Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.

Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan.

BACKGROUND: Observational studies and fatal case reports raise concern about the safety of severe dysglycemia associated with fluoroquinolone use. The objective of this study was to assess the risk of severe dysglycemia among diabetic patients who received different fluoroquinolones. METHODS: In a population-based inception cohort study of diabetic patients covering the period from January 2006 to November 2007, outpatient new users of levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins, and macrolides orally were identified. Study events were defined as emergency department visits or hospitalization for dysglycemia within 30 days following the initiation of antibiotic therapy. Results were analyzed with adjusted multinomial propensity score. RESULTS: A total of 78 433 diabetic patients receiving the antibiotics of interest were included in the study. The absolute risk of hyperglycemia per 1000 persons was 6.9 for moxifloxacin and 1.6 for macrolides. In contrast, the risk of hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of levofloxacin, ciprofloxacin, and moxifloxacin compared with macrolides were 1.75 (1.12-2.73), 1.87 (1.20-2.93), and 2.48 (1.50-4.12), respectively, for hyperglycemia and 1.79 (1.33-2.42), 1.46 (1.07-2.00), and 2.13 (1.44-3.14), respectively, for hypoglycemia. Patients taking moxifloxacin faced a significantly higher risk of hypoglycemia than those receiving ciprofloxacin. A significant increase in the risk of hypoglycemia was also observed among patients receiving moxifloxacin concomitantly with insulin (AOR, 2.28; 95% CI, 1.22-4.24). CONCLUSIONS: Diabetics using oral fluoroquinolones faced greater risk of severe dysglycemia. The risk of hypoglycemia varied according to the type of fluoroquinolone administered, and was most commonly associated with moxifloxacin.

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.

BACKGROUND: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING: The Global Alliance for TB Drug Development (TB Alliance).

Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial.

PURPOSE: To compare the equivalence of moxifloxacin 0.5% with a combination of fortified cefazolin sodium 5% and tobramycin sulfate 1.3% eye drops in the treatment of moderate bacterial corneal ulcers. DESIGN: Randomized, controlled, equivalence clinical trial. PARTICIPANTS AND CONTROLS: Microbiologically proven cases of bacterial corneal ulcers were enrolled in the study and were allocated randomly to 1 of the 2 treatment groups. INTERVENTION: Group A was given combination therapy (fortified cefazolin sodium 5% and tobramycin sulfate) and group B was given monotherapy (moxifloxacin 0.5%). MAIN OUTCOME MEASURES: The primary outcome variable for the study was percentage of the ulcers healed at 3 months. The secondary outcome variables were best-corrected visual acuity and resolution of infiltrates. RESULTS: Of a total of 224 patients with bacterial keratitis, 114 patients were randomized to group A, whereas 110 patients were randomized to group B. The mean ± standard deviation ulcer size in groups A and B were 4.2 ± 2 and 4.41 ± 1.5 mm, respectively. The prevalence of coagulase-negative Staphylococcus (40.9% in group A and 48.2% in group B) was similar in both the study groups. A complete resolution of keratitis and healing of ulcers occurred in 90 patients (81.8%) in group A and 88 patients (81.4%) in group B at 3 months. The observed percentage of healing at 3 months was less than the equivalence margin of 20%. Worsening of ulcer was seen in 18.2% cases in group A and in 18.5% cases in group B. Mean time to epithelialization was similar, and there was no significant difference in the 2 groups (P = 0.065). No serious events attributable to therapy were reported. CONCLUSIONS: Corneal healing using 0.5% moxifloxacin monotherapy is equivalent to that of combination therapy using fortified cefazolin and tobramycin in the treatment of moderate bacterial corneal ulcers. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation.

AIMS: Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. METHODS: Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. RESULTS: A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. CONCLUSIONS: Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects.

AIMS: Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc ) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc . METHODS: Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. RESULTS: Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml(-1) , 399 ± 11.9 pg ml(-1) and 627 ± 21.2 pg ml(-1) ). QTc P, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTc P (ΔΔQTc P) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml(-1) (ΔΔQTc P(avg) ) was -1.13 [-2.11, -0.15). No correlation was observed between ΔΔQTc P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. CONCLUSIONS: These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: a randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study.

Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (aged 18-45 years) in a randomized crossover design, including 4 treatment sequences of therapeutic cangrelor, supratherapeutic cangrelor, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 ms at all times points and all corresponding upper 2-sided 90% confidence intervals (CIs) were <10 ms. Although moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites, and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers (clinicaltrials.gov; identifier NCT00699504).

Moxifloxacin-associated neutropenia.

A 32-y-old woman presented with pneumonia. Treatment was started with moxifloxacin. On day 2 of moxifloxacin treatment the patient developed neutropenia. After discontinuing the moxifloxacin, neutrophil counts were normal on day 4. Clinicians should be aware of the possibility of this adverse effect in patients treated with moxifloxacin.

Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation.

PURPOSE: Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. METHODS: This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. RESULTS: The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. CONCLUSIONS: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

US-based emergency department visits for fluoroquinolone-associated hypersensitivity reactions.

PURPOSE: To estimate the rate of hypersensitivity reactions per 100,000 prescription dispensings of fluoroquinolones based on care rendered in a nationally representative sample of US hospital emergency departments (ED). METHODS: We analyzed the frequency of fluoroquinolone-associated hypersensitivity reactions using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance system (2004-2010) in conjunction with US retail outpatient prescription data from IMS Health (2004-2010). We further categorized reaction severity into three subgroups (mild, moderate, and severe). RESULTS: Based on 1422 cases of fluoroquinolone-associated hypersensitivity reactions and national drug utilization projections, we estimated risk of hypersensitivity reactions for moxifloxacin, ciprofloxacin, and levofloxacin. The absolute risk of a fluoroquinolone-related hypersensitivity reaction of any severity was low (44.0 (95% CI 34.8-53.3) ED visits/100,000 prescriptions); however, we identified a statistically significant difference in the relative risk (rate ratios) of seeking care in an ED attributed to moxifloxacin hypersensitivity compared to either levofloxacin or ciprofloxacin. For all reaction severities, the estimated ED visits/100,000 prescriptions were 141.3 (95% CI 99.9-182.7) for moxifloxacin, 40.8 (95% CI 31.5-50.0) for levofloxacin, and 26.3 (95% CI 20.8-31.9) for ciprofloxacin. When the rates were stratified by reaction severity category (mild or moderate-severe), moxifloxacin continued to be implicated in more ED visits per 100,000 prescriptions dispensed than either levofloxacin or ciprofloxacin. CONCLUSION: Fluoroquinolones may cause hypersensitivity reactions requiring care in an ED, and relative to use, the rate of moxifloxacin-related hypersensitivity reactions is higher compared to levofloxacin or ciprofloxacin.

Sequential intravenous/oral moxifloxacin monotherapy for complicated skin and skin structure infections: a meta-analysis of randomised controlled trials.

OBJECTIVES: The presumed superiority of moxifloxacin for the treatment of complicated skin and skin structure infections (cSSSIs) is based on laboratory data, but has not yet been established on clinical grounds. The aim of this meta-analysis was to evaluate the efficacy and safety of sequential intravenous (i.v.)/oral (p.o.) moxifloxacin monotherapy for the treatment of cSSSIs. METHODS: Randomised controlled trials (RCTs) published prior to November 2012 were systematically retrieved from PubMed, MEDLINE, EMBASE, ScienceDirect, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials. Finally, a meta-analysis of all RCTs eligible for inclusion criteria was performed. RESULTS: Three studies that enrolled 2255 patients were included in the meta-analysis. There were no statistically significant differences between patients given moxifloxacin and those given other antibiotics with regard to clinical success rate [1667 patients, odds ratio (OR) = 0.83, 95% confidence interval (CI) 0.63 to 1.09, p = 0.18], bacteriological success rate (bacteriological success rates: 1502 patients, OR = 0.90, 95% CI 0.68-1.18, p = 0.45) or mortality (2207 patients, OR = 1.96, 95% CI 0.79-4.88, p = 0.15). Significantly, more overall adverse events (AEs) were associated with the use of moxifloxacin than with other antibiotics (2207 patients, OR = 1.21, 95%CI 1.00-1.45, p = 0.04). However, there was no statistically significant difference in the occurrence of drug-related AEs, serious AEs or serious drug-related AEs between patients given moxifloxacin and those given other antibiotics. CONCLUSION: Sequential i.v./p.o. moxifloxacin monotherapy is an effective and relatively safe option for the treatment of cSSSIs. Other benefits of moxifloxacin may make it a more viable option compared with the currently used regimens.

Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis: a prospective, multicenter, observational study (AVANTI).

BACKGROUND: Acute exacerbations of chronic bronchitis (AECB), including chronic obstructive pulmonary disease (AECOPD), represent a substantial patient burden. Few data exist on outpatient antibiotic management for AECB/AECOPD in Eastern/South Eastern Europe, in particular on the use of moxifloxacin (Avelox®), although moxifloxacin is widely approved in this region based on evidence from international clinical studies. METHODS: AVANTI (AVelox® in Acute Exacerbations of chroNic bronchiTIs) was a prospective, observational study conducted in eight Eastern European countries in patients > 35 years with AECB/AECOPD to whom moxifloxacin was prescribed. In addition to safety and efficacy outcomes, data on risk factors and the impact of exacerbation on daily life were collected. RESULTS: In the efficacy population (N = 2536), chronic bronchitis had been prevalent for > 10 years in 31.4% of patients and 66.0% of patients had concomitant COPD. Almost half the patients had never smoked, in contrast to data from Western Europe and the USA, where only one-quarter of COPD patients are non-smokers. The mean number of exacerbations in the last 12 months was 2.7 and 26.3% of patients had been hospitalized at least once for exacerbation. Physician compliance with the recommended moxifloxacin dose (400 mg once daily) was 99.6%. The mean duration of moxifloxacin therapy for the current exacerbation (Anthonisen type I or II in 83.1%; predominantly type I) was 6.4 ± 1.9 days. Symptom improvement was reported after a mean of 3.4 ± 1.4 days. After 5 days, 93.2% of patients reported improvement and, in total, 93.5% of patients were symptom-free after 10 days. In the safety population (N = 2672), 57 (2.3%) patients had treatment-emergent adverse events (TEAEs) and 4 (0.15%) had serious TEAEs; no deaths occurred. These results are in line with the known safety profile of moxifloxacin. CONCLUSIONS: A significant number of patients in this observational study had risk factors for poor outcome, justifying use of moxifloxacin. The safety profile of moxifloxacin and its value as an antibiotic treatment were confirmed. Physicians complied with the recommended 400 mg once-daily dose in a large proportion of patients, confirming the advantages of this simple dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846911.

[Fluoroquinolone associated myasthenia gravis exacerbation: clinical analysis of 9 cases].

OBJECTIVE: To explore the characteristics of acute exacerbations of myasthenia gravis after fluoroquinolone exposure. METHODS: Gender, age, prior type, absolute score, concurrent disease, precipitated disease, use of antibiotic, onset/symptom/degree of exacerbation, therapeutic measures and prognosis at Month 1 were retrospectively analyzed for 9 patients after fluoroquinolone systemic exposure. RESULTS: Ciprofloxacin (n = 4), levofloxacin (n = 1) and moxifloxacin (n = 4) exposure resulted in myasthenia gravis exacerbation. Myasthenia gravis exacerbations developed at 15 minutes to 4 days post-exposure. And the clinical scores of quantitative myasthenia gravis (QMG) increased by an average of 10. The main syndromes included dyspnea, diplopia, ptosis and dysphagia. All patients improved upon the withdrawal of fluoroquinolone in conjunctions with other interventions. CONCLUSION: Fluoroquinolone exposure may result in myasthenia gravis exacerbations in patients with underlying diseases. Healthcare professionals should be aware of this serious drug-disease association.

[Efficacy and safety of moxifloxacin in patients with nursing and healthcare-associated pneumonia].

Moxifloxacin (MFLX) is a respiratory quinolone, and is effective against not only Gram-positive and negative bacteria but also anaerobes. There has been no prospective studies evaluating the efficacy and safety of MFLX in patients with nursing and healthcare-associated pneumonia (NHCAP). Therefore, we assessed the efficacy and safety of MFLX in patients with NHCAP. NHCAP patients with mild and moderate severity assessed by the A-DROP system in community-acquired pneumonia guideline proposed by Japan Respiratory Society visited our hospitals from April 2011 to March 2012. Clinical symptoms, chest X-ray films and/or computed tomography, peripheral white and red blood cell and platelet counts, serum CRP, AST, ALT, BUN, creatinine were evaluated. Forty patients were eventually evaluated, and average age was 74.1 years old, male/female were 21/19, 92.5% (37/40) of them had one or more comorbidities. Median duration of MFLX administration was 7.1 days (4-15 days). The efficacy of MFLX in all patients was 87.5% (35/40). The efficacies in each age group were 87.9% (aged over 65 years old), 85.7% (aged under 64 years old), and in each pneumonia severity group by the A-DROP system were 91.7% (mild), 85.7% (moderate). Diarrhea and swelling of the breast were observed in one patient (2.5%) after starting MFLX administration. Mild elevated transaminases were observed in three patients (7.5%), and mild renal dysfunction was observed in two patients (5.0%). All abnormally increased levels of transaminases and serum creatinine were recovered after a cessation of MFLX. MFLX is effective and safe in patients with NHCAP.

Moxifloxacin versus amoxicillin/clavulanic acid in outpatient acute exacerbations of COPD: MAESTRAL results.

Bacterial infections causing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) frequently require antibacterial treatment. More evidence is needed to guide antibiotic choice. The Moxifloxacin in Acute Exacerbations of Chronic Bronchitis TriaL (MAESTRAL) was a multiregional, randomised, double-blind non-inferiority outpatient study. Patients were aged ≥ 60 yrs, with an Anthonisen type I exacerbation, a forced expiratory volume in 1 s < 60% predicted and two or more exacerbations in the last year. Following stratification by steroid use patients received moxifloxacin 400 mg p.o. q.d. (5 days) or amoxicillin/clavulanic acid 875/125 mg p.o. b.i.d. (7 days). The primary end-point was clinical failure 8 weeks post-therapy in the per protocol population. Moxifloxacin was noninferior to amoxicillin/clavulanic acid at the primary end-point (111 (20.6%) out of 538, versus 114 (22.0%) out of 518, respectively; 95% CI -5.89-3.83%). In patients with confirmed bacterial AECOPD, moxifloxacin led to significantly lower clinical failure rates than amoxicillin/clavulanic acid (in the intent-to-treat with pathogens, 62 (19.0%) out of 327 versus 85 (25.4%) out of 335, respectively; p=0.016). Confirmed bacterial eradication at end of therapy was associated with higher clinical cure rates at 8 weeks post-therapy overall (p=0.0014) and for moxifloxacin (p=0.003). Patients treated with oral corticosteroids had more severe disease and higher failure rates. The MAESTRAL study showed that moxifloxacin was as effective as amoxicillin/clavulanic acid in the treatment of outpatients with AECOPD. Both therapies were well tolerated.

Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine.

OBJECTIVES: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients. PATIENTS AND METHODS: A retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory. RESULTS: Linezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up. CONCLUSIONS: The combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.

No evidence of QT prolongation with supratherapeutic doses of aleglitazar.

Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist in clinical development, designed to offer a balanced activation of PPAR-α and PPAR-γ. A phase 2 trial has demonstrated improvements in dyslipidemia and glycemic control and reduction of cardiovascular risk markers in patients with type 2 diabetes mellitus treated with aleglitazar. This study evaluated whether supratherapeutic doses of aleglitazar affect cardiac repolarization, as detected by changes in the QT interval.Healthy subjects were randomized to receive single oral doses of placebo, 300 µg aleglitazar, 3000 µg aleglitazar, and 400 mg moxifloxacin, in 1 of 4 sequences. Triplicate 12-lead electrocardiogram measurements were recorded predose and regularly (0.75-72 hours) after each treatment. The primary outcome was measurement of QT interval using a study-specific correction factor for heart rate.Administration of aleglitazar (300 µg and 3000 µg) did not cause any significant QT prolongation and after aleglitazar treatment any mean increases from placebo were <5 msec, at all time points. There was a trend for aleglitazar to cause a small dose-dependent decrease in QT interval using a study-specific correction factor for heart rate. The incidence of adverse events was similar with aleglitazar (18%-20%) and placebo (26%).Single supratherapeutic doses of aleglitazar are not associated with prolongation of the QT interval corrected for heart rate.

Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study.

BACKGROUND: Although fluoroquinolones are sometimes associated with mild, transient elevations in aminotransferase levels, serious acute liver injury is uncommon. Regulatory warnings have identified moxifloxacin as presenting a particular risk of hepatotoxicity. Thus, we examined the risk of idiosyncratic acute liver injury associated with the use of moxifloxacin relative to other selected antibiotic agents. METHODS: We conducted a population-based, nested, case-control study using health care data from Ontario for the period April 2002 to March 2011. We identified cases as outpatients aged 66 years or older with no history of liver disease, and who were admitted to hospital for acute liver injury within 30 days of receiving a prescription for 1 of 5 broad-spectrum antibiotic agents: moxifloxacin, levofloxacin, ciprofloxacin, cefuroxime axetil or clarithromycin. For each case, we selected up to 10 age- and sex-matched controls from among patients who had received a study antibiotic, but who were not admitted to hospital for acute liver injury. We calculated odds ratios (ORs) to determine the association between admission to hospital and previous exposure to an antibiotic agent, using clarithromycin as the reference. RESULTS: A total of 144 patients were admitted to hospital for acute liver injury within 30 days of receiving a prescription for one of the identified drugs. Of these patients, 88 (61.1%) died while in hospital. After multivariable adjustment, use of either moxifloxacin (adjusted OR 2.20, 95% confidence interval [CI] 1.21-3.98) or levofloxacin (adjusted OR 1.85, 95% CI 1.01-3.39) was associated with an increase in risk of acute liver injury relative to the use of clarithromycin. We saw no such risk associated with the use of either ciprofloxacin or cefuroxime axetil. INTERPRETATION: Among older outpatients with no evidence of liver disease, moxifloxacin and levofloxacin were associated with an increased risk of acute liver injury relative to clarithromycin.

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.

OBJECTIVE: Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI). METHODS: Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points. RESULTS: A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec. CONCLUSION: Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.