Surgical site infections (SSIs) in cardiovascular surgery

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1 Prolonged Antibiotic Prophylaxis After Cardiovascular Surgery and Its Effect on Surgical Site Infections and Antimicrobial Resistance Stephan Harbarth, MD, MS; Matthew H. Samore, MD; Debi Lichtenberg, RN; Yehuda Carmeli, MD, MPH Background Despite evidence supporting short antibiotic prophylaxis (ABP), it is still common practice to continue ABP for more than 48 hours after coronary artery bypass graft (CABG) surgery. Methods and Results To compare the effect of short ( 48 hours) versus prolonged ( 48 hours) ABP on surgical site infections (SSIs) and acquired antimicrobial resistance, we conducted an observational 4-year cohort study at a tertiary-care center. An experienced infection control nurse performed prospective surveillance of 2641 patients undergoing CABG surgery. The main exposure was the duration of ABP, and main outcomes were the adjusted rate of SSI and the isolation of cephalosporin-resistant enterobacteriaceae and vancomycin-resistant enterococci (acquired antibiotic resistance). Adjustment for confounding was performed by multivariable modeling. A total of 231 SSIs (8.7%) occurred after a median of 16 days, including 93 chest-wound infections (3.5%) and 13 deep-organ-space infections (0.5%). After 1502 procedures using short ABP, 131 SSIs were recorded, compared with 100 SSIs after 1139 operations with prolonged ABP (crude OR, 1.0; CI, 0.8 to 1.3). After adjustment for possible confounding, prolonged ABP was not associated with a decreased risk of SSI (adjusted OR, 1.2; CI, 0.8 to 1.6) and was correlated with an increased risk of acquired antibiotic resistance (adjusted OR, 1.6; CI, 1.1 to 2.6). Conclusions Our findings confirm that continuing ABP beyond 48 hours after CABG surgery is still widespread; however, this practice is ineffective in reducing SSI, increases antimicrobial resistance, and should therefore be avoided. (Circulation. 2000;101: ) Key Words: bypass infection antibiotics The unnecessary and improper use of antibacterial agents in treatment, and particularly for prophylaxis...will have to be modified or stopped completely. Maxwell Finland, Surgical site infections (SSIs) in cardiovascular surgery are associated with adverse outcomes. 2 4 Among the different approaches to prevent these infections, antimicrobial prophylaxis is of substantial importance. Despite evidence from randomized clinical trials and other data supporting antibiotic prophylaxis (ABP) for no longer than 48 hours, 5 8 controversy persists about the optimal duration of prophylaxis. 9,10 In particular, it is still common practice to continue ABP for 48 hours after cardiac surgery until all chest tubes are removed This routine, although never substantiated by scientific evidence, is aimed at reducing SSI rates, but it has generated concerns about the emergence of antibiotic resistance and other adverse events. 16 Therefore, this 4-year observational cohort study was designed to examine the effect of prolonged ABP on the risk of SSI and the selection of antibiotic-resistant microorganisms after coronary artery bypass graft (CABG) surgery. Methods This observational cohort study was conducted at the West Campus of Beth Israel Deaconess Medical Center (Boston, Mass), a 320-bed teaching hospital with 600 cardiovascular operations per year. Patients were included if they had been operated on for CABG or CABG/valve procedure between September 1, 1993, and August 31, Each patient was included only once. An experienced infection-control nurse (D.L.) monitored patients who underwent cardiac operations and reviewed microbiology logs and medical reports to detect SSI. These data were prospectively reviewed and validated by the hospital epidemiologist (M.H.S.). SSIs were defined on the basis of National Nosocomial Infection Surveillance (NNIS) System criteria. 17 All patients were followed up for at least 3 months after hospital discharge to detect late-appearing infections. Received October 26, 1999; revision received January 7, 2000; accepted February 1, From the Department of Epidemiology (S.H.), Harvard School of Public Health, and Division of Infectious Diseases (M.H.S., D.L., Y.C.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Dr Carmeli is now with the Division of Infectious Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Dr Samore is at the Division of Infectious Diseases, University Hospital of Utah, Salt Lake City. Presented in part at the Ninth Annual Meeting of the Society of Healthcare Epidemiology of America, April 18 20, 1999, San Francisco, Calif. Correspondence to Stephan Harbarth, MD, MS, Division of Infectious Diseases, Enders Bldg 609, The Children s Hospital, 300 Longwood Ave, Boston, MA harbarth@a1.tch.harvard.edu 2000 American Heart Association, Inc. Circulation is available at

2 Harbarth et al Prolonged Antibiotic Prophylaxis 2917 Additional demographic and microbiological data were collected from administrative, pharmacy, and laboratory computerized databases by use of a relational database management system (Access, Microsoft Corp). The databases and related methods of data collection were described before. 18 Before surgery, patients took a chlorhexidine shower, and chest hair was clipped without shaving either the night before or on the morning of the operation. Immediately before surgical incision, povidone-iodine was applied for cutaneous disinfection of the operative site. In the operating room, beginning shortly before the first incision, prophylactic intravenous antibiotics (principally cefazolin 1 g; in some cases vancomycin 1 g, ceftriaxone 1 g, or a combination of these agents) were administered to each patient. In case of a prolonged intervention ( 5 hours), the second dose of cefazolin was administered after completion of cardiopulmonary bypass before closure of the sternal wound to ensure an adequate serum level of the antibiotic agent. After surgery, ABP was encouraged to be given for no more than 48 hours, but it could be continued at the surgeon s discretion. The main exposure was duration of ABP ( 48 hours versus 48 hours). The outcomes of interest were the occurrence of SSIs and isolation of a pathogen with acquired antibiotic resistance from a clinical specimen. For the purpose of the logistic regression analysis, patients with both chest and leg infections were classified as chest infections. In addition, first- and third-generation cephalosporin resistance in enterobacteriaceae (eg, Escherichia coli, Klebsiella spp, Proteus mirabilis) and vancomycin resistance in enterococci were considered to be acquired resistance and were the pathogens further examined. Statistical Analysis We used 2 or t tests to screen the following potential risk factors for SSI: Time from admission to operation, previous intensive care unit (ICU) stay, calendar time of the intervention (in 3-month intervals), sex, age, number of comorbidities (defined as pulmonary, renal, gastrointestinal, or hepatic conditions or malignant disease process causing serious disability), American Society of Anesthesiologists (ASA) classification (5-point assessment of the patient s physical condition conducted by the anesthesiologist immediately before surgery), severe obesity (body mass index 37 kg/m 2 ), diabetes mellitus (requiring either oral therapy or insulin treatment), chronic kidney disease (chronic underlying renal disorder), chronic lung disease (resulting in functional disability), emergency operation (surgery performed shortly after admission to avoid unnecessary morbidity or death), direct hospital admission (patients admitted from home), anemia (prebypass hematocrit: men 35%, women 30%), renal insufficiency (prebypass level of serum urea nitrogen 40 mg/dl), internal mammary artery graft, antimicrobial prophylactic agent, surgeon, history of previous cardiac surgery, additional valve replacement, and duration of surgery (time from first incision to wound closure). Variables with a value of P 0.1 in the univariate analysis were candidates for multivariable analysis, as well as the main variable of interest (duration of ABP). Multivariable modeling was performed by use of conventional logistic regression analysis. Variables were tested for significance by a Wald 2 statistic. In a separate analysis, we analyzed the effect of extended ABP on the isolation of microorganisms with acquired antibiotic resistance irrespective of the calendar time and the antibiotic agent used. To avoid confounding by indication and temporal trends, we performed conditional logistic regression matched on the type of prophylactic agent and calendar time. Variables with a value of P 0.1 in the crude analysis were considered candidates for multivariable analysis and were added to the model. Duration of prophylaxis was again forced into the model. In addition, we tested variables for confounding by adding them one at a time to the model and examining their effects on the coefficients of the main exposure variable. Variables that caused substantial confounding (change in coefficient of 10%) were included in the final model. Effect modification was examined by use of clinically important interaction terms. All statistical tests were 2-tailed. Values of P 0.05 were considered significant. Statistics were run on SPSS 8.0 (SPSS) and STATA 5.0 (STATA Corp). Results Study Population From September 1993 through August 1997, 2641 adult patients underwent CABG, including 186 patients who received combined CABG and valve replacement procedures. The median age of the patients was 68 years (range, 29 to 91 years), with 75% of the population 59 years old. Of these patients, 831 (31.5%) were female. A total of 1467 patients (55%) were transferred from another healthcare institution; 116 patients underwent emergency operations shortly after admission. The median preoperative stay for all patients was 2 days (range, 0 to 28 days); 631 patients (23.9%) stayed in the ICU before the operation. Operation time averaged 5 hours ( 1.1 hour). The median overall length of hospital stay was 9 days (range, 2 to 118 days), with a decreasing trend from 10 days in 1994 to 8 days in 1997 (Spearman s r 0.26, P 0.001). With regard to ABP, 2180 patients received cefazolin, 385 patients vancomycin, and 222 patients ceftriaxone; 1502 patients (57%) received ABP for 48 hours (mean, hours) and 1139 (43%) received ABP for 48 hours (mean, hours). Infections Overall, 231 SSIs occurred after a median time interval of 16 days, corresponding to a rate of 8.7 SSIs per 100 operations. Chest wound infections occurred after 93 operations (3.5%), and leg wound infections without chest involvement after 138 interventions (5.2%). The proportion of patients with deeporgan-space involvement (mediastinitis) and sepsis requiring reexploration and drainage was 0.5 per 100 operations. Among 231 SSIs, 176 (76%) were cultured (chest infections, n 82; leg infections, n 94). Positive cultures were recovered in 70% (123 of 176) of the cultured SSIs and most commonly yielded coagulase-negative staphylococci (n 52), enterococci (n 21), and Gram-negative organisms (n 51), whereas Staphylococcus aureus was encountered only infrequently (n 15). It is noteworthy that Enterobacter spp (n 8), Serratia spp (n 11), and Pseudomonas aeruginosa (n 11) were the 3 most prominent Gram-negative organisms obtained in wound cultures. ABP and Risk of SSI The effect of the duration of ABP on the risk of SSI was first examined by univariate analysis and showed that the rates were almost identical in both groups: 131 SSIs (8.7%) were recorded after 1502 procedures with short prophylaxis compared with 100 SSIs (8.8%) after 1139 operations with prolonged prophylaxis (crude OR, 1.0; CI, 0.8 to 1.3). In contrast, 11 other variables were found to be associated with an increased risk of SSI by univariate analysis (P 0.1): female sex, obesity, direct hospital admission, diabetes mellitus, chronic kidney disease, chronic lung disease, number of comorbidities, ASA classification, anemia, renal insufficiency, and duration of surgery (Table 1). After inclusion of

3 2918 Circulation June 27, 2000 TABLE 1. Univariate Analysis of Preoperative and Intraoperative Correlates of SSI (n 231) Variable Total n Percentage of Patients With SSI (n) OR (95% CI) P Female sex Yes (94) 1.5 ( ) No (137) Age, y (66) Reference 60 to (66) 0.8 ( ) to (49) 0.9 ( ) (50) 0.8 ( ) 0.2 Direct hospital admission Yes (116) 1.3 ( ) 0.06 No (115) Emergency operation Yes (14) 1.5 ( ) 0.2 No (217) Prior intensive care exposure Yes (51) 0.9 ( ) 0.5 No (180) Diabetes mellitus Yes (123) 2.2 ( ) No (108) Chronic kidney disease Yes (27) 2.4 ( ) No (204) Chronic lung disease Yes (38) 1.4 ( ) 0.09 No (193) History of cardiac surgery Yes (11) 0.9 ( ) 0.7 No (220) Obesity Yes (12) 2.7 ( ) No (219) Renal insufficiency Yes (27) 2.5 ( ) No (186) Anemia Yes (64) 1.3 ( ) 0.08 No (141) ASA class IV (52) 1.5 ( ) 0.01 III (169) Number of comorbidities (75) Reference (117) 2.4 ( ) (33) 3.1 ( ) (6) 6.2 ( ) 0.001

4 Harbarth et al Prolonged Antibiotic Prophylaxis 2919 TABLE 1. Continued Variable Total n Percentage of Patients With SSI (n) OR (95% CI) P Combined valve and CABG procedure Yes (17) 1.0 ( ) 0.8 No (214) Internal mammary artery graft Yes (182) 1.1 ( ) 0.7 No (49) Duration of prophylaxis, h (131) 1.0 ( ) (100) Prophylactic cefazolin exposure Yes (184) 0.8 ( ) 0.2 No (47) Prophylactic vancomycin exposure Yes (41) 1.3 ( ) 0.2 No (190) Prophylactic ceftriaxone exposure Yes (23) 1.2 ( ) 0.4 No (208) Surgeons A (32) Reference B (7) 0.4 ( ) 0.04 C (75) 1.1 ( ) 0.7 D (41) 0.7 ( ) 0.2 E 83 8 (7) 0.8 ( ) 0.7 F (50) 1.0 ( ) 1.0 Others 82 2 (2) 0.2 ( ) 0.03 Duration of surgery, h (65) 1.3 ( ) (156) these variables in a multivariate logistic regression model and after control for seasonal variation, the risk of SSI was significantly correlated with female sex (OR, 1.6; CI, 1.1 to 2.2), obesity (OR, 2.5; CI, 1.2 to 5.4), number of comorbidities (OR increase per increment, 2.2; CI, 1.1 to 4.4), ASA score IV (OR, 1.6; CI, 1.1 to 2.4), duration of surgery (OR increase in 1-hour increments, 1.1; CI, 1.0 to 1.3), and direct hospital admission (OR, 1.6; CI, 1.1 to 2.2). After adjustment for the above-mentioned independent risk factors for SSI, prolonged ABP was not associated with a decreased risk of SSI (adjusted OR, 1.2; CI, 0.8 to 1.6). In a separate analysis, we confirmed these results for the association between extended prophylaxis and sternal wound infections only (adjusted OR, 0.9; CI, 0.6 to 1.4). ABP and Isolation of Resistant Organisms Of 2641 patients, 1094 (41%) had had cultures taken at any body site. In 426 patients (16%), 1 microorganism resistant to the administered prophylactic agent was isolated; leading pathogens were coagulase-negative staphylococci (20%), Candida spp (19%), and Enterococcus spp (16%). In 166 patients (6%), cephalosporin-resistant enterobacteriaceae (excluding other Gram-negative rods such as Pseudomonas aeruginosa) or vancomycin-resistant enterococci were recovered. Enterobacteriaceae resistant to first-generation cephalosporins were retrieved in 97%, enterobacteriaceae resistant to third-generation cephalosporins in 23%, and enterococci resistant to vancomycin in 4% of these 166 patients. Multivariable analysis including postoperative antibiotic therapy and length of ICU stay, as well as relevant preoperative and perioperative variables, demonstrated that 4 variables were associated with an increased risk of isolation of enterobacteriaceae or enterococci with acquired resistance (Table 2): antibiotic therapy after CABG, age 65 years, combined CABG/ valve surgery, and prolonged ABP. Thus, even after control for confounding, prolonged ABP was associated with an increased risk of acquired antibiotic resistance (OR, 1.6; CI, 1.1 to 2.6). Discussion Antimicrobial prophylaxis complements meticulous technique in reducing the incidence of SSI after cardiovascular

5 2920 Circulation June 27, 2000 TABLE 2. Multivariable Model for Isolation of Acquired Resistant Enterobacteriaceae and Enterococci After CABG, Matched by Calendar Time and the Prophylactic Antibiotic Agents Used Patients With Positive Cultures (n 426) Variable OR P 95% CI Prolonged prophylaxis ( 48 h) Age 65 y Combined CABG/valve surgery Antibiotic therapy after CABG surgery. Although the principles of surgical prophylaxis have been outlined on numerous occasions, there is still misuse of antimicrobials for this purpose. 16,19 Our results demonstrate that prolonging ABP beyond 48 hours after CABG surgery is still frequently practiced but does not decrease the risk of SSI. Moreover, it results in an increased risk of acquired antibiotic resistance and should therefore be avoided. Some researchers have suggested that extended prophylactic use of antibiotics is appropriate when drains or catheters remain in situ for several days after cardiac surgery. 20 The antibiotics would presumably protect the wound from a secondary infection that originated in the foreign body and reached the wound by a hematogenous route. Therefore, surgeons tend to continue antibiotics as long as perioperatively placed transthoracic devices are left in place. For instance, in a survey among 43 pediatric cardiovascular surgery centers in the United States, up to 76% continued antibiotics while chest tubes were in place. 13 A questionnaire sent to 120 UK cardiac surgeons showed that 28% continued antibiotic use until the removal of all chest drains. 12 In a French survey among 1473 anesthetists, 23% prescribed 48 hours of antibiotics after cardiovascular surgery. However, results from our study and other reports appear to invalidate this practice. Already 20 years ago, in a double-blind, randomized clinical trial comparing a 6-day with a 2-day regimen of cephalothin prophylaxis, Goldmann et al 5 showed that a 6-day course of prophylactic antibiotics after cardiac surgery is not justified. The only published study comparing single-dose prophylaxis versus extended prophylaxis after thoracostomy in chest trauma patients showed no need for use of prophylaxis for as long as the chest tube was in place. 21 These findings are also in line with a recent meta-analysis of single- versus multiple-dose prophylaxis for major surgery that indicated no benefit for multiple-dose regimens in preventing SSI in various surgical interventions requiring postoperative drainage. 22 In contrast, prolonged antibiotic use after surgery induces antimicrobial resistance and may facilitate the colonization of foreign devices with antimicrobial-resistant organisms Therefore, in place of extended ABP, meticulous handling of catheters, strict compliance with hand disinfection, maintenance of closed drainage systems, and early catheter removal are the preferred means to avoid infections related to foreign devices. 26 Observational cohort studies should complement controlled clinical trials dealing with ABP, because the latter have a limited ability to detect adverse effects such as acquisition of resistant microorganisms, provide information only about patients who satisfy the criteria for study entry, and often concentrate on the efficacy of specific agents rather than evaluate variations in the duration of prophylaxis. 27 In addition, randomized trials do not provide data on the effect of therapeutic interventions in actual clinical practice. In contrast to many previously reported clinical trials, the present study focused on the duration of prophylaxis rather than on antibiotic choice. All patients undergoing coronary bypass surgery were included in the analysis, thereby increasing the generalizability of the study results. However, as in all observational studies, there may have been unknown or unmeasured confounding factors for which adjustment was not possible. For instance, despite adjustment for important covariates such as age, number of comorbidities, length of ICU stay, and postoperative antibiotic therapy, it is difficult to completely exclude the possibility of residual confounding among subjects with acquired resistance. The inappropriate prophylactic antibiotic administration in our cardiovascular surgery unit may have arisen primarily from misconceptions regarding the optimal use of prophylaxis. In some cases, ceftriaxone was chosen as prophylactic agent because of its pharmacokinetic profile, including high serum levels, high tissue penetration, and long elimination half-life, which makes it potentially suitable for prophylaxis in prolonged surgery. 28 However, shortly before the end of the study period, we introduced strict antibiotic guidelines and stopped this practice because of antibiotic resistance concerns and cost implications. The findings should be interpreted in the context of the study design. First, because routine surveillance cultures were not obtained from study patients, one may raise questions about the possible underestimation of the frequency of acquired antibiotic resistance. However, by matching for antibiotic agent, adjusting for calendar time, and including only patients with positive cultures, we minimized the possibility of significant detection bias. Second, an explanation for the association of combined CABG/valve surgery with increased antibiotic resistance is not directly apparent from our study results. We hypothesize that these patients are more likely to have received previous courses of antibiotics for prophylaxis or treatment of endocarditis due to underlying valve abnormalities, thus increasing the risk of acquiring antibiotic resistance. Third, the patient population reported in this study is notable for a high frequency of diabetes and referral from other institutions. These characteristics may have increased the SSI rate (but not the rate of mediastinitis, which was similar to that reported elsewhere), although the observed overall infection rate also probably reflected the intensive nature of the surveillance program. However, we do not believe that these surveillance methods and patient characteristics distorted the generalizability of our study findings. In conclusion, our study confirms that ABP for CABG surgery is frequently extended beyond 48 hours. It shows that prolonged prophylaxis does not reduce the rate of SSI and is associated with an increased risk of acquired antibiotic resistance. We urge surgeons and all concerned physicians

6 Harbarth et al Prolonged Antibiotic Prophylaxis 2921 not to ignore the potentially harmful and costly effect of prolonged ABP after CABG surgery. Acknowledgments Dr Harbarth was the Harvard University Holtzer Scholar when this work was performed and is currently recipient of Max-Kade Fellowship. References 1. Finland M. Changing ecology of bacterial infections as related to antibacterial therapy. J Infect Dis. 1970;122: Nelson RM, Dries DJ. The economic implications of infection in cardiac surgery. Ann Thorac Surg. 1986;42: Milano CA, Kesler K, Archibald N, et al. Mediastinitis after coronary artery bypass graft surgery: risk factors and long-term survival. Circulation. 1995;92: Hall RE, Ash AS, Ghali WA, et al. Hospital cost of complications associated with coronary artery bypass graft surgery. Am J Cardiol. 1997;79: Goldmann DA, Hopkins CC, Karchmer AW, et al. Cephalothin prophylaxis in cardiac valve surgery: a prospective, double-blind comparison of two-day and six-day regimens. J Thorac Cardiovasc Surg. 1977;73: Nooyen SM, Overbeek BP, Brutel de la Riviere A, et al. Prospective randomised comparison of single-dose versus multiple-dose cefuroxime for prophylaxis in coronary artery bypass grafting. Eur J Clin Microbiol Infect Dis. 1994;13: Niederhäuser U, Vogt M, Vogt P, et al. Cardiac surgery in a high-risk group of patients: is prolonged postoperative antibiotic prophylaxis effective? J Thorac Cardiovasc Surg. 1997;114: Kriaras I, Michalopoulos A, Michalis A, et al. Antibiotic prophylaxis in cardiac surgery. J Cardiovasc Surg. 1997;38: Ariano RE, Zhanel GG. Antimicrobial prophylaxis in coronary bypass surgery: a critical appraisal. DICP Ann Pharmacother. 1991;25: Kreter B, Woods M. Antibiotic prophylaxis for cardiothoracic operations: meta-analysis of 30 years of clinical trials. J Thorac Cardiovasc Surg. 1992;104: Kappstein I, Daschner FD. Use of perioperative antibiotic prophylaxis in selected surgical procedures: results of a survey in 889 surgical departments in German hospitals. Infection. 1991;19: Parry GW, Holden SR, Shabbo FP. Antibiotic prophylaxis for cardiac surgery: current United Kingdom practice. Br Heart J. 1993;70: Lee KR, Ring JC, Leggiadro RJ. Prophylactic antibiotic use in pediatric cardiovascular surgery: a survey of current practice. Pediatr Infect Dis J. 1995;14: Martin C, Pourriat JL. Quality of perioperative antibiotic administration by French anaesthetists. J Hosp Infect. 1998;40: Namias N, Harvill S, Ball S, et al. Cost and morbidity associated with antibiotic prophylaxis in the ICU. J Am Coll Surg. 1999;188: Kreisel D, Savel TG, Silver AL, et al. Surgical antibiotic prophylaxis and Clostridium difficile toxin positivity. Arch Surg. 1995;130: Horan TC, Gaynes RP, Martone WJ, et al. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol. 1992;13: Samore M, Lichtenberg D, Saubermann L, et al. A clinical data repository enhances hospital infection control. Proc AMIA Annu Fall Symp. 1997; Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326: Krieger JN, Kaiser DL, Wenzel RP. Nosocomial urinary tract infections cause wound infections postoperatively in surgical patients. Surg Gynecol Obstet. 1983;156: Demetriades D, Breckon V, Breckon C, et al. Antibiotic prophylaxis in penetrating injuries of the chest. Ann R Coll Surg Engl. 1991;73: McDonald M, Grabsch E, Marshall C, et al. Single- versus multiple-dose antimicrobial prophylaxis for major surgery: a systematic review. Aust N Z J Surg. 1998;68: Archer GL, Armstrong BC. Alteration of staphylococcal flora in cardiac surgery patients receiving antibiotic prophylaxis. J Infect Dis. 1983;147: Kernodle DS, Barg NL, Kaiser AB. Low-level colonization of hospitalized patients with methicillin-resistant coagulase-negative staphylococci and emergence of the organisms during surgical antimicrobial prophylaxis. Antimicrob Agents Chemother. 1988;32: Terpstra S, Noordhoek GT, Voesten HG, et al. Rapid emergence of resistant coagulase-negative staphylococci on the skin after antibiotic prophylaxis. J Hosp Infect. 1999;43: Ehrenkranz NJ. Antimicrobial prophylaxis in surgery: mechanisms, misconceptions, and mischief. Infect Control Hosp Epidemiol. 1993;14: Maki DG, Bohn MJ, Stolz SM, et al. Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations: a double-blind randomized trial. J Thorac Cardiovasc Surg. 1992;104: Boxma H, Broekhuizen T, Patka P, et al. Randomised controlled trial of single-dose antibiotic prophylaxis in surgical treatment of closed fractures: the Dutch Trauma Trial. Lancet. 1996;347: