Optimisation of fluconazole therapy for the treatment of invasive candidiasis in preterm infants.

INTRODUCTION: Fluconazole is an important antifungal in the prevention and treatment of invasive Candida infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a population pharmacokinetic study on fluconazole in preterm neonates in order to optimise dosing through the identified predictive patient characteristics. METHODS: Fluconazole concentrations obtained from preterm infants from two studies were pooled and analysed using NONMEM V.7.3. The developed model was used to evaluate current dosing practice. A therapeutic dosing strategy aiming to reach a minimum target exposure of 400 and 200 mg×hour/L per 24 hours for fluconazole-susceptible C. albicans meningitis and other systemic infections, respectively, was developed. RESULTS: In 41 preterm neonates with median (range) gestational age 25.3 (24.0-35.1) weeks and median postnatal age (PNA) at treatment initiation 1.4 (0.2-32.5) days, 146 plasma samples were collected. A one-compartment model described the data best, with an estimated clearance of 0.0147 L/hour for a typical infant of 0.87 kg with a serum creatinine concentration of 60 µmol/L and volume of distribution of 0.844 L. Clearance was found to increase with 16% per 100 g increase in actual body weight, and to decrease with 12% per 10 µmol/L increase in creatinine concentration once PNA was above 1 week. Dose adjustments based on serum creatinine and daily dosing are required for therapeutic target attainment. CONCLUSION: In preterm neonates, fluconazole clearance is best predicted by actual body weight and serum creatinine concentration. Therefore, fluconazole dosing should not only be based on body weight but also on creatinine concentration to achieve optimal exposure in all infants. ETHICS STATEMENT: The Erasmus MC ethics review board approved the protocol of the DINO Study (MEC-2014-067) and the Radboud UMC ethics review board waived the need for informed consent for cohort 2 (CMO-2021-8302). Written informed consent from parents/legal guardians was obtained prior to study initiation.

Pharmacokinetic characteristics and microbiologic appropriateness of cefazolin for perioperative antibiotic prophylaxis in elective cardiac surgery.

OBJECTIVE: Adequate levels of perioperative antibiotic prophylaxis are essential for prevention of surgical site infections. We examined pharmacokinetic details of 2 g cefazolin administered during induction of anesthesia with repeat dosing shortly after initiation of cardiopulmonary bypass (CPB) in cardiac surgery. METHODS: To identify the microbiologic flora targeted with prophylaxis, pre-, and postoperative swabs were taken from sternal skin. Blood samples for measurement of cefazolin were obtained in 24 patients. Drug levels were used for population pharmacokinetic modeling using Nonmem software (Icon Development Solutions, San Antonio, Tex). RESULTS: More than 90% of bacteria on sternal skin were sensitive to cefazolin, indicating minimal inhibitory concentrations <8 mg/L. All serum levels of cefazolin were above 8 mg/L and might thus effectively prevent infection. Pharmacokinetic modeling in a 1-compartment model predicted a population mean clearance (CL) of 5.23 L/h and a volume of distribution (Vd) of 15.8 L. CPB increased Vd from 14.4 L to 22.1 L with a consecutive reduction to 18 L after the end of extracorporeal circulation. The final model implemented interindividual variability on CL and Vd, incorporating the covariates CPB and albumin on Vd and creatinine clearance on CL. Goodness-of-fit calculations showed that this model adequately describes the data derived from our clinical cohort. CONCLUSIONS: Two grams of cefazolin at induction of anesthesia with a repeat dose after initiation of CPB ensures adequate drug levels to target a majority of pathogens of surgical site infections. Pharmacokinetic modeling demonstrated a significant influence of CPB on the volume of distribution and elimination of cefazolin. Other influences on pharmacokinetic parameters were albumin, protein, and creatinine clearance.