title: Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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 log10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 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 in fluoroquinolone-containing second-line regimens, largely compensating for L's weaker activity.
authors.affiliation: Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, India.
authors.forename: Zahoor
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.forename: Austin
authors.initials: A
authors.lastname: Minkowski
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D024841:Fluoroquinolones; D064704:Levofloxacin; D051379:Mice; D008807:Mice, Inbred BALB C; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D011718:Pyrazinamide; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin