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Background Seizures after cardiac surgery are a serious complication. The antifibrinolytic agent tranexamic acid (TA), which has known proconvulsant properties, may be associated with postoperative seizures. We sought to determine the association between TA and other risk factors for seizures after cardiac surgery. In all, 58.1% were grand mal, 14.5% were associated with a stroke, and 58.1% recurred in hospital. Altogether, 48.3% of the patients were able to discontinue anticonvulsant medications prior to discharge. Compared to the non-seizure group, seizure patients had an increased rate of postoperative neurological complications, defined as delirium and/or stroke (3.2% vs 19.6%, P \ 0.001), increased intensive care unit (ICU) length of stay (1.0 vs 4.7 days, P < 0.001), and increased ICU mortality (1.4 % vs 9.7 %, P = 0.001). Conclusions Our data suggest that multiple risk factors, including TA, are associated with seizures after cardiac surgery. Thus, the TA dose may be a readily modifiable risk factor for postoperative seizures. Methods and results Résumé

To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

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Pharmacodynamic considerations including aggressive dosing with targeted peak/MICs for aminoglycosides and ciprofloxacin are strongly associated with clinical outcome and essential to the appropriate management of P. aeruginosa bacteraemia.

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups-26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K slope pharmacokinetic model relating the elimination rate constant (K 10 ) to renal function, as defined by creatinine clearance (CL CR ), and central distribution volume (V 1 ) to total body weight (TBW). The final model was described by the following equations: K 10 ‫؍‬ 0.0027 ؋ CL CR ؉ 0.071 h ؊1 and V 1 ‫؍‬ TBW ؋ 0.21 liter/kg. The median intercompartmental transfer constants K 12 and K 21 were 0.780 h ؊1 and 0.472 h ؊1 , respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 g/ml, 24.0 g/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of ؊1.64 g/ml, 17.1 g/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 g/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

The objective of this study was to characterize the relationship between gentamicin concentrations during surgery and the development of wound infection following colorectal operations. Despite decades of research in surgical prophylaxis, the relationship between intraoperative antibiotic concentrations and postoperative infection and the concentrations required for effective prophylaxis have not been established. A pharmacodynamic analysis was conducted using data from a previous prospective, randomized, double-blind clinical study which compared two dosage regimens of gentamicin plus metronidazole for prophylaxis in connection with elective colorectal surgery. Univariate and multivariate analyses of risk factors for postoperative wound infection were conducted, and the relationship between intraoperative gentamicin concentrations and surgical outcome was characterized. The gentamicin concentration at the time of surgical closure was one of the strongest independent risk factors for infection (P ‫؍‬ 0.02), along with the presence of diabetes mellitus (P ‫؍‬ 0.02), stoma (P ‫؍‬ 0.04), and advanced age (P ‫؍‬ 0.05). Gentamicin concentrations at closure of less than 0.5 mg/liter were associated with an infection rate of 80% (representing 8 of 10 patients with concentrations below that level) (P ‫؍‬ 0.003). Receiver operating characteristic curve analysis identified a critical closure concentration of 1.6 mg/liter for effective surgical prophylaxis (P ‫؍‬ 0.002; sensitivity, 70.8%; specificity, 65.9%). This study provides new and important information on antibiotic pharmacodynamics in surgical prophylaxis. It demonstrates the critical effect of the antibiotic concentration at closure on wound infection and suggests a significant association between the concentration and other well-established risk factors, like the timing of preoperative antibiotic administration and surgery duration.Surgical site infections, a significant postoperative complication, can lead to considerable patient morbidity and mortality (5, 14). Wound infections account for 38% of surgical infections and 17% of all nosocomial infections (14, 22). The benefits of preoperative antibiotics, which reduce bacterial contamination during clean-contaminated and contaminated operations, are well known (8,14). However, the relationship between intraoperative antibiotic concentrations and postoperative infection and the concentrations required for effective prophylaxis have not been established. Over the past decade, pharmacodynamic research has advanced the treatment of infectious diseases by characterizing relationships between antibiotic concentrations and clinical response (7,12,20). Although the application of similar principles to surgical prophylaxis has been suggested, there is a notable lack of supportive study (1,16,18). It is probable that low antibiotic concentrations during surgery due to inappropriate timing of the preoperative antibiotic (3), prolonged surgery (9, 11, 21), and patient obesity (13,17) contribute to the high infection rates as...

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