Dosing of second-line antituberculosis drugs in children

Drug	Daily pediatric dose	Usual maximum daily dose	Main and rare but serious adverse effects
Amikacin*^¶	15 to 20 mg/kg IM or IV adjusted according to serum concentrations^Δ	1 g	Auditory and vestibular toxic effects, nephrotoxic effects
Amoxicillin-clavulanate	40 mg/kg given twice daily based on the amoxicillin component	Dosed on amoxicillin component: Maximum 4 g per day	GI toxicity
Bedaquiline	For children <15 kg: Consult a specialist For children 15 to <30 kg: 2 tabs (200 mg) daily for 2 weeks, then 1 tab (100 mg) 3 times/week (with at least 48 hours between doses) for 22 weeks For children ≥30 kg: 4 tabs (400 mg) daily for 2 weeks, then 2 tabs (200 mg) 3 times/week (with at least 48 hours between doses) for 22 weeks		QT prolongation, neurologic toxicities such as paresthesia, tremor, anxiety, depression, insomnia, tinnitus and blurred vision
Capreomycin (not available in United States; limited availability elsewhere)*^¶	15 to 30 mg/kg IM	1 g	Ototoxicity, vestibular toxicity, nephrotoxicity, electrolyte disturbances, local pain with IM injections
Clofazimine (not commercially available in the United States; requires application to FDA Division of Special Pathogen and Immunologic Drug Products; telephone 301-796-1600)	2 to 5 mg/kg orally (optimal dose in children is unknown)	300 mg	Red-grey discoloration of skin, eyes, body fluids, GI toxicity, photosensitivity, others
Cycloserine^◊	15 to 20 mg/kg orally in 1 dose or 2 divided doses	1 g	Psychosis, personality changes, seizures, rash
Delamanid	1 to 6 kg: Consult a specialist 7 to 23 kg: 25 mg orally twice daily 24 to 34 kg: 50 mg orally twice daily >34 kg: 100 mg orally twice daily	200 mg	QT prolongation, neurologic toxicities such as paresthesia, tremor, anxiety, depression, insomnia, tinnitus, and blurred vision
Ethionamide	15 to 20 mg/kg orally in 2 or 3 divided doses	1 g	GI tract disturbances, hepatotoxic effects, hypersensitivity reactions, hypothyroidism
Imipenem-cilastatin	§	§	GI toxicity, seizures
Isoniazid, high dose	15 to 20 mg/kg orally, IM, or IV	400 mg	Hepatitis, peripheral neuropathy (administer with pyridoxine), hypersensitivity, others
Kanamycin*^¶	15 to 30 mg/kg IM or IV adjusted according to serum concentrations	1 g	Auditory and vestibular toxic effects, nephrotoxic effects
Levofloxacin^¥	15 to 20 mg/kg orally or IV in 2 divided doses^¥	750 mg^¥	Theoretical effect on growing cartilage, tendonitis, GI tract disturbances, cardiac disturbances, peripheral neuropathy, rash, headache, restlessness, confusion
Linezolid	<16 kg: 15 mg/kg orally or IV once daily >16 kg: 10 to 12 mg/kg orally or IV once daily	600 mg	Myelosuppression
Meropenem^‡	20 to 40 mg/kg IV in 3 divided doses; must be given with oral clavulanate (see amoxicillin-clavulanate above)	6 g	GI toxicity, seizures
Moxifloxacin^¥	10 to 15 mg/kg orally or IV^¥	400 mg^¥	Theoretical effect on growing cartilage, tendonitis, GI tract disturbances, cardiac disturbances, peripheral neuropathy, rash, headache, restlessness, confusion
Para-aminosalicylic acid	200 to 300 mg/kg orally in 2 divided doses (some clinical centers give PAS 200 mg/kg as a single daily dose; this could be considered)	12 g	GI toxicity, hepatotoxicity, hypothyroidism (treat with thyroid replacement)
Streptomycin*^¶	20 to 40 mg/kg IM	1 g	Auditory and vestibular toxic effects, nephrotoxic effects (which must be pre-emptively monitored) and rash
Thiacetazone^† (not available in United States)	3 to 4 mg/kg orally	150 mg	Stevens-Johnson syndrome in HIV-infected patients, GI intolerance, hepatitis, skin reactions

Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail in a separate table (refer to the UpToDate table on regimens for treatment of drug-susceptible tuberculosis) and in the accompanying text. The optimal dosing of many second-line drugs used to treat drug-resistant tuberculosis in children is not known. These drugs should be used in consultation with a specialist in tuberculosis.
Dosing of oral medications for treatment of multidrug-resistant or extensively drug-resistant tuberculosis should be daily, not intermittent.
Doses listed in this table are for patients with normal renal function; dose adjustment of many of these agents is needed in altered renal function.

IM: intramuscular; IV: intravenous; GI: gastrointestinal.

* Generally given five to seven times per week (15 mg/kg or a maximum of 1 g per dose) for an initial two to four months and then (if needed) two to three times per week (20 to 30 mg/kg or a maximum of 1.5 g per dose). Dose should be decreased if renal function is diminished. Amikacin is preferred to kanamycin in children. Since IM injection of amikacin is very painful, IV infusion is preferred.

¶ For patients who are overweight or obese, dose is based on adjusted dosing weight (refer to the UpToDate calculator). When available, serum drug monitoring is advised to establish optimal dosing.

Δ Note dose of amikacin may need to exceed 20 mg/kg to reach a therapeutic level in young children.

◊ When available, serum drug monitoring is advised to establish optimal dosing. Recommended peak (two to four hours post-dose) level is not higher than 30 microg/mL.

§ Experience with imipenem-cilastatin in children with drug-resistant TB is very limited.

¥ According to the American Academy of Pediatrics, fluoroquinolones should not be used routinely as first-line agents in children <18 years old except when specific indications exist or in specific conditions for which there are no alternative agents and the drug is known to be effective for the specific situation.

‡ Dosing of meropenem in the setting of meningitis (in the absence of specific data for tuberculous meningitis) consists of 120 mg/kg in three divided doses.

† Should not be used in patients with HIV because of the serious risk of life-threatening adverse effects.

Data from:

Seddon JA, Furin JJ, Gale M, et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med 2012; 186:953.
World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO, Geneva 2008.
World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. WHO, Geneva 2016.
World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children, 2nd ed. WHO, Geneva 2014.
Treatment Guidelines from The Medical Letter. The Medical Letter 2012; 10:29.
Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition.
World Health Organization. The use of delamanid in the treatment of multidrug-resistant tuberculosis in children and adolescents: Interim policy guidance. WHO, Geneva, 2016.
American Academy of Pediatrics. Red Book: 2021-2024 Report of the Committee on Infectious Diseases, 32nd ed, Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH (Eds), American Academy of Pediatrics, Itasca, IL 2021.
Harausz EP, Garcia-Prats AJ, Seddon JA et al. New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations. Am J Respir Crit Care Med 2017; 195:1300.
http://sentinel-project.org/wp-content/uploads/2019/02/Updated_DRTB-Field-Guide-2019-V3.pdf Management of Drug-Resistant Tuberculosis in Children: A Field Guide. Boston, USA: The Sentinel Project for Pediatric Drug-Resistant Tuberculosis; November 2018, Fourth edition. (Accessed on March 26, 2019).

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Dosing of second-line antituberculosis drugs in children