What is the second line Anti-Tuberculosis Treatment (ATT)?

From the Guidelines

The second-line treatment for drug-resistant tuberculosis (TB) should include a combination of at least 5 effective TB medicines during the intensive phase, including pyrazinamide and 4 core second-line TB medicines, with the selection of drugs based on the patient's resistance pattern and the World Health Organization (WHO) classification of anti-tuberculosis drugs 1. The treatment regimen for multidrug-resistant TB (MDR-TB) should be individualized and include drugs from groups A, B, and C, with the option to add agents from group D2 and D3 if necessary 1.

• Group A includes fluoroquinolones such as levofloxacin, moxifloxacin, and gatifloxacin.
• Group B includes second-line injectables such as amikacin, capreomycin, kanamycin, and streptomycin.
• Group C includes other second-line agents such as ethionamide/prothionamide, cycloserine/terizidone, linezolid, and clofazimine.
• Group D includes add-on agents such as pyrazinamide, ethambutol, and high-dose isoniazid (D1), bedaquiline and delamamid (D2), and p-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, and thioacetazone (D3) 1. The choice of drugs should be guided by the WHO classification and the patient's resistance pattern, with the goal of selecting at least 5 effective TB medicines during the intensive phase 1. It is also important to note that the treatment of MDR-TB should be managed by a team of experts, and that all efforts should be made to avoid the development of further drug resistance 1. The use of new medicines such as bedaquiline and delamanid, along with repurposed medicines like linezolid and clofazimine, should be considered for patients with extensively drug-resistant TB (XDR-TB) or those with resistance to fluoroquinolones or second-line injectables 1. Adverse events following the prescription of second-line drugs should be managed according to international recommendations, with the aim of limiting the probability of losing an effective drug due to such adverse events 1.

From the FDA Drug Label

Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line anti-tuberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible. Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid.

Second line ATT options include ethionamide, which should be used in combination with at least one other drug to which the organism is susceptible, such as ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin 2, 2.

• The choice of companion drug should be based on the results of susceptibility tests.
• Patient compliance is essential to the success of the anti-tuberculosis therapy and to prevent the emergence of drug-resistant organisms.

From the Research

Second-Line Anti-Tuberculosis Treatment

• Second-line anti-tuberculosis medications are used to treat multidrug-resistant tuberculosis (MDR-TB), which is resistant to first-line drugs such as isoniazid and rifampicin 3.
• These medications include fluoroquinolones, aminoglycosides, ethionamide, cycloserine, and linezolid, among others, and are often more toxic than first-line drugs 3.
• The safety and tolerability of second-line anti-tuberculosis medications are crucial, as adverse effects can be life-threatening and may lead to non-adherence or irregular adherence to treatment 3.

Treatment Regimens

• A study published in 2022 found that a regimen consisting of bedaquiline, delamanid, linezolid, and clofazimine was effective in treating MDR-TB with additional resistance to fluoroquinolones or second-line injectable drugs, with a favorable outcome in 91% of patients 4.
• Another study published in 2021 discussed the treatment of tuberculosis, including the use of repurposed and new drugs, and highlighted the importance of selecting drugs without overlapping adverse drug reaction profiles 5.

Drug Resistance and Mechanisms

• A review published in 2007 provided an overview of anti-tuberculosis drugs and their resistance mechanisms, including the classification of drugs into first-line and second-line agents 6.
• The review also discussed the molecular pharmacology of anti-tuberculosis drugs and their resistance mechanisms, including those for isoniazid, rifampicin, and fluoroquinolones 6.

Pharmacokinetics in Children

• A study published in 2019 highlighted the need for pharmacokinetic studies of second-line anti-tuberculosis drugs in children, as limited information is available on their use in pediatric populations 7.
• The study emphasized the importance of generating pharmacokinetic data to ensure adequate drug dosing in children with MDR-TB 7.