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Antimicrobial Agents and Chemotherapy, February 2006, p. 407-413, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.407-413.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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,¹ Department of Paediatrics,² Department of Medicine, College of Medicine, Blantyre, Malawi,⁴ Liverpool School of Tropical Medicine, University of Liverpool, Liverpool, United Kingdom³

Received 26 May 2005/ Returned for modification 31 May 2005/ Accepted 6 November 2005

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 (C_max) failed to reach the MIC for Mycobacterium tuberculosis. The C_max of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The C_max 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 C_max 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.