Trends of Antimicrobial Resistance and Combination Susceptibility Testing of Multidrug-Resistant Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients: a 10-Year Update.

Antimicrobial combination therapy is a time/resource-intensive procedure commonly employed in the treatment of cystic fibrosis (CF) pulmonary exacerbations caused by Pseudomonas aeruginosa Ten years ago, the most promising antimicrobial combinations were proposed, but there has since been the introduction of new ß-lactam plus ß-lactamase inhibitor antimicrobial combinations. The aims of this study were to (i) compare in vitro activity of these new antimicrobials with other antipseudomonal agents and suggest their most synergistic antimicrobial combinations and (ii) determine antimicrobial resistance rates and study inherent trends of antimicrobials over 10 years. A total of 721 multidrug-resistant P. aeruginosa isolates from 183 patients were collated over the study period. Antimicrobial susceptibility and combination testing were carried out using the Etest method. The results were further assessed using the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI). Resistance to almost all antimicrobial agents maintained a similar level during the studied period. Colistin (P < 0.001) and tobramycin (P = 0.001) were the only antimicrobials with significant increasing isolate susceptibility, while an increasing resistance trend was observed for levofloxacin. The most active antimicrobials were colistin, ceftolozane-tazobactam, ceftazidime-avibactam, and gentamicin. All combinations with ß-lactam plus ß-lactamase inhibitors produced some synergistic results. Ciprofloxacin plus ceftolozane-tazobactam (40%) and amikacin plus ceftazidime (36.7%) were the most synergistic combinations, while colistin combinations gave the best median SBPI (50.11). This study suggests that effective fluoroquinolone stewardship should be employed for CF patients. It also presents in vitro data to support the efficacy of novel combinations for use in the treatment of chronic P. aeruginosa infections.

Longitudinal Surveillance and Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Achromobacter Species from Cystic Fibrosis Patients.

Achromobacter spp. are recognized as emerging pathogens in patients with cystic fibrosis (CF). Though recent works have established species-level identification using nrdA sequencing, there is a dearth in knowledge relating to species-level antimicrobial susceptibility patterns and antimicrobial combinations, which hampers the use of optimal antimicrobial combinations for the treatment of chronic infections. The aims of this study were to (i) identify at species-level referred Achromobacter isolates, (ii) describe species-level antimicrobial susceptibility profiles, and (iii) determine the most promising antimicrobial combination for chronic Achromobacter infections. A total of 112 multidrug-resistant (MDR) Achromobacter species isolates from 39 patients were identified using nrdA sequencing. Antimicrobial susceptibility and combination testing were carried out using the Etest method. We detected six species of Achromobacter and found that Achromobacter xylosoxidans was the most prevalent species. Interestingly, sequence analysis showed it was responsible for persistent infection (18/28 patients), followed by Achromobacter ruhlandii (2/3 patients). Piperacillin-tazobactam (70.27%) and co-trimoxazole (69.72%) were the most active antimicrobials. Differences were observed in species-level susceptibility to ceftazidime, carbapenems, ticarcillin-clavulanate, and tetracycline. Antimicrobial combinations with co-trimoxazole or tobramycin demonstrate the best synergy, while co-trimoxazole gave the best susceptibility breakpoint index values. This study enriches the understanding of MDR Achromobacter spp. epidemiology and confirms prevalence and chronic colonization of A. xylosoxidans in CF lungs. It presents in vitro data to support the efficacy of new combinations for use in the treatment of chronic Achromobacter infections.

Withdrawal Symptoms and Nicotine Dependence Severity Predict Virtual Reality Craving in Cigarette-Deprived Smokers.

INTRODUCTION: Virtual reality (VR) has been shown to be effective in eliciting responses to nicotine cues in cigarette smokers. The primary aim of this study was to investigate whether cigarette-deprived smokers would exhibit increased craving and changes in heart rate when viewing cigarette related cues as compared to non-smoking cues in a VR environment, and the secondary aim was to assess the extent to which self-assessed measures of withdrawal and dependence correlated with VR craving. METHODS: Nicotine-dependent cigarette smokers were recruited for a 2 day study. On Day 1, participants smoked as usual and on Day 2 were deprived from smoking overnight. On both days, participants completed self-assessment questionnaires on withdrawal, craving, and nicotine-dependence. Participants completed a VR session during the cigarette deprivation condition only (Day 2). During this session, they were exposed to active smoking and placebo (non-smoking) cues. RESULTS: The data show that self-reported levels of "craving" (p < .01) and "thinking about cigarettes" (p < .0001) were significantly greater after exposure to the active cues versus non-smoking cues. Significant increases in heart rate were found for 3 of 4 active cues when compared to non-smoking cues (p < .05). Finally, significant positive correlations were found between self-reported craving prior to the VR session and craving induced by active VR cues (p < .01). CONCLUSIONS: In this report, active VR cues elicited craving during cigarette deprivation. This is the first study to demonstrate that self-reported craving, withdrawal symptoms, and nicotine dependence severity predict cue-induced craving in the VR setting.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.

Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.

BACKGROUND: Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. OBJECTIVE: The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). METHODS: A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. RESULTS: Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. CONCLUSION: Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. CLINICAL TRIAL REGISTRATION: TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Evaluation of a smartphone photoscreening app to detect refractive amblyopia risk factors in children aged 1-6 years.

PURPOSE: To determine the specificity and sensitivity of a smartphone app (GoCheckKids [GCK] used as a photoscreening tool on the iPhone 7 to detect refractive amblyopia risk factors in children aged 1-6 years. PARTICIPANTS AND METHODS: A prospective, multicenter, 10-month evaluation of children aged 1-6 years old who underwent photoscreening with the GCK app to detect amblyopia risk factors. The first acceptable quality photograph of each study subject was evaluated by trained technicians using GCK's proprietary automated image processing algorithm to analyze for amblyopia risk factors. Trained graders, masked to the cycloplegic clinical data, remotely reviewed photographs taken with the app and compared results to the gold standard pediatric ophthalmology examinations using the 2013 American Association for Pediatric Ophthalmology & Strabismus amblyopia risk factor guidelines. Primary outcome was the ability of the GCK app to identify amblyopia risk factors compared to the cycloplegic refraction. RESULTS: There were 287 patient images analyzed. The overall sensitivity and specificity in detecting amblyopia risk factors were 76% and 85%, respectively using manual grading. The overall automated grading results had a sensitivity and sensitivity in detecting amblyopia risk factors of 65% and 83%, respectively. CONCLUSION: The GCK smartphone app is a viable photoscreening device for the detection of amblyopia risk factors in children aged 1-6 years.

Evaluating the safe living guide: a home hazard checklist for seniors.

PURPOSE: The purpose of this study was to evaluate the utility and reliability of a home hazard checklist published in Health Canada, The Safe Living Guide: A Guide to Home Safety for Seniors (2003). METHODS: 76 community-dwelling seniors evaluated the guide, and inter-rater reliability was determined through comparison of ratings of seniors and experts. RESULTS: Findings revealed that seniors found The Safe Living Guide useful in helping them identify hazards. On the majority of items in the checklist, agreement between raters was moderate to almost perfect, with an overall reliability of 0.509. PRACTICE IMPLICATIONS: This guide can be used with confidence by seniors and community-based caregivers for evaluating hazards and identifying opportunities in order to support and prolong safe, independent living in the community.

Dietary genistein stimulates anion secretion across female murine intestine.

Genistein, a naturally occurring isoflavone, augments in vitro epithelial anion transport via activation of the cystic fibrosis transmembrane conductance regulator chloride channel. In this study, we examined whether chronic dietary exposure to 600 mg/kg genistein (600 G) for 1 mo would stimulate anion secretion across wild-type (Wt, normal) murine intestine. Anion secretion was assessed in freshly excised segments of murine jejuna by measuring short circuit current (I(sc)) and comparing with jejunal segments from mice fed 0 mg/kg genistein (0 G). Basal and forskolin-stimulated anion secretions were augmented (P < 0.05) in female but not in male mice fed 600 G, compared with their counterparts fed 0 G. Serum genistein concentrations were greater in both female and male mice fed 600 G (approximately 3.5-6.9 micromol/L) than those fed 0 G (approximately 100 nmol/L). Anion substitution experiments and bumetanide-sensitivity demonstrated that chloride was the major anion mediating the increased secretion. A smaller bicarbonate component was not augmented by consumption of the genistein diet. These data indicate that chronic exposure to dietary genistein stimulates a sex-dependent increase in basal and forskolin-stimulated chloride secretion across murine intestine.