Table 4– World Health Organization classification of drugs used for the treatment of multidrug-resistant/extensively drug-resistant tuberculosis, dosages and pharmacokinetics
SubstanceRouteDosagePKRemarks
Adults 70 kgGFR<10%Children#Cmax+PK/PD§
Group I
 Ethambutolp.o.
i.v.
1200 mg dailyƒ75% reduction or three times weekly20 (15–25) mg·kg−1·day−1¶¶3–5 mg·L−1 [130]AUC/MIC [143]Monitoring for adverse events mandatory
 Pyrazinamidep.o.2000 mg dailyThree times weekly35 (30–40) mg·kg−1·day−1¶¶40–50 mg·L−1 [131]AUC/MIC [144]MIC unreliable; can be given twice daily in divided doses in case of intolerance
Group II
 Amikacini.m.
i.v.
1000 mg dailyAvoid##15–30 mg·kg−1·day−1¶¶ 30–40 mg·L−1 [132, 133]Cmax/MICCan be given 5 days a week initially
30% dose reduction in the elderly
 Capreomycini.m.
i.v.
1000 mg dailyAvoid##15–30 mg·kg−1·day−1¶¶30–40 mg·L−1 [134]Cmax/MICCan be given 5 days a week initially
30% dose reduction in the elderly
 Kanamycini.m.
i.v.
1000 mg dailyAvoid##15-30 mg·kg−1·day−1¶¶30-40 mg·L−1 [133]Cmax/MICCan be given 5 days a week initially
30% dose reduction in the elderly
Group III
 Levofloxacinp.o.
i.v.
1000 mg daily75% reduction or three times weekly5–10 mg·kg−1·day−1¶¶10–20 mg·L−1 [135]AUC/MIC [145, 146]QT interval prolongation may be potentiated with other drugs
 Moxifloxacinp.o.
i.v.
400 mg dailyNo adjustment7.5–10 mg·kg−1·day−1¶¶3–5 mg·L−1 [135, 136]AUC/MIC [146, 147]QT interval prolongation may be potentiated with other drugs
Group IV
 PASp.o.
i.v.
12 g dailyNo adjustment200–300 mg·kg−1·day−1¶¶0.2 mg·L−1NACan be given twice daily in divided doses
 Prothionamide/ethionamidep.o.750 mg dailyNo adjustment15–20 mg·kg−1·day−1¶¶2 mg·L−1 [137, 138]NACan be given twice daily in divided doses
 Terizidone/cycloserinep.o.750 mg daily75% reduction or three times weekly10–20 mg·kg−1·day−1¶¶20–30 mg·L−1NACan be given twice daily in divided doses
Group V
 Amoxicillin/clavulanic acidp.o.
i.v.
875/125 mg twice daily75% reduction40 mg·kg−1 twice daily¶¶15–25 mg·L−1 [139]T>MICIn case of GI disturbances, i.v. administration may be better tolerated
 Clarithromycinp.o.1000 mg SR once daily50–75% reduction7.5 mg·kg−1 twice daily¶¶2–4 mg·L−1AUC/MICIf SR tablets are not available, 500 mg twice daily
 Clofaziminep.o.100 mg dailyNo adjustment1 mg·kg−1·day−1¶¶0.7–1 mg·L−1 [140]NAIn case of severe skin discoloration, dose reduction to five times a week
 Imipenemi.v. 500 mg twice or thrice daily50% reduction25 mg·kg−1 twice or thrice daily¶¶30–40 mg·L−1T>MICLong-term i.v. access recommended
 Meropenemi.v. 1000 mg twice or thrice daily75% reduction40 mg·kg−1 three times daily¶¶20–25 mg·L−1T>MICLong-term i.v. access recommended
 Linezolidp.o.
i.v.
600 mg dailyNo adjustment10–20 mg·kg−1·day−1¶¶ 15–20 mg·L−1 [141, 142]AUC/MIC [145]
T>MIC [148]
Careful monitoring for adverse events mandatory; dosing intervals of three times per week could be considered when linezolid is re-introduced after interruption of therapy due to toxicity
 INH (high dose)p.o.
i.v.
10 mg·kg−1 daily (if INH MIC ≤1 mg·L−1) or
16–20 mg·kg−1 three times per week (if INH MIC is >1–5 mg·L−1)
No adjustmentIn the absence of data, same dosage as in adults:
10 mg·kg−1 daily (if INH MIC ≤1 mg·L−1) or
16–20 mg·kg−1 three times per week (if INH MIC is >1–5 mg·L−1)¶¶
9–15 mg·L−1AUC/MIC [149, 150]Use in low-level resistance (inhA mutation)
Give with pyridoxine
  • GFR: glomerular filtration rate; PK: pharmacokinetics; Cmax: maximal concentration; PD: pharmacodynamics; PAS: p-aminosalicylic acid; INH: isoniazid; SR: slow release; AUC: area under the curve; MIC: minimum inhibitory concentration; NA: not available/unknown; T>MIC: time for which the concentration is greater than the MIC; GI: gastrointestinal. #: there are very limited PK studies on second-line drugs for children. Most drugs are also not available in child-friendly preparations. Available data for first-line anti-tuberculous drugs show the need for higher doses per kg in young children, determined through PK studies. However, it is not currently established that lower doses (in line with adult regimens) have resulted in treatment failures in children.: references are provided where data were obtained in M. tuberculosis in vitro or in vivo models, or in patients with tuberculosis. If no reference is provided, typical PK data were obtained from non-tuberculosis patients. +: Cmax is mostly observed between 1 and 3 h after oral intake of the drug for some drugs but for others, after intake of food, Cmax is delayed by 1–2 h. Therefore, interpretation of C2 h levels should be performed with care. Preferably, more levels are obtained to get a complete picture of the drug exposure. For some drugs, limited sampling strategies are available enabling adequate assessment of drug exposure without the need for excessive blood sampling. If low drug concentrations are measured, a dosage increase can be advocated to pursue reference values. Preferably, levels are reassessed after dosage adjustment. §: PK/PD parameters can be of help if concentration monitoring of tuberculosis drugs is performed. Low drug levels can be accepted if DST shows a very low MIC, avoiding the need to increase the dose. Preferably, both drug levels and drug susceptibility are combined to optimise the treatment. If only breakpoint data are available, the second best option is to try to achieve normal drug exposure in patients who have very low drug levels. ƒ: ideal body weight is the preferred parameter to dose antimicrobial drugs that are predominantly distributed in body water. ##: or based on drug concentration. ¶¶: in general, recommended doses per kg should not exceed the maximum adult dose, as there are no data on side-effects at higher doses that would justify their use in children.