Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials.

OBJECTIVES: The increase in infections caused by drug-resistant ESBL-producing Enterobacteriaceae (ESBL-ENT) is a global concern. The characteristics and outcomes of patients infected with ESBL-ENT were examined in a pooled analysis of Phase 3 clinical trials of ceftolozane/tazobactam in patients with complicated urinary tract infections (ASPECT-cUTI) and complicated intra-abdominal infections (ASPECT-cIAI). METHODS: Trials were randomized and double blind. The ASPECT-cUTI regimen was 7 days of either intravenous ceftolozane/tazobactam (1.5 g) every 8 h or levofloxacin (750 mg) once daily. The ASPECT-cIAI regimen was 4-14 days of either intravenous ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) or meropenem (1 g) every 8 h. Baseline cultures were obtained in both indications. Enterobacteriaceae were selected for ESBL characterization based on predefined criteria and were verified genotypically. Outcomes were assessed at the test-of-cure visit 5-9 days post-therapy in ASPECT-cUTI and 24-32 days post-randomization in ASPECT-cIAI among microbiologically evaluable (ME) patients. RESULTS: Of 2076 patients randomized, 1346 were included in the pooled ME population and 150 of 1346 (11.1%) had ESBL-ENT at baseline. At US FDA/EUCAST breakpoints of ≤2/≤1 mg/L, 81.8%/72.3% of ESBL-ENT (ESBL-Escherichia coli, 95%/88.1%; ESBL-Klebsiella pneumoniae, 56.7%/36.7%) were susceptible to ceftolozane/tazobactam versus 25.3%/24.1% susceptible to levofloxacin and 98.3%/98.3% susceptible to meropenem at CLSI/EUCAST breakpoints. Clinical cure rates for ME patients with ESBL-ENT were 97.4% (76/78) for ceftolozane/tazobactam [ESBL-E. coli, 98.0% (49 of 50); ESBL-K. pneumoniae, 94.4% (17 of 18)], 82.6% (38 of 46) for levofloxacin and 88.5% (23 of 26) for meropenem. CONCLUSIONS: Randomized trial data demonstrated high clinical cure rates with ceftolozane/tazobactam treatment of cIAI and cUTI caused by ESBL-ENT.

Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

BACKGROUND: Fluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Elevated drug concentrations of fluoroquinolones in the urine and therapy with high-dose levofloxacin are believed to overcome resistance and effectively treat infections caused by resistant bacteria. The ASPECT-cUTI phase 3 clinical trial (ClinicalTrials.gov, NCT01345929 and NCT01345955 , both registered April 28, 2011) provided an opportunity to test this hypothesis by examining the clinical and microbiological outcomes of high-dose levofloxacin treatment by levofloxacin minimum inhibitory concentration. METHODS: Patients were randomly assigned 1:1 to ceftolozane/tazobactam (1.5 g intravenous every 8 h) or levofloxacin (750 mg intravenous once daily) for 7 days of therapy. The ASPECT-cUTI study provided data on 370 patients with at least one isolate of Enterobacteriaceae at baseline who were treated with levofloxacin. Outcomes were assessed at the test-of-cure (5-9 days after treatment) and late follow-up (21-42 days after treatment) visits in the microbiologically evaluable population (N = 327). RESULTS: Test-of-cure clinical cure rates above 90% were observed at minimum inhibitory concentrations ≤4 µg/mL. Microbiological eradication rates were consistently >90% at levofloxacin minimum inhibitory concentrations ≤0.06 µg/mL. Lack of eradication of causative pathogens at the test-of-cure visit increased the likelihood of relapse by the late follow-up visit. CONCLUSIONS: Results from this study do not support levofloxacin therapy for complicated urinary tract infections caused by organisms with levofloxacin minimum inhibitory concentrations ≥4 µg/mL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01345929 and NCT01345955.

Hangover sensitivity after controlled alcohol administration as predictor of post-college drinking.

Predicting continued problematic levels of drinking after the early 20's could help with early identification of persons at risk. This study investigated whether hangover insensitivity could predict postcollege drinking and problems beyond the variance due to drinking patterns. In a preliminary study, 134 college seniors from a laboratory study of hangover (Time 1) were contacted and assessed 1-4 years (M = 2.3) later (Time 2). Hangover severity was studied after controlled alcohol administration to a specific dose while controlling sleep and environmental influences. Hangover severity at Time 1 was used to predict Time 2 drinking volume and problems while controlling for relevant demographics and Time 1 drinking volume. Hangover insensitivity at Time 1 tended to predict a clinical level of alcohol problems with a large statistical effect size. Hangover sensitivity also correlated positively with sensitivity to alcohol intoxication. Hangover severity did not predict future drinking volume. Hangover insensitivity correlates with insensitivity to intoxication and might predict more serious alcohol problems in the future, suggesting that a future larger study is warranted. Hangover insensitivity could result from physiological factors underlying low sensitivity to alcohol or risk for alcoholism.

The acute effects of caffeinated versus non-caffeinated alcoholic beverage on driving performance and attention/reaction time.

AIMS: Marketing that promotes mixing caffeinated 'energy' drinks with alcoholic beverages (e.g. Red Bull with vodka) targets young drinkers and conveys the expectation that caffeine will offset the sedating effects of alcohol and enhance alertness. Such beliefs could result in unwarranted risk taking (e.g. driving while intoxicated). The aim of this study was to assess the acute effects of caffeinated versus non-caffeinated alcoholic beverages on a simulated driving task and attention/reaction time. DESIGN: We conducted a 2 × 2 between-groups randomized trial in which participants were randomized to one of four conditions: beer and non-alcoholic beer, with and without caffeine added. Caffeine was added in the same proportion as found in a commercially available caffeinated beer (69 mg/12 oz of beer at 4.8% alc. by vol). PARTICIPANTS: Participants were 127 non-dependent, heavy episodic, young adult drinkers (age 21-30) who were college students or recent graduates. The target breath alcohol level was 0.12 g%. MEASURES: Driving performance was assessed with a driving simulator; sustained attention/reaction with the Psychomotor Vigilance Task (PVT). FINDINGS: Across the driving and attention/reaction time we found main effects for alcohol, with alcohol significantly impairing driving and sustained attention/reaction time, with mainly large statistical effects; however, the addition of caffeine had no main or interaction effects on performance. CONCLUSION: The addition of caffeine to alcohol does not appear to enhance driving or sustained attention/reaction time performance relative to alcohol alone.

The effects of binge drinking on college students' next-day academic test-taking performance and mood state.

AIM: To assess the effects of binge drinking on students' next-day academic test-taking performance. DESIGN: A placebo-controlled cross-over design with randomly assigned order of conditions. Participants were randomized to either alcoholic beverage [mean = 0.12 g% breath alcohol concentration (BrAC)] or placebo on the first night and then received the other beverage a week later. The next day, participants were assessed on test-taking, neurocognitive performance and mood state. PARTICIPANTS: A total of 196 college students (>or=21 years) recruited from greater Boston. SETTING: The trial was conducted at the General Clinical Research Center at the Boston Medical Center. MEASUREMENTS: The Graduate Record Examinations(c) (GREs) and a quiz on a lecture presented the previous day measured test-taking performance; the Neurobehavioral Evaluation System (NES3) and the Psychomotor Vigilance Test (PVT) measured neurocognitive performance; and the Profile of Mood States (POMS) measured mood. FINDINGS: Test-taking performance was not affected on the morning after alcohol administration, but mood state and attention/reaction-time were affected. CONCLUSION: Drinking to a level of 0.12 g% BrAC does not affect next-day test-taking performance, but does affect some neurocognitive measures and mood state.

Hangover Predicts Residual Alcohol Effects on Psychomotor Vigilance the Morning After Intoxication.

OBJECTIVES: Both hangover and performance deficits have been documented the day after drinking to intoxication after breath alcohol concentration (BrAC) has returned to near zero. But few studies have examined the relationship between hangover and post-intoxication performance. METHOD: We performed secondary analyses of data from a previously reported controlled cross-over laboratory study to assess the relationship of hangover incidence and severity to sustained attention/reaction time the morning after drinking to about 0.11 g% BrAC. Relationships were investigated while controlling for gender, type of alcoholic beverage (bourbon or vodka), and neurocognitive performance after placebo. RESULTS: Hangover severity and neurocognitive performance were significantly correlated. Participants reporting stronger hangover were more impaired than those reporting little or no hangover. Comparing any to no hangover showed a trend in the same direction of effect. CONCLUSIONS: More intense hangover may indicate less fitness for duty in workers in certain safety-sensitive occupations, with implications for occupational alcohol policies.