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J Antimicrob Chemother. 2014 Oct;69(10):2841-7. doi: 10.1093/jac/dku210. Epub 2014 Jun 16.

Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study.

Author information

1
International Reference Laboratory of Mycobacteriology, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark jpl@ssi.dk.
2
Department of Infectious Diseases, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark.
3
Department of Biochemistry, Immunology and Genetics, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark.
4
Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark.
5
Department of Infectious Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen Ø, Denmark.

Abstract

OBJECTIVES:

To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome.

METHODS:

After 6-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis.

RESULTS:

Plasma concentrations below the normal ranges were frequently observed: isoniazid in 71%, rifampicin in 58%, ethambutol in 46%, pyrazinamide in 10% and both isoniazid and rifampicin in 45% of the patients. The plasma concentrations of isoniazid correlated inversely with the C-reactive protein level at the time of sampling (P = 0.001). During 1 year of follow-up, therapy failure occurred in five patients. Therapy failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005).

CONCLUSIONS:

At 2 h, plasma concentrations of isoniazid and rifampicin below the normal ranges were frequently observed. The inverse correlation between the plasma concentrations of isoniazid and C-reactive protein indicate a suboptimal treatment effect at standard dosing regimens. Dichotomization based on median 2 h drug concentrations was more predictive of outcome than dichotomization based on normal ranges.

KEYWORDS:

anti-tuberculosis drugs; therapeutic drug monitoring; tuberculosis

PMID:
25140577
DOI:
10.1093/jac/dku210
[Indexed for MEDLINE]

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