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Published ahead of print on September 11, 2008, doi:10.1164/rccm.200806-892OC
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American Journal of Respiratory and Critical Care Medicine Vol 178. pp. 1180-1185, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200806-892OC

Original Article

Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis

Reynaldo Dietze1, David Jamil Hadad1, Bryan McGee2,3, Lucilia Pereira Dutra Molino1, Ethel Leonor Noia Maciel1, Charles A. Peloquin2,3, Denise F. Johnson4, Sara M. Debanne5, Kathleen Eisenach6, W. Henry Boom4, Moises Palaci1 and John L. Johnson4

1 Núcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Brazil; 2 Division of Mycobacterial and Respiratory Infections and 3 Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, Colorado; 4 Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio; 5 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio; and 6 University of Arkansas for Medical Sciences, Little Rock, Arkansas

Correspondence and requests for reprints should be addressed to Reynaldo Dietze, M.D, Núcleo de Doenças Infecciosas Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468 Maruípe,Vitória–ES Brazil, CEP 29040-091. E-mail: rdietze{at}ndi.ufes.br

Rationale: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.

Objectives: To 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) and linezolid (600 mg twice daily or 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 the 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/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 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 registered with www.clinicaltrials.gov (NCT00396084).

Key Words: tuberculosis • oxazolidinones • linezolid • pharmacokinetics • antituberculosis agents


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Linezolid has in vitro activity against Mycobacterium tuberculosis (MTB). Because of limited treatment options for multidrug-resistant tuberculosis (TB), it is being used despite scarce information about its bactericidal activity in patients with pulmonary TB.

What This Study Adds to the Field
Linezolid has modest early bactericidal activity (EBA) in patients with pulmonary TB, suggesting that it penetrates into tuberculosis lesions and has bactericidal activity against rapidly growing tubercle bacilli in cavities. However, linezolid has minimal extended EBA after the first 2 days of treatment.

 



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