Table 3: Detailed Pediatric DR-TB Drug Information



Table 3: Detailed Pediatric DR-TB Drug Information

|Drug Name |Pharmacology and |Pediatric Dose* |Pharmacokinetic |Common Adverse Drug |Special Considerations |

| |Killing Kinetics | |Information |Reactions | |

|GROUP 1 | | | | | |

|Isoniazid (INH) |- Inhibits mycolic acid |10-15 mg/kg once daily; maximum |- Dose adjustment required in |-Hepatoxocity: |- Pyridoxine (2mg/kg/day) |

|[pic][1-6] |synthesis resulting in |dose: 300 mg/day |renal failure |Baseline liver function |supplementation is not |

| |disruption of the | |- Best absorbed on an empty |tests (LFT’s) and then |routinely required unless |

| |bacterial cell wall |In patients with low level |stomach; absorption decreased |at least monthly during |HIV infected, |

| | |resistance to INH the recommended |by 50% with fatty meal |therapy in those with |nutritionally deficient, |

| |- Bactericidal against |dose is 15-20 mg/kg/day | |pre-existing liver |or breastfeeding infants |

| |actively dividing bacilli| |- Monitor for drug interactions|disease, or history of |whose mothers are |

| | | | |prior hepatitis from the|receiving INH. |

| |- Bacteriostatic against | | |same drug. |- If paresthesias while |

| |non-replicating bacilli | | |- Peripheral neuropathy |taking INH: increase |

| | | | |- Hypersensitivity |pyridoxine |

| | | | |- Gastrointestinal (GI) | |

| | | | |intolerance | |

|Rifampin (RMP), |- Inhibits bacterial RNA |10-20 mg/kg/day once daily; |- Dose adjustment required in |- Orange staining of |- RMP is by definition not|

|Rifabutin (RFB) |synthesis by binding to |maximum dose: 600 mg/day |renal failure |body fluids |used in MDR/XDR TB |

|[pic][1-4, 6, 7] |the beta subunit of | | |- Hepatotoxicity: | |

| |DNA-dependent RNA |Rifabutin – 10 mg/kg/day once |- Monitor for drug |Baseline LFT’s and |- Dose adjustment of |

| |polymerase, blocking RNA |daily doses have been used; |interactions, especially with |repeat in circumstances |anti-retroviral |

| |transcription |maximum dose: 300mg/day (higher |anti-retroviral therapy |similar to INH |medications may be |

| | |doses have been recommended for | |- Hematologic |required in patients |

| |- Bactericidal and |children < 1 year of age, however | |abnormalities |infected with HIV |

| |sterilizing agent |no specific pediatric dosing | |(thrombocytopenia, | |

| | |exists) | |hemolytic anemia): |- Cross-resistance among |

| | | | |Baseline CBC |the rifamycin class of |

| | | | |- Anterior uveitis and |drugs is typical. |

| | | | |other eye toxicities: | |

| | | | |Baseline visual testing | |

| | | | |if possible. | |

| | | | |- Rash and pruritus | |

| | | | |- GI-intolerance | |

|Ethambutol (EMB) |- Suppresses |15-25 mg/kg/day once daily (Higher|- Dose adjustment required in |- Retrobulbar neuritis: |- Dose related retrobulbar|

|[pic][1-4, 6, 8] |mycobacterial |doses up to 25mg/kg/day have been |renal failure |Baseline visual acuity |neuritis and exacerbated |

| |multiplication by |safely used for MDR TB); maximum | |and color discrimination|during renal failure |

| |interfering with RNA |dose: 2.5g/day | |testing and then every |- Use with caution in |

| |synthesis | | |month (if possible) |children < 7 years old |

| | | | | |since optic toxicity |

| |- Bacteriostatic at low | | | |cannot readily be assessed|

| |concentrations | | | | |

|Pyrazinamide (PZA) |- Converted to pyrazinoic|30-40 mg/kg/day in single daily |- Dose adjustment required in |-Hepatotoxicity: | |

|[pic][1-4, 6, 8, 9] |acid in susceptible |dose; maximum dose: 2g/day |renal failure |Baseline LFT’s and | |

| |strains of Mycobacterium | | |repeat similar to INH | |

| |which lowers the pH of | | |- Gout and arthralgias –| |

| |the environment | | |check uric acid level if| |

| | | | |patient develops | |

| |- Bactericidal for | | |arthralgias; reduce | |

| |semi-dormant M. | | |dose, but do not give | |

| |tuberculosis (active in | | |allupurinol, as this may| |

| |acidic environment) | | |cause severe adverse | |

| | | | |effects. | |

| | | | |- GI intolerance | |

| | | | |- Rash | |

| | | | |- Photosensitivity | |

|GROUP 2 | | | | | |

|Aminoglycosides |- Interferes with protein|Amikacin and Kanamycin I.M., I.V. |- For obese patients dosing is |- Nephrotoxicty: |- SM should be |

|(Amikacin (AK), |synthesis in bacterial |– |based on ideal body weight |Baseline serum |used only in XDR-TB with |

|Kanamycin (KM), |cell by binding to |Infants and Children: 15–30 |(IBW) plus 40% of adipose mass |creatinine and blood |resistance to other |

|Streptomycin (SM)) |ribosomal subunit |mg/kg/day once daily |- Dose adjustment required in |urea nitrogen and then |aminoglycosides and |

|[pic][1, 4, 10, 11] | |- maximum dose: 1g/day |renal failure |weekly; baseline |polypeptides and confirmed|

| |- Bactericidal against | |- in children infuse I.V. dose |electrolytes including |in vitro susceptibility to|

| |actively dividing |Streptomycin I.M., I.V. |over 1-2hrs |magnesium and calcium |SM |

| |extracellular bacilli |Infants and Children: 20–40 |- only 40–80% of the dose is |and then every month | |

| | |mg/kg/day once daily; maximum |absorbed if given I.M. thus not|- Ototoxicity: | |

| | |dose: 1g/day |the preferred route |Baseline audiometric | |

| | | | |testing and then every | |

| | | |Levels: |month for prolonged | |

| | | |- Target peak concentrations |therapy | |

| | | |for all three agents are 35 – |- Vestibular toxicity | |

| | | |45 μg/mL 90-120min post | | |

| | | |infusion | | |

| | | |- Trough concentrations are | | |

| | | |generally < 5 μg/mL in patients| | |

| | | |with normal renal function | | |

|Tuberactinomycins |- Capreomycin is a cyclic|Capreomycin I.M., I.V. |- For obese patients dosing is |- Similar to |- Significant |

|(Capreomycin (CM), |polypeptide |15 mg/kg/day once daily; |based on IBW plus 40% of |Aminoglycosides |cross-resistance with |

|Viomycin) |antimicrobial. The |maximum dose: 1g/day |adipose mass |- LFT abnormalities when|viomycin, kanamycin occurs|

|[pic][1, 4, 10, 11] |mechanism of action of | |- Dose adjustment required in |used with other TB | |

| |capreomycin is not well | |renal failure |medications | |

| |understood. | |-Regarding “Levels”: same | | |

| | | |approach as for aminoglycosides| | |

| |- Capreomycin | |above | | |

| |-Bactericidal against non| | | | |

| |replicating bacteria | | | | |

| | | | | | |

| |- Viomycin - Bactericidal| | | | |

| |against actively dividing| | | | |

| |extracellular bacilli | | | | |

|GROUP 3 | | | | | |

|Fluoroquinolones (FQ) |- Inhibits DNA-gyrase and|Moxifloxacin I.V., P.O. – |- Dose adjustment required in |- Rare: tendon rupture, |- The long-term (more than|

|(Moxifloxacin (MFX), |topoisomerase IV in |5mg/kg/dose IV every 24 hours |renal failure except for MFX |arthralgias |several weeks) use of FQ’s|

|Levofloxacin (LFX), |susceptible organisms; |maximum dose: 400 mg/day | |- Baseline ECG to assess|in children and |

|Ciprofloxacin (CFX), |inhibits relaxation of | | |QTc interval (for MFX |adolescents has not been |

|Ofloxacin (OFX)) |supercoiled DNA and |Levofloxacin I.V., P.O. – | |only) |approved because of |

|[pic][1-3, 12] |promotes breakage of |Children 6 months to 5 years: 10 | |- Nausea and bloating |concerns about effects on |

| |double-stranded DNA |mg/kg/dose every 12 hours | |- Headache |bone and cartilage growth.|

| | |Children ≥5 years: 10 mg/kg/dose | | | |

| |- Bactericidal |every 24 hours; maximum dose: 750 | | |- FQ dosing is not TB |

| | |mg/day | | |specific, i.e. data is |

| | | | | |extrapolated from either |

| | |Ciprofloxacin I.V., P.O. – | | |other indications or |

| | |Children: 20-40 mg/kg/day divided | | |clinical experience |

| | |every 12hours; P.O. maximum dose: | | | |

| | |2g/day and I.V. maximum dose: 800 | | |- Moxifloxacin and |

| | |mg/day | | |Levofloxcin have better in|

| | | | | |vitro activity for MTB |

| | |Ofloxacin P.O. – | | |than Ciprofloxacin. |

| | |Children: 15-20 mg/kg/daydivided | | | |

| | |every 12 hours; maximum dose: | | | |

| | |800mg/day | | | |

| | | | | | |

| | | | | | |

| | | | | | |

| | | | | | |

|GROUP 4 | | | | | |

|Thioamides |- Inhibits peptide |Ethionamide 15-20mg/kg/day divided| |- GI intolerance and |-Pyridoxine |

|(Ethionamide (ETO), |synthesis in susceptible |every 12 hours; maximum dose: | |anorexia, metallic |supplementation required |

|Protionamide (PTO)) |organisms |1g/day | |taste. | |

|[pic][1, 3, 4] | | | |- Hepatotoxicity: |- Risk of hypothyroidism |

| |- Bactericidal | | |Baseline LFT’s, and |increases when ethionamide|

| | | | |repeat similar to INH |and PAS are taken together|

| | | | |- Endocrine effects: | |

| | | | |Gynecomastia, hair loss,|- Cross-resistance to INH |

| | | | |acne, impotence, |may occur when there is |

| | | | |menstrual irregularity, |low level resistance to |

| | | | |and reversible |Eto |

| | | | |hypothyroidism (treat | |

| | | | |with thyroid | |

| | | | |replacement) | |

| | | | |- Many individuals | |

| | | | |require gradual ramping | |

| | | | |up of the dose and | |

| | | | |treatment in order to | |

| | | | |monitor for drug | |

| | | | |toxicity or intolerance | |

|Serine analogs |- Inhibits bacterial cell|Cycloserine |- Dose adjustment required in |- CNS toxicity: Inabilty|- Pyridoxine |

|(Cycloserine (CS), |wall synthesis by |Children: 10-20 mg/kg/day in 2 |renal failure |to concentrate, |supplementation required |

|Terizidone (TZ)) |competing with amino acid|divided doses or as single dose; |- Target peak serum levels |lethargy, seizures, |(25mg of pyridoxine per |

|[pic][1, 4, 10] |(D-alanine) for |maximum dose: 1g/day |20-35μg/mL; draw levels 2hrs |depression |250 mg of cycloserine or |

| |incorporation into the | |post dose once a week until at |psychosis, suicidal |terizidone) |

| |bacterial cell wall |Terizidone is a double molecule of|target is reached |ideations |- Avoid in patients with |

| | |cycolserine; given at the same |- A second serum level 6-8 |- Peripheral neuropathy |epilepsy or mental illness|

| |- Bacteriostatic |doses as cycloserine. |hours following dose may be |- Many individuals |-Increased risk of |

| | | |useful to calculate the |require gradual ramping |neurotoxicity if |

| | | |patient’s specific half-life |up of the dose and |concomitant use of INH, |

| | | | |treatment in order to |ethionamide or |

| | | |- Best absorbed on an empty |monitor for drug |fluoroquinolones |

| | | |stomach |toxicity or intolerance | |

|P-aminosalicylic acid |- Is structurally related|Tablets: 200-300 mg/kg/day in 2-4 |- Delayed peak concentration |- Reversible |- Avoid if a patient is |

|(PAS) |to para-aminobenzoic acid|divided doses. |with the granule formulation |Hypothyroidism: Baseline|allergic to aspirin |

|[pic][1, 4] |(PABA) and its mechanism |Granules: 150mg/kg/day in 2 |due to its enteric coating and |TSH and then every month|- Increased risk of |

| |of action is thought to |divided doses. |sustained release | |hypothyroidism when |

| |be similar to the |Maximum dose for both: 10gm/day. | |- Hepatotoxicity: |combined with ethionamide |

| |sulfonamides, a | | |Baseline LFT’s and then | |

| |competitive antagonism | | |every month | |

| |with PABA; disrupts plate| | |- Coagulopathy: Baseline| |

| |biosynthesis in sensitive| | |CBC and then every month| |

| |organisms. | | |- GI intolerance | |

| | | | |- Many individuals | |

| |- Bacteriostatic | | |require gradual ramping | |

| | | | |up of the dose and | |

| | | | |treatment in order to | |

| | | | |monitor for drug | |

| | | | |toxicity or intolerance | |

|GROUP 5 ** | | | | | |

|Clofazimine (CFZ) |- Inhibits mycobacterial |Safety and effectiveness in |- Tissue half-life estimated to|- Discoloration of skin,| |

|[1] |growth and binds |pediatric patients have not been |be around 70 days. |conjunctiva, cornea, and| |

| |preferentially to |established. Cases of pediatric | |body fluids (skin | |

| |mycobacterial DNA. |patients treated with clofazimine | |changes can be | |

| | |1mg/kg/day have been reported in | |irreversible) | |

| |- Bacteriostatic |the literature. | |- GI intolerance | |

| | | | |including bowel | |

| | | | |obstruction and bleeding| |

| | | | |- Photosensitivity | |

| | | | |- Pruritits | |

|Amoxicllin/ |- Clavulanic acid binds |Infants meropenem in | |

| |dehydropeptidase; |Infants ≥3 months and Children: | |children | |

| |imipenem interferes with |60-100 mg/kg/day divided every 6 | | | |

| |bacterial cell wall |hours; maximum dose: 4 g/day | | | |

| |synthesis by binding to | | | | |

| |one or more of the |Meropenem preferred in children | | | |

| |penicillin-binding |when CNS infections suspected: | | | |

| |proteins and causing cell|60-120mg/kg/day divided every 8 | | | |

| |wall death |hours; maximum dose 2g/dose | | | |

| | | | | | |

| |- Bactericidal | | | | |

|Clarithromycin (CLR), |- Inhibits bacterial |Clarithromycin P.O. – |- Monitor for drug interactions|- Hepatotoxicty: | |

|Azithromycin (AZM) |RNA-dependent protein |Children: 15 mg/kg/day divided |(potential for drug |Baseline LFT’s and then | |

|[1, 2] |synthesis by binding to |every 12 hours; maximum dose: 1 |interactions azithromycin |every month | |

| |the 50S ribosomal subunit|g/day | | |

| |initiation complex which | | |3months of therapy or in| |

| |is an essential component| | |patients reporting new | |

| |of the bacterial | | |visual symptoms. | |

| |translation process | | | | |

| | | | | | |

| |- In vitro bactericidal | | | | |

| |activity | | | | |

*Refer to guidelines for duration of selected combination therapy.

**The optimal dose specific to MDR TB is not known for these agents; thus dosing has been adapted from other indications in other areas of pediatrics to provide guidance.

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8. Donald, P.R., The treatment of tuberculosis in childhood. S Afr Med J, 2007. 97(10 Pt 2): p. 992-4.

9. Gupta, P., et al., Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses. Br J Clin Pharmacol, 2008. 65(3): p. 423-7.

10. Peloquin, C.A., Therapeutic drug monitoring in the treatment of tuberculosis. Drugs, 2002. 62(15): p. 2169-83.

11. Peloquin, C.A., et al., Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis, 2004. 38(11): p. 1538-44.

12. Moadebi, S., et al., Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs, 2007. 67(14): p. 2077-99.

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