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BACKGROUND:The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment. METHODS:Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment. RESULTS:121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm). CONCLUSION:For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin. TRIAL REGISTRATION:www.ClinicalTrials.gov NCT00728507.

Summary Background New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment. Methods We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15–20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov, number NCT00082173. Findings 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17·2%, 95% CI 2·8–31·7; p=0·03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). Interpretation Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified. Funding US Food and Drug Administration Office of Orphan Product Development, with additional support from the US National Institutes of Health.

Background Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate markers of treatment response. Methods Using the T-SPOT.TB assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-γ-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment. Results 58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034). Conclusion IFN-γ-producing RD1-specific T cells, as measured in the T-SPOT.TB assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.

Background Being a contact of a pulmonary tuberculosis (TB) case is a risk factor for active and latent TB. The objective of this study is to determine the contact tracing yield using two different programmatic definitions of close contact in the city of Rio de Janeiro, Brazil. Methods This is a retrospective quasi-experimental study. Data were obtained by reviewing the medical records from TB index cases and their close contacts admitted to the Outpatient TB Clinic of the Institute of Thoracic Diseases, University of Rio de Janeiro. From January 2001 to December 2004, a close contact was defined as an individual who shared an enclosed space with a TB index case for a total period of ≥ 100 hours, whereas from January 2005 to December 2008 the definition of close contact was changed to an individual who shared an enclosed space with a TB index case ≥ 4 hours a week. The primary outcome of this study was newly diagnosed pulmonary TB cases and the secondary outcome was the prevalence of latent TB infection (LTBI) among close contacts during both periods. Results From 2001–2004, 810 close contacts from 257 index cases were evaluated and the prevalence of active TB and LTBI were 2% (16/810) and 62% (496/794), respectively. From 2005–2008, 1,310 close contacts from 369 index cases were identified and the prevalence of active TB and LTBI were 2.7% (35/1,310) and 69% (877/1,275), respectively. There was not a statically significant difference in the detection of active TB (p = 0.3) between the 2 time periods, but the detection of LTBI was significant higher (p = 0.003). The number needed to screen (contacts/new cases) decreased from 50 to 37 and the number need to contact trace (index cases/new cases) decreased from 16 to 10 from 2001–2004 to 2005–2008. Conclusion In conclusion, the findings of this study suggest that the less conservative definition of TB close contacts (sharing space ≥ 4 h/week) can be a helpful tool for increasing the rate of diagnosis for newly active pulmonary TB cases and for the detection of LTBI among contacts of active pulmonary TB cases.