Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass.

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Population pharmacokinetics of three alternative prophylactic antibiotics during cardiac surgery with extracorporeal circulation.

AIMS: The aim of this pharmacokinetic study was to describe and quantify population pharmacokinetics of three antibiotics, cefazolin, ampicillin, and ciprofloxacin, used as antibacterial prophylaxis during cardiovascular surgery with the use of extracorporeal circulation (ECC). METHODS: Adult patients undergoing cardiac surgery with ECC were enrolled to this prospective, pharmacokinetic study. An intravenous bolus of 2 g of ampicillin, 2 g of cefazolin or 400 mg of ciprofloxacin was administered 60-30 min before surgery. Blood samples were collected at 15, 30, 45, 60, 120 and 180 min after the administration and at the end of the surgery. Plasma concentrations of the antibiotics were measured using HPLC methods. Serum concentration-time profiles were analyzed using nonlinear mixed-effects modeling approach. RESULTS: A total of 54 patients were enrolled into the study, 20 with ampicillin, 25 cefazolin and 9 ciprofloxacin. For all antibiotics, population pharmacokinetic models have been successfully developed. CONCLUSION: We identified estimated glomerular filtration rate (eGFR) as the main factor determining the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target in ampicillin or cefazolin and body weight in ciprofloxacin prophylaxis during cardiac surgery with ECC support.

[Pharmacological properties of colistin].

Colistin is a narrow-spectrum lipopeptide antimicrobial agent used to treat nosocomial infections caused by multidrug-resistant bacteria, especially in critically ill patients and those with cystic fibrosis. Colistin represents a concentration-time-dependent antibiotic with highly variable pharmacokinetics related to the heterogeneity of the target population and the necessity of bioactivation. Colistin is administered as the inactive prodrug colistimethate sodium. Nephrotoxicity and neurotoxicity are the most frequent adverse effects.

Population Pharmacokinetics of Prophylactic Cefazolin in Cardiac Surgery with Standard and Minimally Invasive Extracorporeal Circulation.

The objectives of this study were to develop a population pharmacokinetic model of prophylactically administered cefazolin in patients undergoing cardiac surgery with and without the use of the cardiopulmonary bypass of both existing types-standard (ECC) and minimallyu invasive extracorporeal circulation (MiECC)-and to propose cefazoline dosing optimization based on this model. A total of 65 adult patients undergoing cardiac surgery were recruited to this clinical trial. A prophylactic cefazolin dose of 2 g was intravenously administered before surgery. Blood samples were collected using a rich sampling design and cefazolin serum concentrations were measured using the HPLC/UV method. The pharmacokinetic population model was calculated using a nonlinear mixed-effects modeling approach, and the Monte Carlo simulation was used to evaluate the PK/PD target attainment. The population cefazolin central volume of distribution (Vd) of 4.91 L increased by 0.51 L with each 1 m2 of BSA, peripheral Vd of 22.07 L was reduced by 0.77 L or 0.79 L when using ECC or MiECC support, respectively, while clearance started at 0.045 L/h and increased by 0.49 L/h with each 1 mL/min/1.73 m2 of eGFR. ECC/MiECC was shown to be covariate of cefazolin Vd, but without relevance to clinical practice, while eGFR was most influential for the PK/PD target attainment. The standard dose of 2 g was sufficient for PK/PD target attainment throughout surgery in patients with normal renal status or with renal impairment. In patients with augmented renal clearance, an additive cefazolin dose should be administered 215, 245, 288 and 318 min after the first dose at MIC of 4, 3, 2 and 1.5 mg/L, respectively.