Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis

Abstract

The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guerin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean ± standard deviation log CFU, 0.2 ± 0.3, compared with 5.9 ± 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 ,ug/ml), although they were still susceptible to rifabutin.

Prospects for development of new antimycobacterial drugs

“…Therapy of MAC-infected mice with RBT (or, in some studies, with RPT) in combination with either EB, CFZ, AZM, KM, EBϩCFZ, CAMϩEB, or CFZϩKM was more effective than that with each drug alone. 86,102,105,107 As indicated in Table 6, in clinical studies, RBT was effective against intractable TB and MAC infections (positive response, 8% to 92%). [88][89][90]109,110 Efficacy was achieved with certain regimens involving RBT (RPT) in combination with other drugs, including EB, CFZ, CAM, INH, and CPFX.…”

“…86,[102][103][104][105][106][107][108] First, RBT displayed appreciable therapeutic efficacy against murine infections caused by MTB and MAC. RBT exhibited potential efficacy in the prophylaxis of tuberculosis in mice.…”

Current Status of Some Antituberculosis Drugs and the Development of new Antituberculous Agents with Special Reference to their In Vitro and In Vivo Antimicrobial Activities

“…First, a prospective, randomized, double-blind study showed that once-weekly RPT (600 mg) with INH (900 mg) was safe and effective for the treatment of pulmonary TB in HIV-negative people without cavitation on chest radiography and the rate of failure/relapse in this regimen (2.9%) was in the same level as that in twice-weekly RIF plus INH (2.5%) [131]. In addition, a subsequent study by Bock et al showed that the rate (4 %) of discontinuation of therapy for any reason and adverse events on once-weekly Jabes (1994), Kelly (1996), , Brooks (1998), Miyazaki (1999), Keung (1999), Lenaerts (1999), Daniel (2000), Weber (2001) continuation phase therapy with RPT (900 mg) plus INH did not increase, compared to that (6%) of once-weekly RPT (600 mg) plus INH [132]. This study suggested that RPT at 900 mg dose may be suitable for continuation phase treatment of TB.…”

“…(1) RBT and RPT exhibit strong therapeutic efficacies in the order RBT, RPT > RIF, when given daily to infected mice [118,122]. In addition, RBT exhibits potent efficacy in prophylaxis of TB in mice.…”

“…Fourth, in vivo studies using mouse experimental TB models have revealed the following ( Table 2) [87,[117][118][119][120][121][122][123].…”