1. Introduction

The preventive effect of the routine use of preoperative surgical antibiotic prophylaxis (SAP) on the occurrence of surgical site infections (SSI) prior to non-clean and implant surgery has long been recognized. However, the benefit of continued SAP after completion of the procedure is unclear. Increasing evidence shows that a single preoperative dose of SAP (and possible additional intraoperative doses according to the duration of the operation) may be non-inferior to additional postoperative multiple doses for the prevention of SSI. Despite this, surgeons still have a tendency to routinely continue SAP up to several days after surgery^1,2.

The use and duration of postoperative prophylaxis has been specified in clinical practice guidelines issued by professional societies or national authorities. Several of these guidelines, such as those published by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)³, and the American Society of Health Care Pharmacists (ASHP)⁴ recommend discontinuing SAP within 24 hours after surgery. The United States (US) Institute of Healthcare Improvement recommends discontinuing SAP within 24 hours in general and within 48 hours in cardiac surgery⁵. Other guidelines published by the United Kingdom (UK) National Institute for Health and Care Excellence (NICE)⁶, the Scottish Intercollegiate Guidelines Network (SIGN)⁷, the Royal College of Physicians of Ireland⁸ and the UK Department of Health⁹, recommend a single dose of preoperative SAP and no postoperative continuation with or without exceptions for specific surgical procedures.

2. PICO question

Does continued postoperative SAP reduce the risk of SSI compared with preoperative and (if necessary) intraoperative prophylaxis only?

• Population: patients of any age undergoing surgical procedures who need to receive SAP
• Intervention: continued postoperative antibiotic prophylaxis
  Comparator: single-dose antibiotic prophylaxis only (and possible additional intraoperative doses according to duration of the operation)
• Outcome: SSI, SSI-attributable mortality

3. Methods

The following databases were searched: Medline (PubMed); Cumulative Index to Nursing and Allied Health Literature (CINAHL); Cochrane Central Register of Controlled Trials (CENTRAL); and WHO regional medical databases. The time limit for the review was between 1 January 1990 and 1 October 2015. Language was restricted to English, German and Spanish. A comprehensive list of search terms was used, including Medical Subject Headings (MeSH) (Appendix 1).

Two independent reviewers screened titles and abstracts of retrieved references for potentially relevant studies. The full text of all potentially eligible articles was obtained. Two authors independently reviewed the full text articles for eligibility based on inclusion criteria. Duplicate studies were excluded. Only studies comparing the same agent in the same dosage (per administration) were included. The first dose was always administered preoperatively.

Two authors extracted data in a predefined evidence table (Appendix 2) and critically appraised the retrieved studies using the Cochrane collaboration tool¹⁰ for assessing risk of bias (Appendix 3). Any disagreements were resolved through discussion after consultation of the senior author, when necessary.

Meta-analyses of available comparisons of SAP were performed using Review Manager version 5.3 as appropriate¹¹ (Appendix 4). Odds ratios (OR) and the mean difference with 95% confidence intervals (CI) were extracted and pooled for each comparison with a random effects model. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology¹² (GRADE Pro software, http://gradepro.org/¹³) was used to assess the quality of the retrieved evidence (Appendix 5).

4. Study selection

Flow chart of the study selection process

5. Summary of the findings

A total of 69 randomized controlled trials (RCTs)^14–82 investigating the optimal duration of antibiotic prophylaxis in a variety of surgical procedures with an SSI outcome were identified. A total of 21 243 patients were included, mostly adults. Only 2 studies^18,58 addressed specifically the paediatric population. Fifteen studies^{16,17,28,30,32,33,51,54,56,69,73–75,83,84} reported that some paediatric patients were included, but most were adult patients. Fourteen^{17,29,34–36,50,51,54,56,69,71,73,75,80} of the included studies were conducted in low- and middle-income countries.

Both the intervention and control group received the same preoperative regimen in all the included studies and only differed in the postoperative continuation of antibiotic prophylaxis. Only studies comparing the same antibiotic agent in the same dosage (per administration) were considered in order to prevent confounding by the type of antibiotic. The first dose of antibiotic prophylaxis was always administered preoperatively. In addition to the single dose, possible additional dose/s according to the duration of the operation were given, depending on the protocol used in the trial.

To investigate the optimal duration of antibiotic prophylaxis, the Guideline Development Group (GDG) agreed to not only assess trials comparing a continued postoperative antibiotic prophylaxis with a single dose antibiotic prophylaxis only (or repeated according to duration of the operation), but also to assess trials that compared different regimens of prolonged postoperative antibiotic prophylaxis.

Accordingly, the following comparisons were made:

1. Any prolonged regimen vs. no postoperative dose (44 RCTs)
2. A prolonged regimen less than 24 hours postoperative vs. a single postoperative dose (one RCT)
3. A prolonged regimen more than 24 hours postoperative vs. a prolonged regimen less than 24 hours postoperative (23 RCTs)
4. A prolonged regimen more than 48 hours postoperative vs. a prolonged regimen less than 48 hours postoperative (3 RCTs)
5. Type of procedure with a prolonged antibiotic regimen

   1. Cardiac surgery
   2. Vascular surgery
   3. Orthognathic surgery

The results of the meta-analyses based on these comparisons are shown in Appendix 4.

1. Forty-four RCTs^14–56,82 including 17 805 patients and comparing any prolonged regimen of antibiotic prophylaxis with no postoperative antibiotic prophylaxis were identified. These studies included a variety of surgical procedures: appendectomy^14–18; colorectal surgery^19–21; upper gastrointestinal tract surgery^22–25; cholecystectomy²⁶; hepatobiliary surgery⁸⁵; mixed general surgery^28–33,82; caesarean section^34–36; gynaecological surgery^37,38; orthopaedic and trauma surgery^39,40; spine surgery⁴¹; cardiac surgery^42,43; thoracic surgery⁴⁴; vascular surgery⁴⁵; transplantation surgery⁴⁶; head and neck surgery^47,86; ear, nose and throat surgery⁴⁹; maxillofacial surgery^50–53; and orthognathic surgery^54–56.
   Only 3 trials^20,43,45 showed a decreased risk of SSI when antibiotic prophylaxis was prolonged postoperatively. The remaining 40 trials showed no difference in risk. The analysis was further stratified according to the type of procedure. No significant difference in the risk of SSI was found with the exception of cardiac, vascular and orthognathic surgery for which prolonged antibiotic prophylaxis resulted in a decreased risk of SSI (Appendix 4, comparisons 5a–5c).
   Meta-analysis of the 44 RCTs^14–56,82 (Appendix 4, comparison 1) demonstrated that prolonged postoperative antibiotic prophylaxis had no benefit when compared to a single dose of antibiotic prophylaxis in reducing SSI after surgery (OR: 0.89; 95% CI: 0.77–1.03).
   The quality of the evidence for this comparison was moderate due to the risk of bias (Appendix 5).
2. One study⁵⁷ including 227 patients undergoing colorectal surgery compared the continuation of antibiotic prophylaxis up to 16 hours postoperatively with a single postoperative dose. The trial⁵⁷ (Appendix 4, comparison 2) demonstrated that the continuation of prolonged antibiotic prophylaxis up to a last dose at 16 hours postoperatively had no benefit in reducing SSI when compared to a single postoperative dose (OR: 0.82; 95% CI: 0.47–1.40).
   The quality of evidence was very low due to risk of bias and imprecision (Appendix 5).
3. Twenty-three trials^{16,17,58–78} including 3084 patients compared any prolonged regimen of more than 24 hours postoperatively with a postoperative regimen of less than 24 hours. These studies included a wide variety of surgical procedures: colorectal surgery^58–61,78; cholecystectomy⁶²; gynaecological surgery⁷⁷; spine surgery⁶³; cardiac surgery^64,65; head and neck surgery^66–68; ear, nose and throat surgery⁶⁹; maxillofacial surgery⁷⁰; orthognathic surgery^71–75; and others⁷⁶.
   Only one trial⁷² in orthognathic surgery showed a decreased risk of SSI when antibiotic prophylaxis was prolonged for more than 24 hours postoperatively. Twenty trials showed no difference in risk and 2 trials had no SSI events^73,78. The analysis was further stratified by the type of surgical procedure, but no significant difference in the risk of SSI was observed according to the procedure. Meta-analysis of these 23 RCTs^{16,17,58–78} (Appendix 4, comparison demonstrated that a prolonged antibiotic prophylaxis regimen of more than 24 hours postoperatively had no benefit in reducing SSI when compared to a prolonged regimen of less than 24 hours (OR: 0.89; 95% CI: 0.69–1.16).
   The quality of evidence was moderate due to the risk of bias (Appendix 5).
4. Three studies^79–81 including 457 patients undergoing hepatobiliary⁷⁹, cardiac⁸⁰ and head and neck surgery⁸¹ compared any prolonged postoperative regimen of more than 48 hours with a prolonged regimen of less than 48 hours. The individual trials showed no difference in the risk of SSI. The analysis was further stratified by the type of surgical procedure, but no significant difference in the risk of SSI was observed according to the procedure. Meta-analysis of the trials^79–81 (Appendix 4, comparison 4) demonstrated that a prolonged antibiotic prophylaxis regimen of more than 48 hours had no benefit when compared to a prolonged regimen for up to 48 hours in reducing SSI (OR: 1.04; 95% CI: 0.50–2.16).
   The quality of evidence was very low due to the risk of bias and imprecision (Appendix 5).
5. Types of procedure associated with a decreased risk of SSI with a prolonged antibiotic regimen.

   a)

   Cardiac surgery

   Five studies^{42,43,64,65,80} compared different postoperative antibiotic regimens in cardiac surgery. Among these, 2 studies^42,43 compared any prolonged regimen with no postoperative antibiotic prophylaxis. Two other studies^64,65 compared continuation of antibiotic prophylaxis for more than 24 hours postoperatively with continuation for less than 24 hours. One study⁸⁰ compared continuation of postoperative antibiotic prophylaxis for longer than 48 hours with regimens continuing for less than 48 hours. Separate meta-analyses were performed for the three comparisons, when appropriate (Appendix 4, comparison 5a).

   1. Meta-analysis of the 2 RCTs^42,43 comparing any prolonged regimen with no postoperative antibiotic prophylaxis demonstrated that the former had a benefit in terms of reducing SSI (OR: 0.43; 95% CI: 0.25–0.76).
      The quality of evidence was low due to the risk of bias and imprecision (Appendix 5).
   2. Meta-analysis of the 2 RCTs^64,65 comparing postoperative prophylaxis for more than 24 hours with continuation for less than 24 hours demonstrated that the former had no benefit in terms of reducing the risk of SSI (OR: 0.74; 95% CI: 0.32–1.73).
      The quality of evidence was very low due to the risk of bias and imprecision (Appendix 5).
   3. One RCT⁸⁰ comparing the continuation of postoperative antibiotic prophylaxis for longer than 48 hours with continuation for less than 48 hours demonstrated that the former had no benefit in terms of reducing the risk of SSI (OR: 0.53; 95% CI: 0.15–1.93).
      The quality of evidence was very low due to the risk of bias and imprecision (Appendix 5).

   b)

   Vascular surgery

   One RCT⁴⁵ in patients undergoing vascular surgery compared the continuation of antibiotic prophylaxis until all lines were removed with a single dose of antibiotic prophylaxis and demonstrated that the former had a significant benefit in terms of reducing the risk of SSI (Appendix 4, comparison 5b; OR: 0.50; 95% CI: 0.25–0.98).

   The quality of evidence was low due to the risk of bias and imprecision (Appendix 5).

   c)

   Orthognathic surgery

   Eight studies^{54–56,71–75} compared different postoperative antibiotic regimens in orthognathic surgery. Among these, 3 studies^54–56 compared any prolonged regimen with no postoperative prolongation of antibiotic prophylaxis. Five other studies^71–75 compared continuation of antibiotic prophylaxis for more than 24 hours postoperatively with continuation for less than 24 hours. Meta-analyses were performed for each of these comparisons (Appendix 4, comparison 5c).

   1. Meta-analysis of the 3 RCTs^54–56 comparing any prolonged regimen with no postoperative antibiotic prophylaxis demonstrated that the former had a benefit in terms of reducing SSI (OR: 0.30; 95% CI: 0.10–0.88).
      The quality of evidence was low due to the risk of bias and imprecision (Appendix 5).
   2. Meta-analysis of the 5 RCTs^71–75 comparing postoperative antibiotic prophylaxis for more than 24 hours with continuation for less than 24 hours demonstrated that the former had no benefit in terms of reducing the risk of SSI (OR: 0.34; 95% CI: 0.08–1.44).
      The quality of evidence was very low due to the risk of bias and imprecision (Appendix 5).

In conclusion, the retrieved evidence can be summarized as follows:

-

Postoperative continuation of antibiotic prophylaxis vs. a single dose of antibiotic prophylaxis (comparison 1):

Overall, a moderate quality of evidence shows that the postoperative continuation of antibiotic prophylaxis has neither benefit nor harm in reducing SSI rates when compared to a single dose of antibiotic prophylaxis.

1. In cardiac surgery (comparison 5a), a low quality of evidence shows that the continuation of antibiotic prophylaxis for up to 24 hours postoperatively has a benefit in reducing the SSI rate when compared to a single dose of antibiotic prophylaxis. A very low quality of evidence showed that continuation beyond 24 hours postoperatively has no benefit.
2. In vascular surgery (comparison 5b), a low quality of evidence shows that the continuation of antibiotic prophylaxis until all lines are removed has a benefit in reducing the SSI rate when compared to a single dose of prophylaxis.
3. In orthognathic surgery (comparison 5c), a low quality of evidence shows that the continuation of antibiotic prophylaxis for up to 24 hours postoperatively had a benefit in reducing the SSI rate when compared to a single dose of antibiotic prophylaxis. A very low quality of evidence showed that continuation beyond 24 hours postoperatively had no benefit in reducing SSI.

The included studies have some limitations. The quality of the included RCTs was moderate. Most studies had an unclear or high risk of bias in at least one or more domains. Differences and inconsistencies were noted in the SSI definitions, patient population and antibiotic regimen.

6. Other factors considered in the review

The systematic review team identified the following other factors to be considered.

7. Key uncertainties and future research priorities

The systematic review team identified the following key uncertainties and future research priorities.

There is a need for further well-designed RCTs in cardiac and vascular surgery as well as in low- and middle-income countries and in the paediatric population. More research is needed to demonstrate the linkage between the prolongation of SAP and the emergence of antibiotic resistance. Furthermore, future trials should investigate the effect of prolonged antibiotic prophylaxis on the microbiome.

Appendices

Appendix 4. Comparisons

Comparison 1Postoperative continuation vs. single dose of antibiotic prophylaxis, outcome SSI

SSI: surgical site infection; GI: gastrointestinal; CI: confidence interval

Funnel plot 1Postoperative continuation vs. single dose of antibiotic prophylaxis, outcome SSI

Comparison 2Postoperative continuation of antibiotic prophylaxis for up to 24 hours vs. a single postoperative dose, outcome SSI

SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Comparison 3SAP – postoperative continuation for more than 24 hours vs. continuation for up to 24 hours, outcome SSI

SAP: surgical antibiotic prophylaxis; SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Funnel plot 3SAP – postoperative continuation for more than 24 hours vs. continuation for up to 24 hours, outcome SSI

Comparison 4SAP – postoperative continuation for more than 48 hours vs. continuation for up to 48 hours, outcome SSI

SAP: surgical antibiotic prophylaxis; SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Funnel plot 4SAP – postoperative continuation for more than 48 hours vs. continuation for up to 48 hours, outcome SSI

Comparison 5aTypes of procedure with a decreased risk of SSI with a prolonged antibiotic regimen: cardiac surgery (i) Prolonged regimen vs. a single dose

Funnel plot 5a. Types of procedure with a decreased risk of SSI with a prolonged antibiotic regimen: cardiac surgery (i) Prolonged regimen vs. a single dose

Comparison 5aTypes of procedure with a decreased risk of SSI with a prolonged antibiotic regimen: cardiac surgery (ii) >24 hours vs. <24 hours

Funnel plot 5aTypes of procedure with a decreased risk of SSI with a prolonged antibiotic regimen: cardiac surgery (ii) >24 hours vs. <24 hours

Comparison 5aTypes of procedure with a decreased risk of SSI with a prolonged antibiotic regimen: cardiac surgery (iii) >48 hours vs. 48 hours

SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Comparison 5bTypes of procedure with decreased risk of SSI with a prolonged antibiotic regimen: vascular surgery (i) Prolonged regimen vs. a single dose

SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Comparison 5cTypes of procedure with decreased risk of SSI with a prolonged antibiotic regimen: orthognathic surgery (i) Prolonged regimen vs. a single dose

Funnel plot 5cTypes of procedure with decreased risk of SSI with a prolonged antibiotic regimen: orthognathic surgery (i) Prolonged regimen vs. a single dose

Comparison 5cTypes of procedure with decreased risk of SSI with a prolonged antibiotic regimen: orthognathic surgery (ii) >24 hours vs. <24 hours

SSI: surgical site infection; M-H: Mantel-Haenszel (test); CI: confidence interval

Funnel plot 5cTypes of procedure with decreased risk of SSI with a prolonged antibiotic regimen: orthognathic surgery (ii) >24 hours vs. <24 hours

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