Cefazolin Concentrations Research Articles

Short-Dwell Cycling Intraperitoneal Cefazolin Plus Ceftazidime in Peritoneal Dialysis Patients.

♦ BACKGROUND: Current guidelines suggest that intraperitoneal (IP) antibiotics should be administered only in a long peritoneal dialysis (PD) dwell (≥ 6 hours). The long dwell might result in low ultrafiltration and volume overload. We aim to examine plasma and dialysate concentration of cefazolin and ceftazidime after IP administration in a short-dwell (≤ 2 hours) automated cycling exchange. ♦ METHODS: Stable PD patients without peritonitis were invited to participate in the present study. Patients underwent 5 2-liter exchanges of PD fluid over 10 hours by the PD cycling machine without last fill or additional dwell. Cefazolin and ceftazidime (20 mg/kg each) were added to the first 5-liter bag of 2.5% dextrose PD fluid that was placed on the warmer of the PD cycling machine. Plasma samples were collected at 12 time-points over 24 hours. Dialysate samples from each exchange were also collected. Antibiotic concentrations in plasma and dialysate were then determined by high-performance liquid chromatography (HPLC). ♦ RESULTS: Six stable PD patients without peritonitis participated in the study. Dialysate cefazolin and ceftazidime were consistently high throughout the PD session in all patients (26 - 360 mg/L). Plasma cefazolin and ceftazidime exceeded the minimal inhibitory concentration (MIC) for susceptible organisms (≤ 8 mg/L) within 2 hours (cefazolin 28.5 ± 8.0 and ceftazidime 12.5 ± 3.4 mg/L), peak at 10 hours (51.1 ± 14.1 and 23.0 ± 5.2 mg/L) and sustained well above the MIC at 24 hours (42.0 ± 9.6 and 17.1 ± 3.1 mg/L). ♦ CONCLUSIONS: The short-dwell cycling IP cefazolin and ceftazidime could provide adequate plasma concentration for up to 24 hours. Daily short-dwell cycling IP cefazolin and ceftazidime might be used to treat peritonitis in PD patients already using a PD cycling machine as well as selected continuous ambulatory PD (CAPD) patients who need shorter dwells during peritonitis due to increasing peritoneal solute transport.

Combination of cephalosporins with vancomycin or teicoplanin enhances antibacterial effect of glycopeptides against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA

Eight heterogeneous vancomycin-intermediate S. aureus (h-VISA) and seven VISA clinical isolates confirmed by the population analysis profile/area under the curve ratio (PAP/AUC) were collected. We further performed the PAP/AUC, time-killing methods and MIC tests using vancomycin/teicoplanin alone or combination with susceptible breakpoint concentrations of cefazolin, cefmetazole, cefotaxime, and cefepime for these isolates. The PAP/AUC MIC curve shifted left after addition of cephalosporins with vancomycin or teicoplanin for both h-VISA and VISA isolates. With the combination of different cephalosporins with vancomycin or teicoplanin, the AUC/Mu3 AUC ratio decreased to <0.9 for the standard Mu3 isolate which are compatible with the definition of vancomycin susceptible S. aureus. These decreases ranged between 1.81–2.02 and 2.37–2.85-fold for h-VISA treated with cephalosporins and vancomycin or teicoplanin, and 2.05–4.59, and 2.93–4,89-fold for VISA treated with cephalosporins with vancomycin or teicoplanin. As measured by time-killing assays, the combinations of different cephalosporins with vancomycin concentrations at 1/2 and 1/4 MIC, exhibited a bactericidal and bacteriostatic effect in VISA. The mean fold of MIC decline for vancomycin base combinations ranged from 1.81–3.83 and 2.71–9.33 for h-VISA and VISA, respectively. Overall, this study demonstrated the enhanced antibacterial activity of vancomycin/teicoplanin after adding cephalosporins against clinical h-VISA/VISA isolates.

Does current cefazolin dosing achieve adequate tissue and blood concentrations in obese women undergoing cesarean section?

BackgroundProphylactic administration of antibiotics preceding cesarean delivery is the most effective measure taken for preventing postpartum infection. While obese women are at greater risk for infection than non-obese women, evidence-based recommendations for modifying dosing in these women are limited. ObjectivesThe purpose of this study was to determine whether obese women undergoing cesarean delivery similarly reach adequate cefazolin concentrations within tissue and blood when weighing <120kg and dosed 2g versus weighing ≥120kg and dosed 3g. Study designWe prospectively studied women ≥18 years old with body mass index ≥30kg/m2 who underwent scheduled cesarean delivery with singleton pregnancy from August 2014 through March 2016. Women were dosed with 2g and 3g of cefazolin for body weights <120kg and ≥120kg, respectively. Samples of subcutaneous adipose tissue (following skin incision and before skin closure), myometrial tissue, fetal cord blood, and maternal blood were collected to assess whether cefazolin concentrations were adequate, i.e., at/above the minimum inhibitory concentration (MIC). Concentrations, based on inhibition zones for Streptococcus sanguinis, were calculated per gram of solid tissue and milliliter of blood. For all sample types, log-transformed concentrations were compared between dosage groups. Using a range of published MICs (1–8μg/mL or μg/g), odds ratios, describing differential odds of falling below the MIC between dosage groups, were also computed. ResultsWomen who received 2g (n=65) versus 3g (n=19) of cefazolin did not significantly differ by maternal or gestational age, race/ethnicity, pre-operative hemoglobin, estimated blood loss, fluid administration, duration of surgery, or timing of sample collections relative to cefazolin administration (Ps>0.05). Dosage groups also did not differ in cefazolin concentration (median [interquartile range]) within adipose tissue following skin incision (5.30μg/g [3.00–9.60] vs. 6.35μg/g [3.90–8.40]; P=0.551), adipose tissue before skin closure (4.45μg/g [2.78–7.25] vs. 6.90μg/g [2.60–10.6]; P=0.342), myometrial tissue (13.1μg/g [8.60–19.6] vs. 15.7μg/g [10.8–21.7]; P=0.116), or maternal blood (41.6μg/mL [26.3–57.0] vs. 45.3μg/mL [36.7–68.3]; P=0.143). However, cord blood concentrations differed significantly (19.5μg/mL [13.7–28.5] vs. 27.9μg/mL [15.8–39.4]; P=0.032), and, in 3 of 5 sample types, group concentrations differed at the dosing cut-point of 120kg (Ps<0.02). Within the range of MICs considered, differences in the odds of concentration inadequacy were not detected between dosage groups for any sample type. Across all patients, inadequate concentrations in one or more solid tissue types were observed in 1.19%, 17.9%, 59.5%, and 86.9% of patients, given the MICs of 1μg/g, 2μg/g, 4μg/g and 8μg/g, respectively. In adipose tissues, specifically, and both dosage groups, mean concentrations were significantly lower than the MIC of 8μg/g (Ps<0.03). Concentrations in one or both blood sample types were inadequate for only 8.33% of patients, given the 8-μg/mL MIC. ConclusionsAdequate cefazolin concentrations were achieved in blood for the majority of our patients. However, concentration adequacy was not achieved in solid tissue for a nearly equally large proportion of patients. Larger scale studies for determining modified protocols for dosing and applying MICs are warranted.

Cefazolin Concentration in the Mediastinal Adipose Tissue of Patients Undergoing Cardiac Surgery.

ObjectiveTo measure the concentration of cefazolin in the anterior mediastinal adipose tissue of patients undergoing cardiac surgery, determining the variation of cefazolin concentration.MethodsTwo samples of approximately 1g of subcutaneous tissue were collected from 19 patients who underwent surgery in December 2015: the first sample was collected right after sternotomy and the second one, before sternal synthesis with steel wires. Antibiotic dosage was administered through high performance liquid chromatography.ResultsWe observed a positive and statistically significant correlation between time 1 and cefazolin concentration (r=0.489 and P=0.039). For time 2 and cefazolin concentration, there was a negative and statistically significant correlation between both variables (r=-0.793 and P<0.001). A negative correlation was also observed between body mass index and cefazolin concentration at time 2 (r=-0.510 and P=0.031). The regression model showed that every 1-minute increase in time 1 corresponded to an increase of 0.240 µg/dL in cefazolin concentration, whereas every 1-minute increase in time 2 corresponded to a reduction of 0.046 µg/dL in cefazolin concentration. As for body mass index, every 1 kg/m2 increase corresponded to a reduction of about 0.510 µg/dL in cefazolin concentration.ConclusionThere was a positive and significant correlation between the initial time of surgery and cefazolin level in the first dosage. The evaluation of the second dosage showed a negative and significant correlation between cefazolin level and the second time of dosage. The concentration of cefazolin is under the influence of body mass index.

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.

Vancomycin (VAN) Combinations with Β-Lactams (BLs) against Methicillin-Resistant Staphylococcus aureus (MRSA), Heterogeneous Intermediate-Level Resistance to Vancomycin (hVISA) and Vancomycin-Intermediate Staphylococcus aureus (VISA)

Background Staphylococcus aureus (S. aureus), especially Methicillin-resistant S. aureus (MRSA) remains a major cause of serious infection and is associated with increased morbidity and mortality. Vancomycin (VAN) has been the mainstay of therapy for MRSA infections. However, decades of selective pressure have led to increasing concerns regarding the efficacy of VAN against MRSA. In vitro data suggest the potential for potent synergy between several Β-lactams (BLs) and VAN. The objective of this study is to further explore the synergistic effect between BLs and VAN against MRSA strains with varying susceptibility to VAN.MethodsFifty randomly selected clinical MRSA strains from the Anti-Infective Research Laboratory library with varying susceptibility to VAN were evaluated for VAN alone and VAN in combination with Cefazolin (CFZ), Cefepime (FEP), Ceftaroline (CPT), and Nafcillin (NAF) minimum inhibitory concentration (MIC) by microdilution in duplicate. The potential for synergy was assessed by 24 hours time-kills (TK). Synergy was defined as >2 log10 CFU/mL difference between combination and the most active single agent at 24 hours.ResultsBLs reduced VAN MIC values against all strains (4–16 fold reduction). In TK studies against MRSA, all BLs demonstrated a similar extent of killing at 24 hours and showed synergy with VAN against all strains. Each combination was superior to any single agent alone, and each was bactericidal (3.42 ± 0.26 log10 CFU/cm2 reduction, P < 0.001 for all comparisons). All single agent exposures demonstrated no activity at 24 hours.Phenotype (Number of Strains)VAN MIC Range (µg/mL)VAN MIC Range with CFZVAN MIC Range with FEPVAN MIC Range with CPTVAN MIC Range with NAFMRSA (15)0.5 – 20.0625 – 0.250.0625 – 10.0625 – 0.250.125 – 0.5hVISA (20)0.5 – 20.125 – 0.50.0625 – 0.50.0625 – 0.50.125 – 1VISA (15)4 (all)0.0625 – 0.50.5 – 20.0625 – 0.250.125 – 1ConclusionThe combination of VAN and BLs significantly improved antibacterial activity against MRSA, hVISA, and VISA compared with any agent alone, supporting the potential use of Vancomycin/BL combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergistic activity of vancomycin against these Staphylococcus strains.Disclosures M. J. Rybak, Allergen: Scientific Advisor, Consulting fee

Population Pharmacokinetics of Cefazolin in Serum and Adipose Tissue From Overweight and Obese Women Undergoing Cesarean Delivery.

The optimal antibiotic prophylaxis dosing regimen of cefazolin for cesarean delivery (CD) in overweight and obese women is unknown. This study was done to compare the duration that cefazolin concentrations remain above the minimum inhibitory concentration (MIC) in adipose tissue (AT). Serum and AT concentrations from 3 previous studies in CD patients were comodeled using the nonparametric adaptive grid algorithm in Pmetrics. AT concentrations for 5000 overweight and obese patients receiving 1-, 2-, and 3-g cefazolin regimens were simulated to calculate the probability that free drug concentrations remained above an MIC of 2μg/mL at 1, 1.5, and 2 hours after administration. Sixty-seven patients (mean body mass index 38.7 kg/m2 ; range 25.5-55.8 kg/m2 ) provided data. A 2-compartment model with 1 of the compartments representing AT fit the data best. Final model parameters were clearance 7.38 ± 5.34L/h, volume of central compartment 11.8±9.36 L, and AT volume of distribution 80.12 ± 55.47 L. The mean±SD (median) penetration ratio of cefazolin into AT was 0.81 ± 2.06 (0.62). At 1.5 and 2 hours, 1-, 2-, and 3-g regimens achieved AT concentrations above the MIC in 71.2%, 92.4%, and 94.7%, and 55.7%, 86.8%, and 91.7%, respectively, of simulated patients. Cefazolin achieved good penetration into AT. Because CD duration is commonly less than 1.5 hours, a 2-g dose has a high probability of providing AT concentrations above the target pathogens' MIC for overweight and obese females. A second dose may be considered for longer surgeries.

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.

Quantification of cefazolin in serum and adipose tissue by ultra high performance liquid chromatography-Tandem mass spectrometry (UHPLC-MS/MS): application to a pilot study of obese women undergoing cesarean delivery.

Higher doses of cefazolin are required in obese patients for preoperative antibiotic prophylaxis, owing to its low lipophilicity. An ultra high performance liquid chromatography-tandem mass spectrometry method was developed to quantify cefazolin in serum and adipose tissue from 6 obese patients undergoing cesarean delivery, and using stable-isotope labeled cefazolin as an internal standard. The method has a 2μg/g lower limit of quantitation. The concentration in adipose tissue was 3.4±1.6μg/mL, which is less than half of the reported minimum inhibitory concentration of 8μg/mL for cefazolin. Serum cefazolin concentrations were more than 30-fold higher than in adipose tissue.

Skeletal muscle and plasma concentrations of cefazolin during complex paediatric spinal surgery

BackgroundSurgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery. MethodsThis prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4–15.4] yr and a median weight of 60.6 (IQR 50.8–66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated. ResultsSkeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8–40.0) µg ml−1 within 30–60 min after the first cefazolin 30 mg kg−1 dose. For patients who received a second 30 mg kg−1 dose, the peak concentrations reached a median of 40.5 (IQR 30.8–45.7) µg ml−1 within 30–60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively. ConclusionsFor children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens.

Cefazolin Hypersensitivity: Toward Optimized Diagnosis

Correct diagnosis of cefazolin hypersensitivity is not straightforward, mainly because of the absence of invitro tests and uncertainties concerning the optimal cefazolin concentration for skin testing. Cross-reactivity studies suggest cefazolin hypersensitivity to be a selective hypersensitivity. The first objective was to confirm that the application of a higher than 2 mg/mL test concentration could increase skin test sensitivity. A second part aimed at investigating the cross-reactivity between cefazolin and other β-lactam antibiotics. A total of 66 patients referred to our clinic after experiencing perioperative anaphylaxis, and exposed to cefazolin, underwent skin testing with cefazolin up to 20 mg/mL. Patients exhibiting a positive skin test with cefazolin had a panel of skin tests with other β-lactams and, if indicated, graded drug challenges to study cross-reactivity. Increasing skin test concentration from the recommended 2 mg/mL to 20 mg/mL identified an additional 7of 19 (27%) patients, who would otherwise have displayed negative skin testing. The concentration was proven nonirritating in 30 cefazolin-exposed control individuals in whom an alternative culprit for perioperative anaphylaxis was identified. Graded challenge testing, after negative skin testing, displayed that all patients tolerated alternative β-lactam antibiotics (ie, amoxicillin, cephalosporins, monobactams, and carbapenems). Of them, 11 individuals also tolerated an alternative cephalosporin, suggesting that cefazolin hypersensitivity (generally) is a selective allergy. Increasing cefazolin concentration for skin tests up to 20 mg/mL benefits the sensitivity of diagnosis. Furthermore, our data confirm that cefazolin hypersensitivity seems to be a selective allergy with good tolerance to otherβ-lactam antibiotics.

Cefazolin in dog: preliminary results for pharmacokinetic and pharmacodynamic parameters

Cefazolin, a first generation cephalosporin, is commonly used in small Cefazolin, a first generation cephalosporin, is commonly used in small animal surgery to avoid post-operative infections. The aims of the study were 1) assess cefazolin pharmacokinetics (PK) in dogs undergoing gonadectomy, 2) correlate PK and pharmacodynamics (PD) parameters and 3) attest the efficacy of dosage regimen through a PK/PD approach. Thirty minutes before surgery, 25 mg/kg of cefazolin were administrated intravenously (IV) to 9 dogs (weight 22±7.5 kg; age 1.3±0.7 years). Blood samples were taken at prefixed times from 0 to 8 h. Quantification of cefazolin concentrations was performed through a validate HPLC method with UV detection (Kunicki, 2012). A two-compartmental model best described the PK profile of cefazolin. Literature MIC50 against canine Pasteurella spp., Staphylococcus spp. and Streptococcus spp. ranged from 0.25 to 0.5 μg/mL (Goldstein, 2012). Distribution and elimination half-lives were 0.3 ± 0.2 h and 3 ± 1.6 h, respectively; area under the curve was 182.3±50.6 h*μg/mL; volume of distribution and clearance at steady state were 383.5±58.1 mL/kg and 150.2±49.8 mL/h/kg, respectively. The PK/PD index for cephalosporins efficacy is time above MIC (T>MIC) for 60% of dosing interval with values 4 times higher the MIC50. Our values of T>MIC, calculated with MIC 0.5 mg/mL, was for 100 % of the observation period from 2 to 6 times higher than MIC. Preliminary results showed a good efficacy of cefazolin against all the bacterial strains evaluated. Therefore, a dosage regimen of 25 mg/kg IV every 8h might represent a valid tool in order to prevent surgical infections in small animal practice.

Effect of dual delivery of antibiotics (vancomycin and cefazolin) and BMP-7 from chitosan microparticles on Staphylococcus epidermidis and pre-osteoblasts in vitro

The main aims of this manuscript are to: i) determine the effect of commonly used antibiotics to treat osteoarticular infections on osteoblast viability, ii) study the dual release of the growth factor (BMP-7) and antibiotics (vancomycin and cefazolin) from chitosan microparticles iii) demonstrate the bioactivity of the antibiotics released in vitro on Staphylococcus epidermidis. The novelty of this work is dual delivery of growth factor and antibiotic from the chitosan microparticles in a controlled manner without affecting their bioactivity. Cefazolin and vancomycin have different therapeutic concentrations for their action in vivo and therefore, two different concentrations of the drugs were used. Osteoblast cytotoxicity test concluded that cefazolin concentrations of 50 and 100μg/ml were found to have positive influence on osteoblast proliferation. A significant increase in osteoblast proliferation was observed in the presence of cefazolin and BMP-7 in comparison with BMP-7 alone group; indicating cefazolin might play a role in osteoblast proliferation. On the other hand, vancomycin concentration of 1000μg/ml was found to significantly reduce (p<0.01) osteoblast proliferation in comparison with controls. The microbial study indicated that cefazolin at a minimum concentration of 21.5μg/ml could inhibit ~85% growth of S. epidermidis, whereas vancomycin at a concentration of 30μg/ml was found to inhibit ~80% bacterial growth.

Antibiotic-tolerant Staphylococcus aureus Biofilm Persists on Arthroplasty Materials.

The continued presence of biofilm may be one cause of the high risk of failure observed with irrigation and débridement with component retention in acute periprosthetic joint infection (PJI). There is a poor understanding of the role of biofilm antibiotic tolerance in PJI. (1) Do increasing doses of cefazolin result in decreased viable biofilm mass on arthroplasty materials? (2) Is cefazolin resistance phenotypic or genotypic? (3) Is biofilm viability a function of biofilm depth after treatment with cefazolin? (4) Is the toxin-antitoxin system, yoeB expression, associated with antibiotic stress? Methicillin-sensitive Staphylococcus aureus biofilm was cultured on total knee arthroplasty (TKA) materials and exposed to increasing doses of cefazolin (control, 0.5, 1.0, 10.0, 100.0 μg/mL). Quantitative confocal microscopy and quantitative culture were used to measure viable biofilm cell density. To determine if cefazolin resistance was phenotypic or genotypic, we measured minimum inhibitory concentration (MIC) after exposure to different cefazolin concentrations; changes in MIC would suggest genotypic features, whereas unchanged MIC would suggest phenotypic behavior. Finally, quantitative reverse transcription-polymerase chain reaction was used to quantify expression of yoeB levels between biofilm and planktonic bacteria after exposure to 1 μg/mL cefazolin for 3 hours. Although live biofilm mass was reduced by exposure to cefazolin when compared with biofilm mass in controls (39.2×10(3) ± 26.4×10(3) pixels), where the level after 0.5 µg/mL exposure also showed reduced mass (20.3×10(3) ± 11.9×10(3) pixels), no further reduction was seen after higher doses (mass at 1.0 µg/mL: 5.0×10(3) pixels ± 1.1×10(3) pixels; at 10.0 µg/mL: 6.4×10(3) ± 9.6×10(3) pixels; at 100.0 µg/mL: 6.4×10(3) ± 3.9×10(3)). At the highest concentration tested (100 µg/mL), residual viable biofilm was present on all three materials, and there were no differences in percent biofilm survival among cobalt-chromium (18.5% ± 15.1%), polymethylmethacrylate (22.8% ± 20.2%), and polyethylene (14.7% ± 10.4%). We found that tolerance was a phenotypic phenomenon, because increasing cefazolin exposure did not result in changes in MIC as compared with controls (MIC in controls: 0.13 ± 0.02; at 0.5 µg/mL: 0.13 ± 0.001, p = 0.96; at 1.0 µg/m: 0.14 ± 0.04, p = 0.95; at 10.0 µg/m: 0.11 ± 0.016, p = 0.47; at 100.0 µg/m: 0.94 ± 0.047, p = 0.47). Expression of yoeB after 1 µg/mL cefazolin for 3 hours in biofilm cells was greater in biofilm but not in planktonic cells (biofilm: 62.3-fold change, planktonic cells: -78.8-fold change, p < 0.001). Antibiotics are inadequate at complete removal of the biofilm from the surface of TKA materials. Results suggest that bacterial persisters are responsible for this phenotypic behavior allowing biofilm high tolerance to antibiotics. Antibiotic-tolerant biofilm suggests a mechanism behind the poor results in irrigation and débridement for acute TKA PJI.

The effect of cefazolin on biogas production from thermophilic and mesophilic anaerobic co-digestion of dairy manure and waste milk

Antibiotic residues in animal waste from concentrated animal feeding operations are of considerable concern because of the potential development of antibiotic resistant bacteria in the environment and the effect of these residues on manure treatment systems. The objective of this study was to determine the effect of cefazolin (10 mg L-1) during thermophilic and mesophilic anaerobic co-digestion of manure and waste milk from cows treated with cefazolin for mastitis. The collected antibiotic free manure samples were mixed with slurry and milk obtained from a healthy cow accordingly to form manure mixture (slurry 50 % and manure 50 %) and milk mixture (slurry 50 %, manure 45 % and milk 5 %), each of which was further separated as the control and cefazolin spiked (10 mg L-1), loaded into triplicate 1 L batch digesters and anaerobically digested at 37 °C and 55 °C for 22 days separately. Control and cefazolin spiked milk mixtures always produced significantly (p 0.05) differences in total and methane gas yields were observed in the respective cefazolin spiked digesters despite the temperature at which the digestion was carried out. Volatile fatty acid (VFA) accumulation and reduction of pH were not observed in any digester of both substrates at both temperatures at the end of the experiment, which confirmed the process stability. However, further investigations are necessary to analyse the effects of increased concentrations of cefazolin in the substrates on digester stability. J.Natn.Sci.Foundation Sri Lanka 2015 43 (4):369-376

A5191 - Single dose of cefazolin 2 grams prophylaxis in bariatric surgery patients: a pilot study

Purpose: Cefazolin is the first line antibiotic for prevention of surgical site infections (SSIs) in bariatric surgery. Staphylococcus aureus is a common cause of SSIs in the deep abdominal space. A minimal inhibitory concentration (MIC) of approximately 1mg/L for Staphylococcus aureus is considered to be acceptable. There are many controversies regarding cefazolin dosing in the morbidly obese population in the current medical literature. Some studies support the use of the 1 gram dose, while others support 2 grams or even higher. The goal of this study was to determine whether a single dose of cefazolin 2 grams IV push used prophylactically can provide an adequate MIC in the blood, subcutaneous adipose tissue, and the deep organ space during bariatric surgery. Methods: This study was a prospective observational pharmacokinetic study. The study recruited 37 patients undergoing Roux-enY Gastric Bypass (RYGB) or Laparoscopic Sleeve Gastrectomy (LSG), aged 18-60 years old, and with a body mass index (BMI) Z35kg/m. Patients who were pregnant, had moderate renal impairment (Serum creatinine41.5mg/dl), or were allergic to penicillin were excluded from this study. Patients received one dose of cefazolin 2 grams IV push within 15 minutes prior to the skin incision. The following samples were collected at the time of initial incision and before the skin closure: 2 grams of superficial fatty tissue, 2 grams of fatty-deep peri-gastric tissue and a serum sample. Cefazolin concentrations were determined by using the high-pressure liquid chromatography (HPLC) method. Results: At the current stage of the study, data from 19 patients was available. The mean cefazolin concentration at incision in the blood, subcutaneous adipose tissue, and peri-gastric adipose tissue were 134.18 þ 47.34 ug/mL, 10.47 þ 5.92 ug/mL, and 9.76 þ 6.23 ug/mL. At the completion of the procedure (last suture), the mean concentration of cefazolin in the blood, subcutaneous adipose tissue, and peri-gastric adipose tissue were 88.95 þ 32.11 ug/mL, 6.71 þ 4.81 ug/mL, and 6.76 þ 2.21 ug/ mL for sleeve only surgeries, 95.5 þ 11.88 ug/mL, 10.51 þ 0.83 ug/mL, and 20.51 þ19.22 ug/mL for sleeve with other procedures, and 71.08 þ 13.36 ug/mL, 8.40 þ 4.98 ug/mL, and 6.78 þ 3.98 ug/mL for gastric bypass. All individual samples, either blood or adipose tissue, had a cefazolin concentration above the MIC of 1 ug/mL. Mean subcutaneous and peri-gastric adipose tissue cefazolin concentrations were approximately 10% of the blood concentration. No surgical site infections (SSIs) were reported within 30 days of surgery for all 19 patients. Conclusions: A single dose of 2 g cefazolin administered by IV push within 15 mins of incision provided a cefazolin serum concentration that exceeded the MIC for Staphylococcus aureus. Only about 10% of the cefazolin penetrated adipose tissue, but the cefazolin concentrations in adipose tissue were above the MIC for Staphylococcus aureus during sleeve gastrectomy or gastric bypass surgery. The study results show that high dose of cefazolin (34 grams IV pre-operation), or re-dosing less than 4 hours to maintain protective level of cefazolin in blood and adipose tissue during bariatric surgeries (sleeve gastrectomy, sleeve gastrectomy with other procedures, or gastric bypass) is not indicated.

Effect of Body Weight on Cefazolin and Vancomycin Trabecular Bone Concentrations in Patients Undergoing Total Joint Arthroplasty

Effective use of prophylactic antibiotics decreases the incidence of surgical site infections (SSIs) after total joint arthroplasty (TJA). The purpose of this prospective study was to determine the viability of weight-based dosing protocols for cefazolin and vancomycin to determine if appropriate minimum inhibitory concentrations (MIC) are met. Trabecular bone was harvested from discarded bone samples from 34 patients undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA). The cefazolin and vancomycin concentrations were determined in the trabecular bone using high-performance liquid chromatography. No difference was noted in bone concentration with respect to patient weight for cefazolin. Regarding vancomycin, a substantial difference was noted in trabecular bone concentrations with respect to patient weight with lower body mass index (BMI) achieving greater concentrations. Using the current weight-based protocol of antibiotic prophylaxis, 84% and 87% of patients receiving vancomycin and cefazolin, respectively, achieved bone concentrations above the MIC. Our assessment of trabecular concentration of cefazolin during TJA did not show any differences with respect to patient weight. However, vancomycin concentrations did show a difference with respect to BMI but this may be the result of the specific weight-based dosing protocol of vancomycin. Whereas the majority of cases were able to achieve adequate antibiotic concentrations in bone, further studies may be required to determine if increasing the pre-operative dosage of antibiotics is mandated given the findings of this pilot study.

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.

Degradation of veterinary antibiotics during anaerobic digestion of dairy manure

This study evaluated antibiotic degradation and biogas production during anaerobic digestion of dairy manure contained two common veterinary antibiotics at 37 °C. After 18 days of digestion, the concentration of chlortetracycline (CTC) decreased more than 80% regardless of the initial CTC concentration. The concentration of cefazolin (CEZ) decreased from 10 to 0.08 mg/L in 6 days. Less than 50 mg/L CTC and 10 mg/L CEZ had negligible impact on biogas production during anaerobic digestion process. The result showed that the anaerobic digestion has a potential to degrade antibiotic residues in livestock manure.

Validation of a Dosing Strategy for Cefazolin for Surgery Requiring Cardiopulmonary Bypass.

A prospective, single center, open-label study was conducted to determine if the standard practice for surgical prophylaxis, which includes standardized dosing of cefazolin, at the University of Maryland Medical Center (UMMC) is adequate for patients placed on bypass during cardiac surgery. All patients were given the same standard dosing regimen regardless of weight: two grams of cefazolin administered within 1 h of incision, an additional one gram injected into the bypass circuit at the onset of bypass, and two grams every 3 h after the initial dose. Cefazolin serum concentrations were collected immediately after incision, after the start of bypass, each hour of bypass, at the end of bypass and at sternal closure. Ten patients were consented and completed the study with an average age of 62 y, average weight of 84.7 kg and average cardiopulmonary bypass time of 116 min. The free serum concentrations of cefazolin stayed above the pre-defined inhibitory threshold of 16 mcg/mL throughout the procedure for 100% of participants. The mean total serum concentration in the blood throughout surgery was 160 mcg/mL. No patients were found to have surgical site infections using standard criteria and no adverse events were observed. For patients undergoing cardiac surgery with cardiopulmonary bypass, the UMMC dosing regimen surpassed targeted cefazolin concentrations during the entire surgical procedure for all patients regardless of weight or time on bypass.