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. 2024 Nov 6;68(11):e0058324.
doi: 10.1128/aac.00583-24. Epub 2024 Oct 16.

Levofloxacin activity at increasing doses in a murine model of fluoroquinolone-susceptible and -resistant tuberculosis

Thomas Maitre  1   2 , Alexandre Godmer  1   3 , Céline Mory  4 , Aurélie Chauffour  1 , Thi Cuc Mai  1 , Najoua El Helali  4 , Alexandra Aubry  1   3 , Nicolas Veziris  1   3
Affiliations

Levofloxacin activity at increasing doses in a murine model of fluoroquinolone-susceptible and -resistant tuberculosis

Thomas Maitre et al. Antimicrob Agents Chemother. .

Abstract

High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 106 CFU of Mycobacterium tuberculosis H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC50) produced an AUC/MIC (AUC0-24h/MIC) ratio of 167.9 ± 27.5, and at EC80 it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis.

Keywords: MDR-TB; XDR-TB; levofloxacin; murine model; tuberculosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
Survival analysis in mice infected with H37Rv WT (A) or isogenic mutants harboring the GyrA A90V (B) and D94G (C) substitutions.
Fig 2
Fig 2
Lung bacillary load in mice according to their experimental group.
Fig 3
Fig 3
Dose-effect model of levofloxacin activity according to exposure expressed as the AUC/MIC ratio. The data were extracted from the previous study (9).
See this image and copyright information in PMC

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