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A previous study demonstrated noninferior efficacy of 4-month rifapentine/moxifloxacin regimen for tuberculosis (TB) treatment compared with the standard regimen. We explored results among study participants with diabetes. Among 2,516 randomized participants, 181 (7.2%) had diabetes. Of 166 participants with diabetes in the microbiologically eligible analysis group, 26.3% (15/57) had unfavorable outcomes in the control regimen, 13.8% (8/58) in the rifapentine/moxifloxacin regimen, and 29.4% (15/51) in the rifapentine regimen. The difference in proportion of unfavorable outcomes between the control and rifapentine/moxifloxacin arms in the microbiologically eligible analysis group was -12.5% (95% CI -27.0% to 1.9%); the difference between the control and rifapentine arms was 3.1% (95% CI -13.8% to 20.0%). Safety outcomes were similar in the rifapentine/moxifloxacin regimen and control arms. Among participants with TB and diabetes, the rifapentine/moxifloxacin arm had fewest unfavorable outcomes and was safe. Our findings indicate that the rifapentine/moxifloxacin regimen can be used in persons with TB and diabetes.

Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Background. Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. Methods. Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20–34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. Results. The mean rifabutin area under the concentration-time curve (AUC0–24) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 µg*h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0–1.4]). Also, the mean efavirenz AUC0–24 in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. Conclusions. The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Moxifloxacin has promising preclinical activity against Mycobacterium tuberculosis, but has not been evaluated in multidrug treatment of tuberculosis in humans. To compare the impact of moxifloxacin versus ethambutol, both in combination with isoniazid, rifampin, and pyrazinamide, on sputum culture conversion at 2 mo as a measure of the potential sterilizing activity of alternate induction regimens. Adults with smear-positive pulmonary tuberculosis were randomized in a factorial design to receive moxifloxacin (400 mg) versus ethambutol given 5 d/wk versus 3 d/wk (after 2 wk of daily therapy). All doses were directly observed. The primary endpoint was sputum culture status at 2 mo of treatment. Of 336 patients enrolled, 277 (82%) were eligible for the efficacy analysis, 186 (67%) were male, 175 (63%) were enrolled at African sites, 206 (74%) had cavitation on chest radiograph, and 60 (22%) had HIV infection. Two-month cultures were negative in 71% of patients (99 of 139) treated with moxifloxacin versus 71% (98 of 138) treated with ethambutol (p = 0.97). Patients receiving moxifloxacin, however, more often had negative cultures after 4 wk of treatment. Patients treated with moxifloxacin more often reported nausea (22 vs. 9%, p = 0.002), but similar proportions completed study treatment (88 vs. 89%). Dosing frequency had little effect on 2-mo culture status or tolerability of therapy. The addition of moxifloxacin to isoniazid, rifampin, and pyrazinamide did not affect 2-mo sputum culture status but did show increased activity at earlier time points.

Natural abundance of N stable isotopes used in combination with concentrations may be useful indicators of N-cycling in wetlands. Concentrations and N signatures of NO 3 − , NH 4 + , and sediment organic nitrogen (SON) were measured in two impacted coastal golf course retention ponds and two natural marshes. Limited NO 3 − was detected in natural site surface water or pore water, but both isotopic signature and concentrations of NO 3 − in surface water of impacted sites indicated anthropogenic inputs. In natural sites, NH 4 + concentrations were greatest in deeper pore water and least in surface water, suggesting diffusion predominates. The natural sites had greater %SON, and N indicated that the natural sites also had greater NH 4 + released from SON mineralization than impacted sites. In NO 3 − -limited systems, neither concentrations nor N natural abundance was able to provide information on N-cycling, while processes associated with NH 4 + were better elucidated by using both concentrations and N natural abundance.

Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited. Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB. Adults with sputum smear-positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol. All doses were directly observed. Sputum was collected for culture every 2 weeks. The primary outcome was negative sputum culture at completion of 8 weeks of treatment. Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%) were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites. Negative cultures at Week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the moxifloxacin arm (P = 0.37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of Week-8 culture negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the moxifloxacin group versus 22/205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, 0.81, 2.25). Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity.

Natural abundance of N stable isotopes used in combination with concentrations may be useful indicators of N-cycling in wetlands. Concentrations and 15N signatures of NO3   −, NH4   +, and sediment organic nitrogen (SON) were measured in two impacted coastal golf course retention ponds and two natural marshes. Limited NO3   − was detected in natural site surface water or pore water, but both isotopic signature and concentrations of NO3   − in surface water of impacted sites indicated anthropogenic inputs. In natural sites, NH4   + concentrations were greatest in deeper pore water and least in surface water, suggesting diffusion predominates. The natural sites had greater %SON, and 15N indicated that the natural sites also had greater NH4   + released from SON mineralization than impacted sites. In NO3   −-limited systems, neither concentrations nor 15N natural abundance was able to provide information on N-cycling, while processes associated with NH4   + were better elucidated by using both concentrations and 15N natural abundance.

Natural abundance of N stable isotopes used in combination with concentrations may be useful indicators of N-cycling in wetlands. Concentrations and 15 N signatures of NO3 - , NH4 + , and sediment organic nitrogen (SON) were measured in two impacted coastal golf course retention ponds and two natural marshes. Limited NO3 - was detected in natural site surface water or pore water, but both isotopic signature and concentrations of NO3 - in surface water of impacted sites indicated anthropogenic inputs. In natural sites, NH4 + concentrations were greatest in deeper pore water and least in surface water, suggesting diffusion predominates. The natural sites had greater %SON, and 15 N indicated that the natural sites also had greater NH4 + released from SON mineralization than impacted sites. In NO3 - -limited systems, neither concentrations nor 15 N natural abundance was able to provide information on N-cycling, while processes associated with NH4 + were better elucidated by using both concentrations and 15 N natural abundance.

Salt marsh estuaries are valuable habitats that perform important functions such as providing habitat and nursery areas for commercially important species, mitigating the effects of storms on coastal communities, and filtering nutrients and other contaminants from water entering the coast. Anthropogenic nitrogen (N) inputs have the potential to degrade the quality of salt marsh estuaries and affect their ability to perform these valuable functions. 15N has been used in field studies at natural abundance and in laboratory studies using an enriched tracer to study N cycle processes occurring in coastal ecosystems. The purpose of this study was to adapt N stable isotope natural abundance techniques to laboratory denitrification assays to examine other N cycle processes that may be occurring. This technique was then used to examine the effects of anthropogenic N loading on N cycle processes in salt marsh estuaries by comparing the results from two study sites, one receiving anthropogenic N inputs from a nearby golf course and one in an undeveloped area. Potential denitrification rates at both sites were directly related to the amount of nitrate (NO3-) added to the overlying water column and potential denitrification rates were higher at the impacted site than the unimpacted site regardless of water column NO3- concentration (0, 700 or 1400 µg NO3--N). Potential dissimilatory NO3- reduction to ammonium (NH4+) (DNRA) rates measured through mass balance did not appear to vary by either NO3- addition or study site. In most instances measured NH4+ accumulation in microcosms was small, but the δ15N of NH4 + changed significantly with time suggesting that microbial assimilation and sediment organic matter (SOM) mineralization were occurring even when N species concentrations were stable. However quantifying the exact proportions of microbial assimilation and SOM mineralization using the stable isotope data was not possible because the fractionation factors of these processes were unknown.