Published ahead of print on September 11, 2008, doi:10.1164/rccm.200806-892OC Am. J. Respir. Crit. Care Med., Volume 178, Number 11, December 2008, 1180-1185 A more recent version of this article appeared on December 1, 2008
Submitted on June 13, 2008 Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary TuberculosisReynaldo Dietze1*,1 Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil, 2 Division of Mycobacterial and Respiratory Infections, National Jewish Medical and Research Center, Denver, CO, USA; Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, CO, USA, 3 Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA, 4 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA, 5 University of Arkansas for Medical Sciences, Little Rock, AR, USA * To whom correspondence should be addressed. E-mail: rdietze{at}ndi.ufes.br.
Rationale: Linezolid, the first oxazolidinone approved for clinical use, has good in vitro and promising in vivo activity against M. tuberculosis. Objectives: Evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis. Methods: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid 300 mg daily, linezolid 600 mg twice-daily or linezolid 600 mg once-daily for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and last 5 days of study drug administration (extended early bactericidal activity). Measurements and Main Results: The mean early bactericidal activity of isoniazid (0.67 log10 cfu/mL/day) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/mL/day, respectively). The extended early bactericidal activity of linezolid between day 2 and 7 was minimal. Conclusions: Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registry information: NCT00396084 registered at www.clinicaltrials.gov Key words: tuberculosis, oxazolidinones, linezolid, isoniazid, pharmacokinetics
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