**8.1 New applications of existing drugs**

### *8.1.1 Rifamycins*

Rifampicin, Rifabutin, and Rifapentine are among the medications in this class. It has been proposed that a greater dose of Rifampicin than the standard 10 mg/kg may be required to reduce treatment duration in new tuberculosis patients. Some mouse trials have provided promising findings in evaluating the role of high-dose rifampicin (15–30 mg/day) in the intense phase of ATT [40]. For the first two months of ATT, a phase II randomised trial comparing rifampicin in dosages of 20 mg/kg/day and 15. mg/kg/day to the usual 10 mg/kg/day is continuing [48]. Preliminary research suggests that greater dosages of Rifampicin are tolerated well, with proportionately higher serum concentration levels [49]. Adults have also been given higher doses of Rifampicin as part of a regular ATT regimen, as well as when combined with other

#### *Perspective Chapter: Tuberculosis Drugs Doses from Indian Scenario – A Review DOI: http://dx.doi.org/10.5772/intechopen.108247*

newer medications like Moxifloxacin and SQ-109 [50]. With such high rifampicin doses, there is the potential for a shorter treatment duration, according to current findings. Rifabutin is often preferred over Rifampicin for individuals with TB and HIV since it has fewer medication interactions and negative effects [51]. In children, the dose is 5 mg/kg, while in adults, it is 150–300 mg/day [52].

Rifapentine, another medicine in the same class, has a longer half-life and has been explored for latent tuberculosis infection (LTBI) rather than active tuberculosis. In adults, a three-month preventive regimen of 300 mg Rifapentine and 900 mg Isoniazid was found to be as efficacious as nine months of 300 mg daily Isoniazid [53]. Doses ranging from 300 to 900 mg have been administered in children with adequate tolerance. In order to obtain systemic exposures consistent with successful treatment of LTBI in adults, higher weight-adjusted dosages are required in children [54].

#### *8.1.2 Flouroquinolones*

Moxifloxacin and Levofloxacin are the most important medications in this class, and their superiority over other quinolones has been thoroughly established [55]. There have been multiple trials with promising results using quinolones in combination with other first-line medicines to reduce the length of ATT [56]. In the intensive phase, a typical ATT regimen was compared to a Gatifloxacin/Moxifloxacincontaining regimen with the goal of reducing the treatment period to four months, however the latter had greater relapse rates than the former. Furthermore, children under the age of five are known to clear quinolones from the body more quickly in the urine and have a lower serum concentration than adults. There is a scarcity of pharmacokinetic data, particularly in children under the age of five. As a result, optimising their use in children for the prevention of drug resistance becomes more important [55]. Children's usage of quinolones has traditionally been restricted due to worries of arthropathy, however there is no evidence of such side effects in either children or adults treated with long-term quinolones, according to available data.

#### *8.1.3 Oxazolidinones*

This family of medicines works by inhibiting protein synthesis by competing with an enzyme involved in translation [57]. Cycloserine was the first oxazolidinone to be used as an antitubercular medication, although linezolid is now the most widely used. Sputum conversion rates in patients with XDR-TB improved in two recent randomised control trials with linezolid [58]. However, higher failure rates at lower doses (300 mg/ day) and more severe adverse effects at higher doses (600 mg/day) limit its long-term use. Common side effects include peripheral neuropathy, gastrointestinal problems, and myelosuppression [59]. Both Cycloserine and Linezolid are currently designated by WHO as core medicines for the treatment of drug-resistant tuberculosis. There is not much information on their use as anti-tubercular agents in youngsters.

#### *8.1.4 Beta-lactams and Macrolides*

The medications included in WHO group D for treating drug-resistant tuberculosis are amoxycillin-clavulanate, imipenem-cilastin, and meropenem. Meropenem and Clavulanate show substantial synergistic antibacterial action against M. tuberculosis in vitro because Clavulanate suppresses â-lactamase and increases Meropenem's antibacterial activity [60]. In vitro activity against tuberculosis bacilli was demonstrated

in a recent research using a triple therapy consisting of amoxicillin, clavulanate, and meropenem [61]. Macrolides, particularly Clarithromycin, have previously proven beneficial in treating non-tubercular mycobacteria, but the outcomes in M. TB have been poor due to fast resistance development [62].

#### *8.1.5 Newer drugs Bedaquiline*

After nearly four decades, the Food and Medicine Administration (FDA) has approved this drug as the first antitubercular agent. It blocks the proton pump, which is essential for ATP generation, as well as the mycobacterium's metabolism [62]. Bedaquiline should only be utilised when the typical MDR regimen cannot be constructed due to in vitro resistance to these medications, known adverse drug reactions, poor tolerance, or contraindications to any of the combination regimen's components. It can only be used as part of second-line ATT in patients over the age of 18 years, according to WHO guidelines. However, in the same dosage as advised for adults, it has been found to be effective and safe in children and adolescents [63]. The dose is 400 mg once a day for two weeks, then 200 mg three times a week for the next 22 weeks, for a total of six months, which is the longest time bedaquiline can be given. The Indian government's Revised National Tuberculosis Control Program (RNTCP) is introducing this medicine through a limited access programme across the country. Nausea, vomiting, dizziness, arthralgia, myalgia, elevated serum amylase and transaminase levels, QT prolongation, and dark urine are all known side effects of bedaquiline. Bedaquiline toxicity is increased by drugs that decrease liver function via CYP3A4 metabolism (e.g., ketoconazole and ritonavir) [64].

#### *8.1.6 Delamanid and pretomanid*

Both of these medications are nitroimidazoles, which work by preventing mycobacterial cell wall formation [65]. Delamanid has been investigated significantly more thoroughly than pretomanid. In patients with MDR-TB/XDR-TB who have a high baseline risk for poor outcomes, WHO recommends using delamanid for just six months of rigorous treatment at a dose of 100 mg twice a day [66]. When delamanid was given in combination with an improved background regimen in patients with drug resistant tuberculosis, higher rates of sputum conversion and lower mortality were seen [67]. Pretomanid, on the other hand, is a prodrug that requires bio-reductive activation of an aromatic group in order to be effective against tuberculosis. In an experimental mouse model of tuberculosis, it also showed significant bactericidal activity during both the intense and continuation stages of treatment. In 2016, the World Health Organisation (WHO) published guidelines for the use of delamanid in children and adolescents, stating that children with MDR-TB who are resistant to quinolones or second-line injectables (or both) should be candidates for this treatment. This medicine should be used as an add-on treatment in longer MDR-TB regimens (18–24 months) in children rather than as part of the shorter MDR-TB regimens introduced by WHO in 2016 [3]. Not only has the use of bedaquiline, delamanid, and pretomanid transformed the treatment of drugresistant tuberculosis, but it has also revolutionised the treatment of HIV-TB coinfection.

#### *8.1.7 Other drugs*

SQ-109 is an ethambutol analogue with 1, 2 ethylenediamine. This drug is now being tested in people after showing promising results in both in vitro and in vivo

mice models of tuberculosis [68]. With isoniazid, rifampicin, and streptomycin, SQ-109 has been demonstrated to have a synergistic effect. SQ-109 reduces Rifampicin's Minimum Inhibitory Concentration (MIC), and this synergy may be important in patients with Rifampicin-resistant TB [1, 69].
