB and XDR-TB cases are currently on the increase and it is expected that the number of their contacts will also increase, especially in densely populated area. Therefore, identifica‐ tion and proper management of these contacts are major components of drug resistant TB containment. In this regard, WHO recommend the identification of all close contacts of MDR-

A contact is defined as an individual who has a risk of acquiring TB because it has been exposed to Mtb by sharing air space with a person with infectious TB (the source case). The index case (a person with suspected or confirmed TB disease) is defined as the initial case of TB for a contact investigation [76]. He is not necessarily identical with the source case [76]. Many guidance documents focus on the source case and not the index case, as it is the source case who will have exposed the contacts, not necessarily the index case. Close contacts are those people sharing common habitation rooms with the source case. This can also include individ‐ uals with evidence of prolonged and frequent exposure to a source case in the workplace, school, prison, hospital ward, or social settings [77]. Contact tracing is defined as the systematic finding of contacts of patients with infectious TB disease [77]. The tracing helps identifying individuals who are particularly at high risk, such as individuals with HIV infection, young

Themanagement of contacts ofdrug-resistantTBpatients, in termofpreventive chemoprophy‐ laxis, remains a complex issue with a significant ethical dimension. In case of drug-susceptible TB, the provision of preventive INH therapy to suspect LTBI individuals is effective at reduc‐ ing the risk of developing disease among infected contacts [10]. In theory, such a preventive approach should also work for LTBI individuals exposed to MDR and XDR Mtb strains. Unfortunately, health care providers cannot predict with certainty the susceptibility pattern of a contact's isolate fromthe source case's isolate.Indeed,manydivergentdrug susceptibility test profiles in source-contact pairs have been reported [78,79], due either to infection of the contact by another source case or to infection before the source case acquires resistance. Such a scenar‐ io likely occurs in high-burden TB areas where different drug resistant strains may circulate in homes, schools, and workplaces.Therefore,the lack of effectivedrugs with acceptable adverseevent profile in an otherwise healthy individual is a prominent barrier to the treatment of drug resistant TB contacts. Indeed, if, to some extent, the occurrence of toxicity is accepted by MDR-TB patients (since the alternative is high risk of death), convincing healthy contacts to cope with

events and replacement of drugs when toxicity cannot be managed.

TB cases through contact tracing and their evaluation for TB infection.

adverse-events during preventive therapy in is fundamentally different.

children and elderly.

**7. Management approaches for the contacts of MDR TB patients**

**Table 3.** Frequency of adverse events and suspected agents among 818 patients receiving MDR-TB treatment.PAS: para-aminosalicyclic acid; TM: thioamides; FQ: fluoroquinolones; CS: cycloserine; AG: aminoglycosides; CM: capreomycin.. Reprinted from Ref. 62 with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union.

agonist of the neuronal NMDA (*N*-methyl-D-aspartate) receptor for glutamate [71], which is a major excitatory neurotransmitter in the mammalian CNS [72]. The most dramatic effect of cycloserine reported so far is the suicide of 2 patients during the postoperative antibiotic treatment course following pulmonary resection [73]. Because of its neurological toxicities, cycloserine was prevented very early from being part of first line TB drugs but was recently reintroduced as one of the cornerstones of treatment for MDR- and XDR-TB [46]. Although coadministration of pyridoxine (vitamin B6) with cycloserine can reduce partially the neurolog‐ ical side effects, the later should be prescribed after psychiatric evaluation for patients with apparent convulsions and agitation [55]. Some clinicians favor terizidone (two cycloserine molecules combined) as they found the side effects associated with it are less severe and more manageable [55]. However, given the little evidence demonstrating safety and efficacy of terizidone, it should be used with caution in TB patients intolerant to cycloserine.

Although adverse events associated with second-line drugs are a major obstacle in the management of MDR-TB, compared with first line treatment, DOTS-Plus programmes have achieved cure rates of greater than 70% even in resource-poor settings [74,75]. In general, the main adverse effects of anti-TB drugs occur during the first two to three weeks of treatment. If they are recognized in time and managed properly, high rates of treatment completion and cure can be achieved. Proper monitoring should include patient education, clinical examina‐ tion and appropriate laboratory tests. Special training for staff on the various adverse events associated with second line drugs is essential for successful management. In particular, staff should consider altering dosages when appropriate, supplementary drugs to treat adverse events and replacement of drugs when toxicity cannot be managed.
