Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): A cluster randomized trial of a computerized clinical decision support tool.

BACKGROUND: Clinical decision support (CDS) tools designed to digest, filter, organize, and present health data are becoming essential in providing clinical and cost-effective care. Many are not rigorously evaluated for benefit before implementation. We assessed whether computerized CDS for primary care providers would improve atrial fibrillation (AF) management and outcomes as compared to usual care. METHODS: Overall, 203 primary care providers were recruited, randomized, and then cluster stratified by location (urban, rural) to usual care (n = 99) or CDS (n = 104). Providers recruited 1,145 adult patients with AF to participate. The intervention was access to an evidenced-based, point-of-care computerized CDS designed to support guideline-based AF management. The primary efficacy outcome was a composite of unplanned cardiovascular hospitalizations and AF-related emergency department visits; the primary safety outcome was major bleeding, both over 1 year. Patients were the units of intention-to-treat analysis. RESULTS: No significant effects on the primary efficacy (130 control, 118 CDS, hazard ratio: 0.98 [95% CI 0.71-1.37], P = .926) or safety (n = 7 usual care, n = 8 CDS, 1.3% total, P = .939) outcomes were observed at 12-months. CONCLUSIONS: IMPACT-AF rigorously assessed a CDS tool in a highly representative sample of primary care providers and their patients; however, no impact on outcomes was observed. Considering the proliferating use of CDS applications, this study highlights the need for efficacy assessments prior to adoption and clinical implementation.

Optimizing primary care management of atrial fibrillation: The rationale and methods of the Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) study.

The Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) is an investigator designed, prospective, randomized, un-blinded, cluster design clinical trial, conducted in the primary care setting of Nova Scotia, Canada. Its aim is to evaluate whether an electronic Clinical Decision Support System (CDSS) designed to assist both practitioners and patients with evidence-based management strategies for Atrial Fibrillation (AF) can improve process of care and outcomes in a cost-efficient manner as compared to usual AF care. At least 200 primary care providers are being recruited and randomized at the level of the practice to control (usual care) or intervention (eligible to access to CDSS) cohorts. Over 1,000 patients of participating providers with confirmed AF will be managed per their provider's respective assignment. The targeted primary clinical outcome is a reduction in the composite of unplanned cardiovascular (CV) or major bleeding hospitalizations and AF-related emergency department visits. Secondary clinical outcomes, process of care, patient and provider satisfaction as well as economic costs at the system and patient levels are being examined. The trial is anticipated to report in 2018.

Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity.

Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV study--a randomized clinical trial.

BACKGROUND: The aim of this study was to show that sequential intravenous and oral moxifloxacin monotherapy (400 mg once per day) is as efficacious and safe as a combination regimen (intravenous ceftriaxone, 2 g once per day, plus sequential intravenous and oral levofloxacin, 500 mg twice per day) in patients hospitalized with community-acquired pneumonia. METHODS: We conducted a prospective, multicenter, randomized, double-blind noninferiority trial. Patients with a Pneumonia Severity Index (PSI) of III-V were stratified on the basis of PSI risk class before randomization. The primary efficacy end point was clinical response at test of cure (4-14 days after the completion of treatment). Secondary efficacy end points were clinical and bacteriological response at end of treatment (days 7-14) and at follow-up assessment (21-28 days after the end of treatment), overall mortality, and mortality attributable to pneumonia. RESULTS: Seven hundred thirty-three patients were enrolled in the study (368 in the moxifloxacin arm and 365 in the comparator arm); 49% had a PSI of IV, and 10% had a PSI of V. Of 569 patients (291 in the moxifloxacin arm and 278 in the comparator arm) valid for per-protocol analysis, the overall clinical cure rates at test of cure were 86.9% for moxifloxacin and 89.9% for the comparator regimen (95% confidence interval, -8.1% to 2.2%). Bacteriological success at test of cure was 83.3% for moxifloxacin and 85.1% for the comparator regimen (95% confidence interval, -15.4% to 11.8%). There were no significant differences between moxifloxacin and comparator treatments in the incidence of treatment-emergent adverse events or in mortality. CONCLUSIONS: Monotherapy with sequential intravenous/oral moxifloxacin was noninferior to treatment with ceftriaxone plus levofloxacin combination therapy in patients with community-acquired pneumonia who required hospitalization.

Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy.

We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam/amoxicillin-clavulanate.

OBJECTIVES: Complicated skin and skin structure infections (cSSSIs), including diabetic foot infections (DFIs), are often polymicrobial, requiring combination or broad-spectrum therapy. Moxifloxacin, a broad-spectrum fluoroquinolone, is approved for cSSSI and can be administered by either intravenous (iv) or oral routes. To assess the efficacy of moxifloxacin for treating DFIs, we analysed a subset of patients with these infections who were enrolled in a prospective, double-blind study that compared the efficacy of moxifloxacin with piperacillin-tazobactam and amoxicillin-clavulanate. METHODS: Patients>or=18 years of age with a DFI requiring initial iv therapy were randomized to either moxifloxacin (400 mg/day) or piperacillin-tazobactam (3.0/0.375 g every 6 h) for at least 3 days followed by moxifloxacin (400 mg/day orally) or amoxicillin-clavulanate (800 mg every 12 h orally), if appropriate, for 7-14 days. DFI was usually defined as any foot infection plus a history of diabetes. Our primary efficacy outcome was the clinical response of the infection at test-of-cure (TOC), 10-42 days post-therapy. RESULTS: Among 617 patients enrolled in the original study, 78 with DFIs were evaluable for treatment efficacy. Clinical cure rates at TOC were similar for moxifloxacin and piperacillin-tazobactam/amoxicillin-clavulanate (68% versus 61%) for patients with investigator-defined infection (P=0.54). Overall pathogen eradication rates in the microbiologically-valid population were 69% versus 66% for moxifloxacin and comparator, respectively (P=1.00). CONCLUSIONS: Intravenous+/-oral moxifloxacin was as effective as iv piperacillin-tazobactam+/-amoxicillin-clavulanate in treating moderate-to-severe DFIs. Moxifloxacin may have potential as a monotherapy regimen for DFIs.

Randomized controlled trial of moxifloxacin compared with piperacillin-tazobactam and amoxicillin-clavulanate for the treatment of complicated intra-abdominal infections.

OBJECTIVE: To compare the safety and efficacy of sequential intravenous (IV) to oral (PO) moxifloxacin treatment against a standard antimicrobial regimen of IV piperacillin-tazobactam followed by PO amoxicillin-clavulanate for the treatment of adults with complicated intra-abdominal infection (cIAI). SUMMARY BACKGROUND DATA: cIAIs are commonly due to mixed aerobic and anaerobic bacteria and require both source control and broad-spectrum antibiotic therapy. METHODS: A prospective, double-blind, randomized, phase III comparative trial. Patients with cIAI were stratified by disease severity (APACHE II score) and randomized to either IV/PO moxifloxacin (400 mg q24 hours) or comparator (IV piperacillin-tazobactam [3.0/0.375 g q6 hours] +/- PO amoxicillin-clavulanate [800 mg/114 mg q12 hours]), each for 5 to 14 days. The primary efficacy variable was clinical cure rate at the test-of-cure visit (days 25-50). Bacteriologic outcomes were also determined. RESULTS: : Of 656 intent-to-treat patients, 379 (58%) were valid to assess efficacy (183 moxifloxacin, 196 comparator). Demographic and baseline medical characteristics were similar between the 2 groups. Clinical cure rates at test-of-cure were 80% (146 of 183) for moxifloxacin versus 78% (153 of 196) for comparator (95% confidence interval, -7.4%, 9.3%). The clinical cure rate at test-of-cure for hospital-acquired cIAI was higher with moxifloxacin (82%, 22 of 27) versus comparator (55%, 17 of 31; P = 0.05); rates were similar for community-acquired infections (80% [124 of 156] versus 82% [136 of 165], respectively). Bacterial eradication rates were 78% (117 of 150) with moxifloxacin versus 77% (126 of 163) in the comparator group (95% confidence interval, -9.9%, 8.7%). CONCLUSIONS: Once daily IV/PO moxifloxacin monotherapy was as least as effective as standard IV piperacillin-tazobactam/PO amoxicillin-clavulanate dosed multiple times daily for the treatment of cIAIs.

Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis.

RATIONALE: Moxifloxacin has promising preclinical activity against Mycobacterium tuberculosis, but has not been evaluated in multidrug treatment of tuberculosis in humans. OBJECTIVE: 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. METHODS: 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. MEASUREMENTS: The primary endpoint was sputum culture status at 2 mo of treatment. RESULTS: 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. CONCLUSIONS: 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.

Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy.

BACKGROUND: Limited prospective data are available for elderly patients with community-acquired pneumonia (CAP). This study aimed to determine the efficacy and safety of moxifloxacin versus that of levofloxacin for the treatment of CAP in hospitalized elderly patients (age, > or = 65 years). METHODS: We conducted a prospective, double-blind, randomized, controlled trial. Eligible patients were stratified by CAP severity before randomization to receive treatment with either intravenous/oral moxifloxacin (400 mg daily) or intravenous/oral levofloxacin (500 mg daily) for 7-14 days. Clinical response at test-of-cure (the primary efficacy end point was between days 5 and 21 after completion of therapy), and clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response were secondary end points. RESULTS: The safety population included 394 patients (195 in the moxifloxacin group and 199 in the levofloxacin group). The population eligible for clinical efficacy analysis (i.e., the clinically valid population) included 281 patients (141 in the moxifloxacin group and 140 in the levofloxacin group); 51.3% were male, and the mean age (+/-SD) was 77.4 +/- 7.7 years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the moxifloxacin arm and 87.9% in the levofloxacin arm (95% confidence interval [CI], -1.9 to 11.9; P = .2). Clinical recovery by days 3-5 after the start of treatment was 97.9% in the moxifloxacin arm vs. 90.0% in the levofloxacin arm (95% CI, 1.7-14.1; P = .01). In the moxifloxacin group, cure rates were 92.6% for patients with mild or moderate CAP and 94.7% for patients with severe CAP, compared with cure rates of 88.6% and 84.6%, respectively, in the levofloxacin group (P = not significant). Cure rates in the moxifloxacin arm were 90.0% for patients aged 65-74 years and 94.5% for patients aged > or = 75 years, compared with 85.0% and 90.0%, respectively, in the levofloxacin arm (P = not significant). There were no statistically significant differences between the treatment groups with regard to drug-related adverse events. CONCLUSIONS: Intravenous/oral moxifloxacin therapy was efficacious and safe for hospitalized elderly patients with CAP, achieving > 90% cure in all severity and age subgroups, and was associated with faster clinical recovery than intravenous/oral levofloxacin therapy, with a comparable safety profile.

Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i.v. therapy.

To compare the efficacy of sequential i.v. to p.o. moxifloxacin with ceftriaxone +/- azithromycin +/- metronidazole for the treatment of patients with community acquired pneumonia (CAP), a multi-centered, prospective, randomized, open label study was performed. CAP patients were randomized to moxifloxacin (400 mg/d-at least one i.v. dose) or ceftriaxone (at least one dose of 2 g i.v. q.d. followed by cefuroxime 500 mg p.o. b.i.d.) +/- azithromycin, +/- metronidazole (cephalosporin/macrolide control: CMC). The primary endpoint was clinical response at test-of-cure (TOC) visit. Bacteriological response at TOC was the secondary endpoint. Clinical cure was found in 83.3% (90/108) of moxifloxacin patients and 79.6% (90/113) of control patients. Microbiological responses were 81.8% (18/22) for moxifloxacin and 60.7% (17/28) for CMC patients. Drug-related adverse events occurred in 18.0% of moxifloxacin and 16% of CMC patients. It is concluded that i.v. to p.o. moxifloxacin is as effective as CMC for treatment of CAP and is a reliable alternative antimicrobial therapy.

Efficacy and tolerability of moxifloxacin in the treatment of acute bacterial sinusitis caused by penicillin-resistant Streptococcus pneumoniae: a pooled analysis.

BACKGROUND: Penicillin-resistant Streptococcus pneumoniae (PRSP) has become a relatively common pathogen in upper and lower respiratory tract infections, including acute bacterial sinusitis (ABS). OBJECTIVE: The goal of this analysis was to assess the efficacy and tolerability of moxifloxacin in the treatment of ABS caused by penicillin-sensitive S pneumoniae (PSSP) and PRSP METHODS: Two prospective, multicenter, open-label, noncomparative US trials of moxifloxacin were included in this pooled analysis. All patients received oral moxifloxacin 400 mg once daily for 7 to 10 days. Minimum inhibitory concentrations (MICs) of moxifloxacin and penicillin were determined using the E-test and standard broth-microdilution methods. The primary end point was clinical success at the test-of-cure visit (21-37 days after completion of therapy) in patients with a positive pretherapy sinus culture. Data are presented for patients with ABS caused by both PSSP and PRSP RESULTS: Of 806 patients enrolled in the 2 studies, 146 had microbiologically confirmed bacterial infection. Sixty-nine patients had ABS caused by S pneumoniae, including 15 confirmed cases of PRSP infection. The majority of the 69 clinically evaluable patients were white (n = 63) and female (n = 46), and the mean age of this population was 43 years. Investigators categorized the episode of ABS as severe in 26 (37.7%) of clinically evaluable patients and of moderate severity in the remainder (62.3% [43]); however, most patients (78.3% [54/69]) reported >/=1 severe symptom. The episode of ABS was classified as severe in 8 (53.3%) of the 15 patients with PRSP infection. Clinical and bacteriologic success at the test-of-cure visit was achieved in 93.3% (14/15) of patients with PRSP infection, compared with 88.4% (61/69) of all patients infected with S pneumoniae regardless of penicillin susceptibility. Moxifloxacin MICs against the 15 PRSP strains ranged from 0.06 to 0.25 microg/mL. Data from 805 patients were available for tolerability analysis. The most commonly occurring adverse events were nausea, headache, and diarrhea. Generally, adverse events were mild to moderate. None of the 6 serious adverse events reported were considered related to moxifloxacin therapy. CONCLUSION: In this small cohort of patients, moxifloxacin provided clinical and bacteriologic cures in the majority of patients with ABS caused by PRSP, including those with severe sinusitis.

Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers.

AIMS: To evaluate the effect of acute dosing of garlic supplements on the single-dose pharmacokinetics of ritonavir. METHODS: Ten healthy volunteers (five male, five female) were equally randomized in a crossover design to receive 400 mg of a single dose of ritonavir within 10 min after eating breakfast either alone or with 10 mg of Natural Source Odourless Garlic. They received a total of eight doses of garlic extract (2 x 5 mg capsules) taken twice daily for 4 days. Ritonavir and the seventh garlic dose were administered simultaneously. RESULTS: Coadministration of garlic nonsignificantly decreased area under the plasma concentration-time curve (AUC(0, infinity )) by -17% (90% confidence interval (CI), -31% to 0%; range -46% to 68%) and peak plasma concentration of ritonavir by -1% (90% CI, -25% to 31%; range -51% to 136%). CONCLUSIONS: Acute dosing of the garlic capsules over 4 days did not significantly alter the single-dose pharmacokinetics of ritonavir in healthy volunteers. Given the complex effects of both ritonavir and garlic on drug metabolism, the results of our study should not be extrapolated to steady-state conditions, where the possibility of an interaction still needs to be evaluated.