M Tobias Heinrichs1, George L Drusano2, David L Brown2, Michael S Maynard2, Sherwin K B Sy3, Kenneth H Rand4, Charles A Peloquin5, Arnold Louie2, Hartmut Derendorf3. 1. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA; Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA. Electronic address: t.heinrichs@ufl.edu. 2. Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA. 3. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA. 4. Department of Pathology, College of Medicine, University of Florida, Gainesville, Florida, USA. 5. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Abstract
INTRODUCTION: There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance. METHODS: Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment. Doses that achieved maximum bacterial kill while suppressing the emergence of drug resistance were determined. Through Monte Carlo simulations the quantitative output of this in vitro study was bridged to the human patient population to inform optimal dosage regimens while accounting for clinical minimum inhibitory concentration (MIC) distributions. RESULTS AND DISCUSSION: Moxifloxacin activity was significantly decreased in an acidified environment. The loss of activity was compensated by accumulation of the drug in TB lung lesions; therefore, moderate efficacy can be expected. Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. Linezolid demonstrated very good activity even at a reduced pH. Linezolid 900 mg once-daily (QD) is likely to achieve a maximum killing effect and prevent the emergence of drug resistance; 600 mg QD in a robust drug regimen may have similar potential.
INTRODUCTION: There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance. METHODS: Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment. Doses that achieved maximum bacterial kill while suppressing the emergence of drug resistance were determined. Through Monte Carlo simulations the quantitative output of this in vitro study was bridged to the humanpatient population to inform optimal dosage regimens while accounting for clinical minimum inhibitory concentration (MIC) distributions. RESULTS AND DISCUSSION: Moxifloxacin activity was significantly decreased in an acidified environment. The loss of activity was compensated by accumulation of the drug in TB lung lesions; therefore, moderate efficacy can be expected. Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. Linezolid demonstrated very good activity even at a reduced pH. Linezolid 900 mg once-daily (QD) is likely to achieve a maximum killing effect and prevent the emergence of drug resistance; 600 mg QD in a robust drug regimen may have similar potential.
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