Cefazolin Plasma Concentrations Research Articles

Prolonged efficacy of cefazolin in intraosseous regional prophylaxis for total knee arthroplasty: a rabbit model study

BackgroundA novel approach known as intraosseous regional administration (IORA) has emerged as a technique for delivering prophylactic antibiotics, and it results in higher tissue concentrations around the knee. It is hypothesized that IORA of cefazolin for antibiotic prophylaxis during total knee arthroplasty will result in sustained effective levels for a longer duration. The aim of the current study was to investigate temporal changes in peri-knee cefazolin blood concentrations after IORA of cefazolin.MethodsTwelve rabbits were randomly divided into two groups, with six rabbits in each group. In control group a single intravenous bolus injection of cefazolin (10 mL, 100 mg) was administered into the marginal ear vein. In experimental groupexperimental group the same dose of cefazolin was injected into the left tibial marrow cavity after tourniquet inflation at the base of the left thigh. Blood samples were collected periodically at different timepoints, and cefazolin concentrations were determined.ResultsThe intraosseous treatment resulted in significant differences in plasma cefazolin concentrations at all timepoints. Experimental group exhibited higher plasma cefazolin concentrations than control group.ConclusionsCefazolin in intraosseous regional prophylaxis exhibits effectiveness in intraoperative antibiotic prophylaxis by maintaining concentrations above the minimum inhibitory concentration for extended durations, rather than relying solely on high concentrations.

Plasma concentration of prophylactic cefazolin best correlates with lean body mass measured by bioimpedance analysis in lumbar spine surgery: Results of a pilot study

The aim of this study was to determine the association between measures of body composition and the concentration of plasma and paraspinal muscle cefazolin. Secondly, we aimed to confirm the efficacy of our hospital dosing regimen in achieving the minimum inhibitory concentration (MIC) at the surgical site. Patients undergoing posterior-based lumbar spine surgery had body composition analysed using bioimpedance analysis. All received 2 g of cefazolin at anaesthetic induction in line with hospital guidelines. Cefazolin concentration was measured in plasma (30-minites) and muscle (30- and 60-minuites) using high-performance liquid chromatography. 20 patients were recruited (mean age 61.5 years; 12 female). Mean plasma cefazolin concentrations were 34.1 +/− 10.2 mg/L; mean muscle concentrations 44.4 +/− 18.6 mg/kg and 43.8 +/− 20.4 mg/kg at 30- and 60-minutes respectively. Univariate analysis showed significant correlation between plasma cefazolin concentration and lean mass weight, absolute body weight, height, dry lean mass, total water, total body water, extracellular and intracellular water volume. Linear regression analysis showed lean mass weight the best predictor of plasma cefazolin concentration. Muscle cefazolin concentration was dependent on the plasma concentration. Using a MIC of 2 mg/L and 2 mg/kg for Staphylococcus aureus, MIC was achieved in all samples. In summary, plasma cefazolin concentration was best predicted by lean body mass. Further work should consider the influence of body composition on antibiotic delivery in extremes of body mass index. Local hospital guidelines are effective at achieving MIC against S. aureus.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients

The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

Rational determination of cefazolin dosage regimen in horses based on pharmacokinetics/pharmacodynamics principles and Monte Carlo simulations.

A pharmacokinetics/pharmacodynamics (PK/PD) approach was used to determine the best empirical dosage regimen of cefazolin (CEZ) after intramuscular (IM) administration of CEZ in horses. Seven horses received a single IM or intravenous (IV) administration of CEZ of 5mg/kg bodyweight (BW) according to a crossover design. CEZ plasma concentrations were measured using LC-MS/MS. The plasma concentrations in these seven horses and those of six other horses obtained in a previous study with an IV CEZ dose of 10mg/kg were modelled simultaneously using NonLinear Mixed-Effect modelling followed by Monte Carlo simulations to establish a rational dosage regimen. A 90% Probability of Target Attainment (PTA) for a PK/PD target of a free plasma concentration exceeding MIC90 (fT > MIC ) for 40% of the dosing interval was set for selecting an effective dosing regimen. The typical half-life of absorption and bioavailability after IM administration were 1.25 h and 96.8%, respectively. A CEZ dosage regimen of 5mg/kg BW q12h IM administration achieved therapeutic concentrations to control both Streptococcus zooepidemicus and Staphylococcus aureus. For the same dose, the fT > MIC after IM administration was significantly longer than after IV administration, and the IM route should be favoured by clinicians for its efficiency and convenience.

Cefazolin prophylaxis in children undergoing cardiac surgery with the use of cardiopulmonary bypass-is the dosing correct?

To determine the recommended concentrations of cefazolin to be used for antibiotic prophylaxis during paediatric cardiac surgery with extracorporeal circulation (ECC). Twenty paediatric patients undergoing cardiac surgery with ECC and cefazolin antibiotic prophylaxis were included in the study. Blood samples for measurement of total cefazolin plasma concentration were collected at the following measurement time points: directly after skin incision, 15 min after ECC start, 5 min after ECC cessation and at skin closure. The target concentration was set for ≥40 mg/l, which corresponded to ≥8 mg/l of unbound cefazolin concentration. The median total cefazolin plasma concentrations at the measurement time points were 62.8, 67.7, 45.8 and 34.2 mg/l, respectively, and target concentrations were achieved in 90%, 85%, 65% and 40% of children, respectively. Among patients who received ≥30 mg of cefazolin per 100 ml of ECC priming, target concentrations after ECC cessation were reached in 80% of patients, while in those with <30 mg cefazolin per 100 ml in 20% of patients (P = 0.031). Direct extrapolation of antibiotic prophylaxis recommendations from adults to children may result in suboptimal antibiotic concentrations. An additional cefazolin dose to ECC priming appears necessary and the dosing should be based on ECC priming volume rather than on the weight of the patient.

Plasma Concentrations of Cefazolin in Pediatric Patients Undergoing Cardiac Surgery

Background:The guideline for antibiotic prophylaxis in pediatric cardiac surgery is currently unavailable, and the effects of cardiopulmonary bypass (CPB) may result in low plasma cefazolin concentrations and subsequent postoperative surgical site infections (SSIs).Aims:To demonstrate the calculated-unbound plasma concentrations of cefazolin during uncomplicated pediatric cardiac surgery.Settings and Design:A prospective observational study that included 18 patients <seven years of age, undergoing elective cardiac surgery with CPB.Materials and Methods:An intravenous infusion of cefazolin (25 mg.kg-1) was administered to patients over 30 minutes within 1 hour before skin incision (first dose). Another 25 mg.kg-1 infusion was administered to the CPB prime volume (second dose). Blood samples were obtained at eight time points: 15 minutes after the first dose (T1); before aortic cannulation (T2); immediately after CPB initiation (T3); 30 (T4), 60 (T5), and 120 (T6) minutes after CPB; 15 minutes after CPB discontinuation (T7), and at skin closure (T8). The total plasma cefazolin concentrations were measured using liquid chromatography tandem mass spectrometry.Results:The unbound cefazolin concentrations were calculated assuming 80%-protein binding. The median cefazolin levels were 18.1 (range 4.3-27.0), 11.9 (2.8-24.1), 31.4 (18.3-66.1), 23.4 (13.7-35.9), 20.2 (15.4-24.9), 17.7 (14.8-18.0), 15.6 (9.8-26.2), and 13.3 (8.3-24.6) μg.mL-1 from T1-T8, respectively. The cefazolin levels remained four times above the minimum inhibitory concentrations (MICs) for Methicillin-sensitive S. aureus (MSSA) and S. epidermidis in most patients, but they were inadequate for Enterobacter and E. coli.Conclusion:This regimen produced adequate plasma cefazolin concentrations for common organisms that cause SSIs after cardiac surgery.

Antimicrobial Prophylaxis for Patients Undergoing Cardiac Surgery: Intraoperative Cefazolin Concentrations and Sternal Wound Infections.

This study characterizes the pharmacodynamics of antimicrobial prophylaxis and sternal wound infections following cardiac surgery. Duration of surgery and cefazolin plasma concentration during wound closure were independently associated with surgical site infection at 30 days. Furthermore, a duration of surgery of >346 min and a total cefazolin closure concentration of <104 mg/liter were significant thresholds for an increased risk of infection. This study provides new data that informs dosing strategies for effective antimicrobial prophylaxis (AP) in patients undergoing cardiac surgery with cardiopulmonary bypass.

The Effect of Blood Loss on Cefazolin Levels in Women Undergoing Cesarean Delivery.

To quantify the effects of operative blood loss during cesarean on tissue and plasma cefazolin concentrations. This was a prospective observational study of singleton pregnancies undergoing scheduled cesarean between 34 and 40 weeks. Cefazolin administered prior to skin incision. Maternal plasma samples were obtained (Time 1[T1]: immediately, T2: 20 minutes, T3: 40 minutes, and T4: 60 minutes after cefazolin infusion). Subcutaneous adipose tissue sampled before and after fascia. Primary outcome was subcutaneous adipose cefazolin level after fascial closure. Formal quantitative blood loss (QBL) performed. Women with higher QBL, those at/above 75% of QBL in this population, were compared with those with lower QBL (QBL below 75%). Data analyzed using bivariable statistics. Ninety-two women were screened, 32 were eligible, and 20 enrolled. Median QBL was 630 mL (interquartile range [IQR]: 473-818) and 1,160 mL (IQR: 1,000-1,560) in the low and high QBL groups, respectively. Demographics and operative characteristics were similar. Median adipose cefazolin level after fascial closure did not differ between the groups (3.5 vs. 3.9 μg/g, p = 0.75). No differences in maternal plasma cefazolin concentrations between the groups at any time point or in pharmacokinetic parameters were seen. Intraoperative maternal plasma concentrations and adipose levels of cefazolin are similar between women with high and low blood loss at the time of cesarean delivery.

Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals.

Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 μg/mL in human plasma, 2 μg/mL in rat plasma, and 0.5 and 0.025 μg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations.

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial

BackgroundPerioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. MethodsPatients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h−1) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics® software. Calculations of PTA and FTA were performed for common pathogens. ResultsTen patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44–80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean (sd) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h−1. Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. ConclusionsOur study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. Clinical trial registrationNCT02058979.

Effect of Maternal Obesity on Maternal-Fetal Transfer of Preoperative Cefazolin at Cesarean Section.

American Congress of Obstetricians and Gynecologists recommends a single dose of antibiotic prophylaxis before all cesarean sections (C/S). This recommendation is based on pharmacokinetic studies that include only non-obese patients. We sought to evaluate 1) cefazolin plasma concentrations among obese and non-obese patients after administration of a 2-g cefazolin dose for prevention of surgical wound infections, and 2) whether cefazolin concentration in fetal circulation may be protective against pathogens that cause early onset neonatal sepsis. Maternal and fetal cefazolin plasma concentrations were compared between obese (body mass index [BMI] ≥ 30 kg/m2) and non-obese (BMI < 25 kg/m2) healthy, term pregnant women undergoing scheduled C/S. Liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods were used for quantification of total and free cefazolin concentrations in maternal blood (MB) and umbilical cord blood (UCB). Eight women were screened and consented. There was no difference between groups in MB total and free cefazolin concentrations. All MB samples had total and free cefazolin concentrations greater than the minimum inhibitory concentration 90 (MIC90) for Group B Streptococcus (GBS), Staphylococcus aureus, and Escherichia coli. All UCB samples had total and free cefazolin concentrations greater than MIC90 for GBS and S aureus, even when administered as briefly as 18 minutes before delivery. A lower concentration of total cefazolin was detected in UCB of neonates of obese women compared to non-obese women (p > 0.05). Administration of 2 g of cefazolin to women undergoing scheduled C/S might be an adequate prophylactic dose for surgical wound infection in both non-obese and obese patients; and cefazolin concentration in fetal circulation may be protective against GBS and S aureus.

Comparative Total and Unbound Pharmacokinetics of Cefazolin Administered by Bolus Versus Continuous Infusion in Patients Undergoing Major Surgery

Abstract Background Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. Methods Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h−1) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics® software. Calculations of PTA and FTA were performed for common pathogens. Results Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44–80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean (sd) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h−1. Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. Conclusions Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. Clinical trial registration NCT02058979.

Cefazolin pharmacokinetics in cats under surgical conditions.

Objectives The aim of this study was to determine the plasma pharmacokinetic profile, tissue concentrations and urine elimination of cefazolin in cats under surgical conditions after a single intravenous dose of 20 mg/kg. Methods Intravenous cefazolin (20 mg/kg) was administered to nine young mixed-breed cats 30 mins before they underwent surgical procedures (ovariectomy or orchiectomy). After antibiotic administration, samples from blood, some tissues and urine were taken. Cefazolin concentrations were determined in all biological matrices and pharmacokinetic parameters were estimated. Results Initial plasma concentrations were high (Cp(0), 134.80 ± 40.54 µg/ml), with fast and moderately wide distribution (distribution half-life [t½(d)] 0.16 ± 0.15 h; volume of distribution at steady state [V(d[ss])] 0.29 ± 0.10 l/kg) and rapid elimination (body clearance [ClB], 0.21 ± 0.06 l/h/kg; elimination half-life [t½], 1.18 ± 0.27 h; mean residence time 1.42 ± 0.36 h). Thirty to 60 mins after intravenous administration, cefazolin tissue concentrations ranged from 9.24 µg/ml (subcutaneous tissue) to 26.44 µg/ml (ovary). The tissue/plasma concentration ratio ranged from 0.18 (muscle) to 0.58 (ovary). Cefazolin urine concentrations were high with 84.2% of the administered dose being eliminated in the first 6 h postadministration. Conclusions and relevance Cefazolin plasma concentrations remained above a minimum inhibitory concentration of ⩽2 µg/ml up to 4 h in all the studied cats. This suggests that a single intravenous dose of 20 mg/kg cefazolin would be adequate for perioperative prophylactic use in cats.

A pilot and feasibility study of the plasma and tissue pharmacokinetics of cefazolin in an immature porcine model of pediatric cardiac surgery.

Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. The purposes of this study were to determine the plasma and tissue concentrations with standard of care, perioperative cefazolin dosing in an immature porcine model of pediatric cardiac surgery, and to determine the feasibility of this model. Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB + DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of the skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, noncompartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. Following the first intravenous dose, maximal cefazolin concentrations in the subcutaneous tissue and skeletal muscle were similar between groups with peak tissue concentrations 15-30 min after administration. After the second cefazolin dose given with the initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle- and subcutaneous-unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed subcutaneous and skeletal muscle concentrations of cefazolin >16 μg·ml(-1) while this percentage was 78-79% for the CPB + DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP + DHCA (P = 0.03). The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of the cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.

Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients.

The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics(®). Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.

Plasma and Tissue Pharmacokinetics of Cefazolin in an Immature Porcine Model of Pediatric Cardiac Surgery

Background: Surgical Site Infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. The purpose of this study was to determine the plasma and tissue concentrations of standard-of-care peri-operative cefazolin dosing in an immature porcine model of cardiac surgery and cardiopulmonary bypass. Methods: Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB+DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, non-compartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. Results: Following the first intravenous dose, maximal cefazolin concentrations for plasma and tissue samples were similar between groups with peak tissue concentrations 15-30 minutes after administration. After the second cefazolin dose given with initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle and subcutaneous unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed tissue cefazolin concentrations greater than16 μg/mL while this percentage was 78-79% for the CPB+DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP+DHCA (P=0.03). Conclusions: The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.

Cefazolin concentration in surgically created wounds treated with negative pressure wound therapy compared to surgically created wounds treated with nonadherent wound dressings.

To compare cefazolin concentrations in biopsied tissue samples collected from surgically created wounds treated with negative pressure wound therapy to those collected from surgically created wounds treated with nonadherent dressings. Prospective, controlled, experimental study. Adult female spayed Beagles (n = 12). Full thickness cutaneous wounds were created on each antebrachium (n = 24). Immediately after surgery, cefazolin (22 mg/kg intravenously [IV]) was administered to each dog and continued every 8 hours during the study. The right wound was randomly assigned to group I or group II whereas the wound on the contralateral antebrachium was assigned to the other group. Group I wounds were treated with negative pressure wound therapy (NPWT) and group II wounds were treated with nonadherent dressings for 3 days. Dressings were changed and tissue biopsies obtained from wound beds at 24 hours intervals for both groups. Cefazolin wound tissue and plasma concentrations were measured by liquid chromatography mass spectrometry (LC-MS/MS). Blood samples for measuring plasma cefazolin concentrations were collected before biopsy sampling. At the time of surgery and at each subsequent bandage change, wound beds were swabbed and submitted for aerobic and anaerobic culture. After initiating cefazolin treatment, wound tissue antibiotic concentrations between treatment groups were not significantly different at any sampling time. Similarly, after initiating cefazolin treatment, plasma cefazolin concentrations were not significantly different at any sampling time for individual dogs. Using a canine experimental model, NPWT treatment of surgically created wounds does not statistically impact cefazolin tissue concentrations when compared with conventional nonadherent bandage therapy.

Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates

Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. Thirty-six neonates [median birth body weight 2720 (range 540-4200) g, current body weight (cBW) 2755 (830-4200) g and postnatal age (PNA) 9 (1-30) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (>60% of the time) in all patients. A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (Bmax) of 136 mg/L and a dissociation constant (KD) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for Bmax, explaining 50%, 58% and 41% of inter-individual variability in V, clearance and Bmax, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates.

Cefazolin plasma protein binding and its covariates in neonates

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Pharmacokinetics and protein binding of cefazolin in morbidly obese patients

The aim of this study was to assess the pharmacokinetics and protein binding of cefazolin in morbidly obese patients undergoing bariatric surgery, to study the influence of bodyweight measures and age on pharmacokinetic parameters and to evaluate unbound cefazolin concentrations over time in this population. Twenty morbidly obese patients (bodyweight 112-260 kg, body mass index 38-79 kg m(-2)) were studied following the administration of cefazolin 2 g at induction of anaesthesia. Blood samples were collected up to 4 h post-dosing to determine total and unbound plasma cefazolin concentrations. Non-compartmental pharmacokinetic data analysis was performed. Cefazolin clearance was 4.2 ± 1.0 L h(-1) (mean ± standard deviation) and showed a negative correlation with age (p = 0.003) but not with bodyweight measures (p > 0.05). Volume of distribution was 13.0 ± 3.1 L and correlated positively with bodyweight measures (p ≤ 0.001). Saturable protein binding was observed with a median protein binding of 79% (interquartile range 74-82), which proved similar to reported protein binding in non-obese patients. In all patients, unbound cefazolin concentrations remained above 1 mg L(-1) (minimal inhibitory concentration for 90% (MIC(90)) of methicillin-sensitive isolates of Staphylococcus aureus in Europe) until 4 h post-dosing. Younger age--and not bodyweight--was significantly associated with higher cefazolin clearance. However, as in all patients with bodyweights up to 260 kg, unbound plasma cefazolin concentrations remained above 1 mg L(-1) until 4 h after the intravenous administration of a 2-g dose. As such, re-dosing within 4 h or dosing with another antibiotic class should only be considered in the case of a higher MIC(90) of the local isolates.