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Eur J Cardiothorac Surg 2000;18:440-446
© 2000 Elsevier Science NL

Review article

Evolution of antimicrobial prophylaxis in cardiovascular surgery

^a Department of Surgical Intensive Care, Onassis Cardiac Surgery Center, 356 Sygrou Avenue, 17674 Athens, Greece
^b Department of Cardiovascular Surgery, University Hospital, Zurich, Switzerland

Received 29 December 1999; received in revised form 20 April 2000; accepted 26 April 2000.

Corresponding author. Tel.: +30-1-949-3335; fax: +30-1-949-3333

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
Objective: To examine the optimal duration of antibiotic prophylaxis in major cardiovascular surgery. Methods: In the past 15 years, four prospective randomized, controlled studies, conducted by the same group of authors, compared seven prophylactic antimicrobial regimens in 2970 patients undergoing major cardiovascular surgery. In 1980/81, a 4-day cefazolin (CFZ) prophylaxis was compared with a 2-day cefuroxime (CFX) administration (n=566). In 1982/83, a 2-day CFX prophylaxis was compared with a two shot ceftriaxone (CRO) prophylaxis (n=512). In 1984/87, a 1-day CFZ prophylaxis was compared with a single shot prophylaxis of CRO (n=883). In 1994/1995, a 4 day combination of amoxicillin (AM) and netilmicin (NET) prophylaxis was compared with a single shot prophylaxis of CFX (n=1009). Results: Total infection rate varied between 4.5 and 5.7%, despite different antimicrobial regimen used and their varying duration. Wound infection rate was 1.1% (range 0.4–2.5%), sepsis rate was 0.8% (range 0.4–1.6%), pneumonia rate 2% (0.7–2.9%), urinary tract infection rate 0.4% (range 0–1.4%), and central venous catheter-related infection rate was 0.4% (0–1%). The 30-day mortality rate was 1.3% (range 0.4–2%). All these differences were not statistically significant. Conclusions: A low infection rate (range 4.5–5.7%) occurred despite changes in duration of various prophylactic antibiotic regimen with cephalosporins of first, second or third generation. As a single shot prophylaxis could nowadays successfully be used in cardiovascular surgery, no postoperative antibiotics should be used, unless an intraoperative or a postoperative infection is documented or in presence of major perioperative complications.

Key Words: Cardiovascular surgery • Antibiotic prophylaxis • Cefazolin • Cefuroxime • Ceftriaxone • Amoxicillin • Netilmicin

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
Prophylactic antibiotics have been used in cardiovascular surgery for several years, in order to reduce the risk of postoperative infections [1,2]. The initial long duration of antimicrobial administration was progressively shortened. In the late 1970s, duration of the antimicrobial regimen given as prophylaxis (cefazolin 4x0.5 g/day, i.v.) has decreased from 7 to 4 days safely. In the following years, seven different antimicrobial regimen with different duration, progressively shorter, (4 days vs. 2 days, 2 days vs. 2 doses, 1 day vs. 1 dose, 4 days vs. 1 dose) were compared in prospective randomized trials by one of the authors (S.G.).

Aim of this study was ‘meta-analysis’ of four consecutive trials dealing with antibiotic prophylaxis in cardiovascular surgery. Main goal of this study was to evaluate the effect of reduction of antibiotic prophylaxis in postoperative infectious complications.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
Between 1980 and 1995, four randomized studies compared seven different perioperative prophylactic antimicrobial regimen in major cardiovascular surgery. The first three studies were performed at the University Hospital of Zurich, the last one at the Onassis Cardiac Surgery Center, in Athens. The procedures followed were in accordance with the Helsinki declaration.

Between September 1980 and July 1981, a 4-day cefazolin (CFZ) prophylaxis (4x0.5 g/day, i.v.) was compared with a 2-day cefuroxime (CFX) administration (2x1.5 g/d, i.v.). Of 569 patients who entered the study, 281 received CFZ and 285 CFX [3]. Between May 1982 and March 1983, a 2-day CFX prophylaxis (4x1.5 g/day, i.v.) was compared with a two shot ceftriaxone (CRO) prophylaxis (2 g plus 1 g 24 h later, i.v.). Of 523 patients enrolled, 258 received CFX and 254 CRO [4]. Between November 1984 and March 1987, a 1-day CFZ prophylaxis (4x0.5 g, i.v.) was compared with a single shot prophylaxis of CRO (1x2 g, i.v.). Of 883 patients enrolled, 439 received CFZ and 444 CRO [5]. Between May 1994 and April 1995, a 4-day amoxicillin (AM) plus netilmicin (NET) prophylaxis (3x2 g+2x150 mg/day, i.v.) was compared with a single shot prophylaxis of CFX (1x3 g, i.v.). Of 1009 patients enrolled, 508 received AM-NET and 501 CFX [6].

All patients aged over 16 years undergoing open heart surgery or major vascular surgery were eligible for trial entry (except the fourth study where no major vascular surgery was included except thoracic aorta aneurysms).

All patients with preoperative infection, those who had received any antibiotic within 48 h prior to operation and those with known allergy to ß-lactamic antibiotics were excluded from the study protocol.

Patients were allocated to one of two treatment groups by means of a randomized code, stratified for cardiac and major vascular operations. The first dose was always given prior to surgery, just prior the induction of anesthesia. Treatment groups were well matched for age, sex, weight, height and type of surgical procedure in all studies. There were no statistically significant differences in co-morbid conditions, such as history of diabetes mellitus and/or renal failure and/or chronic obstructive pulmonary disease (COPD), obesity, and prolonged preoperative hospitalization between groups among these four trials included. In addition, there were no differences between groups regards to bleeding requiring re-exploration. In these studies, there were no patients who underwent coronary artery bypass grafting with bilateral mammary artery. In all patients who received a single shot of antibiotic prophylaxis, regimen was administered just prior the induction of anesthesia. In this case, no additional dosage was administered in the pump priming solution, as well as in patients with a prolonged duration of extracorporeal circulation.

Hematological tests, liver function tests, serum creatinine and urea were measured preoperatively. These measurements were repeated daily during the ICU period, one week after and/or immediately before discharge. Chest X-rays were taken before, immediately after the operation, 1 and/or 2 days later prior to leaving hospital and in between when clinically indicated. Body temperature was measured every 1 or 2 h during the ICU period and in the ward at least twice daily. Surgical wounds were examined daily and swabs of any secretions or pus were taken for bacteriological examinations. Central venous catheters remained in the majority of patients one day. In patients with prolonged ICU length of stay, all central catheters changed in case of suspicion of central venous catheter-associated infection or sepsis. Swan–Ganz catheters were removed prior to the fourth postoperative day. Postoperative infections were treated with appropriate antibiotics and when needed, surgical intervention.

2.1. Definitions
Wound infection was defined as purulent secretion with growth of bacteria, classified into mild (purulent discharge only), moderate (discharge of pus plus constitutional upset) and severe (requiring active surgical intervention such as reoperation) [7]. Urinary tract infection was defined as clinical signs of infection in combination with urine cultures demonstrated a pathogen numbering >100 000 c.f.u. ml^-1 [8].

The diagnosis of pneumonia in the first three studies was made when three of the following criteria were present: purulent sputum, rales, fever, and positive chest X-ray. In the last study, two more criteria were added: leukocytosis, and positive culture. Diagnosis was made when four out of six criteria were present [9].

The patients were defined as having sepsis if they manifested the following: (1) at least two of the following criteria: (a) body temperature >38°C, (b) WBC counts >12x10⁹/l or <4x10⁹/l or immature neutrophils >10%, (c) heart rate >90 beats/min, and (d) respiratory rate >20 breaths/min or P_aCO₂ <32 mm Hg; (2) a documented bacteremia [10].

Chest X-rays, blood cultures and urine sedimentation tests were negative in patients with fever (>39°C) of unknown origin.

2.2. Demographic data
The randomization in each study produced groups with well-matched demographic data (Table 1).

2.4. Statistical analysis
Values are presented as mean±SD or numbers and percentile. A P-value less than 0.05 was considered statistically significant.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
3.1. Infection rate
Wound infection developed in 33 patients (1.1%, range 0.4–2.5%). There were 17 severe sternal wound infections that required reoperation, six moderate sternal wound infections, three moderate inguinal wound infections and seven mild or moderate donor site wound infection (Table 2). Patients with sternal wound infections had prolonged operation times (>120 min.) and major perioperative complications or they were re-explorated because of bleeding.

Total postoperative infection rate was 5.2% (range 4.5–5.7%) (Table 2). There were no statistically significant differences regards to kind of infection between various regimen. Infection rate did not vary significantly during this period, while the duration of the regimen became progressively shorter.

Isolated pathogens for all studies are shown in Table 3. There was no statistically significant difference between the various regimen in the occurrence of Gram positive cocci and Gram negative rods. In contrast, there was a difference in the occurrence of Gram positive cocci and Gram negative rods regarding the type of infection. Pathogens isolated from infected wounds were mainly Gram positive cocci while those isolated from other infections like pneumonia or urinary tract infections were Gram negative rods.

3.3. Hospital stay
During this period, a light decrease of hospital length of stay was observed from 10.5 to 9.3 days (Table 2).

3.4. Mortality
A total of 38 patients (1.3%) died within a month. For 25 patients, main cause of death was cardiogenic shock, for seven patients cause of death was multiple organ failure, while in six patients (0.2%), death was exclusively due to a severe infection. Of these six patients, nosocomial pneumonia was the main cause of death in three patients and sepsis in the remaining three ones.

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
Postoperative infection following cardiovascular surgery is a serious and often life-threatening complication [11,12]. It is associated with a substantial morbidity, prolonged hospital stay and an increasing hospital cost.

Prophylactic antibiotics have been used for several years in order to reduce the risk of postoperative infections [1,2]. Cephalosporins are frequently used because of their broad spectrum of activity and low degree of toxicity [13]. However, the number of resistant microorganisms is increasing, particularly the ß-lactamase producing gram-negative organisms capable of destroying many penicillins and cephalosporins [14].

The reason for the development of resistant strains is probably the long-term application of antibiotics. The shortest effective treatment will be therefore of advantage [15]. An effective prophylactic regimen should be directed against the most likely pathogens but need not to include drugs active against every potential pathogen. Regimens that decrease the total number of exogenous or endogenous infecting organisms permit host defenses to resist clinical infection [16]. Clinical and experimental studies have shown that antibiotics could be effective only under certain conditions. It is necessary to achieve high level concentrations in serum and tissues during the operative procedure, which is the time of maximal contamination [17,18]. When the drug is undetectable during or at the end of operation, infection is relatively common [19]. Therefore, the optimal time for administration of prophylaxis is at the induction of anesthesia [16].

In case of re-exploration, it is recommended to repeat antibiotic prophylaxis in order to achieve again adequate plasma levels during the critical period of the surgery procedure, unless a long acting drug is used. All these recommendations have been followed in the above trials. It is doubtful that postoperative infections can be entirely eliminated. Apart from the use of antibiotics, other measures must be taken in order to decrease the risk of infection. Optimizing the operating room environment, the surgical and operating room protocols and the awareness of personnel can all contribute to lowering infection rates [20].

However, the optimum duration of the antibiotic regimen has been controversial for long time. In the early period of cardiac surgery, antibiotics were administered for several days. The shortest safe period remained unclear, especially in the case of single shot prophylaxis that stayed for a long period controversial.

	5. Historical background

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
Sutherland et al. published, in 1979, a prospective study of 693 consecutive patients showing that in elective coronary surgery no antimicrobial prophylaxis was necessary [21]. The wound infection rate was 0.8%. These results initiated a worldwide discussion.

At that time, in the Department of Surgery at the University Hospital in Zurich, cefazolin (4x0.5 g, i.v.) was applied in routine cardiac surgery for 4 days. However, this treatment was often continued for 7–10 days.

On the occasion of Sutherland's publication we searched retrospectively 500 consecutive patients and found that the postoperative infection rate in the 4-day cefazolin group was 6%, while in the 7-day group rate was 12%. It was clear that such a study had no major value, as high risk patients and those with complications were treated longer with antimicrobials. Nevertheless, it became obvious that a longer antimicrobial application was not of definite advantage.

A prospective randomized study comparing placebo with 4-days of cefazolin administration was considered too risky and most probably unethical due to the results of Fong et al. who had shown a very high infection rate in the placebo group [22]. We therefore designed and performed in 1980/81 our first prospective randomized study comparing a 4-day cefazolin (4x0.5 g/day, i.v.) administration with a 2-day cefuroxime (2x1.5 g/day, i.v.) regimen. In this study, 566 patients were enrolled: 281 in the cefazolin and 285 in the cefuroxime regimen. Neither in the 30 days total infection rate (5.7 vs. 5.3%) nor in the wound infection rate (2.5 vs. 1.1%) statistical difference could be observed, although the trend was in favor of the shorter regimen [3].

In 1982/83, the next study compared the 2-day cefuroxime regimen (2x1.5 g, i.v.) with a 2-dose ceftriaxone (2 g at the induction of anaesthesia plus 1 g 24 h later). Of the 512 patients enrolled in the study, 258 received cefuroxime and 254 ceftriaxone. Again, no difference in total (4.7%) and in wound infection rate (1.2%) was found [4].

In the meantime, in order to be sure that a single dose ceftriaxone application would be sufficient, we conducted an extensive pharmacokinetic study measuring plasma levels in the first 24 h after 2 g ceftriaxone given at the induction of anesthesia [23]. In this study, 110 patients were enrolled. The plasma levels were so high (265 µg/ml at the beginning of the operation, 103 µg/ml at the beginning of the cardiopulmonary bypass, 95 µg/ml at the end of operation, and 24 µg/ml 24 h later), that the MIC90 of bacteria like Enterococci (128 µg/ml), Pseudomonas aeruginosa (64 µg/ml) and Bacteroides (32 µg/ml) were lying under the curve [23].

Therefore, we skipped the above mentioned study and decided to compare the single dose ceftriaxone regimen to the universally used and worldwide accepted antimicrobial prophylaxis regimen with cefazolin (4x0.5 g for 1 day). Out of 883 patients, 439 received cefazolin and 444 ceftriaxone. Again, no difference in the 30 days total infection rate (5 vs. 4.5%) and the 30 days wound infection rate (0.4 vs. 1.3%) was found [5].

In order to be sure that not only the 30 days infection rate was more or less similar between the two treatment groups we continued the study up to 1049 patients and checked the 6 months infection rate [24]. The 30 days total infection rate was 5.1 vs. 5.3% and the 30 days wound infection rate was 0.8 vs. 1.9%. The 6 months total infection rate was 7.6 vs. 9.3%, again not showing any statistically significant difference between the two groups.

In 1993, one of the authors (S.G.) left the University Hospital of Zurich to work for the newly formed Onassis Cardiac Surgery Center, in Athens. Three surgical teams of the Center (trained in USA) had agreed to administer as surgical prophylaxis netilmicin (2x150 mg i.v.) and amoxicillin (3x2 g i.v.) both for 4 days. An ideal situation to compare a single dose prophylaxis to a 4-day regimen.

There had been already a background of 1000 operations with the above regimen before starting in 1994 the next study comparing a single dose cefuroxime vs. a 4-day amoxicillin/netilmicin regimen. Out of 1009 patients enrolled, 508 received amoxicillin plus netilmicin and 501 cefuroxime. Total infection rate (5.6 vs. 5.7%) and wound infection rate (0.6 vs. 1.2%) were again similar in both groups [6].

In the present study we have put together the results of the four major studies which enable the comparison of the various regimen: 4 vs. 2 days, 2 days vs. 2 doses, 1 day vs. single dose, and at the end single dose vs. 4 days. The circle is in this way closed and the results show a unique similarity. Despite the different duration time of the antibiotic administration and the different antibiotics used (cephalosporins of the first, second and third generation, plus a combination of netilmicin and amoxicillin), the total wound infection rate in our meta-analysis (n=2.970 patients) was 1.1%. Range varied between 0.4 and 2.5% and trend was generally in favor of the shorter regimen! Sepsis rate was 0.8% (range 0.4–1.6%); nosocomial pneumonia rate was 2.0% (range 0.7–2.9%); UTI rate was 0.4% (range 0–1.4%). Total infection rate was 5.2% (range 4.5–5.7%).

All these results were similar despite the change of patients’ mean age from 53 to 60 years, the higher risk group, and the change of patients’ mean weight from 68 to 77 kg.

It is interesting to note that in the first three studies the comparison was made between consecutive regimen varying from 4 days to a single dose regimen, but this comparison was not made contemporary. In contrast, in the last study the comparison of single dose versus the 4-day regimen has been made contemporary. In addition, the result of the latter study was not influenced from changes that had been made during those years regarding the perioperative conditions and operating protocols. Total infection rate has not changed during those years. This fact could mean that total infection rate could not easily diminish further by using newer cephalosporins nor by varying the antimicrobial regimen. However, things change rapidly in cardiovascular surgery. For this reason, a continuous re-evaluation of antimicrobial policy is necessary. Data from different institutions should be taken into consideration for the choice of the optimum prophylactic antimicrobial regimen. Local resistance problems with MRSA, MRSCN or vancomycin resistant Enterococci may need other more potent regimen.

	6. Conclusions

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 
The ‘meta-analysis’ of these four studies, which compared seven different regimen since 1980, showed no statistically significant difference in the frequency of postoperative infectious complications. If a cephalosporin is administered properly at the induction of anesthesia, a low infection rate occurs that can not be lowered further by longer duration of antimicrobial administration. A single dose prophylaxis of 2 g ceftriaxone (i.v.) or 3 g cefuroxime (i.v.) is safe, cheep and effective.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Historical background 6. Conclusions References

 

1. Leaper D.J. Prophylactic and therapeutic role of antibiotics in wound care. Am J Surg 1994;167:155-205.
2. Wellens F., Pirlet M., Larbuisson R., De Mereleire F., De Somer P. Prophylaxis in cardiovascular surgery. Eur J Cardio-thorac Surg 1995;9:325-329.[Abstract]
3. Geroulanos S., Oxelbark S., Turina M. Eine prospektive, randomisierte vergleichende Studie zwishen Cefazolin und Cefuroxim als perioperative Antibiotika-Prophylaxe in der Herz- und Gefasschirurgie. Schweiz med Wschr 1984;114:297-303.
4. Geroulanos S., Donfried B., Schumacher F., Turina M. Cefuroxime versus ceftriaxone prophylaxis in cardiovasular surgery. Drugs Exp Clin Res 1985;XI(3):201-205.
5. Soteriou M., Recker F., Geroulanos S., Turina M. Perioperative antibiotic prophylaxis in cardiovascular surgery: a prospective randomized comparative trial of Cefazolin versus Ceftriaxone. World J Surg 1989;13:798-802.[Medline]
6. Kriaras I., Michalopoulos A., Michalis A., Palatianos G., Anagnostopoulos C., Geroulanos S. Antibiotic prophylaxis in cardiac surgery. J Cardiovasc Surg 1997;38:605-610.[Medline]
7. Nichols R.L. Surgical wound infection. Am J Med 1991;91(S3B)):54-64.
8. Nowe P. Piperacillin/tazobactam in complicated urinary tract infections. Intens Care Med 1994;20:S39-S42.
9. Chevret S., Hemmer M., Carlet J., Langer M. and the European Co-operative Group Results from a multicenter prospective study on 996 patients. Intens Care Med 1993;19:256-264.[Medline]
10. American College of Chest Physicians. Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis [review]. Crit Care Med 1992;20:864-874.[Medline]
11. Bryan A.J., Lamarra M., Angellini G.D., Breckenridge I.M. Median sternotomy wound dehiscence: a retrospective case control study of risk factors and outcome. J R Coll Surg Edinburgh 1992;37:305-308.[Medline]
12. Ford E.G., Baisden C.E., Matteson M.L., Picone A.L. Sepsis after coronary bypass grafting: evidence for loss of the gut mucosal barrier. Ann Thorac Surg 1991;52:514-517.[Abstract]
13. Gorbach S.L. The role of cephalosporins in surgical prophylaxis. J Antimicrob Chemother 1989;23:61-70.
14. Goldsberry D.T., Hurst J.M. Adult respiratory distress syntrom and sepsis. New Horizons 1993;2:342-347.
15. Hirschmann J.V., Inui T.S. A critique of recent trials. Rev Infect Dis 1988;2:1-23.
16. Anonymous. The Medical Letter on drugs and therapeutics: antimicrobial prophylaxis for surgery. 1981;23:77–81.
17. Goto S. The in vitro and in vivo antibacterial activity of cefuroxime. Proc R Soc Med 1970;70(Suppl 9):56-62.
18. Culliford A.T., Cunningam J.N., Zeff R.H., Isom O.W., Teico O., Spender F.C. Sternal and costochondral infections following open heart surgery A review of 7949 cases. J Thorac Cardiovasc Surg 1976;72:714-725.[Abstract]
19. Goldmann D.A., Hopkins C.C., Karchmer A.W., Abel A.M., McEnamy M.T., Akins C., Buchkley M.J., Mollering R.C., Jr Cephalothin prophylaxis in cardiac valve surgery. A prospective double blind comparison of two day and six day regimen. J Thorac Cardiovasc Surg 1977;73:470-479.[Abstract]
20. Polk H.C., Simpson S.J., Simmons B.P., Alexander J.W. Guidelines for prevention of surgical wound infection. Arch Surg 1983;118:1213-1217.[Abstract]
21. Sutherland R., LaWayne Miller O., Martinez H., Cuynes W. Coronary arterial bypass operation without antibiotic coverage. Chest 1979;76:174-178.[Abstract]
22. Fong E.W., Baker C.B., McKee D.C. The value of prophylactic antibiotics in aorto-coronary bypass operations. J Thorac Cardiovasc Surg 1979;78:908-913.[Abstract]
23. Schumacher F., Geroulanos S., Turina M. Pharmakokinetik von Ceftriaxon bei Operationen mit der Herz- Lungen Maschine Z Herz. Thorax- Gefasschir 1988;2:25-31.
24. Jemec M. Prospektive, randomisierte Vergleichsstudie mit Cefazolin und Ceftriaxon als perioperative Antibiotika Prophylaxe in der Herz- und Gefasschirurgie. Inaugural Dissertation, Zurich. 1988.

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