Integrated pharmacokinetic-pharmacodynamic modelling to evaluate antimicrobial prophylaxis in abdominal surgery.

OBJECTIVES: To use Monte Carlo simulation with an integrated pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate guideline-recommended antimicrobial prophylaxis (AP) regimens with anaerobic coverage in abdominal surgery. METHODS: AP regimens were tested in simulated subjects undergoing elective abdominal surgery using relevant PK models and pathogen distributions in surgical site infections (SSIs). Predicted cumulative target attainment was the percentage of simulated subjects with free (unbound) antimicrobial plasma concentrations above the MICs for potential SSI pathogens. RESULTS: Cefazolin plus metronidazole covered SSI aerobes in 70% and the Bacteroides fragilis group in 99% of subjects, whereas cefoxitin only covered aerobes and anaerobes in 63% and 27% of cases, respectively. The broad-spectrum ceftriaxone plus metronidazole covered aerobes in 82% and anaerobes in 99% of simulations, while ertapenem covered aerobes in 88% and anaerobes in 90% of cases. Clindamycin covered the B. fragilis group in only 11% of cases. For cefazolin, 2 g doses maintained target attainment in simulated subjects from 80 to 120 kg, whereas 1 g doses were associated with lower target attainment against potential Gram-negative pathogens even in those <80 kg. For gentamicin, 3 mg/kg doses were comparable to the suggested 5 mg/kg, but superior to the traditional 1.5 mg/kg. CONCLUSIONS: This study demonstrates the use of PK-PD to inform decisions regarding AP in abdominal surgery. In this case, the findings support avoiding cefoxitin, avoiding clindamycin for anaerobic coverage, selecting 2 g doses of cefazolin even in patients <80 kg and using 3 mg/kg doses of gentamicin.

Population pharmacokinetics of fentanyl in healthy volunteers.

The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM-derived parameters were a total body clearance of 2.12 +/- 0.28 L/kg/h, distributional clearance of 8.43 +/- 4.58 L/kg/h, central volume of distribution of 1.22 +/- 0.21 L/kg, and peripheral volume of distribution of 1.81 +/- 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics.

Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient.

The numerous drugs to which the acutely ill are exposed place these patients at a significant risk of developing drug-induced thrombocytopenia. Such patients tend to have preexisting hemostatic defects that place them at additional risk of complications as a result of the drug-induced thrombocytopenia. The clinical challenge is to provide rapid identification and removal of the offending agent before clinically significant bleeding or, in the case of heparin, thrombosis results. Drug-induced thrombocytopenic disorders can be classified into three mechanisms: bone marrow suppression, immune-mediated destruction, and platelet aggregation. Clinical characteristics, preliminary laboratory findings, and drug history specific to the mechanisms can assist clinicians in rapidly isolating the causative drug.

Economic impact and clinical benefits of pharmacist involvement on surgical wards.

A one-year pilot project was performed to assess the economic and clinical benefit of pharmacist involvement on the surgical wards of a 600-bed tertiary care, teaching hospital. A total of 405 recommendations were collected with a physician acceptance rate of 90%. From these recommendations, 1416 patient follow-ups were performed to document outcome. The total documented cost avoidance of the pharmacists' activities was $33,265.58. The total annual drug expenditure for the department of surgery declined by $59,662 representing a 9% decrease over the previous year with the greatest decline involving antimicrobials which decreased by $52,587 compared with the previous year. Most of the cost-avoidance in this area was attributable to antimicrobial selection and dosing adjustment in renal impairment. Pharmacist-directed pharmacokinetic monitoring of aminoglycosides resulted in a clinical success rate of 93.8% for treatment regimens and a 6.2% incidence of nephrotoxicity. Housestaff education aimed at improving prescribing practices were identified and provided for select agents including midazolam, ketorolac, vancomycin and aminoglycosides. As well, select recommendations were documented which illustrated the benefit to patient care of pharmacist involvement. Pharmacist involvement on the surgery services produced both financial and clinical benefits.

Comparison of sedative recovery time after midazolam versus diazepam administration.

OBJECTIVE: To compare the sedative recovery rate pharmacology of intravenous midazolam vs. diazepam when used for short-term sedation. DATA SOURCES: English-language articles were identified through a search of the MEDLINE and InPharma databases. Bibliographies of retrieved articles were examined for relevant articles. STUDY SELECTION: Twenty-eight studies were identified based on a priori inclusion criteria. Eight trials had enough information to combine results for sedative recovery rate. DATA EXTRACTION: The difference in mean time to sedative recovery, weighted by sample size, was determined. DATA SYNTHESIS: Of the 28 trials, eight reported a significantly faster sedation recovery rate from diazepam vs. midazolam, whereas 19 trials reported no difference in sedative recovery time, and a single trial reported that midazolam offered significantly faster recovery from sedation than diazepam. A commonly defined time to sedative recovery event was available for only eight trials. The median dosing ratio for these eight trials was 2.1:1 for diazepam over midazolam. The weighted mean time difference was 4 mins 16 secs in favor of diazepam as the agent from which patients recover more quickly. CONCLUSIONS: These results firmly underscore the understanding that elimination half-lives of benzodiazepines do not necessarily correspond with their sedative pharmacodynamic effects, and we conclude that there are no clinically important sedative recovery rate differences between midazolam and diazepam, while midazolam is a more expensive agent.

Lack of in vitro inactivation of tobramycin by imipenem/cilastatin.

OBJECTIVE: Inactivation of aminoglycosides by beta-lactam antimicrobials both in vitro and in vivo has been documented. Such an interaction has not previously been documented between carbapenems and aminoglycosides. Examination of serum concentrations of tobramycin in a patient receiving both agents suggested that this interaction might exist. The purpose of this study was to look at this question in an in vitro model. METHODS: Low concentrations of tobramycin (10 micrograms/mL) were incubated with imipenem/cilastatin (concentrations of 10, 20, and 40 micrograms/mL) in human serum at 37 degrees C. Aliquots of these solutions were withdrawn at 0, 6, 24, 72, and 120 hours and assayed for tobramycin concentrations using a fluorescence polarization immunoassay. Aliquots of tobramycin 10 micrograms/mL and carbenicillin 200 micrograms/mL were analyzed in the same manner, as a positive control. High concentrations of tobramycin (800 micrograms/mL) and imipenem (5000 micrograms/mL)/cilastatin were incubated together at 21 degrees C and sampled at 0, 6, 24, and 72 hours for tobramycin concentrations. RESULTS: The degradation rates for low-concentration tobramycin and the various concentrations of imipenem/cilastatin were not statistically different from those of the controlled incubations. In contrast, carbenicillin significantly enhanced the degradation rate of tobramycin at this concentration (half-life 72 hours and a 34 percent loss at 24 hours, p = 0.0028). Higher in vitro concentrations of imipenem (5000 micrograms/mL)/cilastatin and tobramycin (800 micrograms/mL) resulted in significant, but moderate degradation over controlled incubations (half-life 80 hours and 10 percent loss at 12 hours, p = 0.0031). CONCLUSIONS: These results suggest that inactivation of tobramycin is not a problem at common clinically achievable imipenem serum concentrations in patients.

Once daily aminoglycoside dosing: maintained efficacy with reduced nephrotoxicity?

Animal studies report equal or greater clinical efficacy with once daily versus multiple daily aminoglycoside dosing; however, results are inconsistent. Extrapolation of these animal data to human data is difficult, since marked variability exists in terms of pharmacokinetic disposition of aminoglycosides. Human data suggest that once daily aminoglycoside dosing regimens are as effective as multiple dosing regimens. However, studies need to be performed assessing the efficacy of once daily aminoglycoside dosing for infectious sites other than intra-abdominal and the urinary tract. In addition, the results of these studies should not be extrapolated to those with renal dysfunction, the immunocompromised, or in patients with aminoglycoside treatment durations of greater than 8 days, as the efficacy of once daily dosing in these patient populations has not been proven. Animal studies assessing nephrotoxicity suggest that multiple daily aminoglycoside dosing results in more frequent or more severe nephrotoxicity compared to once daily dosing. Nine human studies have been published comparing the nephrotoxicity of once daily versus multiple daily aminoglycoside dosing. The majority of investigators have studied nonimmunocompromised patients with urinary tract infections. Netilmicin has been the most frequently used aminoglycoside, although other agents such as gentamicin, amikacin, and sisomicin have been studied. The most common netilmicin dosage regimen has ranged from approximately 4 to 6 mg/kg administered once daily. Eight of the nine trials performed have documented no significant differences in serial serum creatinine concentrations between once daily and multiple daily aminoglycoside dosing regimens, by the end of the study period. In conclusion, preliminary data suggest that once daily aminoglycoside dosing in nonimmunocompromised patients is equally efficacious and nephrotoxic compared to multiple daily dosing regimens.

Antimicrobial prophylaxis in coronary bypass surgery: a critical appraisal.

The literature has been examined to assess the optimal prophylactic antimicrobial regimen for patients undergoing coronary bypass surgery. Antimicrobial surgical prophylaxis should be based on the two main potential pathogens, Staphylococcus epidermidis and S. aureus. It is unclear whether the prophylactic use of antimicrobials can or should be guided by in vitro antimicrobial susceptibility testing; data from well-performed clinical trials should be evaluated. The data fail to demonstrate consistently a significant difference within the cephalosporin class of antimicrobials with regard to prevention of infectious complications. Although it does not reach statistical difference, the trend with respect to efficacy appears to be cefuroxime, then cefamandole, and then cefazolin. The lack of significant difference among antimicrobials suggests an institution-individualized approach to the selection of the optimal antimicrobial for prophylaxis. For our facilities we recommend the following regimen: cefazolin sodium 1-2 g iv q8h for two days. There are not enough data at this time to recommend less than two days of antimicrobial prophylaxis for this type of surgery. In addition, aminoglycosides provide no added benefit when added to cephalosporins.