期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 188, 期 1, 页码 97-102出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201212-2328OC
关键词
moxifloxacin; levofloxacin; MDR-TB; pharmacokinetics; mouse model
资金
- National Institutes of Health [N01-AI40007, K08-AI58993]
- Department of Biotechnology, Government of India
- MLP of CSIR, Government of India, through the Indian Institute of Integrative Medicine [GAP-1160, MLP-6010]
Rationale: High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. Objectives: We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. Methods: A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. Measurements and Main Results: After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log(10) lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log(10) lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. Conclusions: In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months influoroquinolone containing second-line regimens, largely compensating for L's weaker activity.
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