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Systematic review on efficacy of preventive measures for surgical site infection by multiple-drug resistant gram-negative bacilli

ABSTRACT

Background:

There are no specific recommendations for prevention of surgical site infection (SSI) caused by multidrug resistant Gram-negative bacilli (MDR-GNB). Our objective was to systematically review the literature evaluating the efficacy and safety of measures specifically designed to prevent MDR-GNB SSI.

Methods:

We searched MEDLINE, EMBASE, CINAHL and LILACS databases up to February 18, 2020. Randomized trials and observational cohort studies evaluating the efficacy of preventive measures against MDR-GNB SSI in adult surgical patients were eligible. We evaluated methodological quality of studies and general quality of evidence using Newcastle-Ottawa scale, Cochrane ROBINS-I and GRADE method. Random-effects meta-analyses were performed using Review Manager V.5.3 software.

Results:

A total of 10,663 titles by searching databases were identified. Two retrospective observational studies, comparing surgical antibiotic prophylaxis (SAP) with or without aminoglycoside in renal transplantation recipients, and one non-randomized prospective study, evaluating ertapenem vs. cephalosporin plus metronidazole for SAP in extended spectrum beta-lactamase producing Enterobacteriales carriers undergoing colon surgery, were included. Risk of bias was high in all studies. Meta-analysis was performed for the renal transplantation studies, with 854 patients included. Combined relative risk (RR) for MDR GNB SSI was 0.57 (95%CI: 0.25-1.34), favoring SAP with aminoglycoside (GRADE: moderate).

Conclusions:

There are no sufficient data supporting specific measures against MDR-GNB SSI. Prospective, randomized studies are necessary to assess the efficacy and safety of SAP with aminoglycoside for MDR-GNB SSI prevention among renal transplantation recipients and other populations. PROSPERO 2018 CRD42018100845.

Keywords:
Surgical wound infection; Infection control; Gram-negative bacterial infections; Drug resistance, multiple; Systematic review

Introduction

Surgical site infection (SSI) occurs in 3% to 20% of procedures, with relevant morbidity and mortality.11 Badia JM, Casey AL, Petrosillo N, Hudson PM, Mitchell SA, Crosby C. Impact of surgical site infection on healthcare costs and patient outcomes: a systematic review in six European countries. J Hosp Infect. 2017;96:1–15. When multidrug resistant (MDR) bacteria are involved, outcomes are worse, with higher cost and longer hospital stay.22 Blumberg TJ, Woelber E, Bellabarba C, Bransford R, Spina N. Predictors of increased cost and length of stay in the treatment of postoperative spine surgical site infection. Spine J. 2018;18:300–6.,33 De Pastena M, Paiella S, Marchegiani G, Malleo G, Ciprani D, Gasparini C, et al. Postoperative infections represent a major determinant of outcome after pancreaticoduodenectomy: results from a high-volume center. Surgery. 2017;162:792–801. Among MDR microorganisms, Gram-negative bacilli (GNB), such as extended spectrum beta-lactamase (ESBL) producing and carbapenem resistant GNB, are of great importance due to the diversity of resistance mechanisms, dissemination capacity, high morbidity, and scarcity of effective treatment.44 Pereira MR, Scully BF, Pouch SM, Uhlemann A-C, Goudie S, EmondJE, et al. Risk factors and outcomes of carbapenem-resistant K lebsiella pneumoniae infections in liver transplant recipients: Klebsiella Pneumoniae Infections in LT Recipients. Liver Transpl. 2015;21:1511–9.,55 Stewardson AJ, Allignol A, Beyersmann J, Graves N, Schumacher M, Meyer R, et al. The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and Staphylococcus aureus in European hospitals, 2010 and 2011: a multicentre retrospective cohort study. Euro Surveill. 2016;21:30319.

Increasing concerns regarding MDR GNB SSI66 Benito N, Franco M, Ribera A, Soriano A, Rodriguez-Pardo D, Sorlí L, et al. Time trends in the aetiology of prosthetic joint infections: a multicentre cohort study. Clin Microbiol Infect. 2016;22. 732.e1-732.e8.,77 Viehman JA, Clancy CJ, Clarke L, Shields RK, Silveira FP, Kwak EJ, et al. Surgical site infections after liver transplantation: emergence of multidrug-resistant bacteria and implications for prophylaxis and treatment strategies. Transplantation. 2016;100:2107–14. led to studies estimating incidence rates, expressed as percentage of all surgeries under surveillance that developed MDR GNB SSI, as high as 5.2% of general surgery in Ghana and 3.2% of major hepatectomy in Japan.88 Bediako-Bowan AAA, Kurtzhals JAL, Mølbak K, Labi A-K, Owusu E, Newman MJ. High rates of multi-drug resistant gram-negative organisms associated with surgical site infections in a teaching hospital in Ghana. BMC Infect Dis. 2020;20(1).,99 Sugawara G, Yokoyama Y, Ebata T, Igami T, Yamaguchi J, Mizuno T, et al. Postoperative infectious complications caused by multidrug-resistant pathogens in patients undergoing major hepatectomy with extrahepatic bile duct resection. Surgery. 2020;167:950–6.

Surgical antibiotic prophylaxis (SAP) adjustment and decolonization is well established for patients colonized by methicillin resistant Staphylococcus aureus (MRSA).1010 Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. However, there is no specific recommendation regarding SAP adjustment or other preventive measures against MDR GNB SSI.77 Viehman JA, Clancy CJ, Clarke L, Shields RK, Silveira FP, Kwak EJ, et al. Surgical site infections after liver transplantation: emergence of multidrug-resistant bacteria and implications for prophylaxis and treatment strategies. Transplantation. 2016;100:2107–14.,1010 Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.

The objective of this study is to systematically review the literature to evaluate the efficacy and safety of measures to prevent SSI caused by MDR GNB.

Materials and methods

We searched MEDLINE (PubMed), EMBASE, CINAHL and LILACS databases, without language or date restrictions, up to February 18th, 2020. Studies that met the following elements were included: (a) Population - adult patients at risk of MDR GNB SSI; (b) Intervention - SAP containing antimicrobials with action on MDR GNB (Appendix - Table A1) or other measures specifically aimed at preventing MDR GNB SSI; (c) Comparator - standard SAP, according to current recommendations for the surgery in question (10); (d) Outcome (main): SSI caused by MDR GNB; secondary outcomes: total incidence of SSI, incidence of any healthcare associated infections (HAI), length of hospital stay, adverse events, and hospital mortality from any cause; (e) Study design - intervention studies, whether randomized or not, and observational cohort studies (see full search strategy on Appendix - Text A1).

Exclusion criteria were: a) unreported incidence of SSI stratified by etiology and antimicrobial resistance status; b) absence of MDR definition; c) two or more intervention measures implemented concomitantly, making it impossible to tease out their individual effects on outcome; d) report of different SSI standard preventive measures (e.g., surgical antisepsis protocol) between intervention and comparator groups.

Four groups of two authors independently reviewed abstracts and titles using Rayyan QCRI tool (Quatar Computing Research Institute), selected full texts and their references, and extracted data using a standardized form on REDCap software.1111 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81. Data extracted comprised authors, country, and date of study; type and characteristics of intervention and comparator; type of surgery; sex and age of participants; study design; outcome data; funding sources. Two authors independently evaluated the methodological quality of studies using the Newcastle-Ottawa (NO) scale for cohort studies1212 Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [Internet]. 2013 [cited 2021 Jan 14]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed on March 29th 2022.
http://www.ohri.ca/programs/clinical_epi...
and Cochrane ROBINS-I, and assessed the general quality of the evidence and strength of the recommendation with the GRADE method.1313 Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336:1049–51. Disagreements were resolved by discussion or, if consensus was not achieved, referred for a third reviewer. For studies with comparable populations and interventions, random-effects meta-analyses were performed using Review Manager Version 5.3. Ethics approval was not required as the research was a systematic review. This review’s protocol was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018100845).

Results

A total of 10.663 titles by searching databases were identified, and 87 additional titles from references of studies selected for full-text evaluation. After removal of replicates, 8,301 abstracts remained for evaluation, of which 39 were selected for full-text evaluation (Fig. 1). Only one study met the criteria for inclusion1414 Nutman A, Temkin E, Harbarth S, Carevic B, Ris F, Fankhauser-Rodriguez C, et al. Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing enterobacteriaceae undergoing colorectal surgery. Clin Infect Dis. 2020;70:1891–7.. Multiple emails were sent for different authors requesting supplementary information. After the authors’ reply, two additional articles met the eligibility criteria1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5.,1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7..

Fig. 1
Inclusion and exclusion flowchart diagram.

In the multicenter, prospective, open and non-randomized study published by Nutman et al.,1414 Nutman A, Temkin E, Harbarth S, Carevic B, Ris F, Fankhauser-Rodriguez C, et al. Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing enterobacteriaceae undergoing colorectal surgery. Clin Infect Dis. 2020;70:1891–7. the population consisted of adult patients colonized with ESBL-producing Enterobacteriales (ESBL-PE) preoperatively, who underwent elective colorectal surgery in three hospitals in Israel, Serbia and Switzerland, between 2012 and 2017 (Table 1).

Table 1
Characteristics of the eligible studies.

In the baseline phase (BP), routine SAP consisted of cefuroxime plus metronidazole. In the intervention phase (IP), for patients colonized with ESBL-PE, ertapenem replaced routine SAP. The primary outcome was any SSI, and secondary outcomes were deep or organ/space SSI and ESBL-PE culture-positive SSI.

Of the 3,600 patients screened preoperatively, 498 had ESBL-PE colonization, of whom 478 were included in the intention to treat (ITT) analysis: 209 in the BP and 269 in the IP.

In the ITT analysis, 45 (21.5%) patients in the BP developed SSI, compared with 47 (17.5%) in the IP, which was not significantly different. Deep SSI rates did not differ significantly as well. The ESBL-PE culture-positive SSI rate was significantly lower in the IP compared to the BP (Table 1).

There were no significant differences regarding postoperative adverse events, including length of stay in the intensive care unit (ICU), acute kidney injury (AKI), recurrent surgery, Clostridioides difficile infection or death. It is noteworthy that these results were reported only for the as-treat analysis, in which participants who actually received the routine prophylaxis (n = 247) were compared to those who received ertapenem (n = 221).

In the study by Freire et al.,1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7. the population consisted of patients undergoing kidney transplantation from January 2009 to December 2012 at the Clinical Hospital of the University of São Paulo, Brazil (Table 1).

From January 2009 to July 2012, the standard SAP was cefazolin administered for three days. In addition, between January 2009 and December 2010, surgeons could change prophylaxis to ceftriaxone or amikacin. Between August 2012 and December 2012, the standard SAP was amikacin. Patients using cephalosporin (n = 576) and amikacin (n = 233) were compared (Table 1).

The main outcome was SSI during the first 60 days after transplantation. Secondary outcomes were SSI by MDR, implanted graft survival, delayed implanted graft function (DGF) and death after one year of transplantation. Incidence rates of SSI and SSI by MDR were expressed as the number of events per 1,000 patients/day. Data on the outcome of MDR GNB SSI expressed as a proportion (cumulative incidence) were supplemented by contact with the authors. Of note, the use of amikacin as antibiotic prophylaxis was associated with significantly less SSI in the multivariate analysis (odds ratio [95%CI] 0.37 [0.15–0.92]).1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7.

In the study by Abboud et al.,1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5. the population consisted of patients undergoing kidney transplantation at the Dante Pazzanese Institute of Cardiology, São Paulo, Brazil. The control group was selected from a historical cohort from September 2009 to June 2010 and consisted of 24 patients who received SAP with cefuroxime (Table 1). Between July 2010 and April 2011, gentamicin was added to the SAP regimen, along with strengthening infection control measures, which was motivated by the observation of an increase in HAI caused by GNB, including carbapenem resistant K. pneumoniae, in renal transplantation patients. Despite reporting that an average of 40 kidney transplants were performed per year, the total number of patients who underwent kidney transplantation during the study period was not described, nor were the criteria for selecting the patients who formed both control and intervention groups. The main outcome was the 30-day HAI rate after kidney transplantation. Other outcomes evaluated were SSI, death within 30 days postoperatively, urinary tract infection (UTI), primary bloodstream infection, and pneumonia. Data on the outcome of MDR GNB SSI were supplemented by contact with the authors.1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5.

We carried out a meta-analysis of data from Abboud et al.1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5. and Freire et al.;1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7. 854 patients were included, with a mean follow-up of 45 days (Fig. 2). The combined relative risk (RR) for MDR GNB SSI was 0.57 (95% CI: 0.25-1.34), with heterogeneity test I2 = 0% (p = 0.37). For the total SSI outcome, the combined RR (95% CI) was 0.48 (0.30-0.77), with I2 = 0% (p = 0.82), thus favoring intervention (GRADE: high). Abboud et al.(15) also reported a lower incidence of HAI in the intervention group (54.2% (13/24) vs. 19% (4/12), p = 0.03). Freire et al.1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7. reported a greater, yet not statistically significant, incidence of DGF in the amikacin group, with an RR (95% CI) = 1.25 (1.01-1.54); on the other hand, loss of renal graft was less frequent among these patients, again without statistical significance. Abboud et al.1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5. mentioned that patients who used gentamicin did not exhibit worsening renal function, but data were not reported.

Fig. 2
Meta-analysis comparing surgical antibiotic prophylaxis (SAP) with minoglycoside (“experimental”) versus standard SAP without aminoglycoside (“control”). (A) outcome surgical site infection (SSI). (B) outcome multidrug resistant Gram negative bacilli SSI.

None of the three studies addressed the impact of intervention on length of hospital stay and on antimicrobial resistance.

The risk of bias assessment with the NO scale (Appendix - Table A2) and ROBINS tool (Fig. 3) returned similar interpretations. Both assessments showed Abboud’s work as more predisposed to bias. Additionally, the dimension regarding the confounders/comparability between cohorts assessment was the main issue increasing the risk of bias of all studies. At ROBINS’ tool, an issue regarding selective reporting was apparent. These interpretations coincided with the understanding of methodological weakness of non-randomized intervention studies and with the review primary objective being slightly different from the original studies, requiring additional data from the authors. Additionally, GRADE assessment showed high certainty of benefit for some outcomes, such as MDR GNB SSI after colorectal surgery and SSI in renal transplantation patients. However, most outcomes have very low to moderate certainty of benefit at GRADE assessment (Appendix - Table A3).

Fig. 3
Result of the risk of bias analysis in assessing the quality of cohort studies using ROBINS-I.

Discussion

Most guidelines about SSI prevention do not recommend specific measures against MDR GNB.1717 Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for disease control and prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784.,1818 World Health Organization. Who global guidelines on the prevention of surgical site infection. [Internet]. 2016. Available from: https://www.who.int/publications/i/item/global-guidelines-for-the-prevention-of-surgical-site-infection-2nd-ed. Accessed on March 29th 2022.
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Despite increasing concerns about MDR GNB SSI, the evidence on this topic is very scarce, as highlighted by the inclusion of only three studies in this review. Another issue regarding the scarcity of evidence is when to recommend prophylaxis against MDR GNB: according to MDR GNB colonization status1414 Nutman A, Temkin E, Harbarth S, Carevic B, Ris F, Fankhauser-Rodriguez C, et al. Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing enterobacteriaceae undergoing colorectal surgery. Clin Infect Dis. 2020;70:1891–7. versus universal anti-MDR GNB SAP in high incidence MDR GNB endemic/epidemic settings.1515 Abboud CS, Bergamasco MD, De Sousa EE, De Cássia Zandonadi E, Cortez D. Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. Braz J Infect Dis. 2013;17:254–5.,1616 Freire MP, Antonopoulos IM, Piovesan AC, Moura ML, de Paula FJ, Spadao F, et al. Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation. Transplantation. 2015;99:521–7.

Colonization by MDR microorganisms increases the risk of infections caused by these pathogens,1919 Hadjiliadis D, Steele MP, Chaparro C, Singer LG, Waddell TK, Hutcheon MA, et al. Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than burkholderia cepacia, compared with patients harboring sensitive bacteria. J Heart Lung Transplant. 2007;26:834–8. and for patients with known or at high risk for MRSA nasal carriage (e.g., history of MRSA colonization or infection, or a very high prevalence of SSI caused by MRSA at the hospital), especially those undergoing high-risk surgery (cardiac, orthopedic), a glycopeptide plus a beta-lactam is recommended as prophylaxis, accompanied by other measures for decolonization.1010 Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.,2020 del Toro López MD, Arias Díaz J, Balibrea JM, Benito N, Canut Blasco A, Esteve E, et al. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. Enfermedades Infecc Microbiol Clínica. 2020. https://doi.org/10.1016/j.eimc.2020.02.017. [Internet]Jul [cited 2021 Jan 5]; Available from https://linkinghub.elsevier.com/retrieve/pii/S0213005X20300513 Accessed on March 29th 2022.
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On the other hand, the role of MDR GNB colonization on SSI risk is not well established, although a higher incidence of SSI caused by ESBL-PE has been already demonstrated in ESBL-PE colonized adult patients who underwent colorectal surgery and in children who underwent cardiac surgery.2020 del Toro López MD, Arias Díaz J, Balibrea JM, Benito N, Canut Blasco A, Esteve E, et al. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. Enfermedades Infecc Microbiol Clínica. 2020. https://doi.org/10.1016/j.eimc.2020.02.017. [Internet]Jul [cited 2021 Jan 5]; Available from https://linkinghub.elsevier.com/retrieve/pii/S0213005X20300513 Accessed on March 29th 2022.
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, 2121 Dubinsky-Pertzov B, Temkin E, Harbarth S, Fankhauser-Rodriguez C, Carevic B, Radovanovic I, et al. Carriage of extended-spectrum beta-lactamase-producing enterobacteriaceae and the risk of surgical site infection after colorectal surgery: a prospective cohort study. Clin Infect Dis. 2019;68:1699–704., 2222 Cheikh A, Belefquih B, Chajai Y, Cheikhaoui Y, El Hassani A, Benouda A. Enterobacteriaceae producing extended-spectrum β- lactamases (ESBLs) colonization as a risk factor for developing ESBL infections in pediatric cardiac surgery patients: «retrospective cohort study». BMC Infect Dis. 2017;17:237. Current SAP guidelines suggest to adapt SAP according to local needs, but do not recommend MDR GNB screening before surgery nor establish MDR SSI prevalence thresholds over which empirical SAP adaptations would be recommended.1010 Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.,2020 del Toro López MD, Arias Díaz J, Balibrea JM, Benito N, Canut Blasco A, Esteve E, et al. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. Enfermedades Infecc Microbiol Clínica. 2020. https://doi.org/10.1016/j.eimc.2020.02.017. [Internet]Jul [cited 2021 Jan 5]; Available from https://linkinghub.elsevier.com/retrieve/pii/S0213005X20300513 Accessed on March 29th 2022.
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Recently, the Spanish Guideline on SAP commented about targeted SAP for colonized ESBL-PE patients, stating that it should only be considered in “high-risk patients” (Level of evidence BIII), even though the term “high risk patients” was not further clarified.2020 del Toro López MD, Arias Díaz J, Balibrea JM, Benito N, Canut Blasco A, Esteve E, et al. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. Enfermedades Infecc Microbiol Clínica. 2020. https://doi.org/10.1016/j.eimc.2020.02.017. [Internet]Jul [cited 2021 Jan 5]; Available from https://linkinghub.elsevier.com/retrieve/pii/S0213005X20300513 Accessed on March 29th 2022.
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World Health Organization (WHO) guidelines for SSI prevention highlighted the urgent need of well-designed studies to address these issues.1818 World Health Organization. Who global guidelines on the prevention of surgical site infection. [Internet]. 2016. Available from: https://www.who.int/publications/i/item/global-guidelines-for-the-prevention-of-surgical-site-infection-2nd-ed. Accessed on March 29th 2022.
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A systematic review that included 12,350 patients submitted to transrectal ultrasound-guided prostate biopsy (TRUSPB) evaluated the effectiveness of targeted antibiotic prophylaxis (TAP) for fluoroquinolone (FQ)-resistant Enterobacteriales colonized patients, versus empiric antibiotic prophylaxis (EAP) in preventing infection.2323 Scott S, Harris PN, Williamson DA, Liss MA, Doi SAR, Roberts MJ. The effectiveness of targeted relative to empiric prophylaxis on infectious complications after transrectal ultrasound-guided prostate biopsy: a meta-analysis. World J Urol. 2018;36:1007–17. Infectious complication incidence was 3.4% in EAP and 0.8% in TAP patients. TRUSPB is not a surgical procedure, but these results raise the issue of the need to adapt the SAP according to the patient MDR GNB colonization profile, especially in clean contaminated or contaminated surgeries involving gastrointestinal or urogenital tracts, where Enterobacteriaceae are highly likely to be involved in surgical wound colonization and infection.2020 del Toro López MD, Arias Díaz J, Balibrea JM, Benito N, Canut Blasco A, Esteve E, et al. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. Enfermedades Infecc Microbiol Clínica. 2020. https://doi.org/10.1016/j.eimc.2020.02.017. [Internet]Jul [cited 2021 Jan 5]; Available from https://linkinghub.elsevier.com/retrieve/pii/S0213005X20300513 Accessed on March 29th 2022.
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Nutman et al. showed a significant reduction of ESBL-PE SSI incidence among ESBL-PE colonized colorectal surgery patients who underwent targeted SAP with ertapenem, compared to standard SAP patients (cephalosporin plus metronidazole), with no short-term adverse events differences between groups.1414 Nutman A, Temkin E, Harbarth S, Carevic B, Ris F, Fankhauser-Rodriguez C, et al. Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing enterobacteriaceae undergoing colorectal surgery. Clin Infect Dis. 2020;70:1891–7.

Transplant patients have a high disease burden due to MDR GNB.2424 Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev. 2018;32:36–57. However, experts disagree on adjusting SAP for patients undergoing solid organ transplantation according to MDR GNB gut colonization status.2424 Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev. 2018;32:36–57.,2525 Pouch SM, Patel G. the AST infectious diseases community of practice. Multidrug-resistant Gram-negative bacterial infections in solid organ transplant recipients — Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33: e13594. In 2018, a Spanish group of specialists recommended that patients colonized with ESBL-PE should receive a targeted prophylaxis regimen, however avoiding carbapenem whenever possible (BIII). The same committee recommended against targeted prophylaxis among carbapenase-producing Enterobacteriales, unless in centers with a high incidence of SSI caused by those agents (BIII)2424 Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev. 2018;32:36–57.. On the other hand, the guidelines from the American Society of Transplantation Infectious Diseases Community of Practice states that “the role of targeted ESBL-PE perioperative prophylaxis remains undefined”.2525 Pouch SM, Patel G. the AST infectious diseases community of practice. Multidrug-resistant Gram-negative bacterial infections in solid organ transplant recipients — Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33: e13594.

The results presented here, although questionable due to high risk of bias, show a significant effect of universal SAP with aminoglycoside in preventing SSI, compared to SAP with cephalosporin alone, in a population of patients submitted to renal transplantation in settings with high incidence of MDR GNB infections. This effect is at least partially due to the reduction in MDR GNB SSI infections, even though the small number of events make it difficult to interpret the observed effect.

Nephrotoxicity associated to SAP with aminoglycoside was not clinically relevant in this population, maybe because in both studies the duration of prophylaxis was short (one dose before incision, and a second one 24 hours later), and administered once a day.2626 Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43:1549–55. In previous SAP regimens, when substantial nephrotoxicity occurred, aminoglycoside was administered twice or three times a day for three to five days.2727 Wilson AP, Sturridge MF, Treasure T. Aminoglycoside toxicity following antibiotic prophylaxis in cardiac surgery. J Antimicrob Chemother. 1990;26:713–20.

It is worthy to interpret these findings with caution. AKI is a frequent complication after major surgery, affecting approximately 10% of patients, and it is associated with increased morbidity and mortality.2828 Long TE, Helgason D, Helgadottir S, Palsson R, Gudbjartsson T, Sigurdsson GH, et al. Acute kidney injury after abdominal surgery: incidence, risk factors, and outcome. Anesth Analg. 2016;122:1912–20. Mean postoperative serum creatinine levels are higher among patients who receive SAP with gentamicin, compared to SAP with amikacin. However, AKI seems to be transient, and serum creatinine levels tend to return to normal after 30 days.2929 Giri VP. Risk of acute kidney injury with amikacin versus gentamycin both in combination with metronidazole for surgical prophylaxis. J Clin Diagn Res. 2016;10:FC09–12.

This scarce evidence of benefit of broad-spectrum SAP is followed by concerns regarding emergence of resistance.3030 Peterson N, Castro S, Barbosa F, Yoon J. Ertapenem use during antibiotic stewardship interventions in community hospitals. Open Forum Infect Dis. 2019;6(Supplement_2):S361.. -S361. This is especially true for carbapenems, as these antibiotics are recognized as increasing the risk for carbapenem-resistant GNB infections.3131 Palacios-Baena ZR, Giannella M, Manissero D, Rodríguez-Baño J, Viale P, Lopes S, et al. Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review. Clin Microbiol Infect. 2021;27:228–35. SAP remarkably contributes to total antibiotic consumption in healthcare facilities, and might correlate to overall increased antibiotic resistance and hospital healthcare costs.3232 Sartelli M, Hardcastle TC, Catena F, Chichom-Mefire A, Coccolini F, Dhingra S, et al. Antibiotic use in low and middle-income countries and the challenges of antimicrobial resistance in surgery. Antibiotics (Basel). 2020;9:497.

The studies included in this systematic review addressed neither the impact of antibiotics used as SAP on the incidence of MDR GNB colonization and infection on hospital level and over time, nor the cost-effectiveness of the described interventions, thus limiting safety and cost-effectiveness assessment.

The results of this systematic review should be cautiously interpreted, due to several methodological aspects ultimately seen as high risk of bias. In addition, given the before-after study design of the three included studies, it is not possible to exclude the potential confounding of other preventive measures implemented simultaneously, especially in the study by Abboud et al, that, even though does not describe new interventions besides changing SAP, recognize the strengthening of infection control measures in a scenario of increased HAI.

In conclusion, there is some low-quality evidence supporting that SAP against MDR GNB, with either aminoglycosides or ertapenem, may prevent MDR GNB SSI after renal transplantation and colon surgery in adults, respectively, in settings with high incidence of MDR GNB SSI and/or in ESBL-PE colonized patients. Risk of nephrotoxicity with aminoglycosides was low; impact on antimicrobial resistance was not assessed and is of great concern. Prospective, randomized studies, in different surgical populations, including children, may further clarify issues regarding confounding effects, choosing the high-risk patients or a prevalence threshold for targeted prevention; elucidate medium and long-term effect on MDR emergence; and better establish the cost-effectiveness and safety of SAP and other measures against MDR GNB SSI.

  • Abbreviations: SAP, Surgical antibiotic prophylaxis; ESBL-PE, extended spectrum beta-lactamase producing Enterobacteriales; DGF, delayed implanted graft function; TRUSPB, transrectal ultrasound-guided prostate biopsy; TAP, targeted antibiotic prophylaxis; EAP, empiric antibiotic prophylaxis; AST, antimicrobial susceptibility testing
  • Funding source
    This research was financially supported by the Brazilian Ministry of Health and the Pan American Health Organization/World Health Organization (PAHO / WHO) (Grant number: SCON2018-00408).

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Publication Dates

  • Publication in this collection
    23 Jan 2023
  • Date of issue
    2022

History

  • Received
    17 May 2022
  • Accepted
    17 Sept 2022
  • Published
    11 Oct 2022
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