Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines

SDC 3

Table 2. Potential adverse effects and suggested drug monitoring recommendations

Adverse effects
[References] / Incidence in children / Potential causative agents / Monitoring parameters / Recommendations
Hearing loss
[1-4] / 7-9 % / All Aminoglycosides
and Tuberactinomycinsa / Baseline audiometric testing and then monthly. Weekly trough and peak levels. / Once a therapeutic steady state has been reached, monitor trough and peak levels of aminoglycosides once weekly. If hearing loss develops, consider stopping the offending agent if possible.
Renal toxicity
[1-3] / 3% / All Aminoglycosides
and Tuberactinomycins / Baseline serum urea (BUN) and creatinine; repeat monthly while receiving an injectable agent; repeat more frequent if the baseline results were abnormal. / Adjust doses and/or frequency with serial monitoring and consult with a clinical pharmacist.
Adjust all other medications according to Creatinine clearance.
Consider stopping the offending agent if severe.
Gastrointestinal symptomsb
[3-7] / 12-50 % / INH, Pyrazinamide, Ethionamide. Fluoroquinolones, PAS, Macrolides, Amoxicillin/ Clavulinate / Clinical observation. c / When initiating a new drug which may cause gastrointestinal symptoms, the dose should be split into 2-3 doses; then combine in single dose as tolerated.
Hepatotoxicity
[1, 2, 4, 5] / 9% / Pyrazinamide, INH, rifampin, PAS, ethionamide, fluoroquinolones, macrolides / Monthly clinical monitoring.
Liver function tests at baseline and repeat if:
- abnormal baseline tests
- develops symptoms
- pre-existing liver disease
- concomitant use of hepatotoxic drugs,
- history of ethanol abuse
- prior hepatitis from the same drug. / Stop therapy if clinical hepatitis develops (liver tenderness, hepatomegaly, or jaundice).
Screen for infectious etiologies.
Treatment may be restarted gradually after normalization of liver enzymes, under hospital supervision and frequent monitoring.
Hypothyroidism
[1-4, 8] / 6-9 % / Ethionamide, PAS / Baseline TSH and then repeat every three months.
Risk of hypothyroidism increases when both ethionamide & PAS used. / Start replacement therapy if hypothyroidism is present. Consult an endocrinologist.
Psychiatric effects
[1, 3, 4, 8] / 6-11% / Cycloserine, fluoroquinolones. thioamides / Clinical observation. c / If symptoms are mild, clinical observation and support is advised, but if symptoms are severe and psychosis is present, lower the dose and consider stopping the suspected agent and provide appropriate antipsychotic therapy.
Skin
manifestationsd
[3-5, 7, 8] / 3-8% / INH, rifampin, fluoroquinolones, cycloserine, ethionamide, ethambutol, clofazimine, amoxicillin/clavulanate / Clinical observation. c / If mild rash, consider anti-histamines for itchiness, Stop the most likely causative agents if severe rash and refer to a dermatologist. When the rash is improved the medications can be restarted one by one.
Obtain platelet count if petechial rash develops while on rifampin therapy, and if low, stop it. Thrombocytopenia is a contraindication for rifampin.
Arthralgia, arthritis
[1, 4, 6] / 0.7-4.5% / Fluoroquinolones, pyrazinamide / Clinical observation. c / Check serum uric acid level if the patient becomes symptomatic; do not give allopurinol but lower dose or stop offending drug (esp. pyrazinamide).
Blurring of vision
[1, 2, 4] / 9% / Ethambutol, linezolid / Baseline then monthly visual acuity and color vision testing. / Stop the causative agent.
Ophthalmology consultation and follow-up is recommended
Electrolyte abnormalities
[1-3] / 3% / All aminoglycosides
and tuberactinomycins / Baseline electrolytes, magnesium and calcium; repeat monthly while on injectable agent (or more frequent if abnormal at baseline). / Treat according to standard of care for hypokalemia or other deficiencies.

a: Tuberactinomycins includes Capreomycin and Viomycin.

b: Symptoms include gastritis, loss of appetite, nausea and/ or vomiting.

c: All patients should be educated for all possible side effects and be instructed to contact their primary physicians in case adverse events are noticed.

d: Symptoms include hypersensitivity reactions, skin rash and/ or itchiness, and skin discoloration.

Data in this table were derived from pediatric studies; other reports on adverse effects from second-line antituberculosis medication were reported in both adults and children [9-11], however, these other studies were not included in this Table, as data relevant to pediatric care could not readily be extracted from them.

1.WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006 [cited 2010 July 4]; Available from: .

2.Curry, F.J. Drug-Resistant Tuberculosis: A Survival Guide for Clinicians. 2008 [cited 2010 June 25]; Second Edition:[Available from: .

3.Drobac, P.C., et al., Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics, 2006. 117(6): p. 2022-9.

4.Feja, K., et al., Management of Pediatric Multidrug-Resistant Tuberculosis and Latent Tuberculosis Infections in New York City From 1995 to 2003. Pediatric Infectious Disease Journal, 2008. 27(10): p. 907-912.

5.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.

6.Schaaf, H.S., et al., Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow- up. Pediatrics, 2002. 109(5): p. 765-771.

7.Schaaf, H.S., K. Shean, and P.R. Donald, Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome. Arch Dis Child, 2003. 88(12): p. 1106-11.

8.Mukherjee, J.S., et al., Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis, 2003. 7(7): p. 637-44.

9.Torun, T., et al., Side effects associated with the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis, 2005. 9(12): p. 1373-7.

10.Geerligs, W.A., et al., Multidrug-resistant tuberculosis: long-term treatment outcome in the Netherlands. Int J Tuberc Lung Dis, 2000. 4(8): p. 758-64.

11.Furin, J.J., et al., Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis, 2001. 5(7): p. 648-55.

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