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Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines SDC 4 Table 3: Detailed Pediatric DR-TB Drug Information Drug Name Pharmacology and Killing Kinetics Pediatric Dose* Pharmacokinetic Information Common Adverse Drug Reactions Special Considerations - Inhibits mycolic acid synthesis resulting in disruption of the bacterial cell wall 10-15 mg/kg once daily; maximum dose: 300 mg/day - Dose adjustment required in renal failure - Best absorbed on an empty stomach; absorption decreased by 50% with fatty meal -Hepatoxocity: Baseline liver function tests (LFT’s) and then at least monthly during therapy in those with pre-existing liver disease, or history of prior hepatitis from the same drug. - Peripheral neuropathy - Hypersensitivity - Gastrointestinal (GI) intolerance - Pyridoxine (2mg/kg/day) supplementation is not routinely required unless HIV infected, nutritionally deficient, or breastfeeding infants whose mothers are receiving INH. - If paresthesias while taking INH: increase pyridoxine - Orange staining of body fluids - Hepatotoxicity: Baseline LFT’s and repeat in circumstances similar to INH - Hematologic abnormalities (thrombocytopenia, hemolytic anemia): Baseline CBC - Anterior uveitis and other eye toxicities: Baseline visual testing if possible. - Rash and pruritus - GI-intolerance - RMP is by definition not used in MDR/XDR TB - Dose related retrobulbar neuritis and exacerbated during renal failure - Use with caution in children < 7 years old since optic toxicity cannot readily be assessed GROUP 1 Isoniazid (INH) [1-6] - Bactericidal against actively dividing bacilli In patients with low level resistance to INH the recommended dose is 15-20 mg/kg/day - Monitor for drug interactions - Bacteriostatic against non-replicating bacilli Rifampin (RMP), Rifabutin (RFB) [1-4, 6, 7] - Inhibits bacterial RNA synthesis by binding to the beta subunit of DNAdependent RNA polymerase, blocking RNA transcription - Bactericidal and sterilizing agent Ethambutol (EMB) [1-4, 6, 8] - Suppresses mycobacterial multiplication by interfering with RNA synthesis 10-20 mg/kg/day once daily; maximum dose: 600 mg/day - Dose adjustment required in renal failure Rifabutin – 10 mg/kg/day once daily doses have been used; maximum dose: 300mg/day (higher doses have been recommended for children < 1 year of age, however no specific pediatric dosing exists) - Monitor for drug interactions, especially with anti-retroviral therapy 15-25 mg/kg/day once daily (Higher doses up to 25mg/kg/day have been safely used for MDR TB); maximum dose: 2.5g/day - Dose adjustment required in renal failure - Retrobulbar neuritis: Baseline visual acuity and color discrimination testing and then every month (if possible) 30-40 mg/kg/day in single daily dose; maximum dose: 2g/day - Dose adjustment required in renal failure -Hepatotoxicity: Baseline LFT’s and repeat similar to INH - Gout and arthralgias – check uric acid level if patient develops arthralgias; reduce dose, but do not give allupurinol, as this may cause severe adverse effects. - GI intolerance - Rash - Photosensitivity - Bacteriostatic at low concentrations Pyrazinamide (PZA) [1-4, 6, 8, 9] - Converted to pyrazinoic acid in susceptible strains of Mycobacterium which lowers the pH of the environment - Bactericidal for semidormant M. tuberculosis (active in acidic environment) - Dose adjustment of anti-retroviral medications may be required in patients infected with HIV - Cross-resistance among the rifamycin class of drugs is typical. GROUP 2 44 Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines SDC 4 Aminoglycosides (Amikacin (AK), Kanamycin (KM), Streptomycin (SM)) [1, 4, 10, 11] - Interferes with protein synthesis in bacterial cell by binding to ribosomal subunit Amikacin and Kanamycin I.M., I.V. – Infants and Children: 15–30 mg/kg/day once daily - maximum dose: 1g/day - Bactericidal against actively dividing extracellular bacilli Streptomycin I.M., I.V. Infants and Children: 20–40 mg/kg/day once daily; maximum dose: 1g/day - For obese patients dosing is based on ideal body weight (IBW) plus 40% of adipose mass - Dose adjustment required in renal failure - in children infuse I.V. dose over 1-2hrs - only 40–80% of the dose is absorbed if given I.M. thus not the preferred route Levels: - Target peak concentrations for all three agents are 35 – 45 g/mL 90-120min post infusion - Trough concentrations are generally < 5 g/mL in patients with normal renal function Tuberactinomycins (Capreomycin (CM), Viomycin) [1, 4, 10, 11] - Capreomycin is a cyclic polypeptide antimicrobial. The mechanism of action of capreomycin is not well understood. - Nephrotoxicty: Baseline serum creatinine and blood urea nitrogen and then weekly; baseline electrolytes including magnesium and calcium and then every month - Ototoxicity: Baseline audiometric testing and then every month for prolonged therapy - Vestibular toxicity - SM should be used only in XDR-TB with resistance to other aminoglycosides and polypeptides and confirmed in vitro susceptibility to SM Capreomycin I.M., I.V. 15 mg/kg/day once daily; maximum dose: 1g/day - For obese patients dosing is based on IBW plus 40% of adipose mass - Dose adjustment required in renal failure -Regarding “Levels”: same approach as for aminoglycosides above - Similar to Aminoglycosides - LFT abnormalities when used with other TB medications - Significant crossresistance with viomycin, kanamycin occurs Moxifloxacin I.V., P.O. – 5mg/kg/dose IV every 24 hours maximum dose: 400 mg/day - Dose adjustment required in renal failure except for MFX - Rare: tendon rupture, arthralgias - Baseline ECG to assess QTc interval (for MFX only) - Nausea and bloating - Headache - The long-term (more than several weeks) use of FQ’s in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. - Capreomycin Bactericidal against non replicating bacteria - Viomycin Bactericidal against actively dividing extracellular bacilli GROUP 3 Fluoroquinolones (FQ) (Moxifloxacin (MFX), Levofloxacin (LFX), Ciprofloxacin (CFX), Ofloxacin (OFX)) [1-3, 12] - Inhibits DNA-gyrase and topoisomerase IV in susceptible organisms; inhibits relaxation of supercoiled DNA and promotes breakage of double-stranded DNA - Bactericidal Levofloxacin I.V., P.O. – Children 6 months to 5 years: 10 mg/kg/dose every 12 hours Children ≥5 years: 10 mg/kg/dose every 24 hours; maximum dose: 750 mg/day Ciprofloxacin I.V., P.O. – Children: 20-40 mg/kg/day divided every 12hours; P.O. maximum dose: 2g/day and I.V. maximum dose: 800 mg/day Ofloxacin P.O. – Children: 15-20 mg/kg/daydivided every 12 hours; maximum dose: 800mg/day - FQ dosing is not TB specific, i.e. data is extrapolated from either other indications or clinical experience - Moxifloxacin and Levofloxcin have better in vitro activity for MTB than Ciprofloxacin. 45 Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines SDC 4 GROUP 4 Thioamides (Ethionamide (ETO), Protionamide (PTO)) [1, 3, 4] Serine analogs (Cycloserine (CS), Terizidone (TZ)) [1, 4, 10] - Inhibits peptide synthesis in susceptible organisms Ethionamide 15-20mg/kg/day divided every 12 hours; maximum dose: 1g/day - Bactericidal - Inhibits bacterial cell wall synthesis by competing with amino acid (D-alanine) for incorporation into the bacterial cell wall - Bacteriostatic Cycloserine Children: 10-20 mg/kg/day in 2 divided doses or as single dose; maximum dose: 1g/day Terizidone is a double molecule of cycolserine; given at the same doses as cycloserine. - Dose adjustment required in renal failure - Target peak serum levels 20-35g/mL; draw levels 2hrs post dose once a week until at target is reached - A second serum level 6-8 hours following dose may be useful to calculate the patient’s specific half-life - Best absorbed on an empty stomach P-aminosalicylic acid (PAS) [1, 4] - Is structurally related to para-aminobenzoic acid (PABA) and its mechanism of action is thought to be similar to the sulfonamides, a competitive antagonism with PABA; disrupts plate biosynthesis in sensitive organisms. - GI intolerance and anorexia, metallic taste. - Hepatotoxicity: Baseline LFT’s, and repeat similar to INH - Endocrine effects: Gynecomastia, hair loss, acne, impotence, menstrual irregularity, and reversible 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 -Pyridoxine supplementation required - CNS toxicity: Inabilty to concentrate, lethargy, seizures, depression psychosis, suicidal ideations - Peripheral neuropathy - Many individuals require gradual ramping up of the dose and treatment in order to monitor for drug toxicity or intolerance - Pyridoxine supplementation required (25mg of pyridoxine per 250 mg of cycloserine or terizidone) - Avoid in patients with epilepsy or mental illness -Increased risk of neurotoxicity if concomitant use of INH, ethionamide or fluoroquinolones - Avoid if a patient is allergic to aspirin - Increased risk of hypothyroidism when combined with ethionamide Tablets: 200-300 mg/kg/day in 24 divided doses. Granules: 150mg/kg/day in 2 divided doses. Maximum dose for both: 10gm/day. - Delayed peak concentration with the granule formulation due to its enteric coating and sustained release - Reversible Hypothyroidism: Baseline TSH and then every month - Hepatotoxicity: Baseline LFT’s and then every month - Coagulopathy: Baseline CBC and then every month - GI intolerance - Many individuals require gradual ramping up of the dose and treatment in order to monitor for drug toxicity or intolerance Safety and effectiveness in pediatric patients have not been established. Cases of pediatric patients treated with clofazimine 1mg/kg/day have been reported in the literature. - Tissue half-life estimated to be around 70 days. - Discoloration of skin, conjunctiva, cornea, and body fluids (skin changes can be irreversible) - GI intolerance including bowel obstruction and - Bacteriostatic - Risk of hypothyroidism increases when ethionamide and PAS are taken together - Cross-resistance to INH may occur when there is low level resistance to Eto GROUP 5 ** Clofazimine (CFZ) [1] - Inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. - Bacteriostatic 46 Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines SDC 4 bleeding - Photosensitivity - Pruritits Amoxicllin/ Clavulinic Acid (AMX/CLV) [1, 2] - Clavulanic acid binds and inhibits betalactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity; amoxicillin interferes with bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins and causing cell wall death Infants <3 months: 30 mg/kg/day divided every 8-12 hours of the amoxicillin component. - Dose adjustment required in renal failure - Diarrhea, abdominal discomfort, nausea, and vomiting are most common. - Hypersensitivity reactions - Dose adjustment required in renal failure - Diarrhea, nausea, or vomiting - Seizure probability imipenem > meropenem in children - Monitor for drug interactions (potential for drug interactions azithromycin <clarithromycin) - Hepatotoxicty: Baseline LFT’s and then every month - Baseline ECG to assess QTc interval - GI intolerance Children: 80 mg/kg/day divided every 12 hours of the amoxicillin component. To avoid large doses of clavulanate and to prevent GI intolerance, amoxicillin/clavulanate and additional amoxicillin can be prescribed to achieve the same total daily dose of amoxicillin - Weakly bactericidal Imipenem/ Cilastatin [1, 2] - Cilastatin prevents renal metabolism of impenem by competitive inhibition of dehydropeptidase; imipenem interferes with bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins and causing cell wall death I.V. – Infants < 3 months: 100 mg/kg/day divided every 6 hours Infants ≥3 months and Children: 60-100 mg/kg/day divided every 6 hours; maximum dose: 4 g/day Meropenem preferred in children when CNS infections suspected: 60-120mg/kg/day divided every 8 hours; maximum dose 2g/dose - Bactericidal Clarithromycin (CLR), Azithromycin (AZM) [1, 2] - Inhibits bacterial RNA-dependent protein synthesis by binding to the 50S ribosomal subunit - Bacteriostatic Linezolid (LZD) [1, 2, 13] - Inhibits initiation of protein synthesis by binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit preventing the formation of a functional 70S initiation complex which is an essential component of the bacterial translation process Clarithromycin P.O. – Children: 15 mg/kg/day divided every 12 hours; maximum dose: 1 g/day Azithromycin I.V., P.O. – Children: 5-10mg/kg/day once daily; maximum dose: 500mg/day P.O., I.V. – 10 mg/kg/dose every 8 hours Maximum dose 600mg/dose - Myelosuppression: Baseline CBC and then every month - Peripheral neuropathy - Optic neuropathy: Baseline visual function in patients requiring > 3months of therapy or in patients reporting new visual symptoms. - In vitro bactericidal activity *Refer to guidelines for duration of selected combination therapy. 47 Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines SDC 4 **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. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Curry, F.J. Drug-Resistant Tuberculosis: A Survival Guide for Clinicians. 2008 [cited 2010 June 25]; Second Edition:[Available from: http://www.nationaltbcenter.edu/drtb. Taketomo CK, H.J.a.K.D., Lexi-Comp’s Drug Reference Handbooks: Pediatric Dosage Handbook 16th ed. 2005: American Pharmacists Association. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006 [cited 2010 July 4]; Available from: http://whqlibdoc.who.int/publications/2006/9241546956_eng.pdf. Blumberg, H.M., et al., American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med, 2003. 167(4): p. 603-62. Donald, P.R., et al., The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol, 2007. 63(7): p. 633-9. Frydenberg, A.R. and S.M. Graham, Toxicity of first-line drugs for treatment of tuberculosis in children: review. Trop Med Int Health, 2009. 14(11): p. 1329-37. Donald, P.R. and H.S. Schaaf, Old and new drugs for the treatment of tuberculosis in children. Paediatr Respir Rev, 2007. 8(2): p. 134-41. Donald, P.R., The treatment of tuberculosis in childhood. S Afr Med J, 2007. 97(10 Pt 2): p. 992-4. 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. Peloquin, C.A., Therapeutic drug monitoring in the treatment of tuberculosis. Drugs, 2002. 62(15): p. 2169-83. 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. Moadebi, S., et al., Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs, 2007. 67(14): p. 2077-99. Schecter, G.F., et al., Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis, 2010. 50(1): p. 49-55. 48