Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, P.O. Box 30096, Blantyre 3, Malawi.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 02/2006; 50(2):407-13. DOI: 10.1128/AAC.50.2.407-413.2006
Source: PubMed

ABSTRACT Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.

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    • "The diagnosis of TB was made on the basis of clinical signs and symptoms; gastric aspirate, sputum or other culture result positive for Mycobacterium tuberculosis; chest radiograph; a household source case with culture-positive TB and induration of ‡10 mm after a tuberculin skin test (TST) with 2 U of tuberculin RT23. Patients were excluded if they were older than 15 years of age, pregnant or lactating, had a history of liver or kidney disease, were HIV-positive [as these conditions may affect the PK of TB drugs (Graham et al. 2006; Schaaf et al. 2009)] or if the medical condition of the patient did not allow participation in the study as judged by the treating physician. HIV status was assessed in all patients upon diagnosis of TB as a routine investigation. "
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    ABSTRACT: Objectives  The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. Methods  Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (C(max) ) and exposure (AUC(0-24) ) were determined. Results  25 patients (83%) had an isoniazid C(max) below 3 mg/l and 23 patients (77%) had a rifampicin C(max) below 8 mg/l. One patient (3%) had a pyrazinamide C(max) below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. C(max) and AUC(0-24) of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower C(max) and AUC(0-24) values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC(0-24) for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). Conclusion  We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.
    Tropical Medicine & International Health 10/2012; 17(12). DOI:10.1111/tmi.12003 · 2.30 Impact Factor
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    • "There are no published data for children. EMB and PZA levels were not significantly different between HIV-infected and HIV-uninfected Malawian children (Graham et al. 2006). However, these are the only published data that try to examine the impact of age, HIV and malnutrition on TB drug levels in children. "
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    ABSTRACT: To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children. Literature review. Overall, children tolerate anti-TB drugs very well when using currently recommended dosages. Serious adverse events are rare and even mild symptoms such as nausea or vomiting are uncommon. There are occasional case reports of severe hepatotoxicity. Surveillance and reporting of adverse events will need to be improved when recommended dosages of the main first-line anti-TB therapy for children are increased. Co-morbidities such as HIV infection and severe malnutrition may affect the incidence and complicate the management of possible adverse events to anti-TB therapy.
    Tropical Medicine & International Health 10/2009; 14(11):1329-37. DOI:10.1111/j.1365-3156.2009.02375.x · 2.30 Impact Factor
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