Local Gentamicin Reduces Sternal Wound Infections After Cardiac ...

Örjan Friberg, MD, Rolf Svedjeholm, MD, PhD, Bo Söderquist, MD, PhD, Hans Granfeldt, MD, Tomas Vikerfors, MD, PhD, and Jan Källman, MD, PhD Departments of Cardiothoracic Surgery, Clinical Microbiology, and Infectious Diseases, Örebro University Hospital, Örebro, Department of Cardiothoracic Surgery, Linköping University Hospital, Linköping, Sweden

Background. Sternal wound infections remain a major cause of morbidity after cardiac surgery. Vancomycin is often the only effective antibiotic available for their treatment but its use for routine prophylaxis is inadvisable for ecological reasons. Local application of gentamicin produces high antibiotic concentrations in the wound. We aimed to determine whether this treatment could have an additive effect on the incidence of sternal wound infections when combined with routine prophylaxis. Methods. Two thousand cardiac surgery patients were randomized to routine prophylaxis with intravenous isoxazolyl-penicillin alone (control group) or to this prophylaxis combined with application of collagen-gentamicin (260 mg gentamicin) sponges within the sternotomy before wound closure. Endpoint was any sternal wound infection within 2 months postoperatively. Evaluations

were double-blind and made on an intention-to-treat basis. Results. Evaluation was possible in 967 and 983 patients in the control and treatment groups, respectively. The incidence of sternal wound infection was 4.3% in the treatment group and 9.0% in the control group (relative risk 0.47; 95% confidence interval 0.33– 0.68; p < 0.001). Early reoperation for bleeding was more common in the treatment group (4.0% vs 2.3%, p ⴝ 0.03). No difference in postoperative renal function was noted. Conclusions. Local collagen-gentamicin reduced the risk for postoperative sternal wound infections. Further studies are warranted to confirm these results, particularly with regard to deep infections.

I

the risk of selection of resistant bacteria with consequent ecological and therapeutic consequences [11]. Also, vancomycin is intrinsically a less active antistaphylococcal agent than are ␤-lactam antibiotics [10]. Hence, alternative approaches to prevent postoperative sternal infections need to be explored. With local application of gentamicin, bound to bovine collagen in padlike sponges (Collatamp-G; ScheringPlough, Stockholm, Sweden), there is evidence that the concentration of gentamicin in the mediastinal fluid reaches levels high enough to be effective against bacteria that are normally considered resistant (including most CoNS) [12]. The aim of this study was to determine whether locally administered gentamicin in addition to routine IV prophylaxis with isoxazolyl-penicillin could reduce the total incidence of SWI after cardiac surgery.

n cardiac surgery, sternal wound infection (SWI) continues to be one of the most serious postoperative complications [1– 4]. Coagulase-negative staphylococci (CoNS) have become the most common causative agents of SWI, followed by Staphylococcus aureus and others, such as gram-negative rods [2, 5–7]. Due to the shift towards CoNS infections, the presentation is often delayed and more insidious, while treatment has become more demanding often requiring radical surgical revision with or without the use of muscle or omental flaps to achieve cure [1]. Prophylaxis with intravenous (IV) ␤-lactam antibiotics (cephalosporins or in Sweden most commonly isoxazolyl-penicillins), during surgery and with continuation for up to 48 hours postoperatively, is routinely practiced [8, 9]. However, most CoNS are methicillin resistant, and are thus resistant to all ␤-lactam antibiotics due to the presence of the mecA gene [10]. Therefore, vancomycin is often the only effective antibiotic available for treatment of sternal infections caused by CoNS, but its use for routine prophylaxis is strongly discouraged because of Accepted for publication June 11, 2004. Address reprint requests to Dr Friberg, Department of Cardiothoracic Surgery, Örebro University Hospital, SE-701 85 Örebro, Sweden; e-mail: [email protected].

© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2005;79:153– 62) © 2005 by The Society of Thoracic Surgeons

Patients and Methods Patients The study was conducted in two cardiothoracic centers in Sweden during the period September 2000 to September 2002. The centers are single referral centers and the sole providers of cardiac surgery in their catchment regions of about 0.6 and 1.0 million inhabitants, respectively. 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.06.043

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Local Gentamicin Reduces Sternal Wound Infections After Cardiac Surgery: A Randomized Controlled Trial

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FRIBERG ET AL LOCAL GENTAMICIN AND STERNAL WOUND INFECTIONS

Eligible for inclusion in the study were all patients undergoing cardiac surgery through median sternotomy, including operations on the ascending aorta. Exclusion criteria were: known allergy to gentamicin; pregnancy or breastfeeding; treatment with aminoglycosides during the last 2 weeks before surgery; and expected difficulty in fulfilling the follow-up requirements, for linguistic or other reasons. The trial was approved by the ethics committees at both participating centers, and written informed consent was obtained from all patients. In accordance with the ethics committees’ approval, emergency patients were included and informed immediately after surgery. If they did not agree to participate they were excluded from further evaluation.

Design and Treatment The study was randomized, prospective, and doubleblind (ie, the patients and those physicians and nurses who collected all the postoperative data and classified the infections were blinded regarding what treatment the patients had received). An external statistician who was not involved in the enrolment or assessment of the patients performed the randomization. The allocation sequence was computergenerated with a variable block size of 8, 12, or 16 patients and was stratified for center. Assignments were concealed in sealed envelopes. At the end of the operation, immediately before sternal closure, the envelope was opened and the patient was allocated to a treatment group (routine IV prophylaxis combined with sternal application of collagen-gentamicin; see below) or a control group (IV prophylaxis alone). No documentation concerning the group to which the patient had been randomized was left in the patient’s file. Collatamp-G consists of a flat absorbable bovine collagen sponge with gentamicin sulfate. A 10 ⫻ 10 ⫻ 0.5-cm sponge contains 280 mg collagen and 130 mg gentamicin (200 mg gentamicin sulfate). The treatment group received two such sponges in the wound immediately before closure. The sponges were cut into appropriate sizes and put between the sternal halves. More than two layers of Collatamp-G were avoided so as not to compromise sternal healing and stability, and any left-over sponge were put behind the sternum at the proximal or distal end. In the control group the wound was closed in a conventional way. The primary end-point was any SWI within 2 months postoperatively.

Surgical Technique A policy of strict hygiene routines to prevent infections has been adopted at both centers including avoidance of unnecessary personnel rotation in the operating rooms. One center had laminar air flow ventilation in the operating rooms, the other had upward displacement ventilation. Most, but not all, surgeons used double gloving. The operations were performed with a standard technique. Cardiopulmonary bypass (CPB) was used in all patients except in 9% of the coronary bypass (CABG)

Ann Thorac Surg 2005;79:153– 62

operations, which were carried out off pump (Table 1). Internal mammary arteries were harvested with a pedicle (not skeletonized). The sternum was sutured with 6 to 8 sternal wires, and the fascia, subcutis and skin were closed with running, monofilament, absorbable sutures. The surgeon who performed the heart operation, usually a senior surgeon, also closed the wound. Antibiotic prophylaxis was given IV, in accordance with the protocol of each center, starting immediately before the skin incision and then with 1 to 2 repetitions during surgery, with cloxacillin at one center and dicloxacillin at the other, at the doses 2 g and 1 g, respectively. This was continued every 8th hour for 24 to 48 hours postoperatively, depending on whether the drainage tubes had been removed. Patients with penicillin intolerance received clindamycin 600 mg at similar intervals. Preoperative topical nasal antibiotics were not used. Preoperative oral mouthwash twice, the night and the morning before surgery, with chlorhexidine solution was implied at one of the centers (Örebro). An approach towards early reoperation at clinical signs of deep infection was applied at both centers.

Follow-Up and Data Collection During the postoperative stay in the surgical department, all reoperations and SWIs were recorded. Serum creatinine was measured preoperatively, on postoperative days 1 and 3, and then on clinical indications. All major complications during the postoperative stay were recorded. After discharge the patients were contacted by telephone 2 months postoperatively and were asked to answer a structured list of standardized questions. Those who could not be reached by phone were sent a letter with a questionnaire containing the same questions. Any reported symptom of impaired wound healing or possible wound infection resulted in a check of medical records from all postoperative contacts with medical services. Data on clinical status, bacterial cultures, laboratory findings, and surgical or antibiotic treatment were recorded. Four infections diagnosed after more than 2 months were discovered (60 to 73 days). These were also included in the analysis because the randomization had not been broken. Mortality data were double-checked against the national Swedish population register.

Classification of Infections All classifications were made by the same person, a senior surgeon (Ö.F.), before the randomization code was broken. A second opinion was obtained from another surgeon or from a specialist in infectious diseases in doubtful cases. Criteria for definition and classification of surgical site infections according to Centers of Disease Control and Prevention [11] were used with minor modifications (Table 2). Depths 1 and 2 were considered as superficial infections, and depths 3 and 4 were considered as deep infections. Strict definition and classification of an infection some-

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Table 1. Baseline Data Control (n ⫽ 967) Number of patients in each center (%) Linkoping University Hospital Orebro University Hospital Sex Number of male (%) Age in years, median (range) Risk factors BMI median (range) Serum creatinine (␮mol/l) median (range) Preop dialysis, number (%) Diabetes, insulin/drug treated, number (%) COPD, number (%) Left ventricular ejection fraction ⬍35%, number (%) Preop medication: number (%) Oral steroid treatment Immunosuppression Preop anticoagulation, any Dalteparin or heparin (within 24 h) Warfarin (within 3 days) Clopidogrel (within 3 days) Aspirin (within 7 days) Dipyridamole Preop hospital stay, days, median (range) Emergency operation, number (%) Type of surgery, number (%) CABG Off pump (% of CABG) Valve Aortic aneurysm Congenital malformation CABG ⫹ other (mostly valve) Other Use of mammary artery, number (%) LIMA only all operations CABG(% of CABG) RIMA only all operations CABG(% of CABG) Bilateral IMA all operations CABG(% of CABG) Times, minutes Operation, duration median (range) CPB, duration median (range)

Treatment (n ⫽ 983)

All Other Operations During Study Perioda (n ⫽ 792)

464 (48.0) 503 (52.0)

474 (48.2) 509 (51.8)

429 (54.2) 363 (45.8)

735 (76.0) 68 (20–87)

753 (76.6) 68 (25–87)

525 (66.3) 70 (16–88)

26.6 (14.8–46.1) 94 (50–1084) 9 (0.9) 174 (18.0) 58 (6.0) 65 (6.7)

26.3 (15.6–42.8) 96 (45–801) 5 (0.5) 180 (18.3) 52 (5.3) 50 (5.1)

154 (19.4) 55 (6.9) 37 (4.7)

47 (4.9) 12 (1.2) 570 (58.9) 338 (35.0) 9 (0.9) 11 (1.1) 465 (48.1) 6 (0.9) 1 (0–40) 23 (2.4)

22 (2.2) 9 (0.9) 622 (63.3) 347 (35.3) 9 (0.9) 9 (0.9) 536 (54.5) 3 (0.3) 1 (0–41) 23 (2.3)

97 (12.2)

698 (72.2) 63 (9.0) 135 (14.0) 18 (1.9) 5 (0.5) 100 (10.3) 11 (1.1)

732 (74.5) 65 (8.9) 131 (13.3) 11 (1.1) 6 (0.6) 95 (9.7) 8 (0.8)

555 (70.1) 51 (9.2) 108 (13.6) 48 (6.0) 4 (0.5) 66 (8.3) 11 (1.4)

679 (70.2) 615 (88.1)

701 (71.3) 641 (87.6)

4 (0.4) 3 (0.4)

6 (0.6) 5 (0.6)

10 (1.0) 9 (1.3)

9 (0.9) 9 (1.2)

195 (65–632) 88 (19–365)

195 (60–778) 87 (30–480)

91 (22–619)

a

Consists of 742 patients never included and the 50 patients excluded from the study; only data retrievable from the centres’ clinical databases are shown for these.

BMI ⫽ body mass index (kg/m2); CABG ⫽ coronary artery bypass grafting; cardiopulmonary bypass; LIMA/RIMA ⫽ left/right internal mammary artery.

COPD ⫽ chronic obstructive pulmonary disease;

CPB ⫽

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Table 2. Classification of Infections Depth

Localization

1 2

Cutis Subcutis

3

Presternal

4

Sternal bone or mediastinum

Description e.g., infected crusts Involving subcutaneous tissue but not reaching down to sternal fixation wires Infections reaching below the superficial fascia, involving sternal wires. Unstable sternal fixation with signs of osteomyelitis or positive bacterial cultures from mediastinum or mediastinal abscess.

times proved difficult. Therefore, the infections were classified as “definite” or “probable.” Infections classified as definite were those with typical symptoms and signs and a positive culture. All probable and definite infections were considered as “infection” in the following calculations unless otherwise stated. Five samples for bacterial culture, of which at least two were tissue samples, were taken intraoperatively at reoperations for deep infection. To be classified as definite mediastinitis or sternitis (depth 4), two of these five cultures had to be positive with the same bacterial isolate. In infected patients handled at referring hospitals, cultures were taken on clinical indications alone.

Statistical Analysis The sample size was chosen so as to detect an approximate 50% reduction in the incidence of any SWI, and the incidence in the control group was assumed to be at least 4%. One thousand eighteen patients in each group provide a power of 80% for distinguishing between infection rates of 4% and 1.9% in the two groups (two-sided type I error of 5%). Therefore the 1000 patients in each group were considered to be appropriate because the incidence

Superficial

Deep

of 4% in the control group was assumed to be somewhat underestimated. Subgroup analyses with regard to bacterial etiology, depth of infection and established preoperative risk groups (diabetes and high body mass index [BMI]) [13– 20] were conducted. The sample size calculations did not account for these subgroup analyses but since the true incidence proved higher than assumed the analyses were considered justifiable. All analyses were made on an intention-to-treat basis, ie, patients who died and those reoperated on for bleeding or other reasons during the follow-up period were included in the analysis. An interim analysis was performed by an external statistician after completion of follow-up of 1000 patients. For categorical variables the relative risk with 95% confidence intervals was calculated and two-sided P values were calculated with Pearson’s ⌾2 test or, if expected frequencies fell below 5, Fisher’s exact test. For continuous variables the Mann-Whitney rank sum test was used. For the statistical analyses, Statistica 6.1 (StatSoft Inc, Tulsa, OK), SPSS 11.5 (SPSS Inc, Chicago, IL) software, and Microsoft Excel (Microsoft, Redmond, WA) were used.

Role of the Funding Source The sponsors had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.

Results Patients

Fig 1. Trial profile.

During the study period from October 2000 to August 2002, a total of 2742 patients underwent cardiac surgery at the two centers. Two thousand eligible patients were identified and preliminarily included (Fig 1). Of these, 8 patients were excluded at the end of the operation for medical reasons (eg, sternotomy could not be primarily closed because of hemodynamic instability or the sternum was reopened immediately for other reasons) and 1 was discovered to have been erroneously included (met exclusion criteria). Thirty-five patients whose operation was an emergency declined further participation. Thus, 1956 patients entered the study. Six of these could not be reached at the follow-up.


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Table 3. Outcome

Outcome Primary end-point All SWIs Treatment Antibiotic treatment Surgically treated SWIa Bacterial etiology Staphylococcus aureus Coagulase-negative staphylococci Gram-negative bacteria Other bacteria or multiple species Missing or negative bacterial samples Subclassifications Probable SWI Definite SWI All superficial SWI Depth 1 Depth 2 All deep SWI Depth 3 Depth 4 General outcome Hospital mortality Total 60-day mortality Early reoperation for bleeding Postop hemodialysisb Postop rise in serum creatinine, median ␮mol/L Mechanical ventilation more than 48 hours a

Any surgical revision of the wound;

CI ⫽ confidence interval;

b

Control (n ⫽ 967) no. (%)

Treatment (n ⫽ 983) no. (%)

RR (95% CI)

p Value

87 (9.0)

42 (4.3)

0.47 (0.33 to 0.68)

⬍0.001

174 (18.0) 38 (3.9)

114 (11.6) 21 (2.1)

0.64 (0.52 to 0.80) 0.54 (0.32 to 0.92)

⬍0.001 0.021

20 (2.1) 33 (3.4) 4 (0.5) 15 (1.6) 15 (1.6)

8 (0.8) 11 (1.1) 1 (0.1) 10 (1.0) 13 (1.3)

0.39 (0.17 to 0.89) 0.33 (0.17 to 0.65) — 0.66 (0.30 to 1.45) 0.85 (0.41 to 1.78)

0.020 ⬍0.001 0.21 0.29 0.67

32 (3.3) 55 (5.7) 55 (5.7) 14 (1.4) 41 (4.2) 32 (3.3) 17 (1.8) 15 (1.6)

15 (1.5) 27 (2.7) 19 (1.9) 8 (0.8) 11 (1.1) 23 (2.3) 10 (1.0) 13 (1.3)

0.46 (0.25 to 0.84) 0.48 (0.31 to 0.76) 0.34 (0.20 to 0.57) 0.56 (0.24 to 1.33) 0.26 (0.14 to 0.41) 0.71 (0.42 to 1.20) 0.58 (0.27 to 1.26) 0.85 (0.41 to 1.78)

0.010 0.001 ⬍0.001

10 (1.0) 17 (1.8) 22 (2.3) 10 (1.0) 5.1 25 (2.6)

11 (1.1) 19 (1.9) 39 (4.0) 10 (1.0) 7.8 31 (3.2)

1.08 (0.46 to 2.54) 1.10 (0.57 to 2.10) 1.74 (1.04 to 2.91) 0.98 (0.41 to 2.35)

0.85 0.77 0.032 0.97 0.28 0.45

0.82 (0.49 to 1.38)

0.20

patients on preoperative hemodialysis not included.

RR ⫽ relative risk;

SWI ⫽ sternal wound infection.

Table 1 shows baseline data of the remaining 1950 patients and of all other patients operated on during the study period (including those excluded during the trial process).

days) in the treatment group and 15 days (range 3 to 62 days) in the control group. All patients, except one (belonging to the control group), with symptoms of sternal dehiscense that required refixation were classified as having a SWI.

Outcome The total incidence of SWI (primary end-point) was 9.0% in the control group and 4.3% in the treatment group (p ⬍ 0.001). There was a reduction in all major microbiological types of infections (Table 3, Fig 2). Significantly fewer patients in the treatment group received antibiotics or needed surgical revision of the sternal wound during the follow-up. There was a risk reduction in all depths that was statistically significant for superficial infections (Table 3) and for deep infections in high-risk groups (diabetes, BMI ⬎ 25; Table 4). Twenty-four of 129 SWIs (17 in the control and 7 in the treatment group; p ⫽ 0.036) were diagnosed before discharge from cardiothoracic center. The median time from operation to diagnosis of SWI was 20 days (range 3 to 73

General Outcome There were no significant differences in mortality, postoperative rise in creatinine or need for dialysis between the groups (Table 3). The total 60-day mortality of the 129 patients with SWI was 1.5% (2 patients with deep SWI, both in the treatment group). There were significantly more reoperations for bleeding in the treatment group (4.0% vs 2.3%). Data retrieved from the clinical databases of the centers showed that 3.5% of the 792 patients not included in the study had had reoperations for bleeding. Four of 39 patients reoperated on for bleeding in the treatment group and 1 of 22 such patients in the control group had postoperative SWI. The reduction of infections was similar when excluding patients who were reoperated for bleeding (n ⫽ 61),

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Fig 2. Incidence of wound infections and their bacterial etiology. □ ⫽ control; o ⫽ treatment. (SWI ⫽ sternal wound infections; CoNS ⫽ coagulase negative Staphylococci.)

reoperated for other reasons (n ⫽ 7), or who died within 2 months (n ⫽ 36) from the analysis (leaving 1850 patients, 927 and 923 in the control and treatment groups, respectively). In this group there were 62 (6.7%) versus 25 (2.7%) superficial infections (p ⬍ 0.001), and 31 (3.3%) versus 19 (2.1%) deep infections (p ⫽ 0.088) in the control and treatment groups, respectively. The mean lengths of postoperative stay until discharge were 6.7 and 7.1 days in the treatment and control groups, respectively, with a median of 6 days in both groups.

Adverse Reactions No case of verified or suspected allergic or other adverse reaction to gentamicin or bovine collagen was identified.

Comment This is the first randomized controlled trial of local gentamicin prophylaxis in cardiac surgery. Local application of collagen-gentamicin between the sternal halves was associated with a 53% relative reduction (4.7% absolute reduction) in the incidence of SWI after sternotomy

on an unselected cardiac surgery patient population. No significant impairment in postoperative renal function or other adverse effects of the treatment were noted. A limitation of our study is the absence of a placebo arm with collagen without gentamicin. However, the patients and those assessing the outcome were blinded regarding treatment. Since the proposed hemostatic effect of collagen did not reduce reoperation rate for bleeding, it is conceivable that the reduction in SWI was due to the gentamicin component. Definition and classification of surgical site infections are, despite classification systems, occasionally subjective. In this study infections were therefore classified as definite or probable. However, the risk reductions in these two classes were almost equal and – scientifically most important – there were significant reductions in the definite infections, in staphylococcal (including CoNS) infections, in surgical revisions and in antibiotic treatment. The reported incidences of postoperative SWI varies considerably, not only because of differences in definitions and classification of infections but also because of variations in follow-up between centers and notably

Table 4. Incidence of Sternal Wound Infections in Risk Groups With Diabetes or Increased BMI Number (% of study population)

Risk Factor(s) Diabetesa

354 (18.2)

BMI ⬎ 25b

1299 (66.6)

Diabetes or BMI ⬎ 25

1385 (71.0)

a

Treated with insulin or oral medication;

BMI ⫽ body mass index (kg/m ); 2

SWI/Total in Group (%)

b

Depth

Control

Treatment

RR (95% CI)

p Value

Superficial Deep Superficial Deep Superficial Deep

13/174 (7.47) 17/174 (9.77) 42/651 (6.45) 29/651 (4.45) 46/687 (6.70) 30/687 (4.37)

3/180 (1.67) 7/180 (3.89) 14/648 (2.16) 16/648 (2.47) 14/698 (2.01) 17/698 (2.44)

0.22 (0.06 to 0.78) 0.40 (0.17 to 0.94) 0.33 (0.18 to 0.61) 0.55 (0.30 to 1.01) 0.43 (0.24 to 0.78) 0.56 (0.31 to 1.00)

0.0086 0.028 ⬍0.001 0.050 ⬍0.001 0.047

WHO definition of overweight.

CI ⫽ confidence interval;

RR ⫽ relative risk;

SWI ⫽ sternal wound infection.

because most published series are retrospective [5, 13, 16, 19, 21–23]. The 9.0% infection rate in our control group is certainly higher than many surgeons would anticipate. However, it should be emphasized that the majority of the infections detected in the present study were not deep infections, as shown in Table 3. Furthermore, in this study, 4 of 5 infections were diagnosed after discharge. This underlines the importance of thorough follow-up. In a recent study with complete 90-day follow-up, the total incidence of SWI was 9.0% [24], which is similar to that found in our control group. In two earlier studies with complete 2-months follow-up, assessing the ASEPSIS wound score [25, 26], the incidence of any sternal wound infection was 8.0% and 7.3%, respectively. The clinical characteristics of CoNS infections also deserve consideration. They have led to more insidious infections that have required extensive antibiotic treatment and not uncommonly delayed extensive surgical revision, consuming substantial healthcare resources [1]. Hence, over the last decade a policy of active surveillance and early aggressive surgical revision was developed at both centers, which has resulted in earlier detection, less complicated revisionary surgery, and reduced length of antibiotic treatment [27]. We suggest that the mortality of only 1.5% during 60 days of follow-up in patients with SWI in the present study is in accordance with this policy. We applied the criteria for definition and classification of Surgical Site Infections according to Centers of Disease Control and prevention [11]. This is a systematic and frequently used classification, made for applying on any surgical site infection. It is focused on the depth, but not on the clinical severity, of the infection. An evaluated clinical wound score system, such as the ASEPSIS score [25], would have given additional information, but to apply this to almost 2000 patients was beyond our resources. Randomized studies of prophylaxis with local collagen-gentamicin have reported a reduction of surgical site infections in “dirty” abdominal surgery [28 –31] and in prosthetic repair of groin hernias [32]. There is one report of successful use of collagen-gentamicin for treatment of mediastinitis [33]. Intravenous aminoglycosides have been used for prophylaxis in cardiac surgery, usually combined with ␤-lactam antibiotics [9]. However, no significant additional effect of the IV combination, compared to cephalosporins alone, has been reported [34 –36]. In a recent meta-analysis IV ␤-lactam antibiotics were superior to glycopeptides, such as vancomycin, for prevention of SWI after cardiac surgery, although glycopeptides were superior for prevention of infections caused by methicillin-resistant gram-positive bacteria [37]. Topical vancomycin has been shown to reduce the incidence of sternal infection in one randomized study [38]. Local application of gentamicin produces high local antibiotic concentrations that may have an effect on bacteria that are normally considered to be resistant [12]. Although gentamicin is generally used for gram-negative


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infections, it does have a spectrum of bactericidal activity for many gram-positive organisms, including staphylococci [39]. Synergism between aminoglycosides and ␤-lactam antibiotics has also been shown [40]. Further detailed analyses of the bacteriological findings, including antibiotic susceptibility patterns, are required. The gentamicin-collagen sponges were placed between the sternal halves. We hypothesized that this is where it is most important to achieve high antibiotic concentrations in order to prevent osteomyelitis. A lower incidence of SWI was found in the treatment group in all four depths but the study was not powered to detect significant differences in subgroups. Even so, the reduction in superficial infections was significant and patients with established risk factors for infection (diabetes or increased BMI) revealed a significant reduction in deep infections. Further studies are warranted to confirm these results. From a clinical perspective, the significant difference in the incidence of infections that required surgical treatment is important. Bovine collagen is rapidly absorbed and is theoretically an attractive vehicle for antibiotics. The product is considered safe regarding BSE and is approved for commercial use in, for example, the countries within the European Union. We found no evidence of allergic reactions or adverse local effects on sternal healing. On the other hand, we found a higher incidence of early reoperation for bleeding in the treatment group. The medical records from the reoperation of the patients in the treatment group provided no obvious explanation, nor was any obvious, repeated or unusual source of the bleeding reported. Notably, the incidence of reoperation for bleeding in the treatment group was close to that seen in our routine practice and among the patients not included in the study. Thus, although this issue needs to be monitored in the future, available data, rather than pointing at any untoward effect, seem to suggest a lower than expected reoperation rate in the control group. Nevertheless, patients reoperated on for bleeding did not become infected to an extent that significantly influenced the overall result in an untoward direction. A potential drawback of the local gentamicin treatment is the risk of selecting gentamicin-resistant bacterial clones over time. However, aminoglycosides have already been used extensively for many years. The pharmacokinetics of local gentamicin, with an early, high peak in the local gentamicin concentration, low serum concentrations and then rapid disappearance of the drug reduces the selection of resistant bacteria and may, in this respect, even be favorable compared to normal IV use [12]. Given the unique role of vancomycin for antibiotic treatment of overt sternal wound infections and the inadvisability of using it for routine prophylaxis in consideration of the ecological drawbacks, local gentamicin provides the potential advantage of reducing the total exposure of the environment to vancomycin. Strict blood glucose control has in recent years been identified as a means of reducing SWI [41]. This was not yet fully in clinical practice during the study period and

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further studies are required to establish if local gentamicin may provide additional benefit in practices employing such strategies. In conclusion, our study indicates a significant risk reduction in postoperative SWI in cardiac surgery. Further studies are warranted to confirm this result particularly with regard to deep infections. Such studies should also address the question whether routine use may be justified or whether high-risk groups that may have particular benefit from this approach should be identified.


13.

14.

15. 16.

The study was financed by grants from the Research Committee of Örebro County Council and from Schering-Plough, who also provided free Collatamp-G. We are indebted to Professor Lennart Bodin, Örebro University, for valuable statistical help and advice; Lars-Göran Dahlin for valuable advice and for help with the classifications; and Berit Anselmius, Jessica Cederblad, Anders Fransson, and Maria Smedeus for all their efforts with patient administration and data collection.

17.

18. 19.

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INVITED COMMENTARY One of the most contentious issues in surgery is the use of prophylactic topical antibiotics to prevent wound infection [1]; cardiac surgery is no exception. Despite regular use of prophylactic intravenous antibiotics, postoperative mediastinitis occurs in a significant number of patients undergoing open heart surgery through median sternototmy. This major complication plagues the most commonly used incision in cardiac surgery, and is associated with a mortality rate as high as 47%. Staphylococcus aureus or S epidermidis are isolated in as many as 70% of the cases. Therefore, prophylactic instillation of antigram-positive antimicrobials during wound closure may reduce the risk of mediastinitis. This concept has indeed been tested in a previous prospective, randomized, controlled study; Vander Salm and associates [2] found that topical vancomycin applied during wound closure after median sternotomy was associated with a significant reduction in the rate of sternal wound infection (from 3.6% in the control group to 0.45% in the treatment group). We found sub-MIC levels of vancomycin in patient’s serum after topical application of 1 g vancomycin during sternotomy closure [3]. This, at least in theory, may encourage the emergence of vancomycin-resistant pathogens. Therefore finding a non–vancomycin antimicrobial that effectively prevents mediastinitis will be a welcome addition to the field. In this issue of The Annals, Friberg and associates report the results of a prospective, randomized clinical trial of using prophylactic collagen-gentamicin sponges placed between the sternal edges at the time of wound closure after mediastinotomy in 2,000 cases undergoing open heart surgery. The incidence of surgical site infection was significantly reduced from 9% in the control group to 4.3% in the treatment group. These apparently higher rates of surgical wound infection were attributed to the fact that this is a prospective randomized study with longer and near complete follow-up. Friberg and colleagues have used their own modification of the Centers for Disease Control (CDC) definition of wound © 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc

infection, where “. . . sternal wire involvement with infection was the cut-off between superficial and deep wound infection . . . .” Based on this definition, the incidence of deep wound infection was also reduced from 3.3% in the control group to 2.3% in the treatment group. The CDC definition for surveillance of surgical site infections [1] identifies the following three categories of surgical site infection: superficial incisional surgical site infection, deep incisional surgical site infection, and organ/space surgical site infection. This classification alone may be adequate for incisions with a reasonable demarcation between the superficial and the deep components of the wounds, as well as well-defined organ and space compartments, such as thoracotomy and laparotomy incisions. In cases of mediastinitis, however, the sternum is considered an organ in the CDC definition, yet it represents the deep layer of the wound and is always involved in the disease process. It is almost impossible to determine whether the infection is confined to the pectoral fascia, the sternal edges, the sternal wires, the retrosternal space, or the mediastinal spaces alone. Infections at the suprastenal notch and around the xiphoid cartilage are also difficult to define as deep-, organ-, or space-site infection. We have previously devised a classification for postmedian sternotomy deep wound infection [4]. In this classification, all deep sternal wound infections were classified according to the time of first presentation, and according to whether the patient had any previous attempts of surgical treatment for mediastinitis. The classification also takes into account the factors that carry a proven risk of developing mediastinits such as diabetes, obesity, and the use of oral steroids or immunosuppressive agents. Friberg and coworkers acknowledge that the application of other wound score systems was beyond their resources; they also highlight other limitations of their study including the lack of a collagen sponge only— without gentamicin— group, and the significantly higher 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.08.051

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