ICVTS Click here to goto Smart Canula website
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Interact CardioVasc Thorac Surg 2009;9:454-458. doi:10.1510/icvts.2009.207514
© 2009 European Association of Cardio-Thoracic Surgery
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Örjan Friberg
Rolf Svedjeholm
Right arrow Permission Requests
Google Scholar
Right arrow Articles by Friberg, O.
Right arrow Articles by Svedjeholm, R.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Friberg, O.
Right arrow Articles by Svedjeholm, R.

Institutional report - Cardiac general

Collagen-gentamicin implant for prevention of sternal wound infection; long-term follow-up of effectiveness{star}

Örjan Friberga,*, Lars-Göran Dahlinb, Jan Källmanc, Erik Kihlströmd, Bo Söderquiste and Rolf Svedjeholmb

a Department of Cardiothoracic Surgery and Anesthesiology, Örebro University Hospital, SE 70185 Örebro, Sweden
b Department of Cardiothoracic Surgery, Linköping University Hospital, Linköping, Sweden
c Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden
d Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
e Department of Clinical Microbiology, Örebro University Hospital, Örebro, Sweden

Received 23 March 2009; received in revised form 22 May 2009; accepted 26 May 2009

{star} This study was financed by the Research Committee of Örebro County Council, Sweden, by Linköping University Hospital, Sweden and by an unconditional grant from EUSA Pharma (Lyon, France). Back

1 Surgical site infection: full guideline. National Institute for Health and Clinical Excellence, 2008. ISBN 978-1-904752-69-1. Accessed at http://www.nice.org.uk/nicemedia/pdf/CG74FullGuideline.pdf.

*Corresponding author. Tel.: +46 19 6025202; fax: +46 19 6113943.

E-mail address: orjan.friberg{at}orebroll.se (Ö. Friberg).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 References
 
In a previous randomized controlled trial (LOGIP trial) the addition of local collagen-gentamicin reduced the incidence of postoperative sternal wound infections (SWI) compared with intravenous prophylaxis only. Consequently, the technique with local gentamicin was introduced in clinical routine at the two participating centers. The aim of the present study was to re-evaluate the technique regarding the prophylactic effect against SWI and to detect potential shifts in causative microbiological agents over time. All patients in this prospective two-center study received prophylaxis with application of two collagen-gentamicin sponges between the sternal halves in addition to routine intravenous antibiotics. All patients were followed for 60 days postoperatively. From January 2007 to May 2008, 1359 patients were included. The 60-day incidences of any SWI was 3.7% and of deep SWI 1.5% (1.0% mediastinitis). Both superficial and deep SWI were significantly reduced compared with the previous control group (OR=0.34 for deep SWI, P<0.001). There was no increase in the absolute incidence of aminoglycoside resistant agents. The majority of SWI were caused by coagulase-negative staphylococci (CoNS). The incidence of deep SWI caused by Staphylococcus aureus was 0.07%. The results indicate a maintained effect of the prophylaxis over time without absolute increase in aminoglycoside resistance. (ClinicalTrials.gov NCT00484055 [ClinicalTrials.gov] )

Key Words: Wound infection; Antibiotics; Mediastinitis; Statistics; Regression analysis; Risk factors; Cardiac surgery; Complications


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 References
 
Intravenous antibiotic prophylaxis for prevention of sternal wound infections (SWIs) after median sternotomy is well established and reduces the wound infection rate [1].

In a previous randomized controlled trial, the LOGIP trial, on almost 2000 patients the addition of local collagen-gentamicin (Collatamp-G®, Innocoll Pharmaceuticals, Athlone, Ireland) between the sternal halves at sternal closure reduced the incidence of postoperative wound infections compared with intravenous prophylaxis only [2].

Rigid sternal fixation, defined as at least seven single sternal fixation wires, was shown to be important to achieve a maximal reduction in deep infections by the collagen-gentamicin implant [3].

After the study period (2000–2002) the technique with local gentamicin was introduced in clinical routine practice and applied in most cardiac surgery patients at both centers.

There were concerns, however, that introduction of this prophylaxis could rapidly induce antibiotic resistance among causative microbiological agents, with subsequent reduced effect of the prophylaxis. Re-evaluation of the technique after its everyday use at both our centers since 2000 was therefore considered important.

The highly significant risk reduction found in the previous trial caused ethical concerns in randomizing patients again to control/placebo. Therefore, the present study was designed for comparison with the previous control group from the LOGIP trial.

The aims were to analyze the SWIs that occurred during a prespecified period regarding the incidence of methicillin- and/or gentamicin-resistance among causative microbes, and also to evaluate if the routine application of local gentamicin still resulted in a similar reduction in the incidence of SWI compared with the previous control group.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Limitations
 References
 
2.1. Patients

Consecutive patients operated at Örebro and Linköping Cardiothoracic Centers, Sweden, were included from January 2007 until May 2008. Eligible for the study were all cardiac surgery patients (including surgery of the thoracic aorta) operated via full median sternotomy.

Exclusion criteria were: existing inclusion of the patient in another study of treatment aimed at reducing postoperative SWI, known allergy or other contraindication to gentamicin or bovine collagen, pregnancy or breast feeding, treatment with aminoglycosides during the last week. The study was approved by the Regional Ethical Review Board. Written informed consent was obtained from the patients. The study was registered at ClinicalTrials.gov (NCT00484055 [ClinicalTrials.gov] ) before study start.

The control group consisted of 967 patients from the LOGIP-trial operated during 2000–2002.

2.2. Surgical technique

At the end of the operation two 5x20 cm Collatamp-G sponges (Innocoll Inc, Athlone, Ireland) were applied between the sternal halves [4].

The use of at least seven single wires for sternal fixation was emphasized in the protocol.

The sub cutis and skin were closed with two or more layers of resorbable monofilament sutures.

Both treatment and control groups received the same intravenous antibiotic prophylaxis with isoxazolylpenicillin repeatedly during surgery and postoperatively for 24 h.

2.3. Follow-up and classification

Follow-up was in accordance with the previous LOGIP trial. All patients were followed-up by telephone two months postoperatively using a standardized questionnaire. Copies of all medical records were collected if the patient reported any wound complications. Definitions of postoperative wound infection were made according to predefined criteria and in accordance to the modified CDC-classification used in the LOGIP trial [2]. Deep SWI included all SWI with sternal dehiscence or infections down to the sternum, also when the sternum remained stable. Infections were classified as definite if both clinical signs of infection and prespecified bacterial cultures were positive. Definite and probable infections were considered as infection in all analyses.

2.4. Bacterial sampling

At surgical revision due to SWI, five samples were taken for bacterial cultures, of which at least two were tissue samples. The other samples were collected as swabs and secretions. A definite SWI had to have more than two of these five samples, or at least half of the bacterial samples if fewer than five, positive with the same bacterial agent.

Samples were cultured on blood agar aerobically and anaerobically for at least two days and incubated in enrichment broth for at least five days.

2.5. Power calculation

In the previous LOGIP trial there was an incidence of 3.3% deep wound infections in the control group (967 patients). We hypothesized that the collagen-gentamicin implant in combination with at least seven single fixation wires would reduce the incidence of deep wound infection to 1.5%. Including 1300 patients provides 80% power to detect a difference of 3.3–1.5% (two-sided test, 0.05 significance level).

2.6. Statistical analyses

All analyses were made according to intention-to-treat.

For categorical variables a two-sided P-value was calculated with Pearson's {chi}2-test. For continuous variables the Mann–Whitney rank sum test was used. Multivariable logistic regression analyses were conducted for correction for differences in baseline data. Factors identified as significant risk factors for SWI in the previous study were entered in the model [5]. For the outcome deep SWI both forward and backward stepwise analyses were made. A P<0.05 was considered statistically significant. All analyses were made using SPSS 15.0 (SPSS Inc, Chicago, IL) and STATISTICA 8.0 (StatSoft Inc, Tulsa, OK).


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Limitations
 References
 
3.1. Patients

Out of totally 1702 patients that were operated during the study period 1359 were included in the study (Fig. 1). Follow-up data were complete for all but four patients that could not be reached. The total 60-day mortality was 24 patients (1.8%). The 60-day mortality among patients with SWI was three patients (6.0%). In no case was the SWI the primary cause of death.


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 1. Flow chart.

 
The characteristics of the patients in the study are given in Table 1 together with data on all patients not included in the study but operated during the same period, as well as the control group of 967 patients operated during 2000–2002. The proportion of coronary surgery was significantly less during the present study compared with the control group, also reflected as significantly less use of internal mammary artery (IMA).


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline data. The proportion of coronary surgery was significantly less during the present study compared with the control group, also reflected as significantly less use of IMA

 
3.2. Sternal wound infection

Twelve patients (0.9%) were diagnosed with an SWI before discharge and additionally 38 patients (2.8%) presented with an SWI during the 60-day follow-up, giving a total incidence of SWI of 3.7% (2.2% superficial, 1.5% deep) (Table 2, Fig. 2). Compared with the control group there were significant reductions in superficial SWI, deep SWI and in SWI requiring surgical revision. The differences remained significant when corrections were made for differences in risk factors (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 2 Results. Liberal criteria for defining SWI were used and positive bacterial samples were not required for the diagnosis of probable SWI. S. aureus caused seven (0.72%) deep SWI in the control group vs. one (0.07%) deep SWI in the study group (P=0.008)

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]

  		Fig. 2. Incidences of sternal wound infections (including both probable and definite infections). There was a parallel, significant, reduction in both superficial and deep infections compared to the control group.

 

View this table:
[in this window]
[in a new window]

  		Table 3 Results from the logistic regression analyses. The table shows independent risk factors for any (deep or superficial) SWI, and for only deep SWI. The type of operation and preoperative P-creatinine were not independent significant risk factors for SWI. Adding these factors to the analysis did not influence the significant, independent reduction in the study group. The significant independent factors for deep SWI were constant irrespective of which regression method (backward or forward stepwise) was used

 
3.3. Microbiological findings

Coagulase-negative staphylococci (CoNS) was the most common cause of SWI (Table 2). Of these, 80% were resistant to aminoglycosides and 81% were resistant to methicillin. CoNS was also the most commonly present agent (7 out of 8) in cases with multiple bacterial agents. There was a total of five cases with SWI caused by Staphylococcus aureus (0.4%), and of these only one was a deep SWI (0.07%). All tested S. aureus isolates were susceptible to aminoglycosides and methicillin.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Limitations
 References
 
The incidences of both superficial and deep SWI were less than half of that in the control group. This reduction was not due to the differences in baseline data (e.g. type of operation or use of internal mammary artery) between the groups. No trend towards decreasing effect of the prophylaxis over time could be seen. Contrarily, the incidence of SWI was slightly lower than that in the treatment group of the primary LOGIP trial (4.3% SWI with 2.3% deep SWI) [2].

There were no important differences in causative bacteria between groups. CoNS dominated. They were resistant to both aminoglycosides and methicillin in approximately 80% of cases. All tested S. aureus were susceptible to both methicillin and aminoglycosides.

In treatment group of the previous LOGIP trial the relative incidence of aminoglycoside resistance among CoNS was 50% and of methicillin resistance 58% [6]. However, the incidence of SWI caused by Propionibacterium acnes, which are constantly aminoglycoside resistant, was 0.7% in that previous treatment group compared with 0.1% in the present study. Therefore, the overall absolute incidence of SWI caused by aminoglycoside resistant species was similar. Furthermore, many ‘resistant’ agents may be susceptible to the extremely high local concentrations achieved with this technique [4].

In the guidelines on ‘Prevention and treatment of surgical site infection’, published in 2008 by the British National Institute for Health and Clinical Excellence, the original LOGIP trial is acknowledged, but the need for evaluation of the long-term effects on microbial resistance is emphasized1. The present study is the first on the long-term results of local collagen-gentamicin implants.

There is evidence that even a slight instability in an osteal fixation promotes the development of clinical infection if there is bacterial contamination [7]. We have previously shown a strong link between usage of seven or more single sternal fixation wires and a lower rate of SWI, compared with only six single wires [3]. Although the collagen is rapidly resorbed it could be argued that placing the collagen sponges between the sternal halves, rather than behind the sternum, might affect the sternal healing. We did not identify any such adverse effect in this study where the importance of a rigid fixation with complete compression of the sponges was emphasized.

It could be hypothesized that an SWI may start either as a local contamination with virulent bacteria or as an instability or complete rupture of the sternal fixation with subsequent growth of skin bacteria, predominantly CoNS and P. acnes that are commonly present in surgical wounds [8]. If so, the combination of local antibiotics and an extra rigid sternal fixation might be particularly desirable.

We used liberal criteria to diagnose probable infection. In two cases with sternal instability, classified as SWI of depth 4, bacterial cultures were negative. In all remaining deepest (depth 4) SWIs cultures showed either CoNS or P. acnes or a combination of those two. Both CoNS and P. acnes are commonly found as contaminants in samples taken close to the skin. To detect P. acnes, the bacterial samples have to be cultured anaerobically for several days, which is not standard practice for wound samples at most laboratories.

There were two cases (0.15%) with sternal instability without infection. Adding these two to the total incidence of deep infections would give a total ‘sternal complication rate’ of 1.2% (16 patients) that underwent refixation of the sternum due to either infection or mechanical instability. In a recent German multi-center trial on patients with at least one risk factor for SWI this ‘sternal complication rate’ was 5% (2.5% dehiscence plus 2.5% deep SWI) [9].


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
References
 
Because of ethical concerns of withholding high-risk patients from a prophylaxis documented to be effective in a large randomized clinical trial the comparisons were made with an historical control group. Retrospective comparisons are inherently subject to bias. To reduce this, the present study had the end points, estimated effect size and size of the study population prespecified. We corrected for the identified differences in baseline data between the groups, but unknown differences may have been present. Surgical results generally improve over time due to a number of factors that are difficult to control for.

Nevertheless, a total SWI-rate of 3.7% is obviously lower than the rates seen in other recent studies with a complete follow-up [9–12].

There are limitations regarding the external validity. The patient population was fairly representative of a common mixed cardiac surgery population but the microbiological findings may not be generalizable outside of Scandinavia. Since there were no cases with methicillin resistant S. aureus (MRSA) the effect on MRSA remains to be examined.

Another limitation concerns the effect of the surgical technique vs. local gentamicin. It is not possible to differentiate the relative effects of each of these. Moreover, the findings of P. acnes and CoNS in a surgical wound with little clinical signs of infection could be argued to be most likely contamination. However, from the patients’ perspective it would seem important to avoid any sternal wound complication.

In conclusion, antibiotic prophylaxis with local collagen-gentamicin in clinical routine was associated with a persistent significant reduction in superficial and deep SWI (OR=0.34). No trend towards less effect over time could be detected after ~7 years of daily use. There was no change in types of causative bacteria and no absolute increase in SWIs caused by aminoglycoside resistant microbes.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 References
 

  1. Kreter B, Woods M. Antibiotic prophylaxis for cardiothoracic operations. Meta-analysis of thirty years of clinical trials. J Thorac Cardiovasc Surg 1992;104:590–599.[Abstract]
  2. Friberg Ö, Svedjeholm R, Söderquist B, Granfeldt H, Vikerfors T, Källman J. Local gentamicin reduces sternal wound infections after cardiac surgery: a randomized controlled trial. Ann Thorac Surg 2005;79:153–161.[Abstract/Free Full Text]
  3. Friberg Ö, Dahlin LG, Söderquist B, Källman J, Svedjeholm R. Influence of more than six sternal fixation wires on the incidence of deep sternal wound infection. Thorac Cardiovasc Surg 2006;54:468–473.[CrossRef][Medline]
  4. Friberg Ö, Jones I, Sjöberg L, Söderquist B, Vikerfors T, Källman J. Antibiotic concentrations in serum and wound fluid after local gentamicin or intravenous dicloxacillin prophylaxis in cardiac surgery. Scand J Infect Dis 2003;35:251–254.[CrossRef][Medline]
  5. Friberg Ö, Dahlin LG, Levin LA, Magnusson A, Granfeldt H, Källman J, Svedjeholm R. Cost effectiveness of local collagen-gentamicin as prophylaxis for sternal wound infections in different risk groups. Scand Cardiovasc J 2006;40:117–125.[CrossRef][Medline]
  6. Friberg Ö, Svedjeholm R, Källman J, Söderquist B. Incidence, microbiological findings, and clinical presentation of sternal wound infections after cardiac surgery with and without local gentamicin prophylaxis. Eur J Clin Microbiol Infect Dis 2007;26:91–97.[CrossRef][Medline]
  7. Friedrich B, Klaue P, Worlock P, Slack R, Harvey L, Mawhinney R, Koury M, Ellis E 3rd. Mechanical stability and post-traumatic osteitis: an experimental evaluation of the relation between infection of bone and internal fixation. Injury 1977;9:23–29.[CrossRef][Medline]
  8. Kuhme T, Isaksson B, Dahlin LG. Wound contamination in cardiac surgery. A systematic quantitative and qualitative study of the bacterial growth in sternal wounds in cardiac surgery patients. APMIS 2007;115:1001–1007.[CrossRef][Medline]
  9. Schimmer C, Reents W, Berneder S, Eigel P, Sezer O, Scheld H, Sahraoui K, Gansera B, Deppert O, Rubio A, Feyrer R, Sauer C, Elert O, Leyh R. Prevention of sternal dehiscence and infection in high-risk patients: a prospective randomized multicenter trial. Ann Thorac Surg 2008;86:1897–1904.[Abstract/Free Full Text]
  10. Dhadwal K, Al-Ruzzeh S, Athanasiou T, Choudhury M, Tekkis P, Vuddamalay P, Lyster H, Amrani M, George S. Comparison of clinical and economic outcomes of two antibiotic prophylaxis regimens for sternal wound infection in high-risk patients following coronary artery bypass grafting surgery: a prospective randomised double-blind controlled trial. Heart 2007;93:1126–1133.[Abstract/Free Full Text]
  11. Eklund AM, Valtonen M, Werkkala KA. Prophylaxis of sternal wound infections with gentamicin-collagen implant: randomized controlled study in cardiac surgery. J Hosp Infect 2005;59:108–112.[CrossRef][Medline]
  12. Jonkers D, Elenbaas T, Terporten P, Nieman F, Stobberingh E. Prevalence of 90 days postoperative wound infections after cardiac surgery. Eur J Cardiothorac Surg 2003;23:97–102.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Örjan Friberg
Rolf Svedjeholm
Right arrow Permission Requests
Google Scholar
Right arrow Articles by Friberg, O.
Right arrow Articles by Svedjeholm, R.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Friberg, O.
Right arrow Articles by Svedjeholm, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS