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.
ABSTRACT: 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 .
Project description: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.
Project description:AIMS:Very little data exist regarding the effect of cardiopulmonary bypass (CPB) on cefuroxime (CXM) pharmacokinetics in children less than one year of age. METHODS:50 mg kg-1 CXM i.v. after induction were followed by 75 mg kg-1 into the CPB circuit. In 42 patients undergoing cardiac surgery, 15-20 samples were obtained between 5 and 360 min after the first dose. Total CXM concentrations were measured by high-performance liquid chromatography and a pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed. RESULTS:Using a fixed protein binding of 15.6% for CXM, peak plasma concentrations of unbound CXM were 229 ± 52 μg ml-1 after the first bolus and 341 ± 86 μg ml-1 on CPB. Nadir concentrations before CPB were 69 ± 20 μg ml-1 and six hours later decreased to 41 ± 19 μg ml-1 with and 24 ± 14 μg ml-1 without CPB. A two-compartment model was fitted with the main covariates body weight, CPB and postmenstrual age (PMA). PK parameters were as follows: systemic clearance, 5.15 [95% CI 4.5-5.8] l h-1 ; central volume of distribution, 11.25 [9.41-13.09] l; intercompartmental clearance, 18.19 [14.79-21.58] l h-1 ; and peripheral volume, 17.07 [15.7-18.5] L. ƒT > MIC of 32 μg ml-1 for an 8-h time period was between 70 and 100% (2.5-10 kg BW). According to our simulation, 25 mg ml-1 CXM as a primary bolus and into the prime plus a 5 mg kg-1 h-1 infusion maintain CXM concentrations continuously above 32 μg ml-1 . CONCLUSIONS:The routine dosing regimen provided was sufficient for prophylaxis, but continuous dosing can provide a higher percentage of ƒT > MIC.
Project description:Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare. Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1,500 mg were measured by microdialysis in brain tissue, as well as in plasma at steady-state (n = 6) or after single-dose administration (n = 1). At steady state, free area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 389.0 ± 210.3 mg/liter·h and 131.4 ± 72.8 mg/liter·h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC0-24 brain/AUC0-24 free plasma) of 0.33 ± 0.1. Plasma and brain tissue concentrations at individual time points correlated well (R = 0.59, P = 0.001). At steady-state time over MIC (t>MIC) values of >40% of dosing interval were achieved up to an MIC of 16 mg/liter for plasma and 4 mg/liter for brain tissue. Although MIC90 values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4 mg/liter. The activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.
Project description:The efficacy and safety of a single dose of ampicillin/sulbactam compared to a single dose of cefuroxime at cord clamp for prevention of post-cesarean infectious morbidity has not been assessed.Women scheduled for cesarean delivery were randomized to receive a single dose of either 3 g of ampicillin-sulbactam or 1.5 g of cefuroxime intravenously, after umbilical cord clamping. An evaluation for development of postoperative infections and risk factor analysis was performed.One hundred and seventy-six patients (median age 28 yrs, IQR: 24-32) were enrolled in the study during the period July 2004-July 2005. Eighty-five (48.3%) received cefuroxime prophylaxis and 91 (51.7%) ampicillin/sulbactam. Postoperative infection developed in 5 of 86 (5.9%) patients that received cefuroxime compared to 8 of 91 (8.8%) patients that received ampicillin/sulbactam (p=0.6). In univariate analyses 6 or more vaginal examinations prior to the operation (p=0.004), membrane rupture for more than 6 hours (p=0.08) and blood loss greater than 500 ml (p=0.018) were associated with developing a postoperative surgical site infection (SSI). In logistic regression having 6 or more vaginal examinations was the most significant risk factor for a postoperative SSI (OR 6.8, 95% CI: 1.4-33.4, p=0.019). Regular prenatal follow-up was associated with a protective effect (OR 0.04, 95% CI: 0.005-0.36, p=0.004).Ampicillin/sulbactam was as safe and effective as cefuroxime when administered for the prevention of infections following cesarean delivery.Clinicaltrials.gov identifier: NCT01138852.
Project description:Surgical site infections (SSIs) were the most common healthcare-associated infection mainly in developing countries. Inappropriate use of surgical antibiotic prophylaxis, in terms of antibiotic choice, timing, and duration, can lead to the selection of resistant microorganisms and high costs. The aim of this study was to investigate the pattern of antibiotic use, incidence and predictors of SSIs at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia.From 131 patients, 55.7% were male study participants. Ninety (68.7%) patients received preoperative prophylaxis. Ceftriaxone was the most 76 (84.5%) prescribed agent for prophylaxis. Twenty-seven (20.6%) patients developed surgical site infection. Previous surgery AOR?=?3.22 (95% CI [1.14-9.13]) and alcohol use AOR?=?7.04 (95% CI [2.56-23.12, p?=?0.000]) were independent predictors of SSIs in multivariate logistic regression analysis.
Project description:Endophthalmitis is a rare, but serious, intravitreal inflammatory disorder that can arise after cataract surgery. The intracameral injection of 1 mg cefuroxime (CEF) followed by three-times daily antibiotic topical administration for a week is generally recognized as the routine method of prophylaxis after cataract surgery. This procedure is controversial because of both the low efficacy and the low adherence to therapy by elderly patients. A unique slow release antibiotic intravitreal injection could solve these problems. The objective of the present study was to design ophthalmic nanocomposite delivery systems based on in situ gelling formulations that undergo sol-to-gel transition upon change in temperature to prolong the effect of CEF. Oil in water (O/W) microemulsion (µE) and solid lipid nanoparticles (SLN), obtained with an innovative formulation technology called cold microemulsion dilution, were evaluated as ocular drug delivery systems for CEF. Drug entrapment efficiency up to 80% was possible by esterifying CEF with 1-dodecanol to obtain dodecyl-CEF (dCEF). Both dCEF-loaded SLN and µE were then added with Pluronic®F127 (20% w/v) to obtain a nanocomposite hydrogel-based long acting system. The prepared thermosensitive formulations were evaluated for their physical appearance, drug content, gelation temperature, injectability and rheological properties, in vitro release studies and stability studies. Moreover, cell proliferation assays on human retinal pigment epithelial ARPE-19 cells were performed to evaluate the influence of this innovative system on the cellular viability. In addition, minimal inhibitory concentration (MIC) was assessed for both CEF and dCEF, revealing the need of dCEF hydrolysis for the antimicrobial activity. Although further experimental investigations are required, the physico-chemical characterization of the nanocomposite hydrogels and the preliminary in vitro release studies highlighted the potential of these systems for the sustained release of CEF.
Project description:BACKGROUND:Colorectal surgery is frequently complicated by surgical site infections (SSIs). The most important consequences of SSIs are prolonged hospitalization, an increased risk of surgical reintervention and an increase in mortality. Perioperative intravenously administered antibiotic prophylaxis is the standard of care to reduce the risk of SSIs. In the last few decades, preoperative orally administered antibiotics have been suggested as additional prophylaxis to further reduce the risk of infection, but are currently not part of routine practice in most hospitals. The objective of this study is to evaluate the efficacy of a preoperative orally administered antibiotic prophylaxis (Pre-OP) in addition to intravenously administered perioperative antibiotic prophylaxis to reduce the incidence of deep SSIs and/or mortality after elective colorectal surgery. METHODS/DESIGN:The PreCaution trial is designed as a multicenter, double-blind, randomized, placebo-controlled clinical trial that will be carried out in The Netherlands. Adult patients who are scheduled for elective colorectal surgery are eligible to participate. In total, 966 patients will be randomized to receive the study medication. This will either be Pre-OP, a solution that consists of tobramycin and colistin sulphate, or a placebo solution. The study medication will be administered four times daily during the 3 days prior to surgery. Perioperative intravenously administered antibiotic prophylaxis will be administered to all patients in accordance with national infection control guidelines. The primary endpoint of the study is the cumulative incidence of deep SSIs and/or mortality within 30 days after surgery. Secondary endpoints include both infectious and non-infectious complications of colorectal surgery, and will be evaluated 30 days and/or 6 months after surgery. DISCUSSION:To date, conclusive evidence on the added value of preoperative orally administered antibiotic prophylaxis in colorectal surgery is lacking. The PreCaution trial should determine the effects of orally administered antibiotics in preventing infectious complications in elective colorectal surgery. TRIAL REGISTRATION:Netherlands Trial Register, ID: NTR6113 . Registered on 11 October 2016; EudraCT 2015-005736-17.
Project description:AIM: To compare the pharmacokinetic parameters of cefuroxime lysine, a new second-generation of cephalosporin antibiotics, after intravenous (IV), intraperitoneal (IP), or intramuscular (IM) administration. METHODS: Twelve male and 12 virgin female Sprague-Dawley rats, weighing from 200 to 250 g, were divided into three groups (n=4 for each gender in each group). The rats were administered a single dose (67.5 mg/kg) of cefuroxime lysine via IV bolus or IP or IM injection. Blood samples were collected and analyzed with a validated UFLC-MS/MS method. The concentration-time data were then calculated by compartmental and non-compartmental pharmacokinetic methods using DAS software. RESULTS: After IV, IP or IM administration, the plasma cefuroxime lysine disposition was best described by a tri-compartmental, bi-compartmental or mono-compartmental open model, respectively, with first-order elimination. The plasma concentration profiles were similar through the 3 administration routes. The distribution process was rapid after IV administration [t(1/2(d)), 0.10 ± 0.11 h vs 1.36 ± 0.65 and 1.25 ± 1.01 h]. The AUMC(0-∞) is markedly larger, and mean residence time (MRT) is greatly longer after IP administration than that in IV, or IM routes (AUMC(0-∞): 55.33 ± 20.34 vs 16.84 ± 4.85 and 36.17 ± 13.24 mg·h(2)/L; MRT: 0.93 ± 0.10 h vs 0.37 ± 0.07 h and 0.65 ± 0.05 h). The C(max) after IM injection was significantly higher than that in IP injection (73.51 ± 12.46 vs 49.09 ± 7.06 mg/L). The AUC(0-∞) in male rats were significantly higher than that in female rats after IM administration (66.38 ± 16.5 vs 44.23 ± 6.37 mg·h/L). There was no significantly sex-related difference in other pharmacokinetic parameters of cefuroxime lysine between male and female rats. CONCLUSION: Cefuroxime lysine shows quick absorption after IV injection, a long retension after IP injection, and a high C(max) after IM injection. After IM administration the AUC(0-∞) in male rats was significantly larger than that in female rats.
Project description:Background and purpose - The incidence of surgical site infections (SSIs) in trauma/orthopedic surgery varies between different body parts. Antibiotic prophylaxis (e.g., with cefazolin) lowers infection rates in closed fracture surgery and in primary arthroplasty. For prophylactic antibiotics to prevent infections, sufficient concentrations at the target site (location of surgery) are required. However, dosage recommendations and the corresponding efficacy are unclear. This review assesses target site cefazolin concentrations and the effect of variation in dose and location of target site during orthopedic extremity surgery. Methods - For this meta-analysis and systematic review, the literature was searched using the following keywords: "cephalosporins," "orthopedic," "extremity," "surgical procedures," and "pharmacokinetics". Trials measuring target site antibiotic concentrations (bone, soft tissue, synovia) during orthopedic surgery after a single dose of cefazolin were included. Results - The search identified 14 studies reporting on concentrations in the shoulder (n = 1), hip (n = 8), knee (n = 8), or foot (n = 1). A large variation was seen between studies, but the pooled results of 4 studies showed higher concentrations in hip than in knee (mean difference: 4 ug/g, 95% CI 0.8-7). Articles comparing different doses of cefazolin reported higher bone concentrations after 2 g than before, but pooling results did not lead to a statistically significant difference. Interpretation - Although not all results could be pooled, this study shows that cefazolin concentrations are higher in the hip than in the knee. These findings suggest that the dose of prophylactic cefazolin might not be sufficient in distal parts of the extremity. Further research should investigate whether a higher dose of cefazolin can lead to higher concentrations and fewer SSIs.
Project description:BACKGROUND:Perioperative antibiotic prophylaxis in non-infected orthopedic surgery is evident, in contrast to prophylaxis during surgery for infection. Epidemiological data are lacking for this particular situation. METHODS AND FINDINGS:It is a single-center cohort on iterative surgical site infections (SSIs) in infected orthopedic patients. We included 2480 first episodes of orthopedic infections (median age 56 years and 833 immune-suppressed): implant-related infections (n = 648), osteoarticular infections (1153), and 1327 soft tissue infections. The median number of debridement was 1 (range, 1-15 interventions). Overall, 1617 infections (65%) were debrided once compared to 862 cases that were operated multiple times (35%). Upon iterative intraoperative tissue sampling, we detected pathogens in 507 cases (507/862; 59%), of which 241 (242/507; 48%) corresponded to the initial species at the first debridement. We witnessed 265 new SSIs (11% of the cohort) that were resistant to current antibiotic therapy in 174 cases (7% of the cohort). In multivariate analysis, iterative surgical debridements that were performed under current antibiotic administration were associated with new SSIs (odds ratio 1.6, 95%CI 1.2-2.2); mostly occurring after the 2nd debridement. However, we failed to define an ideal hypothetic prophylaxis during antibiotic therapy to prevent further SSIs. CONCLUSIONS:Selection of new pathogens resistant to ongoing antibiotic therapy occurs frequently during iterative debridement in orthopedic infections, especially after the 2nd debridement. The new pathogens are however unpredictable. The prevention, if feasible, probably relies on surgical performance and wise indications for re-debridement instead of new maximal prophylactic antibiotic coverage in addition to current therapeutic regimens.