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Objective: Adequate levels of perioperative antibiotic prophylaxis are essential for prevention of surgical site infections. We examined pharmacokinetic details of 2 g cefazolin administered during induction of anesthesia with repeat dosing shortly after initiation of cardiopulmonary bypass (CPB) in cardiac surgery., Methods: To identify the microbiologic flora targeted with prophylaxis, pre-, and postoperative swabs were taken from sternal skin. Blood samples for measurement of cefazolin were obtained in 24 patients. Drug levels were used for population pharmacokinetic modeling using Nonmem software (Icon Development Solutions, San Antonio, Tex)., Results: More than 90% of bacteria on sternal skin were sensitive to cefazolin, indicating minimal inhibitory concentrations <8 mg/L. All serum levels of cefazolin were above 8 mg/L and might thus effectively prevent infection. Pharmacokinetic modeling in a 1-compartment model predicted a population mean clearance (CL) of 5.23 L/h and a volume of distribution (Vd) of 15.8 L. CPB increased Vd from 14.4 L to 22.1 L with a consecutive reduction to 18 L after the end of extracorporeal circulation. The final model implemented interindividual variability on CL and Vd, incorporating the covariates CPB and albumin on Vd and creatinine clearance on CL. Goodness-of-fit calculations showed that this model adequately describes the data derived from our clinical cohort., Conclusions: Two grams of cefazolin at induction of anesthesia with a repeat dose after initiation of CPB ensures adequate drug levels to target a majority of pathogens of surgical site infections. Pharmacokinetic modeling demonstrated a significant influence of CPB on the volume of distribution and elimination of cefazolin. Other influences on pharmacokinetic parameters were albumin, protein, and creatinine clearance., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the pharmacokinetics and tissue disposition of prophylactic cefazolin into skeletal muscle in a pediatric population undergoing cardiac surgery., Methods: The subjects included 12 children, with a median age of 146 days (interquartile range, 136-174) and median weight of 5.5 kg (interquartile range, 5.2-7.3) undergoing cardiac surgery and requiring cardiopulmonary bypass with or without deep hypothermic circulatory arrest. Institutional cefazolin at standard doses of 25 mg/kg before incision and 25 mg/kg in the bypass prime solution were administered. Serial plasma and skeletal muscle microdialysis samples were obtained intraoperatively and the unbound cefazolin concentrations measured. Noncompartmental pharmacokinetic analyses were performed and the tissue disposition evaluated., Results: After the first dose of cefazolin, the skeletal muscle concentrations peaked at a median microdialysis collection interval of 30 to 38.5 minutes. After the second dose, the peak concentrations were delayed a median of 94 minutes in subjects undergoing deep hypothermic circulatory arrest. Skeletal muscle exposure to cefazolin measured by the area under concentration time curve 0-last measurement was less in the subjects who underwent deep hypothermic circulatory arrest than in those who received cardiopulmonary bypass alone (P = .04). The skeletal muscle concentrations of cefazolin exceeded the goal concentrations for methicillin-sensitive Staphylococcus aureus prophylaxis; however, the goal concentrations for gram-negative pathogens associated with surgical site infections were achieved only 42.1% to 84.2% and 0% to 11.2% of the intraoperative time in subjects undergoing cardiopulmonary bypass alone or deep hypothermic circulatory arrest, respectively., Conclusions: This cefazolin dosing strategy resulted in skeletal muscle concentrations that are likely not effective for surgical prophylaxis against gram-negative pathogens but are effective against methicillin-sensitive S aureus in infants undergoing cardiac surgery., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Cefazolin (1-2 g bolus at induction possibly repeated after cardiopulmonary bypass) remains the standard for antibiotic prophylaxis in cardiac surgery. Data indicate, however, that it is underdosed with this dosing schedule. A prospective, randomized study comparing intermittent versus loading dose plus continuous infusion for the same total dose of cefazolin was performed to assess which modality is pharmacokinetically and pharmacodynamically advantageous., Methods: Patients received 2 g cefazolin as a starting dose and then were divided into an intermittent group (receiving another 1 g at 3, 9, and 15 hours after the first dose) and a continuous group (continuous infusion started after the first dose, providing 1 g every 6 hours for 18 hours). Cefazolin levels were measured in blood and atria., Results: Mean total and calculated free trough concentrations in blood varied greatly among patients in the intermittent group and were lower than those in the continuous group (P < .05 at 15, 18 and 24 hours). For 9 of 10 (90%) patients in the continuous infusion group, the targeted pharmacokinetic and pharmacodynamic goal (time above minimal inhibitory concentration >90%) was achieved, whereas the goal was met for only 3 of 10 (30%) in the intermittent group (P < .05). The mean atrial tissue concentration was also higher with continuous infusion (P < .05)., Conclusions: Administration of cefazolin as bolus plus continuous infusion has pharmacokinetic and pharmacodynamic advantages relative to intermittent administration. It provides more stable serum levels, lower interpatient variability, and higher myocardial tissue penetration., (Copyright 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Perioperative surgical antibiotic prophylaxis requires that therapeutically effective drug concentrations be present in the tissues., Methods: Patients undergoing Roux-en-Y gastric bypass for morbid obesity were given 2 g cefazolin preoperatively, followed by a second dose at 3 hours. Thirty-eight patients were each assigned to 1 of 3 body mass index (BMI) groups: (A) BMI=40-49 (N = 17); (B) BMI=50-59 (N=11); (C) BMI > or= 60 (N=10). Multiple timed serum (baseline; incision, 15, 30, 60 minutes; prior to second prophylactic dose; and closure) and tissue (skin, subcutaneous fat, and omentum) specimens were collected and cefazolin concentration analyzed by microbiological assay., Results: No significant difference was observed in intraoperative fluid replacement or blood loss among BMI groups. Serum antimicrobial concentrations exceeded resistance breakpoint (32 microg/mL) in 73%, 68%, and 52% of BMI groups A, B, and C, respectively. No significant difference in cefazolin concentration was observed in mean incisional skin and closure tissue specimens in groups A, B, and C. A significant decrease in cefazolin concentration was noted in closure adipose (p=.04), initial (p=.03) and closure omentum (p=.05) tissues in groups B and C compared with A. Over 90% of serum samples exhibited therapeutic concentrations covering 53.8% of gram-positive and 78.6% of gram-negative surgical pathogens. However, therapeutic tissue levels were achieved in only 48.1%, 28.6%, and 10.2% of groups A, B, and C, respectively., Conclusions: Pharmacokinetic analysis suggests that present dosing strategies may fail to provide adequate perioperative prophylaxis in gastric bypass patients.

Objective: Cephalosporins, especially cefazolin, are widely used in the prevention of postoperative wound infections after cardiac operations. As more and more Staphylococcus aureus and Staphylococcus epidermidis strains are becoming resistant to cephalosporins and other antibiotics, alternative agents, such as glycopeptides, are often used as prophylaxis. We performed a multicenter double-blind randomized controlled trial comparing teicoplanin, a glycopeptide antibiotic, with cefazolin., Methods: A total of 3027 adult patients undergoing elective coronary artery bypass grafting, valve operations, or both were randomized to a single dose of teicoplanin (15 mg/kg) or a 2-day course of cefazolin (2 g initial dose, followed by 1 g every 8 hours for 6 more doses). Patients were followed up for a total of 6 months postoperatively. The primary objective was to compare, between groups, the incidence of surgical infections up to 30 days postoperatively. Secondary objectives were incidence of other infections, other complications, and death., Results: A total of 3027 patients were randomized to receive either teicoplanin (n = 1518) or cefazolin (n = 1509). Thirty days postoperatively, there was a trend to more deep sternotomy wound infections in the teicoplanin group (31 vs 18, P =. 087), which became significant by 6 months (36 vs 19, P =.032). One hundred percent of the gram-positive strains infecting patients were susceptible to teicoplanin, whereas 8.3% were resistant to cefazolin. Pneumonia and urinary tract infections were more common in the teicoplanin group. Deep wound infections of the leg were more common in the cefazolin group., Conclusions: Cefazolin was more effective prophylaxis than teicoplanin against postoperative wound infections after elective cardiac operations. Infection rates were low with either treatment.

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.

The rate of wound infections in morbidly obese patients who underwent gastroplasty surgery at our institution was 16.5% compared with a rate of 2.5% in normal-weight patients who underwent clean-contaminated surgery. Both groups received 1 gm of cefazolin intramuscularly before surgery was performed. We hypothesized that this regimen of prophylaxis did not provide adequate tissue levels in the morbidly obese. Morbidly obese patients who were undergoing gastroplasty were randomly selected to receive 1 gm cefazolin in the buttock fat, buttock muscle, or by intravenous injection. A fourth group of morbidly obese patients received 2 gm of cefazolin intravenously. Normal-weight patients who were undergoing upper abdominal surgery received 1 gm of cefazolin intravenously. At incision and closure, both blood and tissue levels of cefazolin were significantly (p less than 0.001) lower for all morbidly obese patients who received 1 gm cefazolin when compared with the blood and tissue levels of the drug found in normal-weight patients. The cefazolin levels obtained were below the minimal inhibitory concentrations of greater than 2 micrograms/ml for gram-positive cocci and of greater than 4 micrograms/ml for gram-negative rods. Only when the morbidly obese patient received 2 gm cefazolin were both the serum and adipose tissue levels adequate. For a 4-month period, all morbidly obese patients received 2 gm cefazolin prophylaxis, and the wound infection rate dropped to 5.6% compared with the previous rate of 16.5% (p less than 0.03). We conclude that antibiotic prophylaxis must be specially tailored to the needs of these obese patients.