Gentamicin-Collagen Implants to Reduce Surgical Infection
Gentamicin-Collagen Implants to Reduce Surgical Infection
This study has demonstrated that the use of gentamicin-collagen implants reduces SSIs. These results are demonstrated via a cumulative analysis of almost 7000 patients undergoing various different surgical procedures and are consistent in both clean and clean-contaminated surgical procedures. No benefit was observed in contaminated or dirty surgery, which may be due to paucity of trials in this category. A high amount of heterogeneity was seen in the results as a likely reflection of variable trial methodology.
The clinical efficacy of gentamicin-collagen implants can be explained by their intrinsic properties. The common pathogens for SSIs are Staphylococcus aureus and coagulase-negative staphylococci. Gentamicin has good antimicrobial activity against these organisms including gram-negative bacilli that are responsible for SSIs in gastrointestinal surgery. The design and drug incorporation provides both a rapid and sustained release of antibiotic that cannot be achieved by local injection or topical application of antibiotic powder. After implantation, they have been shown to produce a high tissue concentration of greater than 170 μg/mL within 24 hours. This concentration then drops to an average of 10 μg/mL that lasts up to 10 days in animal models. This exceeds the minimum inhibitory concentration of 4 μg/mL for sensitive organisms and thus theoretically may eradicate pathogens from surgical incisions.
The cost of treatment with gentamicin-collagen implants in the clinical setting has been estimated to be between US $224 and $336. In a previous cost-benefit analysis, Friberg et al concluded that these products are cost-effective when used prophylactically in sternal incision closure. The observed economic benefits have also been shown to be much greater in high-risk patients. In colorectal surgery, the mean increase in cost as a result of SSI is approximately US $17,324. A conservative estimate in a hypothetical clinical scenario of 1000 patients undergoing colorectal surgery with a 3% rate of SSIs and a cost of implant of US $350, the additional cost incurred through SSIs (30 × US $17,324 = US $519,720) seems to justify the initial outlay (1000 × US $350 = US $350,000). This is based on a conservative rate of SSIs as the observed prevalence of SSIs in colorectal surgery approaches 15% to 23% and could potentially lead to higher cost saving.
Since the introduction of gentamicin-collagen implants in the 1980s, there have been no reports of increased risk of incision dehiscence in clinical trials. Moreover, synthetic collagen-based products have been used extensively in other fields such as dermatology and reconstructive surgery for their angiogenic properties and their role as a matrix or "scaffold" to promote fibroblast migration for granulation tissue formation, thereby favoring tissue healing. Incision healing was assessed in 4 of the included RCTs but could not be meta-analyzed as different measures were reported.
The concept of local delivery of antibiotics either through topical application or drug delivery system is highly appealing but the evidence remains inconclusive. Efficacy has been demonstrated predominantly in nonrandomized or small RCTs that suffer from methodological flaws. On the contrary, high-quality evidence is limited and the efficacy is confirmed only in certain clinical setting and drug delivery system. For example, antibiotic-impregnated cement is effective in reducing SSIs in hip arthroplasty whereas antibiotic irrigation to open fractures has shown no difference in SSIs. Similarly, nonrandomized trials have shown promising results on antibacterial sutures but meta-analysis of RCTs has not demonstrated any benefit. There is a need for high-quality studies to identify the specific benefits and route of local delivery of antibiotics before routine clinical use, and this review may represent another evidence for this concept.
The results of this study showed high statistical heterogeneity. This is a likely consequence of the trials being conducted in different surgical settings with unaccounted heterogeneity in the surgical technique and perioperative care that is difficult to quantify. This problem is highlighted by the 2 large multicenter trials conducted by Bennett-Guerrero et al. Although multicenter trials are recognized as preferable to single-center trials, it may be difficult to standardize the aforementioned confounders across all centers even with a stringent protocol.
All except 1 trial in this meta-analysis showed either clinical benefit from using gentamicin-collagen implants or no difference between the 2 groups. The trial from Bennett-Guerrero et al in the setting of colorectal surgery, however, showed an increased risk of SSI in the patients randomized to receive gentamicin-collagen implants. The authors postulated that gentamicin-collagen implants may provide an early transient benefit before drug concentration decreased allowing resistant organisms to emerge or that the collagen itself may have an adverse effect due to its intrinsic properties or by acting as a mechanical barrier to closure of the incision. Of relevance also, as patients randomized to the control group did not have an implant inserted, it was not possible in this study to blind surgeons inserting the sponges.
This review is potentially limited by the differences in the definition of SSIs that may influence the overall prevalence and NNT of gentamicin-collagen implants, although the treatment benefit seen is not in question because the same criteria were applied to both arms of the trial. The greatest body of evidence is in cardiac surgery, encompassing up to two-thirds of patients in the meta-analysis, which limits the generalizability into other fields such as vascular or orthopedic surgery. Although these large positive trials by Friberg et al and Schimmer et al seem to exert a dominant influence on the aggregated OR in Figure 4, sensitivity analysis by excluding each individual trial did not affect the overall estimate. Although these results could be extrapolated to some other models of surgery, their use in the presence of other surgical prostheses has not been formally evaluated. In addition, there was considerable variability in the amount of gentamicin administered via the implant and thus the optimum dose has not been clearly defined. In summary, this study has conducted a cumulative analysis of almost 7000 patients from RCTs in different surgical settings and demonstrated clinically important reductions in SSIs with the use of gentamicin-collagen implants.
Discussion
This study has demonstrated that the use of gentamicin-collagen implants reduces SSIs. These results are demonstrated via a cumulative analysis of almost 7000 patients undergoing various different surgical procedures and are consistent in both clean and clean-contaminated surgical procedures. No benefit was observed in contaminated or dirty surgery, which may be due to paucity of trials in this category. A high amount of heterogeneity was seen in the results as a likely reflection of variable trial methodology.
The clinical efficacy of gentamicin-collagen implants can be explained by their intrinsic properties. The common pathogens for SSIs are Staphylococcus aureus and coagulase-negative staphylococci. Gentamicin has good antimicrobial activity against these organisms including gram-negative bacilli that are responsible for SSIs in gastrointestinal surgery. The design and drug incorporation provides both a rapid and sustained release of antibiotic that cannot be achieved by local injection or topical application of antibiotic powder. After implantation, they have been shown to produce a high tissue concentration of greater than 170 μg/mL within 24 hours. This concentration then drops to an average of 10 μg/mL that lasts up to 10 days in animal models. This exceeds the minimum inhibitory concentration of 4 μg/mL for sensitive organisms and thus theoretically may eradicate pathogens from surgical incisions.
The cost of treatment with gentamicin-collagen implants in the clinical setting has been estimated to be between US $224 and $336. In a previous cost-benefit analysis, Friberg et al concluded that these products are cost-effective when used prophylactically in sternal incision closure. The observed economic benefits have also been shown to be much greater in high-risk patients. In colorectal surgery, the mean increase in cost as a result of SSI is approximately US $17,324. A conservative estimate in a hypothetical clinical scenario of 1000 patients undergoing colorectal surgery with a 3% rate of SSIs and a cost of implant of US $350, the additional cost incurred through SSIs (30 × US $17,324 = US $519,720) seems to justify the initial outlay (1000 × US $350 = US $350,000). This is based on a conservative rate of SSIs as the observed prevalence of SSIs in colorectal surgery approaches 15% to 23% and could potentially lead to higher cost saving.
Since the introduction of gentamicin-collagen implants in the 1980s, there have been no reports of increased risk of incision dehiscence in clinical trials. Moreover, synthetic collagen-based products have been used extensively in other fields such as dermatology and reconstructive surgery for their angiogenic properties and their role as a matrix or "scaffold" to promote fibroblast migration for granulation tissue formation, thereby favoring tissue healing. Incision healing was assessed in 4 of the included RCTs but could not be meta-analyzed as different measures were reported.
The concept of local delivery of antibiotics either through topical application or drug delivery system is highly appealing but the evidence remains inconclusive. Efficacy has been demonstrated predominantly in nonrandomized or small RCTs that suffer from methodological flaws. On the contrary, high-quality evidence is limited and the efficacy is confirmed only in certain clinical setting and drug delivery system. For example, antibiotic-impregnated cement is effective in reducing SSIs in hip arthroplasty whereas antibiotic irrigation to open fractures has shown no difference in SSIs. Similarly, nonrandomized trials have shown promising results on antibacterial sutures but meta-analysis of RCTs has not demonstrated any benefit. There is a need for high-quality studies to identify the specific benefits and route of local delivery of antibiotics before routine clinical use, and this review may represent another evidence for this concept.
The results of this study showed high statistical heterogeneity. This is a likely consequence of the trials being conducted in different surgical settings with unaccounted heterogeneity in the surgical technique and perioperative care that is difficult to quantify. This problem is highlighted by the 2 large multicenter trials conducted by Bennett-Guerrero et al. Although multicenter trials are recognized as preferable to single-center trials, it may be difficult to standardize the aforementioned confounders across all centers even with a stringent protocol.
All except 1 trial in this meta-analysis showed either clinical benefit from using gentamicin-collagen implants or no difference between the 2 groups. The trial from Bennett-Guerrero et al in the setting of colorectal surgery, however, showed an increased risk of SSI in the patients randomized to receive gentamicin-collagen implants. The authors postulated that gentamicin-collagen implants may provide an early transient benefit before drug concentration decreased allowing resistant organisms to emerge or that the collagen itself may have an adverse effect due to its intrinsic properties or by acting as a mechanical barrier to closure of the incision. Of relevance also, as patients randomized to the control group did not have an implant inserted, it was not possible in this study to blind surgeons inserting the sponges.
This review is potentially limited by the differences in the definition of SSIs that may influence the overall prevalence and NNT of gentamicin-collagen implants, although the treatment benefit seen is not in question because the same criteria were applied to both arms of the trial. The greatest body of evidence is in cardiac surgery, encompassing up to two-thirds of patients in the meta-analysis, which limits the generalizability into other fields such as vascular or orthopedic surgery. Although these large positive trials by Friberg et al and Schimmer et al seem to exert a dominant influence on the aggregated OR in Figure 4, sensitivity analysis by excluding each individual trial did not affect the overall estimate. Although these results could be extrapolated to some other models of surgery, their use in the presence of other surgical prostheses has not been formally evaluated. In addition, there was considerable variability in the amount of gentamicin administered via the implant and thus the optimum dose has not been clearly defined. In summary, this study has conducted a cumulative analysis of almost 7000 patients from RCTs in different surgical settings and demonstrated clinically important reductions in SSIs with the use of gentamicin-collagen implants.
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