Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass

Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass Abstract Objectives Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L. Methods Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥ 40 mg/L (≥8 mg/L unbound, assuming 80% protein binding). Results Fifty-five subjects (64.9 ± 10.4 years, 89.7 ± 16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of ≥ 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Conclusions The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery. Introduction Guidelines for antimicrobial prophylaxis (AP) recommend cefazolin regimens consisting of 1, 2 or 3 g within 60 min prior to incision and every 4 h during surgery.1 The goal is to maintain ‘adequate serum and tissue concentrations during the period of potential contamination’ thereby inhibiting possible pathogens and preventing surgical site infections (SSIs).1 Given the significant alterations in cefazolin pharmacokinetics during cardiac surgery requiring cardiopulmonary bypass (CPB), it is important to study AP regimens in this patient population. Although alternative cefazolin regimens are described in the literature (Table S1, available as Supplementary data at JAC Online), to our knowledge, this is the first study of concentrations achieved during cardiac surgery with CPB using the standard cefazolin AP regimen. The goal was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target closure concentrations ≥40 mg/L. The hypothesis was that target cefazolin concentrations for AP would not be achieved in all patients undergoing cardiac surgery with CPB. Methods The study was approved by the University of Manitoba Health Research Ethics Board (no. H2014:142-May 2014) and St Boniface Hospital Research Review Committee (no. RRC/2014/1408-July 2014). It was conducted through the Cardiac Sciences Program at the St Boniface Hospital from August 2014 to May 2015. Patients ≥18 years (with written consent) undergoing elective cardiac surgery with CPB and receiving cefazolin AP were eligible for inclusion. Those with CLCR <50 mL/min/72 kg,2 infection at the time of surgery, antimicrobial therapy within 3 days of surgery or chronic liver disease were excluded. Subject characteristics including medical and surgical history were documented along with antimicrobial therapy or hospitalization within 3 months. Information regarding the cardiac surgery including type of procedure, relevant time points, fluid administration and loss, intraoperative complications and re-explorations following primary wound closure was detailed. Relevant clinical and laboratory data were collected from hospital medical records, including those from the preoperative assessment clinic and operating room. Participants received cefazolin AP according to protocol (i.e. 1 or 2 g based on body weight administered within 60 min prior to incision, every 4 h during surgery and every 8 h for 48 h postoperatively). All cefazolin doses and timings were recorded. Cefazolin doses were also represented per kg of total body weight or dosing weight (DW) for subjects with class II or III obesity (BMI ≥35 kg/m2); DW (kg) = ideal body weight + 0.3(total body weight − ideal body weight) and ideal body weight was 50 kg for males or 45 kg for females plus 2.3 kg for every inch (2.54 cm) over 5 feet (152.4 cm).3 Blood samples were collected 30 min after the preoperative cefazolin dose (peak sample), prior to intraoperative cefazolin doses (intraoperative trough sample) and within 15 min of wound closure (closure sample). Total cefazolin concentrations were measured using a previously developed LC-MS/MS assay.4 In our study, the assay was validated from 4 to 100 mg/L with 93% accuracy and 97% precision using the methods outlined in the FDA Guidance for Industry: Bioanalytical Method Validation document.5 Total intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥40 mg/L (≥8 mg/L unbound, assuming 80% protein binding). Univariate analysis was conducted to identify associations between subject-, surgery- and AP-related variables with regards to target closure concentration utilizing the two-tailed Student’s t-test, Mann–Whitney U-test, Pearson χ2 test or Fisher’s exact test, as appropriate. Significant variables (P < 0.05) were included in a multivariate analysis using backward stepwise, binary logistic regression modelling. The models were evaluated using Akaike Information Criteria and tested for goodness-of-fit. All statistical analyses were conducted using SYSTAT 12 (Systat Software Inc., San Jose, CA, USA). Results Sixty patients were enrolled, and 55 subjects completed the study. Four patients did not undergo surgery and one subject was removed owing to an immediate hypersensitivity reaction to the preoperative cefazolin dose. Subject characteristics are detailed in Table 1. Most subjects (78.2%, 43 of 55) received intermittent 2 g doses of cefazolin. Only 23.6% (13 of 55) of subjects received a single preoperative dose, whereas 67.3% (37 of 55) received one and 9.1% (5 of 55) received two or more intraoperative doses. Preoperative doses (21.4 ± 4.4 mg/kgDW) were administered 35 ± 14 min prior to incision, and 94.5% (52 of 55) were within 60 min. The subsequent intraoperative doses (n = 48) were given every 3.9 ± 0.3 h. Table 1. Study subject characteristics (n = 55) Male  38 (69.1)  Age (years)  64.9 ± 10.4  Body weight (kg)  89.7 ± 16.5  BMI (kg/m2)  30.9 ± 5.3  CLCR (mL/min/72 kg)  80 ± 19  Smoker (current/past)  8 (14.5) / 26 (47.3)  Comorbidities   hypertension  40 (72.7)   ischaemic heart disease  34 (61.8)   diabetes mellitus  16 (29.1)   myocardial infarction  11 (20.0)   peripheral vascular disease  3 (5.5)  Charlson comorbidity index  3 (2–4)  Previous cardiac surgery  2 (3.6)  Antimicrobial within 3 months  13 (23.6)  Hospitalization within 3 months  6 (10.9)  Surgery   coronary artery bypass graftings  26 (47.3)   valve repairs or replacements  14 (25.5)   mixed proceduresa  15 (27.3)   procedures with grafts (n = 38)    number of grafts  3 (1–4)    saphenous vein  31 (81.6)    internal mammary artery  28 (73.7)   blood products administered during surgery (mL) (n = 17)  1944 ± 2107   net fluid balance during surgery (mL)  3547 ± 1301   albumin plasma concentration (g/L)      preoperative  39.5 ± 2.4    postoperative  31.4 ± 3.1   duration of surgery (min)  258 ± 99   duration of CPB (min)  129 ± 78   intraoperative complications  3 (5.5)   postoperative hospital stay (days)  5 (4–7)  Male  38 (69.1)  Age (years)  64.9 ± 10.4  Body weight (kg)  89.7 ± 16.5  BMI (kg/m2)  30.9 ± 5.3  CLCR (mL/min/72 kg)  80 ± 19  Smoker (current/past)  8 (14.5) / 26 (47.3)  Comorbidities   hypertension  40 (72.7)   ischaemic heart disease  34 (61.8)   diabetes mellitus  16 (29.1)   myocardial infarction  11 (20.0)   peripheral vascular disease  3 (5.5)  Charlson comorbidity index  3 (2–4)  Previous cardiac surgery  2 (3.6)  Antimicrobial within 3 months  13 (23.6)  Hospitalization within 3 months  6 (10.9)  Surgery   coronary artery bypass graftings  26 (47.3)   valve repairs or replacements  14 (25.5)   mixed proceduresa  15 (27.3)   procedures with grafts (n = 38)    number of grafts  3 (1–4)    saphenous vein  31 (81.6)    internal mammary artery  28 (73.7)   blood products administered during surgery (mL) (n = 17)  1944 ± 2107   net fluid balance during surgery (mL)  3547 ± 1301   albumin plasma concentration (g/L)      preoperative  39.5 ± 2.4    postoperative  31.4 ± 3.1   duration of surgery (min)  258 ± 99   duration of CPB (min)  129 ± 78   intraoperative complications  3 (5.5)   postoperative hospital stay (days)  5 (4–7)  Data are presented as n (%), mean ± standard deviation or median (IQR). a Combination of coronary artery bypass grafting, valve or other procedure, e.g. aortic root replacement. A total of 134 plasma concentrations including 53 peak, 30 intraoperative trough and 51 closure concentrations were analysed. The mean total cefazolin peak concentration was 145.2 ± 36.6 mg/L and the total intraoperative trough concentration was 46.5 ± 17.5 mg/L. Forty per cent of intraoperative troughs (12 of 30) were <40 mg/L. The mean total cefazolin closure concentration was 103.0 ± 55.7 mg/L [median (IQR) 89.4 mg/L (55.3–140.9)] with 9.8% (5 of 51) below the target of 40 mg/L. In 30.9% (17 of 55) of subjects, cefazolin concentrations fell below target at some time during surgery. In univariate analyses, lower body weight (P < 0.0001), shorter duration of surgery (P < 0.0001) and female gender (P = 0.04) were significantly associated with cefazolin closure concentrations <40 mg/L (Table 2). Only body weight (P = 0.027) and duration of surgery (P = 0.045) remained in the multivariate model. These variables were incorporated into a total cefazolin exposure (preoperative and intraoperative doses) that was normalized for DW and duration of surgery. In subjects with closure concentrations <40 mg/L and ≥40 mg/L, the cefazolin dose for every hour of surgery (intermittent dosing) was 5.8 ± 1.7 mg/kgDW and 8.2 ± 2.0 mg/kgDW, respectively (P = 0.03). Based on classification and regression tree (CART) analysis, a cefazolin exposure of 7.6 mg/kgDW for every hour of surgery was a significant threshold for achieving target closure concentrations. Table 2. Univariate analysis of subject and surgery-related variables with regards to achieving target cefazolin closure concentrations ≥40 mg/L Variable  Total cefazolin closure concentration   P  <40 mg/L (n = 5)  ≥40 mg/L (n = 46)  Female  4 (80)  13 (28)  0.04  Age (years)  68.4 ± 9.5  64.8 ± 9.9  0.46  Body weight (kg)  73.1 ± 6.1  91.3 ± 16.9  <0.0001  CLCR (mL/min/72 kg)  82.6 ± 25.9  79.9 ± 18.2  0.83  Net fluid balance during surgery (mL)  3350 ± 579  3634 ± 1352  0.41  Duration of surgery (min)  191 ± 15  260 ± 84  <0.0001  Variable  Total cefazolin closure concentration   P  <40 mg/L (n = 5)  ≥40 mg/L (n = 46)  Female  4 (80)  13 (28)  0.04  Age (years)  68.4 ± 9.5  64.8 ± 9.9  0.46  Body weight (kg)  73.1 ± 6.1  91.3 ± 16.9  <0.0001  CLCR (mL/min/72 kg)  82.6 ± 25.9  79.9 ± 18.2  0.83  Net fluid balance during surgery (mL)  3350 ± 579  3634 ± 1352  0.41  Duration of surgery (min)  191 ± 15  260 ± 84  <0.0001  Data are presented as n (%) or mean ± SD. Discussion Our study characterized cefazolin concentrations achieved during cardiac surgery with CPB using the standard AP regimen. There was significant variability in cefazolin concentrations most notably at wound closure when values ranged from 32 to 222 mg/L (Figure S1). Almost 10% of cefazolin closure concentrations were below the target of 40 mg/L, as were 40% of intraoperative trough concentrations at the scheduled re-dosing time. This is an important observation given the association between low AP closure concentrations and increased risk of SSI.6 We evaluated total cefazolin closure concentrations against a target of ≥40 mg/L (≥8 mg/L unbound) for effective AP. Although reports of cefazolin protein binding in this population range from 40% to 80%, we used the latter as the most conservative estimate of unbound (active) drug.7–10 An unbound concentration of 8 mg/L is consistent with the CLSI susceptible breakpoint for Enterobacteriaceae spp. before being lowered to 2 mg/L for improved detection of ESBLs.11 It is also the last susceptible breakpoint for antistaphylococcal cephalosporins before inferring susceptibility from oxacillin (or cefoxitin) testing for methicillin resistance. Finally, an unbound concentration of 8 mg/L represents the threshold for bactericidal activity (i.e. four times the MIC) against the common susceptible skin flora with MICs ≤2 mg/L. Our study found that lower body weight and shorter duration of surgery were significant predictors of below-target closure concentrations in patients undergoing cardiac surgery with CPB. Lower body weight was also associated with intermittent 1 g doses thereby confirming that at least 2 g should be used regardless of weight. The association between shorter duration of surgery and lower closure concentration was another important observation. Given that re-dosing did comply with the ‘every 4 h’ recommendation, our findings suggest that more frequent re-dosing every 3 h should be considered for patients with normal renal function. Finally, our analysis of total cefazolin exposure incorporated patient weight and duration of surgery into a modifiable variable that could be used to optimize cefazolin AP regimens. The relationship between body or dosing weight, re-dosing interval and intermittent cefazolin doses required to maintain closure concentrations ≥40 mg/L in our study population are shown in Table S2. Using the significant threshold of 7.6 mg/kgDW for every hour of surgery, these data also support a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery. A limitation of our study was the analysis of total as opposed to unbound (active) cefazolin concentrations. Similar to other studies, cefazolin closure concentrations were evaluated against targets that exceed the MICs for potential pathogens as opposed to those directly associated with clinical outcome. The limitation is indicative of the paucity of pharmacokinetic/pharmacodynamic research in the area of AP for surgery. Finally, as our study was conducted in subjects with relatively normal renal function, the findings do not apply to patients with significant renal insufficiency. In conclusion, the standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. In our study, a cefazolin exposure of ≥7.6 mg/kgDW for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Acknowledgements We would like to acknowledge the St Boniface Hospital and Winnipeg Regional Health Authority (WRHA) Cardiac Sciences Program including surgeons, anaesthesiologists, nurses and other staff who supported the study. In particular, the contributions of B. Brett Hiebert (Programmer/Statistical Analyst) are appreciated. Funding This work was supported by a Canadian Society of Hospital Pharmacists Foundation Grant (no. 317380), Leslie F. Buggey Professorship (S. A. Z.) and University of Manitoba Graduate Fellowship (D. C.). Additional support was provided by the Dr Paul H. T. Thorlakson Foundation Fund, University of Manitoba Research Grants Program (UM Project no. 43887, 2015), Natural Sciences and the Engineering Research Council Canada (RGPIN-2015–06543, 2015–2020) (T. M. L.), Leslie F. Buggey Graduate Scholarships (D. C., R. L.), Beatrice Faiman Graduate Scholarship (R. L.) and Research Manitoba Fellowship (R. L.). Transparency declarations None to declare. Supplementary data Tables S1 and S2 and Figure S1 are available as Supplementary data at JAC Online. References 1 Bratzler DW, Dellinger EP, Olsen KM et al.   Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect  2013; 14: 73– 156. Google Scholar CrossRef Search ADS   2 Ariano RE, Zelenitsky SA, Poncsak KR et al.   No role for patient body weight on renal function assessment for drug dosing. J Antimicrob Chemother  2017; 72: 1802– 11. Google Scholar CrossRef Search ADS PubMed  3 Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis  1997; 25: 112– 8. Google Scholar CrossRef Search ADS PubMed  4 Lillico R, Sayre CL, Sitar DS et al.   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. J Chromatogr B Analyt Technol Biomed Life Sci  2016; 1031: 94– 8. Google Scholar CrossRef Search ADS PubMed  5 US Department of Health and Human Sciences FDA. Guidance for Industry: Bioanalytical Method Validation. 2001. http://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf. 6 Zelenitsky SA, Ariano RE, Harding GKM et al.   Antibiotic pharmacodynamics in surgical prophylaxis: an association between intraoperative antibiotic concentrations and efficacy. Antimicrob Agents Chemother  2002; 46: 3026– 30. Google Scholar CrossRef Search ADS PubMed  7 Hutschala D, Skhirtladze K, Kinstner C et al.   In vivo microdialysis to measure antibiotic penetration into soft tissue during cardiac surgery. Ann Thorac Surg  2007; 84: 1605– 10. Google Scholar CrossRef Search ADS PubMed  8 Andreas M, Zeitlinger M, Hoeferl M et al.   Internal mammary artery harvesting influences antibiotic penetration into presternal tissue. Ann Thorac Surg  2013; 95: 1323– 9; discussion 1329–30. Google Scholar CrossRef Search ADS PubMed  9 Andreas M, Zeitlinger M, Wisser W et al.   Cefazolin and linezolid penetration into sternal cancellous bone during coronary artery bypass grafting. Eur J Cardiothorac Surg  2015; 48: 758– 64. Google Scholar CrossRef Search ADS PubMed  10 Hollis AL, Heil EL, Nicolau DP et al.   Validation of a dosing strategy for cefazolin for surgery requiring cardiopulmonary bypass. Surg Infect (Larchmt)  2015; 16: 829– 32. Google Scholar CrossRef Search ADS PubMed  11 Turnidge JD; on behalf of the Subcommittee on Antimicrobial Susceptibility Testing of the Clinical and Laboratory Standards Institute. Cefazolin and Enterobacteriaceae: rationale for revised susceptibility testing breakpoints. Clin Infect Dis  2011; 52: 917– 24. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass

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Abstract

Abstract Objectives Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L. Methods Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥ 40 mg/L (≥8 mg/L unbound, assuming 80% protein binding). Results Fifty-five subjects (64.9 ± 10.4 years, 89.7 ± 16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of ≥ 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Conclusions The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery. Introduction Guidelines for antimicrobial prophylaxis (AP) recommend cefazolin regimens consisting of 1, 2 or 3 g within 60 min prior to incision and every 4 h during surgery.1 The goal is to maintain ‘adequate serum and tissue concentrations during the period of potential contamination’ thereby inhibiting possible pathogens and preventing surgical site infections (SSIs).1 Given the significant alterations in cefazolin pharmacokinetics during cardiac surgery requiring cardiopulmonary bypass (CPB), it is important to study AP regimens in this patient population. Although alternative cefazolin regimens are described in the literature (Table S1, available as Supplementary data at JAC Online), to our knowledge, this is the first study of concentrations achieved during cardiac surgery with CPB using the standard cefazolin AP regimen. The goal was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target closure concentrations ≥40 mg/L. The hypothesis was that target cefazolin concentrations for AP would not be achieved in all patients undergoing cardiac surgery with CPB. Methods The study was approved by the University of Manitoba Health Research Ethics Board (no. H2014:142-May 2014) and St Boniface Hospital Research Review Committee (no. RRC/2014/1408-July 2014). It was conducted through the Cardiac Sciences Program at the St Boniface Hospital from August 2014 to May 2015. Patients ≥18 years (with written consent) undergoing elective cardiac surgery with CPB and receiving cefazolin AP were eligible for inclusion. Those with CLCR <50 mL/min/72 kg,2 infection at the time of surgery, antimicrobial therapy within 3 days of surgery or chronic liver disease were excluded. Subject characteristics including medical and surgical history were documented along with antimicrobial therapy or hospitalization within 3 months. Information regarding the cardiac surgery including type of procedure, relevant time points, fluid administration and loss, intraoperative complications and re-explorations following primary wound closure was detailed. Relevant clinical and laboratory data were collected from hospital medical records, including those from the preoperative assessment clinic and operating room. Participants received cefazolin AP according to protocol (i.e. 1 or 2 g based on body weight administered within 60 min prior to incision, every 4 h during surgery and every 8 h for 48 h postoperatively). All cefazolin doses and timings were recorded. Cefazolin doses were also represented per kg of total body weight or dosing weight (DW) for subjects with class II or III obesity (BMI ≥35 kg/m2); DW (kg) = ideal body weight + 0.3(total body weight − ideal body weight) and ideal body weight was 50 kg for males or 45 kg for females plus 2.3 kg for every inch (2.54 cm) over 5 feet (152.4 cm).3 Blood samples were collected 30 min after the preoperative cefazolin dose (peak sample), prior to intraoperative cefazolin doses (intraoperative trough sample) and within 15 min of wound closure (closure sample). Total cefazolin concentrations were measured using a previously developed LC-MS/MS assay.4 In our study, the assay was validated from 4 to 100 mg/L with 93% accuracy and 97% precision using the methods outlined in the FDA Guidance for Industry: Bioanalytical Method Validation document.5 Total intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥40 mg/L (≥8 mg/L unbound, assuming 80% protein binding). Univariate analysis was conducted to identify associations between subject-, surgery- and AP-related variables with regards to target closure concentration utilizing the two-tailed Student’s t-test, Mann–Whitney U-test, Pearson χ2 test or Fisher’s exact test, as appropriate. Significant variables (P < 0.05) were included in a multivariate analysis using backward stepwise, binary logistic regression modelling. The models were evaluated using Akaike Information Criteria and tested for goodness-of-fit. All statistical analyses were conducted using SYSTAT 12 (Systat Software Inc., San Jose, CA, USA). Results Sixty patients were enrolled, and 55 subjects completed the study. Four patients did not undergo surgery and one subject was removed owing to an immediate hypersensitivity reaction to the preoperative cefazolin dose. Subject characteristics are detailed in Table 1. Most subjects (78.2%, 43 of 55) received intermittent 2 g doses of cefazolin. Only 23.6% (13 of 55) of subjects received a single preoperative dose, whereas 67.3% (37 of 55) received one and 9.1% (5 of 55) received two or more intraoperative doses. Preoperative doses (21.4 ± 4.4 mg/kgDW) were administered 35 ± 14 min prior to incision, and 94.5% (52 of 55) were within 60 min. The subsequent intraoperative doses (n = 48) were given every 3.9 ± 0.3 h. Table 1. Study subject characteristics (n = 55) Male  38 (69.1)  Age (years)  64.9 ± 10.4  Body weight (kg)  89.7 ± 16.5  BMI (kg/m2)  30.9 ± 5.3  CLCR (mL/min/72 kg)  80 ± 19  Smoker (current/past)  8 (14.5) / 26 (47.3)  Comorbidities   hypertension  40 (72.7)   ischaemic heart disease  34 (61.8)   diabetes mellitus  16 (29.1)   myocardial infarction  11 (20.0)   peripheral vascular disease  3 (5.5)  Charlson comorbidity index  3 (2–4)  Previous cardiac surgery  2 (3.6)  Antimicrobial within 3 months  13 (23.6)  Hospitalization within 3 months  6 (10.9)  Surgery   coronary artery bypass graftings  26 (47.3)   valve repairs or replacements  14 (25.5)   mixed proceduresa  15 (27.3)   procedures with grafts (n = 38)    number of grafts  3 (1–4)    saphenous vein  31 (81.6)    internal mammary artery  28 (73.7)   blood products administered during surgery (mL) (n = 17)  1944 ± 2107   net fluid balance during surgery (mL)  3547 ± 1301   albumin plasma concentration (g/L)      preoperative  39.5 ± 2.4    postoperative  31.4 ± 3.1   duration of surgery (min)  258 ± 99   duration of CPB (min)  129 ± 78   intraoperative complications  3 (5.5)   postoperative hospital stay (days)  5 (4–7)  Male  38 (69.1)  Age (years)  64.9 ± 10.4  Body weight (kg)  89.7 ± 16.5  BMI (kg/m2)  30.9 ± 5.3  CLCR (mL/min/72 kg)  80 ± 19  Smoker (current/past)  8 (14.5) / 26 (47.3)  Comorbidities   hypertension  40 (72.7)   ischaemic heart disease  34 (61.8)   diabetes mellitus  16 (29.1)   myocardial infarction  11 (20.0)   peripheral vascular disease  3 (5.5)  Charlson comorbidity index  3 (2–4)  Previous cardiac surgery  2 (3.6)  Antimicrobial within 3 months  13 (23.6)  Hospitalization within 3 months  6 (10.9)  Surgery   coronary artery bypass graftings  26 (47.3)   valve repairs or replacements  14 (25.5)   mixed proceduresa  15 (27.3)   procedures with grafts (n = 38)    number of grafts  3 (1–4)    saphenous vein  31 (81.6)    internal mammary artery  28 (73.7)   blood products administered during surgery (mL) (n = 17)  1944 ± 2107   net fluid balance during surgery (mL)  3547 ± 1301   albumin plasma concentration (g/L)      preoperative  39.5 ± 2.4    postoperative  31.4 ± 3.1   duration of surgery (min)  258 ± 99   duration of CPB (min)  129 ± 78   intraoperative complications  3 (5.5)   postoperative hospital stay (days)  5 (4–7)  Data are presented as n (%), mean ± standard deviation or median (IQR). a Combination of coronary artery bypass grafting, valve or other procedure, e.g. aortic root replacement. A total of 134 plasma concentrations including 53 peak, 30 intraoperative trough and 51 closure concentrations were analysed. The mean total cefazolin peak concentration was 145.2 ± 36.6 mg/L and the total intraoperative trough concentration was 46.5 ± 17.5 mg/L. Forty per cent of intraoperative troughs (12 of 30) were <40 mg/L. The mean total cefazolin closure concentration was 103.0 ± 55.7 mg/L [median (IQR) 89.4 mg/L (55.3–140.9)] with 9.8% (5 of 51) below the target of 40 mg/L. In 30.9% (17 of 55) of subjects, cefazolin concentrations fell below target at some time during surgery. In univariate analyses, lower body weight (P < 0.0001), shorter duration of surgery (P < 0.0001) and female gender (P = 0.04) were significantly associated with cefazolin closure concentrations <40 mg/L (Table 2). Only body weight (P = 0.027) and duration of surgery (P = 0.045) remained in the multivariate model. These variables were incorporated into a total cefazolin exposure (preoperative and intraoperative doses) that was normalized for DW and duration of surgery. In subjects with closure concentrations <40 mg/L and ≥40 mg/L, the cefazolin dose for every hour of surgery (intermittent dosing) was 5.8 ± 1.7 mg/kgDW and 8.2 ± 2.0 mg/kgDW, respectively (P = 0.03). Based on classification and regression tree (CART) analysis, a cefazolin exposure of 7.6 mg/kgDW for every hour of surgery was a significant threshold for achieving target closure concentrations. Table 2. Univariate analysis of subject and surgery-related variables with regards to achieving target cefazolin closure concentrations ≥40 mg/L Variable  Total cefazolin closure concentration   P  <40 mg/L (n = 5)  ≥40 mg/L (n = 46)  Female  4 (80)  13 (28)  0.04  Age (years)  68.4 ± 9.5  64.8 ± 9.9  0.46  Body weight (kg)  73.1 ± 6.1  91.3 ± 16.9  <0.0001  CLCR (mL/min/72 kg)  82.6 ± 25.9  79.9 ± 18.2  0.83  Net fluid balance during surgery (mL)  3350 ± 579  3634 ± 1352  0.41  Duration of surgery (min)  191 ± 15  260 ± 84  <0.0001  Variable  Total cefazolin closure concentration   P  <40 mg/L (n = 5)  ≥40 mg/L (n = 46)  Female  4 (80)  13 (28)  0.04  Age (years)  68.4 ± 9.5  64.8 ± 9.9  0.46  Body weight (kg)  73.1 ± 6.1  91.3 ± 16.9  <0.0001  CLCR (mL/min/72 kg)  82.6 ± 25.9  79.9 ± 18.2  0.83  Net fluid balance during surgery (mL)  3350 ± 579  3634 ± 1352  0.41  Duration of surgery (min)  191 ± 15  260 ± 84  <0.0001  Data are presented as n (%) or mean ± SD. Discussion Our study characterized cefazolin concentrations achieved during cardiac surgery with CPB using the standard AP regimen. There was significant variability in cefazolin concentrations most notably at wound closure when values ranged from 32 to 222 mg/L (Figure S1). Almost 10% of cefazolin closure concentrations were below the target of 40 mg/L, as were 40% of intraoperative trough concentrations at the scheduled re-dosing time. This is an important observation given the association between low AP closure concentrations and increased risk of SSI.6 We evaluated total cefazolin closure concentrations against a target of ≥40 mg/L (≥8 mg/L unbound) for effective AP. Although reports of cefazolin protein binding in this population range from 40% to 80%, we used the latter as the most conservative estimate of unbound (active) drug.7–10 An unbound concentration of 8 mg/L is consistent with the CLSI susceptible breakpoint for Enterobacteriaceae spp. before being lowered to 2 mg/L for improved detection of ESBLs.11 It is also the last susceptible breakpoint for antistaphylococcal cephalosporins before inferring susceptibility from oxacillin (or cefoxitin) testing for methicillin resistance. Finally, an unbound concentration of 8 mg/L represents the threshold for bactericidal activity (i.e. four times the MIC) against the common susceptible skin flora with MICs ≤2 mg/L. Our study found that lower body weight and shorter duration of surgery were significant predictors of below-target closure concentrations in patients undergoing cardiac surgery with CPB. Lower body weight was also associated with intermittent 1 g doses thereby confirming that at least 2 g should be used regardless of weight. The association between shorter duration of surgery and lower closure concentration was another important observation. Given that re-dosing did comply with the ‘every 4 h’ recommendation, our findings suggest that more frequent re-dosing every 3 h should be considered for patients with normal renal function. Finally, our analysis of total cefazolin exposure incorporated patient weight and duration of surgery into a modifiable variable that could be used to optimize cefazolin AP regimens. The relationship between body or dosing weight, re-dosing interval and intermittent cefazolin doses required to maintain closure concentrations ≥40 mg/L in our study population are shown in Table S2. Using the significant threshold of 7.6 mg/kgDW for every hour of surgery, these data also support a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery. A limitation of our study was the analysis of total as opposed to unbound (active) cefazolin concentrations. Similar to other studies, cefazolin closure concentrations were evaluated against targets that exceed the MICs for potential pathogens as opposed to those directly associated with clinical outcome. The limitation is indicative of the paucity of pharmacokinetic/pharmacodynamic research in the area of AP for surgery. Finally, as our study was conducted in subjects with relatively normal renal function, the findings do not apply to patients with significant renal insufficiency. In conclusion, the standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. In our study, a cefazolin exposure of ≥7.6 mg/kgDW for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Acknowledgements We would like to acknowledge the St Boniface Hospital and Winnipeg Regional Health Authority (WRHA) Cardiac Sciences Program including surgeons, anaesthesiologists, nurses and other staff who supported the study. In particular, the contributions of B. Brett Hiebert (Programmer/Statistical Analyst) are appreciated. Funding This work was supported by a Canadian Society of Hospital Pharmacists Foundation Grant (no. 317380), Leslie F. Buggey Professorship (S. A. Z.) and University of Manitoba Graduate Fellowship (D. C.). Additional support was provided by the Dr Paul H. T. Thorlakson Foundation Fund, University of Manitoba Research Grants Program (UM Project no. 43887, 2015), Natural Sciences and the Engineering Research Council Canada (RGPIN-2015–06543, 2015–2020) (T. M. L.), Leslie F. Buggey Graduate Scholarships (D. C., R. L.), Beatrice Faiman Graduate Scholarship (R. L.) and Research Manitoba Fellowship (R. L.). Transparency declarations None to declare. Supplementary data Tables S1 and S2 and Figure S1 are available as Supplementary data at JAC Online. References 1 Bratzler DW, Dellinger EP, Olsen KM et al.   Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect  2013; 14: 73– 156. Google Scholar CrossRef Search ADS   2 Ariano RE, Zelenitsky SA, Poncsak KR et al.   No role for patient body weight on renal function assessment for drug dosing. J Antimicrob Chemother  2017; 72: 1802– 11. Google Scholar CrossRef Search ADS PubMed  3 Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis  1997; 25: 112– 8. Google Scholar CrossRef Search ADS PubMed  4 Lillico R, Sayre CL, Sitar DS et al.   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. J Chromatogr B Analyt Technol Biomed Life Sci  2016; 1031: 94– 8. Google Scholar CrossRef Search ADS PubMed  5 US Department of Health and Human Sciences FDA. Guidance for Industry: Bioanalytical Method Validation. 2001. http://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf. 6 Zelenitsky SA, Ariano RE, Harding GKM et al.   Antibiotic pharmacodynamics in surgical prophylaxis: an association between intraoperative antibiotic concentrations and efficacy. Antimicrob Agents Chemother  2002; 46: 3026– 30. Google Scholar CrossRef Search ADS PubMed  7 Hutschala D, Skhirtladze K, Kinstner C et al.   In vivo microdialysis to measure antibiotic penetration into soft tissue during cardiac surgery. Ann Thorac Surg  2007; 84: 1605– 10. Google Scholar CrossRef Search ADS PubMed  8 Andreas M, Zeitlinger M, Hoeferl M et al.   Internal mammary artery harvesting influences antibiotic penetration into presternal tissue. Ann Thorac Surg  2013; 95: 1323– 9; discussion 1329–30. Google Scholar CrossRef Search ADS PubMed  9 Andreas M, Zeitlinger M, Wisser W et al.   Cefazolin and linezolid penetration into sternal cancellous bone during coronary artery bypass grafting. Eur J Cardiothorac Surg  2015; 48: 758– 64. Google Scholar CrossRef Search ADS PubMed  10 Hollis AL, Heil EL, Nicolau DP et al.   Validation of a dosing strategy for cefazolin for surgery requiring cardiopulmonary bypass. Surg Infect (Larchmt)  2015; 16: 829– 32. Google Scholar CrossRef Search ADS PubMed  11 Turnidge JD; on behalf of the Subcommittee on Antimicrobial Susceptibility Testing of the Clinical and Laboratory Standards Institute. Cefazolin and Enterobacteriaceae: rationale for revised susceptibility testing breakpoints. Clin Infect Dis  2011; 52: 917– 24. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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