Beta-lactam antibiotic concentrations in critically ill patients with standard and adjusted dosages: A prospective observational study.

INTRODUCTION: Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and those with bacterial species with intermediate susceptibility. The aim of this study was to investigate the variation of antibiotic concentration in critically ill patients with standard or adjusted dosing regimens. METHODS: The concentration of three beta-lactam antibiotics used in the intensive care unit (ICU) setting, cefotaxime, piperacillin/tazobactam, and meropenem, was measured in patients with confirmed or suspected infection. Mid-dose and trough values were collected during a single dosing interval. The pharmacokinetic endpoints were a free antibiotic concentration that, during the whole dosing interval, was above MIC (100% ƒT > MIC, primary endpoint) or above four times MIC (100% ƒT > 4MIC, secondary endpoint). Non-species related MIC breakpoints were used (1 mg/L for cefotaxime, 8 mg/L for piperacillin/tazobactam, and 2 mg/L for meropenem). RESULTS: We included 102 patients (38 cefotaxime, 30 piperacillin/tazobactam, and 34 meropenem) at a single ICU, with a median age of 66 years. In total, 73% were males, 40% were obese (BMI ≥30) and the median SAPS 3 score was 63 points. Of all patients, 78 patients (76%) reached the primary endpoint (100%ƒT > MIC), with 74% for cefotaxime, 67% for piperacillin/tazobactam and 88% for meropenem. Target attainment for 100% ƒT > 4MIC was achieved in 40 (39%) patients, overall, with 34% for cefotaxime, 30% for piperacillin/tazobactam and 53% for meropenem. In patients with standard dose 71% attained 100%ƒT > MIC and 37% for 100%ƒT > 4MIC. All patients with reduced dose attained 100%ƒT > MIC and 27% attained 100% ƒT > 4MIC. In patients with increased dose 79% attained 100%ƒT > MIC and 48% 100%ƒT > 4MIC respectively. CONCLUSIONS: Beta-lactam antibiotics concentration vary widely in critically ill patients. The current standard dosing regimens employed during the study were not sufficient to reach 100% ƒT > MIC in approximately a quarter of the patients. In patients where dose adjustment was performed, the group with increased dose also had low target attainment, as opposed to patients with dose reduction, who all reached target. This suggests the need for further individualization of dosing where therapeutic drug monitoring can be an alternative to further increase target attainment.

Clinical outcomes in combination versus mono antibiotic therapy in ICU admitted patients with a suspected infection - A substudy of the DIANA study.

PURPOSE: In a retrospective cohort study of intensive care unit (ICU) admitted adult patients with suspected or confirmed infection, associations between combination versus mono empirical antibiotic therapy and clinical cure at day 7 as well as mortality at day 7 and 28, were investigated. MATERIALS AND METHODS: Patients from the DIANA study were grouped and analysed by combination versus mono antibiotic therapy. Clinical cure was defined as survival and resolution of all signs and symptoms related to the infection. Odds ratios (ORs) were calculated by logistic regression analyses. RESULTS: Of the 1398 included patients, 568 patients (41%) received combination therapy. In total, 641(46%) patients achieved clinical cure and 135 (10%) patients had died as of day 7. There were no significant associations between combination and mono therapy relating to clinical cure and mortality. CONCLUSIONS: This study found no differences in clinical cure and mortality between empirical combination versus mono therapy in a large cohort of ICU patients with a suspected infection.

Randomized cross-over evaluation of investigator gender on pain thresholds in healthy volunteers.

Background and aims: This randomized cross-over study in healthy volunteers was designed primarily to evaluate the potential impact of investigator gender on electrical pain threshold (EPT) and corresponding pain intensity levels, and secondly to evaluate potential differences in those interventions between female and male study participants. Methods: Forty adult volunteers (22 females) were included. An electrical stimulation device was used to determine EPT levels (in pain magnitude scores) in series of three in each study participant - once by a female, and once by a male investigator - according to a predefined cross-over design schedule. Corresponding levels of pain intensity were scored on a visual analog scale (VAS) slide ruler. Results: Study data was obtained and analysed in all participants. Significantly higher EPT levels were determined by the female investigator compared with the male investigator (median 22 (IQR 12-31) vs. 8 (6-10) pain magnitude scores; p<0.0001), despite similar levels of reported pain intensity (1.9 (1.2-3.0) vs. 2.0 (1.1-3.4) VAS units; p>0.300). There were no differences in EPT levels between female and male subjects evaluated by female (p>0.300) and male (p=0.125) investigators, or between the first and second series of stimulation (p>0.300). Conclusions: Our finding of significantly higher EPT levels when study participants of both genders - despite no difference in reported pain intensity - were evaluated by a female than by a male investigator, indicates a potential impact of investigator gender on the individual perception of pain. Implications: By contributing to a better understanding of how individual pain threshold levels are potentially influenced by investigator gender, this study might facilitate future evaluation of pain conditions in both preclinical and clinical settings.

Fluid deficits during prolonged overnight fasting in young healthy adults.

BACKGROUND: Overnight fasting is often prolonged before scheduled surgery, and the extent of perioperative fluid replacement may influence outcome. In clinical practice, basic requirements are estimated at 1.2-2.0 mL·kg-1 ·h-1 , but there is little contemporary clinical data on what deficits result from complete fasting. This prospective preclinical study was designed to determine total fluid loss during overnight fasting, prolonged during daytime. METHODS: Twenty (10 female) healthy adult volunteers, aged 24 (range 21-46) years, fasted from 22:00 until 16:00, and had their body weight and urine output measured at predefined time intervals. RESULTS: The median (interquartile range) fluid deficits were 0.82 (0.73-1.00) kg, corresponding to 1.26 (1.11-1.41) g·kg-1 ·h-1 for the initial overnight fasting period, 0.59 (0.40-0.70) kg and 0.99 (0.83-1.31) g·kg-1 ·h-1 for the consecutive daytime period, and 1.47 (1.27-1.64) kg and 1.19 (1.05-1.28) g·kg-1 ·h-1 for the total period of fasting. Urine output accounted for 52% of total weight loss and was 36% of the baseline hourly level during the last four-hour period of fasting. CONCLUSIONS: Ten hours of overnight fasting in young adults induces fluid deficits at the lower limit of estimated intervals referred to in clinical practice, and hourly weight loss gradually decreases further during prolonged daytime fasting. These findings indicate that current routine procedures do slightly overestimate fluid deficits resulting from prolonged fasting in perioperative clinical practice.