Background Retreatment tuberculosis (TB) has become a major source of drug-resistant TB. In contrast to the combination of isoniazid (INH) and rifampicin (RIF), that of pasiniazid (Pa) and rifabutin (RFB) or rifapentine (RFP) appears to have better activity in vitro against drug-resistant Mycobacterium tuberculosis (MTB), especially when combined with moxifloxacin (MXF). However, there has been limited study of potential synergism among Pa, RFB, RFP, and MXF, or simultaneous comparison with the standard INH and RIF combination. Methods In vitro synergism of four two-drug combinations (INH and RIF, Pa and RFB, Pa and RFP, MXF and Pa) and two three-drug combinations (MXF and Pa combined with RFB or RFP) was evaluated against 90 drug-resistant MTB strains isolated from retreatment TB patients by the checkerboard method. The fractional inhibitory concentration index (FICI) was calculated for each combination. Results The synergistic activity of the combination of Pa with RFB or RFP was higher than that of INH and RIF or MXF and Pa, and the synergistic activity of Pa in combination with RFP was even higher than that of RFB, although RFP yielded an MIC 90 of 64 mg/liter, higher than that of RFB of 8 mg/liter against 90 drug-resistant MTB strains. Meanwhile, for three-drug combinations, the synergistic effects of MXF and Pa combined with RFB or RFP were similar. Further stratification analysis showed that, for XDR-MTB strains, the synergistic effect of the Pa and RFP combination was also better than those of other two-drug combinations. Conclusion The combination of Pa with RFP shows better in vitro synergism than Pa with RFB and standard INH with RIF combinations, which can provide a reference for new regimens for retreatment TB patients.
In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity ( P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.
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