Cefazolin Plasma Research Articles

Improving cefazolin exposure in critically ill children using a population pharmacokinetic model.

Population pharmacokinetics (PK) models may be effective in improving antibiotic exposure with individualized dosing. The aim of the study is to assess cefazolin exposure using a population PK model in critically ill children. We conducted a single-centre observational study including children under 18 years old who had cefazolin plasma monitoring before and after a cefazolin model implementation. The first concentration at steady state of each cefazolin course was analysed. The optimal exposure was defined by concentration values ranging from free concentration over four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval to total trough or plateau concentration under 100 mg. L-1. A total of 58 patients were included, of whom 39 and 19 children received conventional dosing or model-informed dosing, respectively. Median [range] age was 2.3 [0.1-17]years old, and median weight was 14.2 [2.9-72]kg. There were more continuous infusions (CI) in the model group than in the conventional group (n= 19/19 [100%] vs. n= 23/39 [59%]). Compared to conventional dosing, model-informed dosing provided more optimal exposure (n= 17/39 [44%] vs. n= 15/19 [79%], P= .01) and less underexposure (n= 18/39 [46%] vs. n= 2/19 [10%], P= .008), without increasing overexposure (n= 4/39 [10%] vs. n= 2/19 [11%], P= 1). Moreover, the time to C-reactive protein decrease by 50% was significantly shorter in the model group than the conventional group (3 [0.5-13] vs. 4 [1-34]; P= .045). Use of individualized cefazolin model-informed dosing improves critically ill children's exposure. Further studies are needed to assess the clinical benefit of cefazolin PK model application.

A validated LC-MS/MS method for simultaneous quantitation of piperacillin, cefazolin, and cefoxitin in rat plasma and twelve tissues

BackgroundThe investigation of drug disposition in tissues is critical to improving dosing strategy and maximizing treatment effectiveness, yet developing a multi-tissue bioanalytical method could be challenging due to the differences among various matrices. Herein, we developed an LC-MS/MS method tailored for the quantitation of piperacillin (PIP), cefazolin (CFZ), and cefoxitin (CFX) in rat plasma and 12 tissues, accompanied by validation data for each matrix according to the FDA and EMA guidelines. ResultsThe method required only a small sample volume (5 μL plasma or 50–100 μL tissue homogenates) and a relatively simple protocol for simultaneous quantitation of PIP, CFZ, and CFX within different biological matrices. Mobile phase A was composed of 5 mM ammonium formate and 0.1 % formic acid in water, while mobile phase B contained 0.1 % formic acid in acetonitrile. The mobile phase was pumped through a Synergi Fusion-RP column equipped with a guard column with a gradient elution program at a 0.3 mL/min flow rate. The mass spectrometer was operated in positive ionization mode (ESI+) using multiple reaction monitoring. SignificanceThe validated method has been successfully applied to quantify PIP, CFZ, and CFX from the plasma and tissue samples collected in a pilot rat study and will further be used in a large pharmacokinetic study. To our knowledge, this is also the first report presenting long-term, freeze-thaw, and autosampler stability data for PIP, CFZ, and CFX in rat plasma and multiple tissues.

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.

Morphomics-informed population pharmacokinetic and physiologically-based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis.

Cefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity. To compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery. This prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics-informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically-based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n = 21, body mass index ≥35 kg/m2 with one or more co-morbid conditions). Morphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma-to-subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCLcr ) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 μg/mL for 100% of a 4-h surgical period was below 90% when eCLcr ≥105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 min. Kidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented.

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.

An LC-MS/MS method for the simultaneous determination of 18 antibacterial drugs in human plasma and its application in therapeutic drug monitoring.

Antimicrobial resistance (AMR) is a major threat to global health due to the wide use of antibacterial drugs. Multiple studies show that the pharmacokinetic/pharmacodynamic (PK/PD) studies of antibiotics are an approach to prevent/delay AMR. The pharmacokinetic parameters of antibiotics are the basis of PK/PD studies, and therapeutic drug monitoring (TDM) is the key method to obtain pharmacokinetic information. We developed an ultra-performance liquid chromatography-tandem mass spectrometry to determine 18 antibacterial drugs (piperacillin, cefazolin, cefuroxime, cefoperazone, ceftriaxone, cefepime, aztreonam, meropenem, imipenem, levofloxacin, moxifloxacin, azithromycin, clindamycin, tigecycline, linezolid, vancomycin, voriconazole and caspofungin) in human plasma for practical clinical usage. Samples were prepared using protein precipitation with methanol. Chromatographic separation was accomplished in 6min on a BEH C18 column (2.1 × 100mm, 1.7µm) using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.3ml/min. The electrospray ionization source interface was operated in the positive and negative ionization modes. Inter- and intra-day precision, accuracy, recovery, matrix effect, and stability were validated according to the Food and Drug Administration guidance. The correlation coefficients of calibration curves were all greater than 0.99. The accuracies of the 18 antibacterial drugs ranged from 89.1% to 112.4%. The intra-day precision of the analytes ranged from 1.4% to 9.3% and the inter-day precision from 2.1% to 7.2%. The matrix effects ranged from 93.1% to 105.8% and the extraction recoveries ranged between 90.1% and 109.2%. The stabilities of the 18 antibacterial drugs in plasma were evaluated by analyzing three different concentrations following storage at three storage conditions. All samples displayed variations less than 15.0%. The validated method was successfully applied to routine clinical TDM for 231 samples.

LC–MS/MS method for simultaneous quantification of ten antibiotics in human plasma for routine therapeutic drug monitoring

BackgroundOptimizing antimicrobial therapy to attain drug exposure that limits the emergence of resistance, effectively treats the infection, and reduces the risk of side effects is of a particular importance in critically ill patients, in whom normal functions are augmented or/and are infected with pathogens less sensitive to treatment. Achievement of these goals can be enhanced by therapeutic drug monitoring (TDM) for many antibiotics. A liquid chromatography tandem mass spectrometry (LC–MS/MS) method is presented here for simultaneous quantification of ten antimicrobials: cefazolin (CZO), cefepime (CEP), cefotaxime (CTA), ceftazidime (CTZ), ciprofloxacin (CIP), flucloxacillin (FLU), linezolid (LIN), meropenem (MER), piperacillin (PIP) and tazobactam (TAZ) in human plasma. MethodsPlasma samples were precipitated with acetonitrile and injected into the LC–MS/MS. Chromatographic separation was on a Waters Acquity BEH C18 column. Compounds were eluted with water and acetonitrile containing 0.1 % formic acid, using a gradient (0.5–65 % B), in 3.8 min. The flow rate was 0.4 mL/min, and the run time was 5.8 min. ResultsThe calibration curves were linear across the tested concentration ranges (0.5–250, CZO, CEP, CTA, CTZ and FLU; 0.2–100, MER and TAZ; 0.1–50, CIP and LIN and 1–500 mg/L, PIP). The intra and inter-day imprecision was < 11 %. Accuracy ranged from 95 to 114 %. CTZ and MER showed ionization suppression while CIP showed ionization enhancement, which was normalized with the use of the internal standard. ConclusionAn LC–MS/MS method for simultaneous quantification of ten antimicrobials in human plasma was developed for routine TDM.

Plasma and Interstitial Fluid Pharmacokinetics of Prophylactic Cefazolin in Elective Bariatric Surgery Patients.

Guidelines for surgical prophylactic dosing of cefazolin in bariatric surgery vary in terms of recommended dose. This study aimed to describe the plasma and interstitial fluid (ISF) cefazolin pharmacokinetics in patients undergoing bariatric surgery and to determine an optimum dosing regimen. Abdominal subcutaneous ISF concentrations (measured using microdialysis) and plasma samples were collected at regular time points after administration of cefazolin 2 g intravenously. Total and unbound cefazolin concentrations were assayed and then modeled using Pmetrics. Monte Carlo dosing simulations (n = 5,000) were used to define cefazolin dosing regimens able to achieve a fractional target attainment (FTA) of >95% in the ISF suitable for the MIC for Staphylococcus aureus in isolates of ≤2 mg · L-1 and for a surgical duration of 4 h. Fourteen patients were included, with a mean (standard deviation [SD]) bodyweight of 148 (35) kg and body mass index (BMI) of 48 kg · m-2. Cefazolin protein binding ranged from 14 to 36% with variable penetration into ISF of 58% ± 56%. Cefazolin was best described as a four-compartment model including nonlinear protein binding. The mean central volume of distribution in the final model was 18.2 (SD 3.31) L, and the mean clearance was 32.4 (SD 20.2) L · h-1. A standard 2-g dose achieved an FTA of >95% for all patients with BMIs ranging from 36 to 69 kg · m-2. A 2-g prophylactic cefazolin dose achieves appropriate unbound plasma and ISF concentrations in obese and morbidly obese bariatric surgery patients.

Development and validation of a simple and sensitive LC-MS/MS method for the quantification of cefazolin in human plasma and its application to a clinical pharmacokinetic study

Cefazolin is widely used during surgery to prevent surgical site infections (SSIs). Although cefazolin redosing is often needed due to its short half-life, the appropriate redosing schedule remains controversial and there is limited information on cefazolin disposition following repeated doses during surgery. In parallel with an ongoing cefazolin redosing clinical study, we have developed and fully validated a simple and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of cefazolin in human plasma. A simple protein precipitation was used for sample preparation. MS/MS analysis was performed using multiple reaction monitoring (MRM) under a positive ionization mode. The lower limit of quantification (LLOQ) for cefazolin was evaluated at 0.25 µg/mL and a linearity ranging from 0.25 to 300 µg/mL. Accuracy was ≤ 114.3% for quality controls and ≤ 118.2% for LLOQ; intra-day and inter-day precision ranging from 1.9% to 14.2% for all quality controls and LLOQ. Matrix effect, extraction recovery, stability testing, dilution integrity, hemolysis effects and whole blood stability have all been investigated. A total of 17 parameters were validated and passed their validation criteria. The method was applied in the quantification of cefazolin in clinical plasma samples and was able to successfully determine the concentrations in patients undergoing various surgeries. In comparison with other prior published methods, our method has a simple sample preparation combined with a short analysis run time, a wide dynamic range and low limit of quantification, and is a fully validated assay that abides by FDA guidance.

Population pharmacokinetics of cefazolin in maternal and umbilical cord plasma, and simulated exposure in term neonates.

Intra-partum cefazolin is used to prevent group B Streptococcus (GBS) vertical transmission in mothers allergic to penicillin without a history of anaphylaxis. To investigate the maternal cefazolin dose-exposure relationship and subsequent maternal and neonatal target attainment at delivery. Data were obtained from 24 healthy, GBS-colonized pregnant women (20-41 years), undergoing vaginal delivery (gestational age ≥37 weeks). During labour, all women received a 2 g cefazolin IV infusion. Eight hours later, eight women received another 1 g in the event of delayed (>8 h) delivery. Next to maternal plasma concentrations (up to 10 per dosing interval, until delivery), venous and arterial umbilical cord concentrations were determined at delivery. Target attainment in maternal/neonatal plasma was set at 1 mg/L for 60% of the dosing interval (unbound cefazolin, worst-case clinical breakpoint). A population pharmacokinetic (popPK) model was built (NONMEM 7.4). ClinicalTrials.gov Identifier: NCT01295606. At delivery, maternal blood and arterial umbilical cord unbound cefazolin concentrations were >1 mg/L in 23/24 (95.8%) and 11/12 (91.7%), respectively. The popPK of cefazolin in pregnant women was described by a two-compartment model with first-order elimination. Two additional compartments described the venous and arterial umbilical cord concentration data. Cefazolin target attainment was adequate in the studied cohort, where delivery occurred no later than 6.5 h after either the first or the second dose. PopPK simulations showed adequate maternal and umbilical cord exposure for 12 h following the first dose. PopPK simulations showed that standard pre-delivery maternal cefazolin dosing provided adequate target attainment up to the time of delivery.

Excessive unbound cefazolin concentrations in critically ill patients receiving veno-arterial extracorporeal membrane oxygenation (vaECMO): an observational study

The scope of extracorporeal membrane oxygenation (ECMO) is expanding, nevertheless, pharmacokinetics in patients receiving cardiorespiratory support are fairly unknown leading to unpredictable drug concentrations. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This study aims to evaluate the pharmacokinetics (PK) of cefazolin in patients undergoing ECMO treatment. Total and unbound plasma cefazolin concentration of critically ill patients on veno-arterial ECMO were determined. Observed PK was compared to dose recommendations calculated by an online available, free dosing software. Concentration of cefazolin varied broadly despite same dosage in all patients. The mean total and unbound plasma concentration were high showing significantly (p = 5.8913 E−09) greater unbound fraction compared to a standard patient. Cefazolin clearance was significantly (p = 0.009) higher in patients with preserved renal function compared with CRRT. Based upon the calculated clearance, the use of dosing software would have led to lower but still sufficient concentrations of cefazolin in general. Our study shows that a “one size fits all” dosing regimen leads to excessive unbound cefazolin concentration in these patients. They exhibit high PK variability and decreased cefazolin clearance on ECMO appears to compensate for ECMO- and critical illness-related increases in volume of distribution.

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.

Perioperative administration of cefazolin and metronidazole in obese and non-obese patients: a pharmacokinetic study in plasma and interstitial fluid.

To assess plasma and tissue pharmacokinetics of cefazolin and metronidazole in obese patients undergoing bariatric surgery and non-obese patients undergoing intra-abdominal surgery. Fifteen obese and 15 non-obese patients received an IV short infusion of 2 g cefazolin and 0.5 g metronidazole for perioperative prophylaxis. Plasma and microdialysate from subcutaneous tissue were sampled until 8 h after dosing. Drug concentrations were determined by HPLC-UV. Pharmacokinetic parameters were calculated non-compartmentally. In obese patients (BMI 39.5-69.3 kg/m2) compared with non-obese patients (BMI 18.7-29.8 kg/m2), mean Cmax of total cefazolin in plasma was lower (115 versus 174 mg/L) and Vss was higher (19.4 versus 14.2 L). The mean differences in t½ (2.7 versus 2.4 h), CL (5.14 versus 4.63 L/h) and AUC∞ (402 versus 450 mg·h/L) were not significant. The influence of obesity on the pharmacokinetics of metronidazole was similar (Cmax 8.99 versus 14.7 mg/L, Vss 73.9 versus 51.8 L, t½ 11.9 versus 9.1 h, CL 4.62 versus 4.13 L/h, AUC∞ 116 versus 127 mg·h/L). Regarding interstitial fluid (ISF), mean concentrations of cefazolin remained >4 mg/L until 6 h in both groups, and those of metronidazole up to 8 h in the non-obese group. In obese patients, the mean ISF concentrations of metronidazole were between 3 and 3.5 mg/L throughout the measuring interval. During the time of surgery, cefazolin concentrations in plasma and ISF of subcutaneous tissue were lower in obese patients, but not clinically relevant. Regarding metronidazole, the respective differences were higher, and may influence dosing of metronidazole for perioperative prophylaxis in obese patients.

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.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.

The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16mg/L was proposed. PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.

Intraperitoneal cefazolin and ceftazidime during short-dwell exchange in peritoneal dialysis patients with peritonitis.

Intraperitoneal (IP) cefazolin and ceftazidime during the short-dwell (≤ 2 h) automated exchange has been shown to provide adequate dialysate and plasma concentrations for up to 24 h in peritoneal dialysis (PD) patients without peritonitis. This study aimed to evaluate plasma and dialysate concentration of this novel IP cefazolin and ceftazidime regimen during the first 24 h in PD patients with peritonitis. Cefazolin and ceftazidime (2500 mg each) were added to in to a 5-L bag containing 2.5% of dextrose PD fluid which was placed on the warmer of PD cycling machine. Patients underwent five exchanges of 2-L PD fluid over 10 h by the PD cycling machine without last fill or additional dwell. Plasma samples and dialysate samples were collected over 24 h. Cefazolin and ceftazidime concentrations in plasma and dialysate were determined by high-performance liquid chromatography. Seven PD patients with peritonitis participated in this study. Plasma cefazolin and ceftazidime levels increased substantially within the first few hours, peaked around 6-10 h, and sustained well above the target plasma concentrations (10 mg L-1 for cefazolin and 16 mg L-1 for ceftazidime) until 24 h. Dialysate cefazolin and ceftazidime levels were sustained above the target peritoneal concentrations (2 mg L-1 for cefazolin and 8 mg L-1 for ceftazidime) throughout the PD session except in some samples which the antibiotics levels were unusually low, probably from beta-lactamase activity. IP cefazolin and ceftazidime during the short-dwell automated exchange could provide adequate dialysate and plasma concentrations in peritonitis patients. This novel regimen is a promising regimen for peritonitis in PD patients.

Simultaneous determination of eight β-lactam antibiotics in human plasma and cerebrospinal fluid by liquid chromatography coupled to tandem mass spectrometry

Therapeutic drug monitoring of β-lactam antibiotics is increasingly used for dose optimization in the individual patient to increase efficacy and reduce the risk of toxicity. The objective of this work is to develop and validate a fast and reliable method using liquid chromatography coupled to tandem mass spectrometric detection to quantify simultaneously amoxicillin, cloxacillin, cefazolin, cefotaxime, ceftazidime, cefepime, meropenem and piperacillin in plasma and cerebrospinal fluid (CSF).Sample clean-up included protein precipitation with acetonitrile followed by evaporation of the supernatant and reconstitution of the residue with mobile phase solvents. Eight deuterated β-lactam antibiotics were used as internal standards. Chromatographic separation was performed on a C18 column (50 mm x 2.1 mm) using a binary gradient elution of water and acetonitrile both containing 0.1% (v/v) formic acid. The total run time was 8 min. The method was then used to perform therapeutic drug monitoring on 2221 patient plasma samples. 32 CSF samples were also analyzed.This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma and cerebrospinal fluid concentration of β-lactam antibiotics and can be used for therapeutic drug monitoring.

Determination of total or free cefazolin and metronidazole in human plasma or interstitial fluid by HPLC-UV for pharmacokinetic studies in man

Cefazolin (CFZ) plus metronidazole (MTZ) is commonly used for perioperative antibiotic prophylaxis. An HPLC-UV method is described for the simultaneous determination of total or free cefazolin and metronidazole in human plasma or in microdialysate of subcutaneous tissue. Separation was performed isocratically using a reversed phase column and phosphate buffer/acetonitrile as mobile phase. The validation characteristics were similar for both drugs. Linearity has been shown down to 0.1 mg/L (R > 0.9990). Intra- and inter-assay precision (CV) and in-accuracy were < 5%. The method was applied to the determination of cefazolin and metronidazole in plasma and microdialysate of surgical patients following 30-min intravenous infusion of cefazolin/metronidazole 2.0/0.5 g.

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.