Early Bactericidal Activity - DMID 01-553

Randomized, Open Label, Multiple Dose Phase I Study of the Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin and Moxifloxacin in HIV-non-infected Adults with Initial Episodes of Smear-Positive Pulmonary Tuberculosis

Information:

DMID Protocol Number: 01-553

Goal of Study:

This study was designed to evaluate the early and extended early bactericidal activity (EBA) of fluoroquinolone antibiotics gatifloxacin, levofloxacin, moxifloxacin, and linezolid compared with an isoniazid (INH) control arm. The study was conducted in two parts.

Objectives of Study:

Primary Objectives:

1. The primary objective of this study was to compare the EBA of moxifloxacin, levofloxacin, and gatifloxacin, as well as once and twice daily 600 mg doses of linezolid, a new oxazolidinone antibiotic, compared with an INH control arm in adults with newly-diagnosed, sputum smear-positive pulmonary TB.

Secondary Objectives:

1. Immunologic
   1. Compare the results of sputum MTB mRNA clearance with the results of a standard EBA study [change in sputum viable counts (CFU)].
   2. Compare the rate of clearance of sputum cytokine proteins with the results of a standard EBA assay (CFU) [change in sputum viable counts (CFU)].
2. Pharmacokinetic
   1. Determine the pharmacokinetics of the study drugs (moxifloxacin, levofloxacin, gatifloxacin, linezolid, and isoniazid) in patients with smear positive pulmonary tuberculosis.
   2. Demonstrate that lack of EBA activity is not due to low serum drug concentrations.

Part 1 compared the bactericidal activity of levofloxacin, gatifloxacin and gatifloxacin, and isoniazid (INH). Forty patients (10 per arm) were assigned to receive isoniazid 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. All subjects were then treated with 6 months of standard short course chemotherapy. Sputum for quantitative culture (cfu assay) was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity, EBA) and last 5 days of monotherapy (extended early bactericidal activity). Laboratory staff were blinded to treatment assignment. The EBA of isoniazid (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day). Bactericidal activity between day 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison the extended EBA of the three fluoroquinolones was greater than INH. Moxifloxacin, gatifloxacin, and high dose levofloxacin have excellent EBA only slightly less than INH and greater extended EBA.

In Part 2 of the study, the EBA and extended EBA of linezolid and INH were compared using a similar study design as Part 1. Thirty patients (10 per arm) were assigned to receive linezolid 600 mg twice daily, linezolid 600 mg once daily and INH 300 mg daily for 7 days. The mean EBA of INH (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 EBA of linezolid between days 2 and 7 was minimal. Linezolid has modest EBA against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended EBA.

The results of this completed study can be found in:

Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10:605-612.

Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008; 52:852-857. PMCID: PMC2258503.

Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, Johnson DF, Debanne SM, Eisenach K, Boom WH, Palaci M, Johnson JL. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J. Respir Crit Care Med 2008; 178:1180-1185. PMCID: PMC2588492.