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Gentamicin Containing Collagen Implants and Groin Wound Infections in Vascular Surgery: A Prospective Randomised Controlled Multicentre Trial

Open ArchivePublished:February 21, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.01.010

      Objective

      The aim of this study was to assess the effectiveness of gentamicin containing collagen implants in the reduction of surgical site infections (SSIs) in patients undergoing an inguinal incision for vascular surgery.

      Methods

      Prospective blinded randomised controlled multicentre trial (RCT), performed in four hospitals in The Netherlands and Belgium. This study included 288 patients who underwent an inguinal incision for primary arterial repair (femoral endarterectomy, femorofemoral or femoropopliteal bypass, aortobifemoral bypass, thrombectomy, embolectomy, endovascular aneurysm repair) between October 2012 and December 2015. Patients were randomised to receive a gentamicin implant (study group) or no implant (control group). The calculated sample sizes of 304 patients per group were not reached. Primary outcome was SSI incidence after six weeks. Secondary outcomes were time to onset of infection, length of hospital stay, allergic reactions, treatment with antibiotics, need for re-admission, re-operation and mortality.

      Results

      One hundred fifty-one patients were allocated to the study group (mean age 69 ± 9.2 years) and 137 patients were allocated to the control group (mean age 70 ± 10.4 years). Both groups were homogeneous regarding baseline and intra-operative characteristics. Gentamicin implants did not result in a significant overall reduction of SSIs in the study group (7% vs. 12%, p = .17). In a post hoc analysis comparing two study sites with low (<10%) and two study sites with high (>10%) infection rates in the control group, gentamicin implants significantly reduced SSIs in high risk centres (22% vs. 1%, p < .001), whereas there was no significant effect in low risk centres (13% vs. 7%, p = .30). There were no allergic reactions and all secondary outcomes were comparable between groups.

      Conclusion

      Gentamicin implants did not result in a significant overall reduction of SSIs in this RCT. Gentamicin implants did reduce the incidence of SSIs in high risk centres and may be a valuable adjunct to improve outcomes in such vascular centres with a high incidence of wound infections. However, the limitation of not reaching the calculated sample sizes should be considered.

      Keywords

      In this prospective randomised controlled multicentre trial, gentamicin implants did not result in a significant overall reduction in surgical site infection following vascular surgery via inguinal incision. In a post hoc subgroup analysis comparing study sites with a low (<10%) and study sites with a high (>10%) infection rate in the control group, gentamicin implants significantly reduced surgical site infections in high risk centres. Therefore, preventive use of gentamicin implants cannot be routinely advised based on current evidence but may be considered in vascular centres with a high incidence of wound infections.

      Introduction

      Surgical site infections (SSIs) following vascular interventions are an important healthcare problem, with a serious impact on patients’ morbidity and mortality and increased healthcare costs due to longer hospital stays.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      ,
      • Chang W.K.
      • Srinivasa S.
      • MacCormick A.D.
      • Hill A.G.
      Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials.
      In the literature, a wide variation in the incidence of SSIs following vascular surgery is described, varying from 4% to 43% in retrospective studies.
      • Turtiainen J.
      • Saimanen E.
      • Partio T.
      • Karkkainen J.
      • Kiviniemi V.
      • Makinen K.
      • et al.
      Surgical wound infections after vascular surgery: prospective multicenter observational study.
      • Nguyen L.L.
      • Brahmanandam S.
      • Bandyk D.F.
      • Belkin M.
      • Clowes A.W.
      • Moneta G.L.
      • et al.
      Female gender and oral anticoagulants are associated with wound complications in lower extremity vein bypass: an analysis of 1404 operations for critical limb ischemia.
      • Chang J.K.
      • Calligaro K.D.
      • Ryan S.
      • Runyan D.
      • Dougherty M.J.
      • Stern J.J.
      Risk factors associated with infection of lower extremity revascularization: analysis of 365 procedures performed at a teaching hospital.
      • Lee E.S.
      • Santilli S.M.
      • Olson M.M.
      • Kuskowski M.A.
      • Lee J.T.
      Wound infection after infrainguinal bypass operations: multivariate analysis of putative risk factors.
      In a recent prospective multicentre study, the authors estimated the average costs per patient of developing a SSI at 3220 euro.
      • Turtiainen J.
      • Saimanen E.
      • Partio T.
      • Karkkainen J.
      • Kiviniemi V.
      • Makinen K.
      • et al.
      Surgical wound infections after vascular surgery: prospective multicenter observational study.
      SSIs following vascular surgery, defined as wound infections within 30 days after operation or within one year if an implant was used, are associated with several independent predictive factors, most importantly obesity and infra-inguinal intervention.
      • Turtiainen J.
      • Saimanen E.
      • Partio T.
      • Karkkainen J.
      • Kiviniemi V.
      • Makinen K.
      • et al.
      Surgical wound infections after vascular surgery: prospective multicenter observational study.
      ,
      • Nguyen L.L.
      • Brahmanandam S.
      • Bandyk D.F.
      • Belkin M.
      • Clowes A.W.
      • Moneta G.L.
      • et al.
      Female gender and oral anticoagulants are associated with wound complications in lower extremity vein bypass: an analysis of 1404 operations for critical limb ischemia.
      ,
      • Lee E.S.
      • Santilli S.M.
      • Olson M.M.
      • Kuskowski M.A.
      • Lee J.T.
      Wound infection after infrainguinal bypass operations: multivariate analysis of putative risk factors.
      • Mangram A.J.
      • Horan T.C.
      • Pearson M.L.
      • Silver L.C.
      • Jarvis W.R.
      Guideline for prevention of surgical site infection, 1999. centers for disease control and prevention (CDC) hospital infection control practices advisory committee.
      • Patel V.I.
      • Hamdan A.D.
      • Schermerhorn M.L.
      • Hile C.
      • Dahlberg S.
      • Campbell D.R.
      • et al.
      Lower extremity arterial revascularization in obese patients.
      • Richet H.M.
      • Chidiac C.
      • Prat A.
      • Pol A.
      • David M.
      • Maccario M.
      • et al.
      Analysis of risk factors for surgical wound infections following vascular surgery.
      Major advances in reducing the incidence of SSIs have been made by improved operating room ventilation, sterilisation methods, antiseptic precautions of surgeon and patient and antibiotic prophylaxis.
      • Mangram A.J.
      • Horan T.C.
      • Pearson M.L.
      • Silver L.C.
      • Jarvis W.R.
      Guideline for prevention of surgical site infection, 1999. centers for disease control and prevention (CDC) hospital infection control practices advisory committee.
      ,
      • Tanner J.
      • Swarbrook S.
      • Stuart J.
      Surgical hand antisepsis to reduce surgical site infection.
      • Dumville J.C.
      • McFarlane E.
      • Edwards P.
      • Lipp A.
      • Holmes A.
      Preoperative skin antiseptics for preventing surgical wound infections after clean surgery.
      Scottish Intercollegiate Guidelines Network (SIGN)
      Antibiotic Prophylaxis in Surgery.
      • Stewart A.
      • Eyers P.S.
      • Earnshaw J.J.
      Prevention of infection in arterial reconstruction.
      However, despite these preventive methods, SSIs remain a substantial cause of morbidity, associated with an increased risk of removal of the vascular prosthesis and subsequent amputation.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      ,
      • Mangram A.J.
      • Horan T.C.
      • Pearson M.L.
      • Silver L.C.
      • Jarvis W.R.
      Guideline for prevention of surgical site infection, 1999. centers for disease control and prevention (CDC) hospital infection control practices advisory committee.
      More effective SSI prevention in vascular surgery is needed. Local delivery of antibiotics within the surgical incision has the potential to combine higher target site concentrations with a reduced risk of systemic side effects and nephrotoxicity.
      • Formanek M.B.
      • Herwaldt L.A.
      • Perencevich E.N.
      • Schweizer M.L.
      Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis.
      Collagen represents a favourable matrix for such an on-site drug delivery, because it is completely biodegradable and does not require subsequent removal. Furthermore the positive effects of local antibiotics on wound healing and homeostasis have been described.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      ,
      • Formanek M.B.
      • Herwaldt L.A.
      • Perencevich E.N.
      • Schweizer M.L.
      Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis.
      ,
      • Ruszczak Z.
      • Friess W.
      Collagen as a carrier for on-site delivery of antibacterial drugs.
      The application of resorbable gentamicin containing collagen implants to prevent SSIs has been assessed in different studies, but without consistent results.
      • Chang W.K.
      • Srinivasa S.
      • MacCormick A.D.
      • Hill A.G.
      Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials.
      ,
      • Formanek M.B.
      • Herwaldt L.A.
      • Perencevich E.N.
      • Schweizer M.L.
      Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis.
      Three systematic reviews, two with meta-analysis, analysed the effectiveness of gentamicin implants in SSI reduction and in all three studies a protective effect and a reduced SSI rate was reported.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      ,
      • Chang W.K.
      • Srinivasa S.
      • MacCormick A.D.
      • Hill A.G.
      Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials.
      ,
      • Formanek M.B.
      • Herwaldt L.A.
      • Perencevich E.N.
      • Schweizer M.L.
      Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis.
      Importantly, only Hussain et al. focused on vascular surgery patients and no randomised controlled trials (RCTs) were available for inclusion in this systematic review.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      Therefore, additional randomised studies are required for further investigation of the effectiveness of gentamicin implants in vascular surgery.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      In 2014, a prospective pilot study with 60 vascular surgery patients confirmed SSI reduction in the groin incision, but again validation in a multicentre RCT was still necessary.
      • Costa Almeida C.E.
      • Reis L.
      • Carvalho L.
      • Costa Almeida C.M.
      Collagen implant with gentamicin sulphate reduces surgical site infection in vascular surgery: a prospective cohort study.
      There is clearly a lack of knowledge about the effectiveness of gentamicin implant application in vascular surgery. The greatest body of evidence can be found within the field of cardiac surgery.
      • Chang W.K.
      • Srinivasa S.
      • MacCormick A.D.
      • Hill A.G.
      Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials.
      Based on the promising results of these studies and the pilot study it can be hypothesised that the use of gentamicin implants can reduce SSIs following vascular surgery as well.
      • Costa Almeida C.E.
      • Reis L.
      • Carvalho L.
      • Costa Almeida C.M.
      Collagen implant with gentamicin sulphate reduces surgical site infection in vascular surgery: a prospective cohort study.
      To confirm this hypothesis, a randomised multicentre trial was initiated. The aim was to assess the effectiveness of gentamicin containing collagen implants in SSI reduction in patients with peripheral arterial occlusive disease following vascular surgery via an inguinal incision.

      Materials and Methods

      A prospective, randomised controlled trial was performed in four hospitals in The Netherlands (Maastricht University Medical Centre (MUMC+), Zuyderland Medical Centre in Heerlen, the Elisabeth-TweeSteden Hospital in Tilburg) and Belgium (Leuven University Hospital). Ethical Committee approval was obtained, and the trial is registered in the Netherlands Trial Register with the following code: NTR3754. The gentamicin implants used in this study were funded by EUSA Pharma.
      A total of 288 patients were included between October 2012 and December 2015. All patients provided informed consent before inclusion in this study, in accordance with the principles of the Declaration of Helsinki and the Medical Research Involving Human Subjects Act. The CONSORT Statement for reporting randomised controlled trials (CONsolidated Standards Of Reporting Trials) was followed (Fig. S1).

      Study population

      All patients undergoing first longitudinal inguinal incision for primary arterial repair were eligible to participate in this study: more precisely all patients undergoing a femorofemoral bypass, femoral endarterectomy, femoropopliteal bypass, aortobifemoral bypass, thrombectomy, embolectomy, combinations of these operations or patients undergoing endovascular aneurysm repair. For all operations, the groin incision was the study incision of interest. For bilateral groin incisions for vascular surgery, the right groin was included in the study and the left groin was excluded.
      All patients were operated on in one of the participating hospitals described above. Patients were 18 years or older, and both sexes were included. Patients with a known sensitivity or allergy to gentamicin and patients being either pregnant or breast feeding were excluded from this study. Patients with previous groin operations were also excluded.

      Study design and randomisation

      An external statistician, who was not involved in the enrolment or assessment of the patients, coordinated randomisation. Randomisation was stratified for study site. A computer based randomised block design was used for randomisation. Patients were allocated in a blinded fashion to one of two groups: the treatment group received a gentamicin containing collagen implant (study group) and the other group did not (control group). Numbered blinded envelopes were placed in the operating rooms, containing a notification whether the patient was allocated to the study or the control group and a standard clinical registration form that was completed by the surgeon. The envelopes were opened at the end of the operation, immediately before wound closure. The observer assessing the wound post-operatively in the outpatient clinic was blinded to the allocation. Therefore, both the wound assessors and the patients were blinded, only the surgeon was not. For registering the baseline characteristics before operation and for follow up of the groin wound and clinical condition of the patient post-operatively, a standard clinical registration form was used.

      Treatment

      The allocated study group received a gentamicin containing collagen implant, whereas the control group did not. The implants (Garacol® 130 mg) were made available by EUSA Pharma, United Kingdom (€112.87 per implant). This flat absorbable bovine collagen implant of 10 × 10 × 0.5 cm contained a dose of 130 mg gentamicin. The aminoglycoside gentamicin has antimicrobial activity against Pseudomonas aeruginosa, E. coli, Proteus spp., Klebsiella spp., Enterobacter spp., Serratia spp., Providencia spp., Acinetobacter spp. and Citrobacter spp., Morganella spp., S. aureus., Staphylococcus spp., Str. Viridans, Enterococcus spp., Mycobacterium spp. It was implanted in the wound in the subfascial plane before closure of the groin incision. All surgeons in the four participating centres were trained to perform the implantation of the gentamicin implant in a standardised way, according to the study protocol. There was no specific dissection technique instructed; the dissection itself was performed according to the preferences of the operating surgeon, following the generally accepted and practiced techniques in vascular surgery. The implant was sealed under a running facial suture with absorbable material. Skin closure was performed with absorbable suture material intracutaneous. Independent of this study treatment, the standard pre-operative protocol for the prevention of SSIs was applied in both groups in each participating hospital. This included standard operating room protocols, applying prophylactic pre-operative antibiotics (MUMC+: 1 × 2 g cefazoline intravenously, 30 min before operation; Heerlen, Tilburg and Leuven: amoxicillin/clavulate or amoxicillin, 30 min before operation), standard skin care and aseptic skin care of patient and surgeon.

      Follow up and data collection

      The study follow up period was six weeks. Patients were examined on day 1 post-operatively, on discharge and two, four and six weeks after operation respectively. As described above, a standard clinical registration form was used. Up to week 6 after discharge, wound healing was also recorded using photography. Gender, age at intervention, body mass index (BMI), smoking in the past five years, use of antibiotics within 30 days before operation and the comorbidities (diabetes mellitus type 1 and 2, chronic kidney disease (glomerular filtration rate (GFR) < 30 mL/min/1.73 m2), history of hypertension or use of antihypertensive medication, history of hypercholesterolaemia or use of statins) were collected as general baseline characteristics. Collected intra-operative characteristics were type of operation, operation duration, use of prosthetic material, blood loss and length of incision (in cm).
      Wound assessment was performed at the pre-set time points up to six weeks of follow up and wound infections meeting the criteria for SSIs as described by the Centres for Disease Control and Prevention (CDC) were analysed as SSI.
      • Szilagyi D.E.
      • Smith R.F.
      • Elliott J.P.
      • Vrandecic M.P.
      Infection in arterial reconstruction with synthetic grafts.
      ,
      • Horan T.C.
      • Gaynes R.P.
      • Martone W.J.
      • Jarvis W.R.
      • Emori T.G.
      CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections.
      Therefore, patients with a positive wound culture or documented purulent drainage were classified to have a SSI and the time until infection was documented. Wound cultures were not taken routinely but in clinically suspicious cases due to symptoms such as redness or wound dehiscence.

      Study endpoints

      The primary outcome was the overall incidence of SSIs, according to the CDC definitions. Secondary outcomes were length of hospital stay (in days), allergic reactions, treatment with antibiotics, need for re-admission and re-operation and mortality during follow up. In addition, the mean time until infection was analysed.

      Statistical analysis

      A sample size calculation was performed, expecting 15% SSIs in the control group and 50% fewer in the study arm receiving the gentamicin implant. With a confidence level of 5% and statistical power of 80%, the calculated sample size was 304 patients per group.
      All statistical analyses were performed with SPSS Statistics 24. Data analysis was performed comparing both groups (with gentamicin implant vs. without gentamicin implant) and by intention to treat analysis. Owing to protocol violation, the allocated randomisation group of all patients at the moment of statistical analysis could not be revealed; therefore, few patients had to be excluded after randomisation (n = 17). Descriptive statistics were presented for the baseline characteristics. Categorical data were expressed as percentages, continuous data as mean with the standard deviation (SD). Differences in patient characteristics and outcomes between the two age groups were assessed by Chi-squared tests. To compare the means of continuous variables, independent samples t tests were used. Outcome analysis was stratified for centre of inclusion. The primary outcome was also analysed in a post hoc subgroup analysis for study sites with low (<10%) and high (>10%) incidence of infection in the control group because of significant heterogeneity in treatment effect between study sites. The endpoint remained the same, namely “surgical site infection” as was defined in the overall analysis, making the study design suitable for this subgroup comparison as well. In addition, a post hoc sensitivity analysis was performed excluding patients with endovascular interventions only (n = 34). Time to infection was analysed using Kaplan–Meier plots and differences between study groups were assessed by the log rank test. A p value < .05 was considered statistically significant.

      Results

      A total of 288 patients/groins were analysed in this randomised controlled trial performed between October 2012 and December 2015. According to the sample size calculation, 304 patients should have been included per group. These numbers were not reached. Details of the study enrolment and allocation process and reasons for exclusion or dropout are shown in the flow chart according to the CONSORT Statement (Fig. 1). Follow up was six weeks and the loss to follow up rate was 15.6%, equally distributed between groups. A total of 151 patients received a gentamicin implant (study group) and 137 patients did not (control group).
      Figure 1
      Figure 1Flowchart illustrating the study enrolment process and follow up according to the CONSORT Statement. Statistical analysis following intention to treat analysis. Protocol violation = not able to reveal the randomisation group of 17 patients at the moment of statistical analysis; therefore, these patients had to be excluded after randomisation.

      Baseline characteristics

      The patient baseline characteristics are shown in Table 1 and no significant differences were found between groups. The mean age was 69 years in the study group and 70 years in the control group. The study population was predominantly male (70% study group and 72% control group). Patients were balanced regarding all risk factors and comorbidities analysed at baseline. Regarding the intra-operative characteristics, no significant differences were found between groups. In both groups, half of the patients were operated for isolated femoral endarterectomy, thrombectomy and/or embolectomy (50%). The use of prosthetic material, the mean operation time and the mean incision length were comparable between groups.
      Table 1Baseline characteristics of patients with an inguinal incision for primary arterial repair treated without (control group) or with gentamicin containing collagen implant (study group)
      CharacteristicStudy group (n = 151)Control group (n = 137)
      Age – years (range)69 ± 9.2 (43–87)70 ± 10.4 (38–90)
      Male sex105 (70)99 (72)
      Risk factors and comorbidity
       Body mass index – kg/m226.0 ± 4.526.1 ± 3.9
       Diabetes mellitus (type I and II)45 (30)36 (27)
       Smoking64 (43)55 (41)
       Chronic kidney disease – GFR <30 mL/min/1.73 m215 (10)14 (10)
       Arterial hypertension and/or antihypertensive medication108 (73)105 (77)
       Hypercholesterolaemia and/or statin medication124 (83)107 (79)
       Pre-operative antibiotics – 30 days10 (7)12 (11)
      Operative characteristics
      Type of operation
      Endarterectomy – thrombectomy or/and embolectomy76 (50)68 (50)
      Supragenicular bypass34 (23)33 (24)
      Infragenicular bypass14 (9)13 (10)
      Aorta/axillobifemoral bypass9 (6)7 (5)
      Endovascular aortic aneurysm repair18 (12)16 (11)
       Use of prosthetic material110 (83)98 (77)
       Operation time – min165 ± 73160 ± 74
       Incision length – cm7.9 ± 2.17.9 ± 2.7
       Blood loss – mL486 ± 674543 ± 798
      Data are presented as mean ± standard deviation or n (%). Differences between the two treatment groups were assessed by chi-squared tests (in case of categorical data) or independent sample t-test (in case of continuous data). There were no statistically significant differences between study groups. GFR = glomerular filtration rate.

      Primary outcome

      The outcomes for both groups are shown in Table 2. The use of a gentamicin implant was not associated with a significant overall reduction of SSIs. The overall wound infection rate was 7% in the study group and 12% in the control group (p = .17). Because of a significant heterogeneity in treatment effect between study sites a subgroup analysis was performed. Two centres had higher risks for infection in the control group (19% and 25%) than two other centres with a lower risk (6% and 9%). In the two centres with a high SSI incidence in the control group (>10%), a greater reduction in SSIs by means of the gentamicin implants was found, reaching statistical significance (1% vs. 22%, p < .001; Table 3). In the two centres with low incidence of infection in the control group, this effect was not observed. In the sensitivity analysis, excluding patients with an endovascular aortic aneurysm repair (n = 34), all findings were consistent with the results of the primary analysis.
      Table 2Primary and secondary outcomes of patients with an inguinal incision for primary arterial repair treated without (control group) or with gentamicin containing collagen implant (study group)
      OutcomeStudy group (n = 151)Control group (n = 137)p value
      Differences between the treatment groups were assessed by chi-squared tests (in case of categorical data) or independent sample t test (in case of continuous data), stratified for the centre of inclusion.
      Total wound infections11 (7)17 (12).17
      Length of hospital stay – d6 ± 5.27 ± 6.3.06
      Post-operative antibiotics27 (21)30 (25).55
      Re-admission9 (7)10 (8).81
      Re-operation11 (8)8 (7).64
      Death4 (3)3 (3)1.00
      Data are presented as mean ± standard deviation or n (%).
      Differences between the treatment groups were assessed by chi-squared tests (in case of categorical data) or independent sample t test (in case of continuous data), stratified for the centre of inclusion.
      Table 3Subgroup analysis for the primary outcome of patients with inguinal incision for primary arterial repair treated without (control group) or with gentamicin containing collagen implant (study group). Centres at high risk of infection in the control group (19% and 25%) and centres with low baseline risk of infection (6% and 9%)
      OutcomeStudy groupControl groupp value
      Differences between the two treatment groups were assessed by chi-squared tests, stratified for the centre of inclusion.
      High risk centres (>10% infections in the control group)
       Number of patients7251
       Total wound infections1 (1)11 (22)<.001
      Low risk centres (<10% infections in the control group)
       Number of patients7985
       Total wound infections10 (13)6 (7).30
      Data are presented as mean ± standard deviation or n (%).
      Differences between the two treatment groups were assessed by chi-squared tests, stratified for the centre of inclusion.

      Secondary outcome

      The mean time to infection was comparable in both groups (20 ± 10.7 days vs. 20 ± 11.6 days, p = .93). In Kaplan–Meier analysis, the difference between groups was not statistically significant (Fig. 2). A total of 17 wound cultures were taken in each group (11% study group vs. 13% control group, p = .74). In the control group, all wound cultures were positive, whereas in the study group there were only 10 positive wound cultures (p = .09). Regarding the other secondary outcomes, mean length of hospital stay was comparable between the study group and the control group (6 ± 5.2 and 7 ± 6.3 days, p = .06). No allergic reactions were observed in either group and no significant differences were found in the secondary outcomes, antibiotics, re-admission or re-operation. Mortality rates were 3% in both groups.
      Figure 2
      Figure 2Cumulative Kaplan–Meier estimate of surgical site infection (SSI; according to the Centres for Disease Control and Prevention definition) rates after inguinal incision for primary arterial repair treated without (Gentamicin -) or with gentamicin containing collagen implant (Gentamicin +). Differences in infection rates between groups, assessed by the log rank test, stratified for centre of inclusion, were not statistically significant (p = .13).

      Discussion

      SSIs following vascular surgery remain a major healthcare problem and reduction of SSIs and more effective SSI prevention in vascular surgery are absolutely needed.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      • Chang W.K.
      • Srinivasa S.
      • MacCormick A.D.
      • Hill A.G.
      Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials.
      • Turtiainen J.
      • Saimanen E.
      • Partio T.
      • Karkkainen J.
      • Kiviniemi V.
      • Makinen K.
      • et al.
      Surgical wound infections after vascular surgery: prospective multicenter observational study.
      In the present randomised controlled trial, no significant reduction of SSIs was achieved using gentamicin implants in patients undergoing an inguinal incision for vascular surgery. Overall wound infection rates of 7% and 12% were found in the respective allocation arms, which is comparable to the literature.
      • Turtiainen J.
      • Saimanen E.
      • Partio T.
      • Karkkainen J.
      • Kiviniemi V.
      • Makinen K.
      • et al.
      Surgical wound infections after vascular surgery: prospective multicenter observational study.
      • Nguyen L.L.
      • Brahmanandam S.
      • Bandyk D.F.
      • Belkin M.
      • Clowes A.W.
      • Moneta G.L.
      • et al.
      Female gender and oral anticoagulants are associated with wound complications in lower extremity vein bypass: an analysis of 1404 operations for critical limb ischemia.
      • Chang J.K.
      • Calligaro K.D.
      • Ryan S.
      • Runyan D.
      • Dougherty M.J.
      • Stern J.J.
      Risk factors associated with infection of lower extremity revascularization: analysis of 365 procedures performed at a teaching hospital.
      • Lee E.S.
      • Santilli S.M.
      • Olson M.M.
      • Kuskowski M.A.
      • Lee J.T.
      Wound infection after infrainguinal bypass operations: multivariate analysis of putative risk factors.
      Interestingly, in two centres with high incidence of infection in the control group, a greater reduction in SSIs was found in the study group, reaching statistical significance.
      The results were less promising than hypothesised based on the results of the pilot study of Costa Almeida et al. In their prospective study of 60 vascular surgery patients, no SSI occurred in the implant group, compared with six infections in the control group and this difference was found to be significant. In addition, length of hospital stay was also significantly reduced.
      • Costa Almeida C.E.
      • Reis L.
      • Carvalho L.
      • Costa Almeida C.M.
      Collagen implant with gentamicin sulphate reduces surgical site infection in vascular surgery: a prospective cohort study.
      These results could not be validated in the multicentre randomised controlled trial. There was an essential difference in patient characteristics, since Costa Almeida et al. only included non-diabetic and non-obese patients. In the current study, only in a subgroup with high risk of infection was there a significant reduction in SSIs. This post hoc subgroup analysis was performed because a significant heterogeneity in treatment effect between study sites was found during statistical analysis. Two centres had a remarkably higher SSI incidence in their control group (19% and 25%) than the two other centres (6% and 9%). An incidence of SSIs greater than 10% in the control group was therefore defined as a high risk centre. Subgroup analysis showed a significant difference in infection rate in these high risk centres. In the analysis, operating time was not different between study sites and not correlated with the incidence of infection. The two low risk centres did not have a higher proportion of endovascular aortic aneurysm repairs and the results of the sensitivity analysis excluding these endovascular interventions were consistent with the results of the primary analysis, making any influence unlikely. In addition, incision length and the use of prosthetic material were not associated with surgical site infections either. Also baseline characteristics (gender, age > 80 years, BMI > 25, smoking and diabetes) did not show any correlation with the outcome and were not unevenly distributed between study sites. One reason might be differences in peri-operative tissue handling by different operators, but no attempt has been made to correlate infection with surgeon. Also, differences in operating room facilities or more operations performed by assistant surgeons could have influenced the outcomes. In conclusion, an explanation for the difference in SSI incidence based on the data provided could not be found.
      In a systematic review, Hussain et al.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      analysed five clinical studies, involving 109 patients, and all reviewed publications demonstrated that the SSI rate was reduced by prophylactic use of gentamicin implants.
      • Horch R.
      • Kronung G.
      [Prevention of infection in Teflon prostheses for dialysis access. Experiences with a resorbable combined collagen-antibiotic system].
      • Holdsworth J.
      Treatment of infective and potentially infective complications of vascular bypass grafting using gentamicin with collagen sponge.
      • Jorgensen L.G.
      • Sorensen T.S.
      • Lorentzen J.E.
      Clinical and pharmacokinetic evaluation of gentamycin containing collagen in groin wound infections after vascular reconstruction.
      However, all the included studies involved very small study populations and were rather dated. The present randomised controlled trial is the largest series to date. Despite presenting the largest clinical trial to date on this matter, the calculated sample sizes were not reached due to slow enrolment, even though it was a multicentre design. This could explain why the overall reduction in SSIs did not reach statistical significance. In larger study populations this clear trend might have reached statistical significance. Also, the reduction in hospital stay almost reached statistical significance in this study and might have become significant in larger study groups.

      Limitations

      There are a number of limitations that should be considered. First, all results of this study should be interpreted with caution, since the required 304 patients per group was not reached. Another drawback is the multicentre nature of the study. However, this multicentre set up is also advantageous since the external validity is higher compared with a single centre set up. The severity of the SSI was not assessed due to insufficient standardisation of wound assessment and interpretation difficulties across centres. Wound assessment and classification are clinical and rather subjective decisions. All forms of serous leakage, seroma or cellulitis with an intact dermis are widely interpretable. One physician might interpret local erythema or serous leakage as clinical wound infection, whereas another physician might interpret it as regular variant of the healing process. The aim was to make the assessment of wound healing as objective as possible by using photography and judgement by a second, independent physician. Unfortunately, assessment of wound healing using photos appeared unreliable due to factors such as lighting conditions. Finally, CDC definitions were used, since positive wound cultures and purulent drainage could be analysed more objectively.
      Despite all limitations described above, on the positive side both groups were homogeneous at baseline. No confounding factors were found regarding the baseline intra-operative characteristics. No allergic reactions or other adverse side effects were observed, underlining that gentamicin implants can used safely.

      Future perspectives

      The promising results of previous studies could not be validated in this multicentre randomised controlled trial. A reduction in SSIs was found; however, only statistically significant in a subgroup at high risk of infection. Additional studies with adequate group sizes to reach adequate statistical power would be needed to further confirm these results. Objective wound assessment by a restricted number of physicians is of major importance to obtain valid results. A control group receiving a collagen implant without gentamicin would be of interest as well, since collagen itself is known to have positive effects on wound healing and homeostasis.
      • Hussain S.T.
      Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery.
      ,
      • Formanek M.B.
      • Herwaldt L.A.
      • Perencevich E.N.
      • Schweizer M.L.
      Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis.
      ,
      • Ruszczak Z.
      • Friess W.
      Collagen as a carrier for on-site delivery of antibacterial drugs.
      In addition, further research has to be focused on cost effectiveness analysis as well. Even if a significant decrease in infection rate and hospital stay were to be observed, it would still be necessary to assess a possible reduction of the health care costs as well.

      Conclusion

      The use of gentamicin implants did not result in a significant overall reduction of SSIs. However a significant reduction in the incidence of SSIs was found in high risk centres (>10% infections in the control group) but not in low risk centres. The use of gentamicin implants may therefore be a valuable adjunct to improve outcomes in vascular centres with a high incidence of wound infections, however, the limitation of not reaching the calculated sample sizes should be considered.

      Conflict of Interest

      None.

      Funding

      Gentamicin implants were generously made available by EUSA Pharma.

      Acknowledgements

      We would like to thank all colleagues and patients who participated in this project. Especially, we want to thank Ms S. Schreurs for her commitment in including and processing study patients and Dr M. Snoeijs for his critical view and advice on our statistical analyses.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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