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J Thorac Cardiovasc Surg 2000;120:1120-1130
© 2000 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Comparative efficacy of teicoplanin and cefazolin for cardiac operation prophylaxis in 3027 patients

From the Department of Medicine, The University of Ottawa, Ottawa,^a Infectious Diseases Research Center, Université Laval, Québec City,^c and Aeterna Laboratory, Québec City,^b Canada.

Supported by Hoechst Marion Roussel Canada Research Inc.

Presented in part at the 19th International Congress of Chemotherapy, Montreal, July 16-21, 1995.

Address for reprints: Michel G. Bergeron, MD, FRCPC, Centre de Recherche en Infectiologie, Université Laval, CHUQ, Pavillon CHUL, 2705 Boul Laurier, Québec, QC G1V 4G2 Canada (E-mail: Michel.G.Bergeron{at}crchul.ulaval.ca).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix: References

 
Objective: Cephalosporins, especially cefazolin, are widely used in the prevention of postoperative wound infections after cardiac operations. As more and more Staphylococcus aureus and Staphylococcus epidermidis strains are becoming resistant to cephalosporins and other antibiotics, alternative agents, such as glycopeptides, are often used as prophylaxis. We performed a multicenter double-blind randomized controlled trial comparing teicoplanin, a glycopeptide antibiotic, with cefazolin.
Methods: A total of 3027 adult patients undergoing elective coronary artery bypass grafting, valve operations, or both were randomized to a single dose of teicoplanin (15 mg/kg) or a 2-day course of cefazolin (2 g initial dose, followed by 1 g every 8 hours for 6 more doses). Patients were followed up for a total of 6 months postoperatively. The primary objective was to compare, between groups, the incidence of surgical infections up to 30 days postoperatively. Secondary objectives were incidence of other infections, other complications, and death.
Results: A total of 3027 patients were randomized to receive either teicoplanin (n = 1518) or cefazolin (n = 1509). Thirty days postoperatively, there was a trend to more deep sternotomy wound infections in the teicoplanin group (31 vs 18, P = .087), which became significant by 6 months (36 vs 19, P = .032). One hundred percent of the gram-positive strains infecting patients were susceptible to teicoplanin, whereas 8.3% were resistant to cefazolin. Pneumonia and urinary tract infections were more common in the teicoplanin group. Deep wound infections of the leg were more common in the cefazolin group.
Conclusions: Cefazolin was more effective prophylaxis than teicoplanin against postoperative wound infections after elective cardiac operations. Infection rates were low with either treatment.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix: References

 
An estimated 760,000 cardiac surgical procedures were performed in the United States in 1997, including 607,000 coronary bypass operations. ¹ In Canada there were over 18,000 coronary artery bypass graft (CABG) procedures in 1995-1996. ² In Europe 153,670 CABG procedures and 56,574 valve replacements were done in 1993. ³ Infectious complications are a major source of morbidity and mortality postoperatively. The incidence of infection at the surgical sites, chest and leg, ranges from less than 1% to greater than 10% ^4-6 and increases according to the severity of underlying disease. ⁷ Infection ranges from superficial involvement of the wound to deeper soft tissue infection, sternal osteomyelitis, and mediastinitis, requiring surgical drainage and debridement, as well as antimicrobial therapy.

Ten to thirty percent of cardiac surgical patients with deep wound infections die during their hospitalization. The duration of hospital stay is markedly prolonged by a mean of 12 to 16 days. ^8,9 The attributable cost is enormous, estimated at approximately $37,000 in one American study or an increase of 180% over that of uninfected patients. ⁴ Patients undergoing cardiac surgery are also at risk for the development of infections unrelated to the surgical site, such as pneumonia, urinary tract infection, and bacteremia, with the latter often related to line sepsis.

The most common pathogens associated with these infections are Staphylococcus epidermidis, Staphylococcus aureus, and gram-negative bacilli, such as Enterobacter species. ^10-12 Antibiotic prophylaxis is widely used to reduce the incidence of postoperative infection. Limited placebo-controlled data suggest that this prophylactic use of antimicrobials is efficacious in preventing infection at the surgical site. ¹³ In North America the antibiotics of choice are cephalosporins. ¹⁴ Cefazolin, cefamandole, and cefuroxime have been found to be safe and effective. ^15-19 There is no consistent advantage of one over the others. Vancomycin, the glycopeptide available in the United States and Canada, is widely used in patients with ß-lactam allergy.

A high incidence of ß-lactam–resistant S epidermidis and a rising tide of methicillin-resistant S aureus (MRSA) susceptible to vancomycin have raised interest in glycopeptides as prophylaxis in cardiac operations.

Doubts have been cast about the efficacy of a cephalosporin, cefazolin, in preventing infection caused by S aureus. ²⁰ Furthermore, there has been concern about the selection or induction of resistance in organisms, such as coagulase-negative staphylococci and Enterobacter species, in cephalosporin recipients.

Two rigorous comparative studies have assessed the use of glycopeptides as prophylactic agents in cardiac operations. Wilson and colleagues ²¹ compared teicoplanin with the combination of flucloxacillin and tobramycin in a total of 517 patients. Teicoplanin was less effective than the combination.

Maki and associates ²² compared vancomycin with cefamandole and cefazolin in a population of 321 patients undergoing cardiovascular (mostly cardiac) operations. In that study vancomycin was more effective than the cephalosporins. However, hypotension was a significant complication of vancomycin, occurring in 8% of patients.

The ESPRIT study group sought to compare teicoplanin with cefazolin for cardiac operation prophylaxis. The pharmacokinetic properties of teicoplanin lend themselves to surgical prophylaxis. The drug has a long half-life, 130 to 166 hours with a 3-compartment model, allowing the use of a single high dose. ^23-25 The antibiotic is concentrated in cardiac tissue. ²⁶ Clearance of teicoplanin during cardiopulmonary bypass is similar to that found in nonsurgical patients. ²⁷ Unlike vancomycin, teicoplanin does not result in histamine release, which may cause rash and hypotension, and the drug can be given by means of rapid infusion without toxicity. ²⁸ It is less nephrotoxic than vancomycin. ²⁹

	Methods

Top Abstract Introduction Methods Results Discussion Appendix: References

 
Design
This was a randomized controlled double-blind study done at 13 university-affiliated cardiac surgical centers across Canada. At each site, only the pharmacist was unblinded, and he or she was responsible for the distribution of drugs. The study nurses, surgeons, anesthetists, and physicians were unaware of each patient's prophylaxis regimen assignment. Randomization was done within 3 strata: CABG, valve replacement-repair, or both. The randomization was generated for each site by an independent statistician using a computer-generated list.

Patients
Adult (18 years of age) patients undergoing elective CABG, valve operations (replacement or repair), or both were eligible for the trial. An elective operation was defined as a procedure planned at least 24 hours ahead. A signed written informed consent was obtained from each patient. Blood counts, serum creatinine levels, and urine cultures were procured. At each center, there was approval by the local research ethics board.

Exclusion criteria included the following: patients who were pregnant and those who had previously undergone sternotomy procedures; patients with severe concomitant diseases, such as the immunocompromised; patients who were morbidly obese; and individuals with osteotomies. Medically unstable patients and those with ventricular assist devices and/or requiring intra-aortic balloon pumps, transplant, or total artificial hearts were not enrolled. Patients who had received systemic antibiotics in the preoperative week and those allergic to glycopeptides, penicillins, or cephalosporins were not eligible. Active bacterial infections precluded entry into the study, but asymptomatic bacteriuria was allowed. Patients with serum creatinine levels of 250 µmol/L or more (2.8 mg/dL) or neutropenia of 1000 cells/mm³ or less were excluded. Use of an investigational drug or device in the 30 days before the operation was not allowed nor was prior participation in a trial with teicoplanin. Patients of mental capacity so limited as to preclude informed consent were not enrolled.

An outbreak of MRSA occurred at one study center during the course of the study. Enrollment was interrupted at that site for the duration of the outbreak and then resumed.

Drug administration
Teicoplanin or cefazolin was packaged in 50-mL bags of normal saline solution to be infused over 15 minutes. Teicoplanin was given as a single preoperative dose of 15 mg/kg within 30 minutes of initial skin incision at the donor site or sternum, followed by placebo (normal saline solution, 50 mL) every 8 hours for 6 more doses. Cefazolin was administered as a 2-g preoperative dose, followed by 1 g every 8 hours for 6 more doses. The preoperative dose of study drug was covered with an opaque container to prevent identification of infusate in the bag, with teicoplanin solution being yellow-brown in color.

Assessment
Patients were seen by the research team before their operations, the first postoperative day, and at least 3 times weekly until discharge.

There was a follow-up visit or telephone contact of all patients at 30 days and 6 months postoperatively. All patient assessments and interpretations of patient outcomes were done before the data were unblinded.

Date of onset of infection was defined as the day of first physician visit or culture for the infectious illness or the date of readmission for infection, whichever came first.

Definitions were made before the onset of the study for important infectious syndromes relevant to the study:

1. Superficial thoracic wound infection: cellulitis, with systemic signs of infection, and/or purulent wound discharge (spontaneous or by aspiration)
   
2. Deep thoracic infections
   
1. Deep wound infection: wound infection requiring drainage and/or debridement
   
2. Sternal osteomyelitis: a deep sternal wound infection with evidence of bony infection (gross appearance, histopathology, and/or culture of bone) at operation for infection
   
3. Mediastinitis: a deep sternal wound infection with evidence of mediastinal involvement (gross appearance, histopathology, and/or culture) documented at operation for infection
   
4. Endocarditis: at least 2 of the following: (1) compatible clinical illness with evidence of cardiac involvement or no evidence of extracardiac source; (2) at least 2 positive blood cultures for the same organism; and (3) microbiologic or histopathologic evidence of valvular infection at reoperation or at autopsy
   
5. Pericarditis: infection of the pericardium defined at the operation and/or by aspiration
   
3. Donor site infections
   
1. Superficial donor site infection: cellulitis, with systemic signs of infection, and/or purulent wound discharge (spontaneous or by aspiration)
   
2. Deep donor site infection: wound infection requiring drainage and/or debridement
   
4. Bacteremia: at least one positive blood culture for a gram-negative microorganism or 2 positive blood cultures for the same gram-positive bacterium
   
5. Respiratory tract infections
   
1. Pneumonia. Definite: presence of a consistent syndrome (eg, fever or cough), infiltrate on chest x-ray film, and positive cultures of respiratory secretions (expectorated sputum showing less than 10 squamous epithelial cells per low-power field and more than 25 polymorphonuclear leukocytes per high-power field). Probable: purulent sputum (>25 polymorphonuclear neutrophils per high-power field) plus an atypical infiltrate on chest x-ray film. Possible: atypical infiltrate
   
2. Tracheobronchitis: cough and purulent sputum in the absence of an infiltrate on chest x-ray film
   
6. Urinary tract infections: greater than 10⁵ colonyforming units per milliliter in a cleanly voided specimen. In the presence of asymptomatic bacteriuria caused by the same organism preoperatively, the urinary tract infection was considered not attributable to the intervention and not counted
   

Definitions for other infections were based on those proposed by Pirsch and Maki. ³⁰

Objectives
The primary objective of the study was to compare the efficacy of single-dose teicoplanin with multiple-dose cefazolin in the prophylaxis of surgical infections 1 month after elective cardiac operations.

Secondary objectives were to compare both drugs in the prevention of surgical infections at the time of hospital discharge and 6 months postoperatively; to compare both drugs in the prevention of nonsurgical infections, noninfectious complications, and mortality at discharge, 1 month, and 6 months after the operation; to compare the microorganisms responsible for infections after operations; and to compare the safety of the 2 drugs.

Sample size estimation
The sample size was based on a surgical infection rate of approximately 2% among participating centers on the basis of informal surveys, which is consistent with literature reports in the 1% to 10% range. With a significance level of 5% and a power of 80% and using a 2-sample ² test, this required 1239 patients per arm.

Safety monitoring committee
Interim analysis was performed by an independent safety monitoring committee, consisting of a methodologist, a statistician, and a pediatric infectious disease specialist. Three analyses were performed (ie, one each after 600, 1200, and 1800 patients). The criterion for statistical significance was modified because of the 3 interim analyses.

	Results

Top Abstract Introduction Methods Results Discussion Appendix: References

 
Of 12,198 individuals screened for inclusion into the study, 8973 were ineligible, 3225 were eligible, and 178 withdrew before their operation or their operation was canceled. Twenty others withdrew for other reasons. A total of 3027 were randomized: 1518 received teicoplanin, and 1509 received cefazolin.

Patient demographics are outlined in Table I. There was no significant difference between groups in sex, age, race, weight, severity of heart disease, or duration of preoperative stay. The number of patients with diabetes was similar in both arms of the study.

Perioperative data are outlined in Table II. Mean preoperative stay in both groups was 1 week. Drugs were administered a mean of 42 minutes before incision in both groups. Duration of operations (3.9 hours) and time on cardiopulmonary bypass (1.5 hours) were the same in both arms. There was similar blood loss. An intra-aortic balloon pump was required in 2.0% of the teicoplanin group and 1.4% of the cefazolin group. Skin antisepsis was similar in both groups, with antiseptic agents being predominantly povidone-iodine and chlorhexidine. Fewer than a quarter of the wounds in either group were irrigated. Superficial sternal wound infection rates were identical at the time of hospital discharge but rose over the first postoperative month to 71 (4.7%) in the teicoplanin arm and 44 (3.0%) in the cefazolin arm (P = .015). At 6 months, the cumulative number of infections was 80 and 50, respectively (P = .011; Table III).

The proportion of patients with superficial infections of the donor site in the leg was similar in both groups (Table IV). There was a trend to more deep leg infections in the cefazolin group (9 [0.7%] vs 4 [0.3%] after 1 month and 13 [1.1%] vs 4 [0.3%] after 6 months; P = .047). There was more pneumonia with teicoplanin. There was significantly more tracheobronchitis with teicoplanin at all time intervals. Postoperative urinary tract infection was 4 times more common in the teicoplanin group.

Overall, more infections were caused by coagulase-negative staphylococci and gram-negative rods in the teicoplanin group. Enterococcal infections were more common in the cefazolin arm. Gram-positive isolates were all susceptible to teicoplanin. Eight percent of the gram-positive infections and 34% of the gram-negative infections were resistant to cefazolin (Table VIII). All teicoplanin wound infections were caused by gram-positive bacteria, which were shown to be susceptible in vitro to teicoplanin. A similar observation was made with cefazolin in that all but 5 gram-positive isolates from surgical infections were sensitive to cefazolin. One hundred ninety-six gram-positive strains, including 82 S aureus, 84 S epidermidis, and 30 other Staphylococcus species (1 S hominis, 3 S capitis, 9 S haemolyticus, 12 S simulans, and 5 S warneri), were tested for the presence of the mec A gene by using a PCR primer (Table IX). ²¹ There were 5 mec A–positive S aureus (6%) strains and 42 mec A–positive S epidermidis (50%) strains. This resistance gene was not observed in the other staphylococcal species. Three S epidermidis strains harbored this gene, and they were susceptible to oxacillin, as determined by standard phenotypic susceptibility testing. We were successful in inducing resistance in vitro to oxacillin in all of these strains.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix: References

Infection was not associated with increased mortality in this group of patients. However, in both arms of the study, deep thoracic infections dramatically prolonged hospitalization by 20 days.

The 1.1% absolute difference in deep thoracic infections noted after 6 months of observation (ie, from 2.4% to 1.3% in the respective arms) is small. That there was a significant difference between groups reflects the statistical power of the study, which was the largest of its kind yet reported, and the 6-month period of observation, which allowed delayed surgical site infections to become manifest.

In view of the fact that this study was performed in 13 centers over a vast geographic area, it reflects more than a local idiosyncrasy of microbial flora. The nature of the glycopeptide-cephalosporin comparison is complex. Glycopeptides are more reliably active in vitro against staphylococci harboring the mec A gene, notably S epidermidis, and enterococci. Glycopeptides are more narrow in spectrum and should therefore be less of a disruption to the patient's endogenous flora.

Because 50% of the S epidermidis strains isolated in our study were resistant to methicillin and harbored the mec A gene, the greater number of gram-positive surgical infections in the teicoplanin group was unexpected. Inexplicably, although 100% of the gram-positive pathogens isolated in our patients remained susceptible to teicoplanin in vitro, gram-positive bacteria were more common in the teicoplanin group than the cefazolin group in thoracic wound infections, both deep and superficial, as well as in respiratory tract infections. Of particular concern was the high proportion (6/7) of gram-positive infections among the patients with sternal osteomyelitis, all of which occurred in teicoplanin recipients. In leg incisions and in the urinary tract, there were more gram-positive infections in the cefazolin group than in the teicoplanin group.

On the basis of in vitro antimicrobial activity and pharmacokinetic data, teicoplanin appeared to be a very promising prophylactic agent for cardiac operations. Previous studies had shown that the ratio of teicoplanin concentrations (ie, cardiac tissue/serum) varied between 1.1 and 10, which was higher than those obtained previously with fusidic acid (0.33), cloxacillin (0.73), cefamandole (0.35), cefazolin (0.23), and vancomycin (0.2-0.4). ^26,32

Moreover, 24 hours after the preoperative infusion of a 12 mg/kg dose, which was less than the 15 mg/kg used in this study, patients undergoing cardiac surgery had serum teicoplanin levels above the minimal inhibitory concentrations (MICs) for 90% of gram-positive pathogens. Mean concentrations detected in heart tissue were 10 to 20 times higher than the MICs for 90% of methicillin-susceptible and methicillin-resistant S aureus and S epidermidis, Enterococcus faecalis, and Corynebacterium jeikeium. This was in contrast to the concentration of vancomycin in heart tissue, which approximates the MIC for these organisms. Moreover, although maximum levels of cefamandole, cloxacillin, and flucloxacillin were 4 to 8 times higher than the MICs of these antibiotics against methicillin-susceptible bacteria, they were lower than the MICs for methicillin-resistant bacteria. The same applies for cefazolin. ³²

Interestingly, all the escape bacteremia (ie, bacteremia caused by microorganisms susceptible to antimicrobials) associated with teicoplanin prophylaxis was caused by S epidermidis. In contrast, most of the cases of gram-positive pneumonia and tracheobronchitis were caused by S aureus, against which teicoplanin has excellent in vitro activity.

Why was teicoplanin less effective than cefazolin against sternal wound infections? The kinetics of teicoplanin may have played against the drug. Teicoplanin is highly protein bound (ie, approximately 90%). ^33,34 Levels of free drug are relatively low, and activity is correspondingly reduced. ^35,36 Although levels of teicoplanin are high in cardiac tissue, ²⁶ they are low in presternal subcutaneous fat. ³⁷ Teicoplanin penetrates sternal bone poorly. ³⁸ We attempted to overcome these negative features by using a high dose of teicoplanin (ie, 15 mg/kg).

Furthermore, although glycopeptides, including teicoplanin, exhibit good in vitro activity against gram-positive bacteria, as determined by MICs, these drugs are only slowly bactericidal compared with ß-lactams. ³⁵ This may be an important detriment to activity in prophylaxis. Also, when compared with vancomycin, teicoplanin has only modest activity against S epidermidis. ^39-42

Glycopeptides provide no activity against facultative gram-negative rods, which may cause operative and nonoperative site infections. A priori we were concerned about the potential for gram-negative infections in the teicoplanin group. This concern was realized in urinary and respiratory tract infections and in bacteremia. Of particular interest is the fact that there were more gram-negative deep and superficial donor site infections in the cefazolin group than in the teicoplanin arm and that these infections were due, for the most part, to cefazolin-susceptible enterobacteriaceae. For gram-negative infections at other sites, cefazolin provided effective prophylaxis, despite a 34% resistance rate of gram-negative pathogens to cefazolin in this study. With such high levels of resistance, one would have expected more gram-negative infections in the cefazolin group than those observed. The conventional concept of MIC may not be entirely applicable to prophylaxis. Other factors, such as rate of kill and inoculum effect, may also explain some of the apparent discrepancies observed here.

Previous studies have suggested that male sex, old age, obesity, and prolonged preoperative stay were determinant factors increasing the likelihood of infectious complications. In our present clinical trial, diabetes mellitus and the duration of operation appear as the only significant risk factors for the development of infections.

Adverse events in both groups were relatively uncommon and generally inconsequential. Of note, hypotension was not a problem with teicoplanin, occurring with similar frequency as with cefazolin. This supports the data of Sahai and associates, ²⁸ differentiating teicoplanin from vancomycin. Whereas vancomycin induces histamine release, teicoplanin does not.

This study was done in centers with a low prevalence of MRSA. Vancomycin would be indicated if MRSA were the predominant strain of S aureus One historically controlled study suggested equivalence of vancomycin and teicoplanin. A rigorous randomized controlled trial between these 2 drugs would be of great interest. Until that time, no definite statement can be made about the comparative efficacy of vancomycin and teicoplanin.

In conclusion, cefazolin provided more effective prophylaxis than teicoplanin in preventing postoperative infections after cardiac operations.

	Appendix:

Top Abstract Introduction Methods Results Discussion Appendix: References

 

	Acknowledgments

 
We thank Francis Martineau for expert performance of mec A gene detection.

	Footnotes

 
*For members of the ESPRIT Group, see end of article.

	References

Top Abstract Introduction Methods Results Discussion Appendix: References

 

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