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: 4.48). 02/2006; 50(2):407-13. DOI: 10.1128/AAC.50.2.407-413.2006
Source: PubMed


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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Available from: Elizabeth M Molyneux
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    • "As a consequence, although some advances have been made, the evidence base on which treatment of childhood TB is determined is weak and the recommendations in childhood TB remain based on extrapolation from observations in adult patients [1]–[3]. The World Health Organisation (WHO) recognised the problem of potential under-dosing in children, especially for isoniazid (INH) and rifampicin (RIF) [4]–[6]. The dose regimen recommendation in children was amended in 2010 and the dose of all the first-line anti-TB drugs increased [7]. "
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    ABSTRACT: SettingIn most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets.ObjectiveTo determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis.DesignDrug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets.ResultsAll whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings.ConclusionIn split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.
    Full-text · Article · Jul 2014 · PLoS ONE
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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 (Cmax) and exposure (AUC0-24) were determined. Results: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 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.
    Full-text · Article · Oct 2012 · Tropical Medicine & International Health
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    • "However the variability of CSF penetration of the different first-line TB-drugs may warrant a need for adjustment of these regimens accordingly. In particular, the penetration of rifampicin, the key drug, is poor, as is that of ethambutol [6-10]. The mortality rate of TBM patients may reflect both poor antibacterial activity of current treatment regimes and poor penetration of these drugs into the central nervous system. "
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    ABSTRACT: Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. International Standard Randomised Controlled Trial Number ISRCTN61649292.
    Full-text · Article · Feb 2011 · Trials
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