Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Abstract

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 in fluoroquinolonecontaining second-line regimens, largely compensating for L's weaker activity.

Role of pncA and rpsA Gene Sequencing in Detection of Pyrazinamide Resistance in Mycobacterium tuberculosis Isolates from Southern China

“…This result is similar to those in South Africa and Thailand (4,27). The importance of PZA in treating MDR-TB has been proved recently in a murine model in that all PZA-containing regimens tested showed better activities than those corresponding regimens without PZA when combined with second-line drugs (33). All these findings emphasized the importance of rapid detection of PZA resistance in controlling MDR-TB.…”

Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

“…One patient even showed a very low AUC of 31.2 (23,24). These differences may be the result of the severity of the disease, but they may also have been influenced by individual factors in the TB patients, such as renal function, body mass index (BMI), drug interaction, comorbidity, and polymorphism of the drug resistance-related mutation in MDR isolates from diverse geographical regions (14,(25)(26)(27)(28). We found a good correlation between C max and AUC 0 -24 .…”

Novel Regimens Identified in Mice for Treatment of Latent Tuberculosis Infection in Contacts of Patients with Multidrug-Resistant Tuberculosis

“…MFX alone was less effective than INH in an earlier iteration of this model, but the combination of MFX with Pa was more active than INH (11). Although MFX is more potent than LFX against M. tuberculosis, LFX may have a lower propensity to prolong the corrected QT (QTc) interval and may therefore be safer to use in combination with TMC and other agents which also prolong the QTc interval (17,18).…”