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Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

ABSTRACT: The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure.To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures.This secondary analysis of a double-masked, multicenter, randomized clinical trial included patients with culture- or smear-positive filamentous fungal corneal ulcer and a baseline visual acuity of 20/40 to 20/400. Culture-positive samples with susceptibility testing were included in this analysis. The patients were treated at multiple locations of the Aravind Eye Care Hospital system in South India. Data were collected from April 3, 2010, to December 31, 2011, and analyzed from July 15 to September 1, 2015.Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen.Minimum inhibitory concentration of voriconazole and natamycin in baseline cultures.Of 323 participants with smear-positive specimens (183 men [56.7%]; 140 women [43.3%]; median [interquartile range] age, 47 [38-56] years), fungal-positive cultures were obtained for 256 (79.3%). The MIC data were available for 221 of 323 participants (68.4%), because 35 samples had no growth during susceptibility testing. A 2.14-fold increase per year (95% CI, 1.13-4.56; P?=?.02) in voriconazole MICs after controlling for the infectious organism was found. This association was not found when looking at natamycin MICs of baseline cultures after controlling for the infectious organism (1.26; 95% CI, 0.13-12.55; P?=?.85).Susceptibility to voriconazole appeared to decrease during the relatively short enrollment period of the clinical trial. This decrease may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, because presenting with azole treatment was not a risk factor for resistance.clinicaltrials.gov Identifier: NCT00996736.

SUBMITTER: Prajna NV

PROVIDER: S-EPMC4962688 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

Prajna N Venkatesh NV Lalitha Prajna P Rajaraman Revathi R Krishnan Tiruvengada T Raghavan Anita A Srinivasan Muthiah M O'Brien Kieran S KS Zegans Michael M McLeod Stephen D SD Acharya Nisha R NR Keenan Jeremy D JD Lietman Thomas M TM Rose-Nussbaumer Jennifer J

JAMA ophthalmology 20160601 6

<h4>Importance</h4>The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure.<h4>Objective</h4>To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures.<h4>Design, setting, and participants</h4>This secondary analysis of a double-masked, multicente ...[more]

PMID: 27054515

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Project description:To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis.The Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis.Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%.The primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use.A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P?=?.29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Šidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P?=?.03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P?<?.001 after Holms-Šidák correction for multiple comparisons).There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world.clinicaltrials.gov Identifier: NCT00996736.

Project description:ImportanceStatins decrease levels of low-density lipoprotein (LDL) and triglycerides as well as cardiovascular events but increase the risk for a diagnosis of type 2 diabetes mellitus (T2DM). The risk factors associated with incident T2DM are incompletely characterized.ObjectiveTo investigate the association of lipoprotein subclasses and size and a novel lipoprotein insulin resistance (LPIR) score (a composite of 6 lipoprotein measures) with incident T2DM among individuals randomized to a high-intensity statin or placebo.Design, setting, and participantsThis secondary analysis of the JUPITER trial (a placebo-controlled randomized clinical trial) was conducted at 1315 sites in 26 countries and enrolled 17 802 men 50 years or older and women 60 years or older with LDL cholesterol levels less than 130 mg/dL, high-sensitivity C-reactive protein levels of at least 2 mg/L, and triglyceride levels less than 500 mg/dL. Those with T2DM were excluded. A prespecified secondary aim was to assess the effect of rosuvastatin calcium on T2DM. Incident T2DM was monitored for a median of 2.0 years. Data were collected from February 4, 2003, to August 20, 2008, and analyzed (intention-to-treat) from December 1, 2013, to January 21, 2016.InterventionsRosuvastatin calcium, 20 mg/d, or placebo.Main outcomes and measuresSize and concentration of lipids, apolipoproteins, and lipoproteins at baseline (11 918 patients with evaluable plasma samples) and 12 months after randomization (9180 patients). The LPIR score, a correlate of insulin resistance, was calculated as a weighted combination of size and concentrations of LDL, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) particles.ResultsAmong the 11 918 patients (4334 women [36.4%]; median [interquartile range] age, 66 [60-71] years), rosuvastatin lowered the levels of LDL particles (-39.6%; 95% CI, -49.4% to -24.6%), VLDL particles (-19.6%; 95% CI, -40.6% to 10.3%), and VLDL triglycerides (-15.2%; 95% CI, -35.9% to 11.3%) and shifted the lipoprotein subclass distribution toward smaller LDL size (-1.5%; 95% CI, -3.7% to 0.5%), larger VLDL size (2.8%; 95% CI, -5.8% to 12.7%), and lower LPIR score (-3.2%; 95% CI, -20.6% to 16.9%). In analyses adjusted for age, sex, race or ethnic origin, exercise, educational level, family history, and smoking, the hazard ratio (HR) for T2DM per SD of LPIR score in the placebo arm was 1.99 (95% CI, 1.64-2.42); in the rosuvastatin arm, 2.06 (95% CI, 1.74-2.43). After additional adjustment for systolic blood pressure, body mass index, high-sensitivity C-reactive protein, hemoglobin A1c, HDL cholesterol, LDL cholesterol, and triglycerides, the LPIR score remained associated with T2DM in the placebo arm (HR, 1.35; 95% CI, 1.03-1.76) and rosuvastatin arm (HR, 1.60; 95% CI, 1.27-2.03). Similar trends were seen at 12 months. The LPIR score improved the model likelihood ratio (χ2 = 18.23; P < .001) and categorical net reclassification index (0.039; 95% CI, 0.003-0.072).Conclusions and relevanceIn apparently healthy people, LPIR score was positively associated with incident T2DM, including during rosuvastatin therapy.Trial registrationclinicaltrials.gov Identifier: NCT00239681.

Project description:Importance:Photoaging, which is premature skin aging caused by long-term UV exposure, is of aesthetic concern to many patients. Objective:To investigate the effect of topical fluorouracil, 5%, cream on photoaging using validated photonumeric scales. Design, Setting, and Participants:The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized clinical trial of 932 US veterans with a recent history of 2 or more keratinocyte carcinomas performed from September 30, 2011, through June 30, 2014, to assess the chemopreventive effects of a standard course of topical fluorouracil. Photographs were taken at baseline and at numerous time points for up to 4 years. In our secondary analysis, 2 independent dermatologists graded these photographs using 4 validated photonumeric scales. A total of 3042 photographs from 281 participants randomized to apply topical fluorouracil or placebo were evaluated at baseline, 6 months, 12 months, and 18 months using 4 photonumeric scales (Griffiths scale, Allergan forehead lines scale, melomental folds scale, and crow's feet scale). Data analysis was performed from November 1, 2016, to January 1, 2017. Interventions:Participants were randomized to apply topical fluorouracil, 5%, cream or a vehicle control cream to the face and ears twice daily for 2 to 4 weeks for a total of 28 to 56 doses. Main Outcomes and Measures:Effect of a standard course of fluorouracil on the extent of photodamage as measured using 4 photonumeric scales. Results:The study population was predominantly male (274 [97.5%]) and white (281 [100%]), with a mean (SD) age of 71.5 (0.57) years. No statistically significant changes were found in photodamage between baseline and 6 months (Griffiths scale: ?2?=?0.01, P?=?.93; Allergan forehead lines scale: ?2?=?0.18, P?=?.67; melomental fold scale: ?2?=?0.03, P?=?.87; crow's feet scale: ?2?=?2.41, P?=?.12), 12 months (Griffiths scale: ?2?=?1.39, P?=?.24; Allergan forehead lines scale: ?2?=?0.64, P?=?.43; melomental fold scale: ?2?=?0.12, P?=?.73; crow's feet scale: ?2?=?1.07, P?=?.30), and 18 months (Griffiths scale: ?2?=?3.11, P?=?.08; Allergan forehead lines scale: ?2?=?0.89, P?=?.34; melomental fold scale: ?2?=?1.64, P?=?.20; crow's feet scale: ?2?=?0.46, P?=?.50). Conclusions and Relevance:This study did not demonstrate improvement in photoaging with a standard course of topical fluorouracil, 5%, cream, a finding that may be attributable to a true lack of effect in photodamage or limitations of the photonumeric scales in capturing the effect. The development of photonumeric scales that include manifestations of photoaging other than rhytids, such as lentigines, hyperpigmentation, and telangiectasias, should be considered. Trial Registration:clinicaltrials.gov Identifier: NCT00847912.

Project description:BackgroundMultiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)" study, which aimed to improve rates of intravenous thrombolysis in Australia.MethodsA posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups.ResultsThere was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-and post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56-2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active- (odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52).ConclusionThe TIPS multi-component implementation approach was not effective in reducing the odds of post-treatment severe disability at 90 days, or post-thrombolysis hemorrhage.Trial registrationClinical Trial Registration-URL: http://www.anzctr.org.au/ Unique Identifier: ACTRN12613000939796 .

Project description:ImportanceEpicardial and pericardial adipose tissues are emerging as important risk factors for cardiovascular disease, and there is a growing interest in discovering strategies to reduce the accumulation of fat in these depots.ObjectiveTo investigate whether a 12-week endurance or resistance training intervention regulates epicardial and pericardial adipose tissue mass.Design, setting, and participantsSecondary analysis of a randomized, assessor-blinded clinical trial initiated on August 2016 and completed April 2018. This single-center, community-based study included 50 physically inactive participants with abdominal obesity.InterventionsParticipants were randomized to a supervised high-intensity interval endurance training (3 times a week for 45 minutes), resistance training (3 times a week for 45 minutes), or no exercise (control group).Main outcomes and measuresChange in epicardial and pericardial adipose tissue mass assessed by magnetic resonance imaging, based on a prespecified secondary analysis plan including 3 of 5 parallel groups.ResultsOf 50 participants (mean [SD] age, 41 [14] years, 10 men [26%]; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32 [5]), 39 [78%] completed the study. Endurance training and resistance training reduced epicardial adipose tissue mass by 32% (95% CI, 10%-53%) and 24% (95% CI, 1%-46%), respectively, compared with the no exercise control group (56% [95% CI, 24%-88%]; P = .001 and 48% [95% CI, 15%-81%]; P < .001, respectively). While there was a nonsignificant reduction in pericardial adipose tissue mass after endurance training (11% [95% CI, -5% to 27%]; P = .17), resistance training significantly reduced pericardial adipose tissue mass by 31% (95% CI, 16%-47%; P < .001) when compared with the no exercise control group. Compared with the no exercise control group, there was an increase in left ventricular mass by endurance (20 g [95% CI, 11%-30%]; P < .001) and resistance training (18 g [95% CI, 8%-28%]; P < .001). Other cardiometabolic outcomes remained unchanged after the 12-week trial period.Conclusions and relevanceIn individuals with abdominal obesity, both endurance and resistance training reduced epicardial adipose tissue mass, while only resistance training reduced pericardial adipose tissue mass. These data highlight the potential preventive importance of different exercise modalities as means to reduce cardiac fat in individuals with abdominal obesity.Trial registrationClinicalTrials.gov identifier: NCT02901496.

Project description:ImportanceInterventions that improve clinician performance through feedback should not contribute to job dissatisfaction or staff turnover. Measurement of job satisfaction may help identify interventions that lead to this undesirable consequence.ObjectiveTo evaluate whether mean job satisfaction was less than the margin of clinical significance among clinicians who received social norm feedback (peer comparison) compared with clinicians who did not.Design, setting, and participantsThis secondary, preregistered, noninferiority analysis of a cluster randomized trial compared 3 interventions to reduce inappropriate antibiotic prescribing in a 2 × 2 × 2 factorial design from November 1, 2011, to April 1, 2014. A total of 248 clinicians were enrolled from 47 clinics. The sample size for this analysis was determined by the number of nonmissing job satisfaction scores from the original enrolled sample, which was 201 clinicians from 43 clinics. Data analysis was performed from October 12 to April 13, 2022.InterventionsFeedback comparing individual clinician performance to top-performing peers, delivered in monthly emails (peer comparison).Main outcomes and measuresThe primary outcome was a response to the following statement: "Overall, I am satisfied with my current job." Responses ranged from 1 (strongly disagree) to 5 (strongly agree).ResultsA total of 201 clinicians (response rate, 81%) from 43 of the 47 clinics (91%) provided a survey response about job satisfaction. Clinicians were primarily female (n = 129 [64%]) and board certified in internal medicine (n = 126 [63%]), with a mean (SD) age of 48 (10) years. The clinic-clustered difference in mean job satisfaction was greater than -0.32 (β = 0.11; 95% CI, -0.19 to 0.42; P = .46). Therefore, the preregistered null hypothesis that peer comparison is inferior by resulting in at least a 1-point decrease in job satisfaction by 1 in 3 clinicians was rejected. The secondary null hypothesis that job satisfaction was similar among clinicians randomized to social norm feedback was not able to be rejected. The effect size did not change when controlling for other trial interventions (t = 0.08; P = .94), and no interaction effects were observed.Conclusions and relevanceIn this secondary analysis of a randomized clinical trial, peer comparison did not lead to lower job satisfaction. Features that may have protected against dissatisfaction include clinicians' agency over the performance measure, privacy of individual performance, and allowing all clinicians to achieve top performance.Trial registrationClinicalTrials.gov Identifiers: NCT05575115 and NCT01454947.

Dataset Information

Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

Publications

Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

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