Halloysite nanotubes-based hybrid silica monolithic spin tip for hydrophilic solid-phase extraction of sulbactam, cefoperazone, and cefuroxime in whole blood.

In this study, we proposed a novel method utilizing polyethyleneimine (PEI)-modified halloysite nanotubes (HNTs)-based hybrid silica monolithic spin tip to analyze hydrophilic ß-lactam antibiotics and ß-lactamases inhibitors in whole blood samples for the first time. HNTs were incorporated directly into the hybrid silica monolith via a sol-gel method, which improved the hydrophilicity of the matrix. The as-prepared monolith was further modified with PEI by glutaraldehyde coupling reaction. It was found that the PEI-modified HNTs-based hybrid silica monolith enabled a large adsorption capacity of cefoperazone at 35.7 mg g-1. The monolithic spin tip-based purification method greatly reduced the matrix effect of whole blood samples and had a detection limit as low as 0.1 - 0.2 ng mL-1. In addition, the spiked recoveries of sulbactam, cefuroxime, and cefoperazone in blank whole blood were in the range of 89.3-105.4 % for intra-day and 90.6-103.5 % for inter-day, with low relative standard deviations of 1.3-7.2 % and 4.9-10.5 %, respectively. This study introduces a new strategy for preparing nanoparticles incorporated in a hybrid silica monolith with a high adsorption capacity. Moreover, it offers a valuable tool to monitor sulbactam, cefoperazone, and cefuroxime in whole blood from pregnant women with the final aim of guiding their administration.

A fast, cost-saving and sensitive method for determination of cefuroxime in plasma by HPLC with ultraviolet detection.

Cefuroxime (CFX) is a broad-spectrum second-generation cephalosporin and one of the best choices for antibiotic prophylaxis. However, when used in critically ill patients, it may present changes in its pharmacokinetic properties. Therefore, therapeutic drug monitoring of CFX is necessary for effective dosing strategies. A simple, rapid and sensitive liquid chromatographic method with UV detection was developed and validated for the quantification of CFX in plasma. The method involved a single-step precipitation of proteins with methanol and trifluoroacetic acid. Cefuroxime was analyzed on a Brisa LC2 C18 column in isocratic mode consisting of 0.1% trifluoroacetic acid in water and acetonitrile (75:25) with UV detection at a wavelength of 280 nm. The retention times of CFX and cephazolin (internal standard) were 9.8 and 7.4 min, respectively. The calibration curve was linear over a concentration range of 0.25-50 µg/ml. The limits of detection and quantification were 0.1 µg/ml and 0.25 µg/ml, respectively. The accuracy and precision were always <10%. The mean recovery was 93.52%. This fast and simple method could be applied in routine analysis and pharmacokinetic studies.

Simultaneous quantification of cefuroxime and clindamycin in human lumbar anulus fibrosus, nucleus pulposus and serum via UPLC-MS/MS.

BACKGROUND: This study aimed to develop a sensitive, accurate method for simultaneously quantifying cefuroxime and clindamycin in human serum, lumbar anulus fibrosus and nucleus pulposus. METHODS: Cefuroxime and clindamycin were quantified using ultra high-performance liquid chromatography-electrospray ionization tandem mass spectrometry in multiple-reaction-monitoring mode on a triple-quadrupole AB Qtrap 5500 system in positive ion mode. Internal standards were D3-cefuroxime and D3,13C-clindamycin. Samples were pretreated by precipitating total protein. RESULTS: The method showed high sensitivity and good linearity over broad calibration ranges from 100 to 100 000 ng/mL for cefuroxime and 10 to 10 000 ng/mL for clindamycin in serum, and from 10 to 10 000 ng/mL for cefuroxime and 1 to 1 000 ng/mL for clindamycin in lumbar nucleus pulposus. In all sample types, correlation coefficients were greater than 0.99, intra- and inter-day precision (relative standard deviation) was less than 15%, and accuracy (relative error) was within 14% for both analytes. This method was effective at quantifying penetration of cefuroxime and clindamycin in patients undergoing oblique lumbar interbody fusion surgery. CONCLUSIONS: A very sensitive, specific method for simultaneous detection of cefuroxime and clindamycin has been developed for human lumbar anulus fibrosus, nucleus pulposus and serum samples.

Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women.

AIM: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs. METHOD: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature. RESULTS: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data. CONCLUSIONS: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women.

Quantification of total and unbound cefuroxime in plasma by ultra-performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure.

BACKGROUND: Pharmacokinetic studies of cefuroxime by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC-MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. METHODS: Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC-MS/MS. Sampling times were categorized as trough (180-1 min prior to administration), peak (10-30 min after administration), mid (30-360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). RESULTS: Intra-assay and inter-assay precision was <3%. Recovery was 99.7%-100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54-77). Median albumin serum concentrations and eGFR were 19 g/L (range 11-40 g/L) and 48 mL/min/1.73 m2 (range 7-115 mL/min/1.73 m2 ), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42-54.03 mg/L) and 71.49 mg/L (range 53.87-73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%-99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85-32.39 mg/L) (trough) and 55.62 mg/L (range 10.03-62.62 mg/L) (mid). CONCLUSION: The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5-100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.

Population pharmacokinetics of cefuroxime and uptake into hip and spine bone of patients undergoing orthopaedic surgery.

OBJECTIVES: To reduce the incidence of peri- or postoperative infections in orthopaedic surgery, patients are prophylactically treated with antibiotics. Here, we wanted to know whether effective bone and intervertebral disc concentrations of cefuroxime are reached. METHODS: Patients undergoing surgery of hip (N = 40; 62.5% male) or spine (N = 40; 55% male) were pretreated with 1.5 g of the second-generation cephalosporin cefuroxime before surgery. We studied plasma population kinetics and bone and intervertebral disc (C5/6 till L5/S1) concentrations of cefuroxime using high-performance liquid chromatography. KEY FINDINGS: The plasma kinetics of cefuroxime in 80 patients was analysed using a population approach. The clearance amounted to 7.86 l/h. The peripheral and central volumes of distribution were estimated as 8.45 and 10.4 l, respectively. The concentrations in hip samples amounted to 9.8 ± 0.6 µg/g in cancellous bone and 8.9 ± 0.8 µg/g in cortical bone. Cefuroxime concentrations in vertebral bone and intervertebral discs were calculated as 9.6 ± 1.3 and 8.9 ± 1.1 µg/g, respectively. CONCLUSION: Even if a majority of patients undergoing hip or spine surgery probably achieved adequate concentrations of cefuroxime, not all patients reached bone concentrations of cefuroxime above a recommended breakpoint for susceptible germs at the time of surgery.

Bone, subcutaneous tissue and plasma pharmacokinetics of cefuroxime in total knee replacement patients - a randomized controlled trial comparing continuous and short-term infusion.

Cefuroxime is widely used as antibiotic prophylaxis for orthopaedic procedures. We evaluated bone, subcutaneous tissue (SCT) and plasma pharmacokinetics of cefuroxime in male patients undergoing total knee replacement (TKR) after both traditional short-term infusion (STI) and continuous infusion (CI). Eighteen male patients undergoing TKR were randomly assigned to STI or CI of 1.5 g of cefuroxime. Measurements were obtained in plasma, SCT, cancellous and cortical bone every 30 min for 8 h following surgery. For sampling in solid tissues, microdialysis was applied. Population pharmacokinetic modelling was performed in order to estimate pharmacokinetic parameters, and to assess the probability of attaining cefuroxime concentrations above clinically relevant minimal inhibitory concentrations (MICs) for 65% and 90% of the 8 h dosing interval. Low SCT and cortical bone penetration were found in both the STI and the CI group, but the findings were only significant in the STI group. Irrespective of MIC, tissue and target, CI leads to improved probability of attaining relevant pharmacokinetic targets compared with STI. For the Staphylococcus aureus MIC breakpoint (4 µg/mL), STI leads to inadequate probability of target attainment. CI of 1.5 g of cefuroxime leads to improved probability of attaining relevant pharmacokinetic targets in male TKR patients compared with traditional STI. These findings suggest that application of CI may improve antibiotic prophylaxis for male TKR patients.

Physiologically based pharmacokinetic evaluation of cefuroxime in perioperative antibiotic prophylaxis.

AIMS: Adequate plasma concentrations of antibiotics during surgery are essential for the prevention of surgical site infections. We examined the pharmacokinetics of 1.5 g cefuroxime administered during induction of anaesthesia with follow-up doses every 2.5 hours until the end of surgery. We built a physiologically based pharmacokinetic model with the aim to ensure adequate antibiotic plasma concentrations in a heterogeneous population. METHODS: A physiologically based pharmacokinetic model (PK-Sim® /MoBi® ) was developed to investigate unbound plasma concentrations of cefuroxime. Blood samples from 25 thoracic surgical patients were analysed with high-performance liquid chromatography. To evaluate optimized dosing regimens, physiologically based pharmacokinetic model simulations were conducted. RESULTS: Dosing simulations revealed that a standard dosing regimen of 1.5 g every 2.5 hours reached the pharmacokinetic/pharmacodynamic target for Staphylococcus aureus. However, for Escherichia coli, >50% of the study participants did not reach predefined targets. Effectiveness of cefuroxime against E. coli can be improved by administering a 1.5 g bolus immediately followed by a continuous infusion of 3 g cefuroxime over 3 hours. CONCLUSION: The use of cefuroxime for perioperative antibiotic prophylaxis to prevent staphylococcal surgical site infections appears to be effective with standard dosing of 1.5 g preoperatively and follow-up doses every 2.5 hours. In contrast, if E. coli is relevant in surgeries, this dosing regimen appears insufficient. With our derived dose recommendations, we provide a solution for this issue.

Preparation and evaluation of cefuroxime axetil gastro-retentive floating drug delivery system via hot melt extrusion technology.

Cefuroxime Axetil (CA) is a poorly soluble, broad spectrum antibiotic which undergoes enzymatic degradation in gastrointestinal tract. The objective of the present study was to develop lipid-based gastro-retentive floating drug delivery systems containing CA using hot-melt extrusion (HME) to improve absorption. Selected formulations of CA and lipids were extruded using a twin screw hot-melt extruder. Milled extrudates were characterized for dissolution, floating strength, and micromeritic properties. Solid-state characterization was performed using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and hot-stage microscopy. In vitro characterization demonstrated that the formulations exhibited a sustained drug release profile for 12 h. All formulations showed desired floating and flow properties. Solid-state characterization revealed no phase separation and no chemical interactions between the drug and excipients. Based on in vitro study results, an optimized formulation (F8) was further evaluated for in vivo performance. Oral bioavailability (Cmax and AUC0-24h) of F8 was significantly higher than that of pure CA. This study describes the use of lipid-based gastro-retentive floating drug delivery systems to achieve desired sustained release profile for more complete dissolution which could potentially reduce enzymatic degradation. This study also highlights the effectiveness of HME technology to improve dissolution and bioavailability.

Colo-Pro: a pilot randomised controlled trial to compare standard bolus-dosed cefuroxime prophylaxis to bolus-continuous infusion-dosed cefuroxime prophylaxis for the prevention of infections after colorectal surgery.

Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus-infusion (intervention arm) targeting free serum cefuroxime concentrations of 64 mg/L, or 1.5 g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500 mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2 h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64 mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30 days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). These infection rates can be used to power future clinical trials. This study demonstrates the feasibility of cefuroxime bolus-continuous infusion of antibiotic prophylaxis trials, and provides safety data for infusions targeting free serum cefuroxime concentrations of 64 mg/L. Trial registration: NCT02445859 .

Synthesis and characterization of triazole based supramolecule for interaction with cefuroxime in tap water and blood plasma.

In this study a new calix[4]arene triazole 5 was successfully synthesized using click reaction and characterized through UV-visible, FT-IR, 1H NMR spectroscopes and Mass Spectrometry. The supramolecular interaction of compound 5 towards commonly used drugs has been carried out using UV-Visible spectroscopy. The supramolecule 5 showed characteristic enhancement in the absorbance intensity after mixing with Cefuroxime at pH (2-12). Compound 5 displayed considerably good interactions with cefuroxime in the presence of other drugs. Compound 5 exhibits linear relationship with cefuroxime concentration in the range of (10-80µM) with regression value of 0.9954. The standard deviation for 50µM Cefuroxime was found to be 0.01 and the limit of detection for cefuroxime was calculated to be 2µM. Job's plot experiments showed 1:1 (5: cefuroxime) binding stoichiometry between compound 5 and cefuroxime. Supramolecule 5 displayed fairly good spectrophotometric recognition of Cefuroxime in human blood plasma and tap water thus showing that the ingredients of tap water and plasma sample was inert in the recognition of cefuroxime.

Pharmacokinetics of Cefuroxime in Synovial Fluid.

Cefuroxime is frequently used as preoperative antibiotic prophylaxis and may be used for the treatment of septic arthritis. A prerequisite for successful treatment of septic arthritis is the ability of an antibiotic agent to penetrate into the target site. Therefore, the concentration of cefuroxime in synovial fluid was evaluated. Ten patients who underwent elective knee arthroscopy were included in this study. Patients were treated with a single dose of 1,500 mg cefuroxime intravenously, and subsequently, the concentrations in plasma, the interstitial fluid of muscle tissue, and synovial fluid were measured by using microdialysis. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing were performed using the epidemiologically defined MIC90 for clinical isolates and CLSI breakpoints. Cefuroxime penetrated excellently into muscle tissue (ratio of the area under the concentration-time curve [AUC] for muscle tissue/AUC for free plasma, 1.79) and synovial fluid (ratio of the AUC for synovial fluid/AUC for free plasma, 1.94). The cefuroxime concentration was greater than the MIC90 for Staphylococcus aureus and S. epidermidis strains (≤2 mg/liter) over the complete dosing interval (the percentage of the dosing interval during which the free cefuroxime concentration exceeded the MIC for the pathogen [fTMIC]). CLSI defines staphylococci with MICs of ≤8 mg/liter to be susceptible to cefuroxime. For staphylococci with MICs of ≤8 mg/liter, the fTMIC in plasma was 52.5%, while the fTMIC in muscle tissue and synovial fluid was 93.6% and 96.3%, respectively. Cefuroxime may be used to treat septic arthritis caused by susceptible bacterial strains (MIC ≤ 8 mg/liter). The activity of cefuroxime in septic arthritis might be underestimated when relying exclusively on plasma concentrations.

Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml-1) from only 1 µl of serum. The system's applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Treatment of cefuroxime-induced neurotoxicity with continuous venovenous haemofiltration.

A 61-year-old woman with decreased consciousness, myoclonus, tremors, nystagmus and bradypnoea, due to cefuroxime-induced neurotoxicity, was admitted to the intensive care unit. Continuous venovenous haemofiltration (CVVH) rapidly reduced plasma cefuroxime concentrations and improved neurological manifestations within the next few hours. Retrospective pharmacokinetic assessment showed a total cefuroxime clearance of 166 ml/min during the CVVH.

Quantification of three beta-lactam antibiotics in breast milk and human plasma by hydrophilic interaction liquid chromatography/positive-ion electrospray ionization mass spectrometry.

The use of cephalosporins during breast feeding raises several issues, including the risk of drug exposure through breast milk for the infant. In this paper, a hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometric assay (HILIC/ESI-MS) was developed for the quantitation of cefuroxime, cefoxitin, and cefazolin in breast milk and human plasma. The assay was based on the use of small sample size, 25 µL of biological samples, following acetonitrile precipitation of proteins and filtration that enabled injection into the HILIC/ESI-MS system. All analytes and the internal standard, alfuzosin, were separated by using a ZIC®-HILIC analytical column (150.0 × 2.1 mm i.d., particle size 3.5 µm, 200 Å) with isocratic elution. The mobile phase was composed of a 6% 12.5 mM ammonium acetate water solution in acetonitrile and pumped at a flow rate of 0.25 mL min-1 . The assay was linear over a concentration range of 0.2 to 5 µg mL-1 and 0.4 to 20 µg mL-1 for all the analytes in breast milk and in human plasma, respectively. Intermediate precision was found to be less than 4.2% over the tested concentration ranges. A run time of less than 12 min for each sample made it possible to analyze a large number of biological samples per day. The method is the first reported application of HILIC in the analysis of antibiotics in breast milk and human plasma and it can be used to support a wide range of clinical studies. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of Implant-Associated Osteomyelitis on Cefuroxime Bone Pharmacokinetics: Assessment in a Porcine Model.

BACKGROUND: The prolonged antibiotic therapy that is often needed for successful management of osteomyelitis may be related to incomplete penetration of antibiotics into the target site. The objective of this study was to assess the effects of implant-associated osteomyelitis on cefuroxime penetration into bone. METHODS: Implant-associated osteomyelitis using a Staphylococcus aureus strain was induced in the right tibia in ten pigs. After five days and following administration of 1500 mg of cefuroxime, measurements of cefuroxime were obtained using microdialysis for eight hours in the implant-related bone cavity, in the adjacent infected cancellous bone and infected subcutaneous tissue, and in healthy cancellous bone and subcutaneous tissue in the contralateral leg. Measurements of the corresponding free plasma concentrations were also obtained. The extent of the infection was assessed by postmortem computed tomography (CT) scans and cultures of blood, swabs, and bone specimens. RESULTS: Bone destruction was found in the implant cavities. No structural bone changes in the adjacent infected cancellous bone were visible on CT scans. S. aureus was grown on culture of specimens from all implant cavities and from eight of ten swabs and seven of ten bone samples from the infected bone. The areas under the concentration-time curves for the different tissues differed significantly, with the lowest area under the curve found in the implant cavity (analysis of variance; p < 0.001). Although not as notable as for the implant cavity, cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. Despite poorer tissue penetration, slightly increased time with concentrations above the minimal inhibitory concentration (MIC) was achieved in the implant cavity up to MICs of 2 mg/L compared with the other tissues, but the time was shorter for higher MICs. CONCLUSIONS: Cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. The destructive bone processes associated with acute osteomyelitis reduced cefuroxime penetration further. CLINICAL RELEVANCE: These findings support the general clinical perception that fast diagnosis and early initiation of antibiotics before the development of implant-associated cavities is important in nonsurgical management of acute osteomyelitis.

Decreased placental and transcellular permeation of cefuroxime in pregnant women with diabetes.

BACKGROUND: The present study investigated the transcellular and placental permeation of cefuroxime, an antibiotic used in cesarean sections, in pregnant women with diabetes and hypertension. METHODS: Fifty-three women scheduled for cesarean section were divided into three groups: healthy women (n = 18), women with arterial hypertension (n = 21), and women with gestational diabetes (n = 14). All women received 1.5 g, i.v., cefuroxime. Cefuroxime concentrations were measured in maternal venous plasma before, during, and after delivery, as well as in fetal umbilical cord vein and artery plasma during delivery. The effects of diabetes and hypertension on cefuroxime placental-permeation were assessed by the fetomaternal plasma concentration ratios. Pharmacokinetic non-compartmental model analyses were performed and results were compared using anova. RESULTS: Fetomaternal drug concentration ratios were lower in the diabetic group than in the hypertensive and control groups. There were no significant differences in umbilical arterial : venous plasma drug concentration ratios in the diabetic and hypertensive groups compared with the control group. Apparent volume of distribution and clearance were significantly lower in the diabetic group compared with the control and hypertensive groups. CONCLUSIONS: Diabetes led to decreased placental transfer of cefuroxime, as well as volume of distribution and clearance, but did not affect other pharmacokinetic parameters. Hypertension had no significant effect on the permeation of cefuroxime or on its pharmacokinetics. Prophylactic concentrations of cefuroxime were reached in all groups, but the dosing time of cefuroxime should not be less than 30 min or greater than 2 h prior to delivery.

Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs.

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12-h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (Cmax ), time-to-peak plasma concentration (Tmax ), and bioavailability for the intramuscular and subcutaneous administration were (mean ± SD) 22.99 ± 7.87 µg/mL, 0.43 ± 0.20 h, and 79.70 ± 14.43% and 15.37 ± 3.07 µg/mL, 0.99 ± 0.10 h, and 77.22 ± 21.41%, respectively. Elimination half-lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 ± 0.19 h and 1.49 ± 0.21 h; 1.13 ± 0.13 and 1.79 ± 0.24 h; and 1.04 ± 0.23 h and 2.21 ± 0.23 h, respectively. Significant differences were found between routes for Ka , MAT, Cmax , Tmax , t½(a) , and MRT. T > MIC = 50%, considering a MIC of 1 µg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 µg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.

Targeting cefuroxime plasma concentrations during coronary artery bypass graft surgery with cardiopulmonary bypass.

BACKGOUND: Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. OBJECTIVE: The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). SETTING: A Dutch teaching hospital. METHODS: In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an 'iterative two-stage Bayesian population procedure'. MAIN OUTCOME MEASURE: Unbound plasma concentrations of cefuroxime. RESULTS: 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age <60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. CONCLUSION: Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value.

Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model.

The relatively short half-lives of most ß-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 µg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach.