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Ann Thorac Surg 2002;74:1187-1190
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Serum levels of prophylactic cefazolin during cardiopulmonary bypass surgery

Erika K. Fellinger, MDa, Bruce J. Leavitt, MDa*, James C. Hebert, MD, FACSa

a Department of Surgery, University of Vermont College of Medicine, Burlington, Vermont, USA

Accepted for publication March 18, 2002.

* Address reprint requests to Dr Leavitt, University of Vermont, Fletcher House 4, 111 Colchester Ave, Burlington VT 05401, USA.
e-mail: bruce.leavitt{at}vtmednet.org


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Controversy exists regarding the appropriate prophylactic dose of cefazolin for coronary artery bypass grafting (CABG) surgery requiring cardiopulmonary bypass (CPB) because the effect of CPB on serum drug levels is poorly understood. Current standards of prophylaxis are based primarily on empiric studies. Few studies have attempted to quantify serum cefazolin levels in either cardiac or noncardiac surgeries. This study was conducted to measure and assess the adequacy of the intraoperative serum levels of prophylactic cefazolin in CPB surgery.

METHODS: This prospective study serially measured six intraoperative serum cefazolin levels in 10 subjects undergoing elective and urgent CABG surgery. We compared the serum levels with the minimum inhibitory concentrations (MIC90) for the most common organisms causing postoperative infection.

RESULTS: Serum-free cefazolin levels fluctuated considerably during the operation but remained above the MIC90 for Staphylococcus aureus and S. epidermidis. The serum levels fell below the MIC90 for Enterobacter, Serratia, Escherichia coli, and Proteus mirabilis.

CONCLUSIONS: Serum cefazolin levels during CPB remained consistently above the MIC for two of the three main organisms causing postoperative infection but were suboptimal for the remainder. Additional studies are needed to assess the intraoperative serum levels of single-dose cefazolin prophylaxis and to explore alternate dosing methods that minimize intraoperative fluctuations in serum cefazolin levels.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Prophylactic antibiotics reduce the incidence of postoperative infection [1–3]. Cephalosporins are the standard prophylactic antibiotics for cardiac surgery because of the low toxicity and broad microbial coverage [1, 3, 4]. Current standards of prophylaxis in cardiopulmonary bypass (CPB) surgery were developed from empiric studies that observed postoperative infection in both cardiac and noncardiac surgeries [3, 4–7]. The current accepted practice consists of 1 to 2 g of cefazolin IV given on call to the operating room (OR) or at the induction of anesthesia. It is unclear if this cefazolin dosing regimen produces adequate blood levels of antibiotic, given the physiologic changes associated with CPB.

We first reviewed the literature to determine what constitutes an "adequate" dose of prophylactic cefazolin. We then carried out this investigation with the hypothesis that our current practice of administering 1 g of cefazolin IV on call to the OR or at the induction of anesthesia, followed by a second dose of 1 g IV into the pump just after the initiation of CPB, does not constitute an adequate dose of prophylactic antibiotic.

A standard definition of postsurgical infection has been established by the Centers for Disease Control/National Nosocomial Infection Surveillance (CDC/NNIS) [9]. Postoperative wound infection rates in cardiac surgery vary from 7% to 18%, with deep sternal wound infections averaging 1% to 3% [3, 5, 6, 15]. The most common organisms causing postoperative infection in cardiac surgery are Staphylococcus epidermidis (27 to 40%), S. aureus (17 to 32%), and, increasingly, gram-negative enteric organisms, including Enterobacter (4 to 26%), Enterococcus (1 to 7%), Serratia (9%), Escherichia coli, and P. mirabilis (both < 5%) [6, 15].

In theory, the body may be divided into three compartments: intravascular, interstitial, and intracellular. Bacteria causing infection live primarily in the interstitial compartment. Antibiotic levels in tissues and the interstitium are directly related to serum drug levels and thus are dependent on the drug’s unbound (free) concentration in the serum, its solubility, the blood supply to the tissue, and the presence of inflammation in the tissue [2, 16]. The level of antibiotic in the interstitial space determines effectiveness in preventing infection [3, 16].

It is generally accepted that an "adequate" dose of antibiotic achieves a free concentration above the minimum inhibitory concentration (MIC) for the targeted organism [2]. Some evidence exists that concentrations of antibiotic below the MIC alter the morphology and adherence of bacteria and, thus having only detectable quantities of antibiotic, may provide sufficient protection [17]. Regardless, we chose the definition most widely accepted for this study. For cephalosporins, the length of time above the MIC, rather than the concentration above the MIC, dictates killing ability [10, 12, 18].


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
A prospective pilot study approved by the Committee on Human Research at Fletcher Allen Health Care was carried out from January 1998 through March 1998. Ten subjects aged 45 to 70 years undergoing elective and urgent coronary artery bypass grafting (CABG) were recruited during preoperative visits to the surgeon’s office and from an inpatient setting after emergency room evaluation and referral from cardiology. Participants were given informed consent and were assigned an identifying number to maintain confidentiality. All subjects were matched for CDC/NNIS infection risk classification (1 of a possible 3) and ASA score (all had an ASA of 3) as determined by the attending anesthesiologist during preoperative evaluation (Table 1) [14].


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  		Table 1. NNIS Surgical Patient Risk Index

 
Subjects were not significantly different with respect to age and comorbidity (Table 2). All had normal hepatic and renal function. Seventeen patients were approached and 7 excluded for scheduling and logistical reasons. There were no withdrawals.


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  		Table 2. Patient Characteristics (N = 10)

 
Patients were excluded from the study for age less than 18 or greater than 75 years, previous cardiac surgery, concurrent infection or antibiotic use within 4 weeks, penicillin allergy, renal or hepatic disease, and use of intraaortic balloon pump. All participants received the same standard preoperative, operative, and postoperative care as nonparticipants.

Subjects received cefazolin 1 g IV in preoperative hold or at the induction of anesthesia, and a second dose of cefazolin 1 g IV immediately after the onset of CPB. Blood samples were drawn from the radial artery catheter by the anesthesiologist or directly off the pump by the perfusionist during CPB. Two liters of priming fluid with heparin was used in the bypass machine. Samples were collected into labeled, nonheparinized tubes and allowed to clot. Samples were centrifuged for 15 minutes and the serum was poured off, stored, and shipped at –20°C for analysis. Sample collection time points are listed in Table 3.


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  		Table 3. Sample Collection Time Points

 
Total serum cefazolin levels were determined at Mayo Laboratories (Mayo Medical Laboratories, Rochester, MN) using standard high-performance liquid chromatography (HPLC) techniques. Free serum levels were calculated from total levels, assigning cefazolin an 80% protein-bound state. Free levels were not corrected for hemodilution because the uncorrected levels were thought to represent more accurately the reality of the hemodiluted state of the patient on CPB. Raw data were graphed using Sigma Plot and Excel software (Fig 1). Minimum, maximum, and mean free cefazolin levels were calculated for all time points (Table 4). The free serum cefazolin levels were compared with the MICs of important organisms that cause infection (Table 5).



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  		Fig 1. Mean serum cefazolin levels versus organism MICs. (—•—) Mean cefazolin level at each time point; (——) MIC for S. aureus (0.08 µg/mL); (....) MIC for S. epidermidis (0.5–4 µg/mL); (— —) MIC for Enterobacter (64 µg/mL); (—··–) MIC for E. coli (12–64 µg/mL); (— –) MIC for P. mirabilis (8–25 µg/mL); (—·—) MIC for Serratia (100 µg/mL). (CPB = cardiopulmonary bypass; MIC= minimum inhibitory concentration.)

 

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  		Table 4. Cefazolin Maximum and Minimum Free Serum Levels (µg/mL)

 

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  		Table 5. Common Organisms Causing Infection and Their MIC90s

 

   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
The highest serum levels of free cefazolin, with a mean of 35.56 µg/mL, occurred at sample time 3, just after the administration of the second dose of cefazolin during CPB (Table 4). The lowest serum cefazolin levels, with a mean of 6.34 µg/mL, were found at sample time 2, just after the onset of CPB and before the administration of cefazolin dose 2. The levels of free cefazolin remained consistently above the MIC90s for S. aureus and S. epidermidis throughout all procedures. The levels fell below the MIC90s for E. coli and P. mirabilis briefly after the onset of CPB, and were below the MIC90s for Enterobacter and Serratia during the entire case (Fig 1).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Pharmacokinetic studies of cefazolin have been conducted almost exclusively in non-CPB surgeries. Serum levels were highly variable and unlikely to be a useful guideline to antibiotic dosing in CPB surgery [5, 10, 12, 13]. One study measuring serum levels during CPB surgery [7] concluded that a 1-g intramuscular dose of cefazolin given at the induction of anesthesia produced "adequate" serum levels for operations up to 4 hours. A more recent study determined that CPB alters the time course of antibiotic serum concentrations (ceftazidime, ciprofloxacin, clindamycin) by decreases from 42% to 78% [11].

During cardiac surgery and CPB, reduced cardiac output and organ perfusion decrease the cefazolin volume of distribution [8, 9]. Cefazolin is normally 80% to 85% protein bound [9, 10]. The amount of protein binding is decreased by hypothermia, hemodilution of plasma binding proteins, and the heparin-induced release of free fatty acids, which compete with cefazolin for protein binding spots. This decrease in binding results in increased free blood concentrations and, consequently, an apparent increase in the volume of distribution of cefazolin [8, 9]. Cefazolin is 100% eliminated by the kidney. Renal elimination decreases during surgery in proportion to decreases in glomerular filtration rate and organ perfusion. One study found that this contributes to an increase in the volume of distribution, but that elimination is not affected by CPB [9].

Using our current protocol for infection prophylaxis during CPB surgery, free serum cefazolin levels remained above the MIC90 for the two most common gram-positive organisms causing postoperative infection. This suggests that patients are well protected against these organisms. Indeed, our infection rate has remained at or below the national average for the past 10 years. Because toxicity is not an issue at these fairly low dosages, cost is the motivating factor to fine-tune the dosage of cefazolin needed to maintain a level consistently above the desired MIC and no more.

Cefazolin-free levels were all subtherapeutic for Enterobacter, an organism responsible for 4% to 26% of postoperative infections and, less importantly, Serratia, causing about 9% of infections. The levels at sample times 1, 4, 5, and 6 were not statistically different from the MICs for E. coli and P. mirabilis; therefore, we cannot determine if patients are protected from these organisms. As previously mentioned, whether sub- or peritherapeutic levels imply an increased risk of infection is still a matter open for debate. A better understanding of the factors involved in causing infection (for example, the role of operator technique, OR environment, age, and comorbidity) is needed.

Because the time above a given MIC determines the killing ability of cefazolin, the fluctuations of the serum levels during surgery are of concern, in particular, the low levels seen at the onset of CPB and before the second cefazolin dose. A single 2-g dose of cefazolin given at the induction of anesthesia might avoid sub-MIC levels (for E. coli and P. mirabilis) just before CPB. It may be difficult to achieve serum cefazolin levels sufficient to cover Enterobacter (MIC90 = 64). If this organism is found to be unusually problematic, it may be necessary to further increase the cefazolin dose or add an additional prophylactic agent.

We recommend a larger study measuring the serum levels achieved with 2 g cefazolin given at the induction of anesthesia. We also suggest exploring alternatives to bolus dosing, for example, 1 to 2 g of cefazolin in an IV drip or a bolus/drip combination. Continued evaluation of the specific infection patterns and prophylactic regimens in each individual institution is recommended.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We would like to acknowledge Jody Ciano for her astute editing work and the UVM Department of Surgery for its funding and technical support.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 1995;37:79-82.[Medline]
  2. Bergamini T.M., Polk H.C., Jr Pharmacodynamics of antibiotic penetration of tissue and surgical prophylaxis. Surg Gynecol Obstet 1989;168:283-289.[Medline]
  3. Fong I.W., Baker C.B., McKee D.C. The value of prophylactic antibiotics in aorta-coronary bypass operations. J Thorac Cardiovasc Surg 1979;73:625-629.[Abstract]
  4. Akl B.F., Richardson G. Serum cefazolin levels during cardiopulmonary bypass. Ann Thorac Surg 1980;29:109-112.[Abstract]
  5. Curtis J.J., Boley T.M., Walls J.T., Hamory B., Schmaltz R.A. Randomized, prospective comparison of first- and second-generation cephalosporins as infection prophylaxis for cardiac surgery. Am J Surg 1993;166:734-737.[Medline]
  6. Ariano R.E., Zhanel G.G. Antimicrobial prophylaxis in coronary bypass surgery: a critical appraisal. DICP 1991;25:478-484.[Abstract]
  7. Saginur R., Croteau D., Bergeron M.G. Comparative efficacy of teicoplanin and cefazolin for cardiac operation prophylaxis in 3027 patients. The ESPRIT group. J Thorac Cardiovasc Surg Dec 2000;120:1120-1130.
  8. Buylaert W.A., Herregods L.L., Mortier E.P., Bogaert M.G. Cardiopulmonary bypass and the pharmacokinetics of drugs: an update. Clin Pharmacokinet 1989;17:10-26.[Medline]
  9. Miller K.W., McCoy H.G., Chan K.K., et al. Effect of cardiopulmonary bypass on cefazolin disposition. Clin Pharmacol Ther 1990;27:550-556.
  10. Drug Dex System, Thomson Micromedex Inc, Greenwood Village, Colorado, Vol. 93, 1974–1997
  11. Lonsky V., Dominik J., Mand’ak J., et al. Changes of serum antibiotic levels during open heart surgery (cetazidime, ciprofloxacin, clindamycin). Acta Medica 2000;43:23-27.
  12. Craig W.A. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995;22:89-96.[Medline]
  13. Ishiyama S., Nakayama I., Iwamoto H., Iwai S., Okui M. Absorption, tissue concentration, and organ distribution of cefazolin. Antimicrobial Agents Chemother 1970;10:476-480.
  14. Culver D.H., Horan T.C., Gaynes R.P., et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index: National Nosocomial Infections Surveillance System. Am J Med 1991;91(Suppl 3B):152S-157S.[Medline]
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  16. Barza M. Pharmacokinetics of antibiotics in shallow and deep compartments. J Antimicrob Chemother 1993;31(Suppl D):17-27.
  17. Lorian V. Medical relevance of low concentrations of antibiotics. J Antimicrob Chemother 1993;31(Suppl D):137-148.
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