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J Thorac Cardiovasc Surg 2002;123:326-332
© 2002 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease (ACD) |
From Rambam Medical Centera and Technion-Israel Institute of Technology,b Haifa, Israel.
Received for publication April 23, 2001; revisions requested June 6, 2001 Revisions received July 12, 2001. Accepted for publication July 20, 2001. Address for reprints: R. Finkelstein, MD, Infectious Diseases Unit, Rambam Medical Center, Haifa 31096, Israel (E-mail: rfinkelstein{at}rambam.health.gov.il).
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Abstract |
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18 years) scheduled for cardiac surgery requiring sternotomy were randomly assigned to receive vancomycin (1 g every 12 hours) or cefazolin (1 g every 8 hours). Prophylaxis was started during the induction of anesthesia and continued for only 24 hours. Patients were followed up for at least 30 days (1 year for those receiving a cardiac implant). Surgical site infections were stratified according to the National Nosocomial Infections Surveillance System risk index. |
Introduction |
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An estimated 468,000 coronary artery bypass grafting (CABG) procedures and more than 60,000 valve implantations are performed annually in the United States.
1,2 Surgical site infections (SSIs), particularly organ-space infections, have serious implications when associated with these operations because of the substantial morbidity, mortality, and expense that they add to the health care system. The benefits of antibiotic prophylaxis in cardiovascular surgery have been clearly demonstrated in several placebo-controlled studies, 3-6 but the choice of the optimal agent remains controversial. Cephalosporins have been the mainstay of prophylaxis in cardiac surgery because staphylococci are the most common organisms isolated from both vein donor sites and chest wound infections. 7,8 A recent review, sponsored by the Infectious Diseases Society of America and endorsed by both it and the Surgical Infection Society, recommended, "Vancomycin can be given instead of cefazolin to patients who are allergic to cephalosporins or in settings where infections with methicillin-resistant Staphylococcus aureus (MRSA) are prevalent." 9 At the time this study was started, only one published clinical trial had investigated the efficacy of vancomycin relative to that of cephalosporins in preventing SSIs in cardiovascular surgery. 10 That double-blind control study showed the superiority of vancomycin to cefazolin in preventing thoracic SSIs other than mediastinitis. This trial was undertaken to compare the efficacy of cefazolin and vancomycin in preventing SSIs in cardiovascular surgery at a large university hospital with a high prevalence of MRSA infections.
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Methods |
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11 A recently published consensus panel's definitions for discriminating high rates of MRSA transmission have suggested a threshold of 0.5 new nosocomial cases of MRSA per 100 admissions for hospitals with at least 500 beds. 12 According to our computerized records, in 1995 and 1996 there were 3.0 and 2.6 new cases of MRSA infection or colonization, respectively, per 100 admissions in our cardiac surgery ward, easily meeting the criterion for high transmission of MRSA.
The study was approved by the local ethical review committee. Informed consent was not required because we had been using both drugs for prophylaxis in cardiovascular surgery before the trial. All adult patients (18 years) scheduled for cardiac surgery requiring sternotomy were considered eligible for the trial. Exclusion criteria included the presence of active infection, the use of antibiotics within 2 weeks before the operation, and a previous cardiac operation requiring sternotomy within 1 year of enrollment in this trial.
Random assignment and antibiotic regimens
Random assignment was performed according to the last digit of the patient's national identification number (similar to US social security number). Patients whose identification number ended in an even digit were scheduled to receive 1.0 g vancomycin intravenously at the induction of the anesthesia over a period of 60 minutes and a similar dose 12 hours later. Patients whose identification number ended in an odd digit were scheduled to receive 1 g cefazolin intravenously over a period of 20 to 30 minutes at the induction of the anesthesia and two additional similar doses at 8-hour intervals. Because the timing of administration of prophylaxis is of great importance in preventing SSIs, 13 we defined the antibiotic regimen as "preoperative prophylaxis" if the antibiotic drug was administered in an optimal period of 2 hours or less before the first surgical incision.
Surgical preparation and technical details
The patients showered with a 7.5% povidone-iodine scrub (Polydine Cleanser; Fisher Pharmaceutical Laboratories, Tel Aviv, Israel) the night before the scheduled operation and again on the morning of the operation. The sites of operation were depilated on the morning of the operation with a hair-removing cream (Vito; Heibel Co, Hadera, Israel). In the operating room all operative sites were scrubbed with the povidone-iodine soap solution and then painted with a 10% povidone-iodine–ethanol tincture (Polydine Tincture; Fisher Pharmaceutical Laboratories). The area of sternotomy was covered with an iodine membrane (Loban; 3M Health Care, St Paul, Minn). All operations were done under conventional cardiopulmonary bypass and moderate hypothermia (rectal temperature 28°C-30°C) with a membrane oxygenator (SpiralGold; Baxter Healthcare Corporation CardioVascular Group, Irvine, Calif). Myocardial protection was achieved with short antegrade and continuous retrograde undiluted blood cardioplegia. The internal thoracic arteries were used in 96% of the patients undergoing CABG operations and were harvested either pedicled or skeletonized according to the surgeon's preference with low-grade diathermy. The greater saphenous vein was harvested through a single skin incision by means of standard surgical procedures. All subcutaneous tissues were approximated with continuous absorbable multifilament sutures (Coated Vicryl; Ethicon, Inc, Somerville, NJ), and skin wounds were closed with stainless steel clips (Weck Closure Systems, Research Triangle Park, NC). All operations were performed by the same team headed by four experienced cardiac surgeons (Y.B., Z.A., V.K., S.M.).
Patient evaluation
During hospitalization, patients were evaluated daily by cardiac surgeons and three times a week by an infection control nurse. At the discretion of the attending physician, an infectious diseases specialist was also involved in the evaluation and treatment of patients. Cultures were obtained as clinically indicated and processed in the hospital's microbiology laboratory according to standard procedures. All patients were followed up for the appearance of postdischarge SSI with at least two visits, the first 1 week after discharge and the second 3 weeks later. Follow-up was done in the hospital's cardiac surgery outpatient clinics with the presence of an infection control nurse or infectious diseases physician. Patients receiving a cardiac implant were followed up for at least 1 year. Six patients who did not return to the outpatient clinic were contacted by telephone by the infection control nurse.
Definitions
Nosocomial SSIs were defined according to the Centers for Disease Control and Prevention definitions. 14 The criteria are described here.
Superficial SSI
This was an infection involving only skin and subcutaneous tissue with at least one of the following: purulent drainage from the incision, positive results of incisional culture, and classic inflammatory signs that led to the incision being deliberately reopened by the surgeon unless results of an incisional culture were negative.
Deep incisional SSI
This was an infection involving deep soft tissues of the incision with at least one of the following: purulent drainage from the deep incision, a deep incision that spontaneously dehisced or was deliberately opened by the surgeon in the presence of fever (temperature 38°C) or localized pain or tenderness unless results of an incisional culture were negative, and evidence of infection involving the deep incision found in direct examination or reoperation.
Mediastinitis
Mediastinitis was reported as a specific organ-space SSI and was an infection characterized by one of the following: positive results of a culture obtained from mediastinal tissue or fluid during a surgical operation, a patient fever (temperature 38°C), chest pain or sternal instability, mediastinal involvement suggested by a computed tomographic scan, and organisms cultured from the mediastinal area.
Sternal osteomyelitis
Sternal osteomyelitis was reported as a specific organ-space SSI and was indicated by a persistent purulent drainage from the sternotomy confirmed by microbiologic and histopathologic findings.
Pericarditis
Pericarditis was reported as a specific organ-space SSI and was indicated by organisms cultured from pericardial tissue or fluid obtained by needle aspiration or during surgical operation.
Endocarditis
Endocarditis was reported as a specific organ-space SSI and was defined according to the Duke criteria. 15
SSI risk stratification
SSIs were stratified according to the National Nosocomial Infections Surveillance System risk index. 16 Because all surgical wounds included in our study were classified as clean, the index values ranged from 0 to a maximum of 2.
Statistical analysis
Before the start of this trial, cefazolin had been used for many years as the routine prophylactic regimen for cardiovascular surgery in our institution. We estimated the number of patients that would be required for an adequate examination of the hypothesis that prophylaxis with vancomycin may result in a significant reduction in the overall rate of SSIs as follows. Because our rate of SSIs with cefazolin was not precisely known, we established this baseline rate by calculating SSI rates occurring during the first 12 months of the study. The overall SSI rate observed among 136 patients receiving cefazolin prophylaxis and included in the study during this period was 10.5%. A total of 405 operations were required in each group for the study to have the ability to show a significant reduction of the SSI rate to 5% with an 
level of .20 and ß error of .05. The reduction to 5% was chosen as a maximal figure approximating the median of SSI rate reported by the National Nosocomial Infections Surveillance System for CABG operations (chest and leg) among patients in risk category 2. 17 The significance of the differences between the two groups was determined by the Student t test or Wilcoxon rank-sum test for continuous variables and by the Fisher exact test or 
2 test for categoric variables. Calculation was performed with the SPSS statistical program version 9 (SPSS Inc, Chicago, Ill).
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Results |
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Table 3 summarizes the distribution of pathogens isolated in both groups of patients according to the different types and sites of SSI. Pathogens isolated from SSIs were similarly distributed in both groups, although some differences were found that did not reach statistical significance. More than 60% of SSIs were due to gram-positive cocci. S aureus was the leading pathogen, closely followed by coagulase-negative staphylococci. Gram-negative bacilli caused approximately 50% of SSIs. Nevertheless, there was a trend toward more common infections with ß-lactam–resistant gram-positive cocci (eg, MRSA and methicillin-resistant enterococci) in the cefazolin group (18 of 433 patients, 4.2%, vs 9 of 452 patients, 2%, P = .09). In contrast, SSIs due to methicillin-susceptible S aureus and coagulase-negative staphylococci were significantly more frequent among patients who received vancomycin prophylaxis (17 of 452 patients, 3.7%, vs 6 of 433 patients, 1.3%, P = .04). The mean preoperative stays among patients with SSIs caused by methicillin-susceptible staphylococci and by MRSA were similar (4.65 ± 5.0 days vs 5.7 ± 10.5 days, P = .7). Polymicrobial infection rates were also similar in the two groups; 8 of 43 infections (18.6%) in the vancomycin group were polymicrobial, as compared with 11 of 39 infections (28.2%) in the cefazolin group (P = .4).
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Discussion |
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18,19 Despite a relatively large number of studies, no cephalosporin drug has emerged as clearly superior to the others in reducing SSI rates. A meta-analysis of antibiotic prophylaxis that included six studies of cefazolin versus cefamandole or cefuroxime 20 concluded that the second-generation cephalosporins were associated with lower prevalence of wound infection than seen with cefazolin. However, subsequent randomized double-blind trials failed to show the superiority of cefamandole or cefuroxime over first-generation cephalosporins in cardiac surgery. 10,21 The use of vancomycin for prophylaxis in cardiac surgery, although much more controversial, might be justified in the light of many observations. First, organ-space infections, although infrequent, have devastating consequences. Second, coagulase-negative staphylococci and S aureus, the most important pathogens responsible for SSIs in cardiac surgery, are frequently resistant to ß-lactam antibiotics. Third, some studies have shown that more than 80% of surgical patients who receive a first-generation cephalosporin for prophylaxis become colonized with methicillin-resistant coagulase-negative staphylococci by the seventh postoperative day. 22,23 Finally, the superiority of vancomycin over cephalosporins in cardiac surgery has been suggested in two previous studies. Maki and colleagues 10 showed in a prospective, double-blind trial that vancomycin, relative to cefazolin and cefuroxime, was associated with a statistically significant reduction in the rate of thoracic surgical SSIs other than mediastinitis. In addition, the mean duration of postoperative hospitalization in the vancomycin group was significantly reduced relative to that observed in the cefazolin group. In a preliminary report, Nafziger and colleagues 24 showed that prophylaxis with a first-generation cephalosporin instead of vancomycin appeared to be a risk factor for mediastinitis.
On the other hand, two major problems with the prophylactic use of vancomycin in surgery should be seriously considered. First, several studies have concluded that the use of vancomycin prophylaxis in cardiac and noncardiac surgery may result in serious untoward effects, particularly hypotension. 25,26 Second, and more important, are the alarming problems of vancomycin-resistant enterococci 27 and more recently glycopeptide-intermediate–resistant S aureus. 28 Reports of these emerging resistances have significantly altered attitudes toward the use of vancomycin prophylaxis in surgery. As a consequence, recent guidelines for prevention of SSIs strongly recommend avoiding the routine use of vancomycin for antimicrobial prophylaxis in surgery. 29 These recommendations may be strengthened by a recently published trial 30 that showed similar results when vancomycin and cefuroxime were used for antimicrobial prophylaxis in CABG.
The major objective of our trial was to investigate whether SSI rates associated with cardiac surgery could be reduced by the use of vancomycin prophylaxis in an institution with a high prevalence of MRSA infections. Although we observed a trend toward more serious infections occurring among patients who received cefazolin prophylaxis, this trend did not reach statistical significance. As could be expected, SSIs caused by methicillin-resistant gram-positive cocci were more common among patients who received cefazolin prophylaxis. However, the overall results were counterbalanced by the fact that infections with methicillin-susceptible staphylococci were significantly more frequent in the vancomycin group. Paradoxically, infections with gram-negative bacilli were equally common in the two groups.
Although a prolonged preoperative stay is a likely surrogate for severity of illness, it is frequently suggested as a patient characteristic associated with increased SSI risk. 29 Moreover, infections with resistant organisms, including MRSA, are typically hospital acquired. Therefore one could make a point in favor of the use of vancomycin as surgical prophylaxis for patients with a prolonged preoperative stay. In this study, however, SSI rates and infections with MRSA were not affected by a more prolonged preoperative stay. Thus our results do not support the use of vancomycin prophylaxis in this setting.
It appears that the random assignment achieved a good balance among the various covariates of the two groups(Table 1
). Nevertheless, the fact that the trial could not be performed in a double-blinded fashion represents an important limitation of this study. Taking this limitation in consideration, we conclude that this study could not show any clear advantage of vancomycin over cefazolin in reducing SSI rates in cardiac surgery at our institution, where the prevalence of MRSA infections is high. Possible explanations may include the superiority of cefazolin over vancomycin in preventing infections with ß-lactam–susceptible organisms or the possibility that some serious infections complicating cardiac operations are initiated after the operation in a critical care setting, rather than being acquired during operation. 31,32 Our data appear to support the continuing efforts to restrict the prophylactic use of vancomycin in surgical practice.
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