134 Data sources and searches
We searched the PubMed and Cochrane databases for RCTs that measured the efficacy of antibiotic prophylaxis in preventing postoperative infections (SSIs following the 3 surgical procedures and a combination of urinary tract infections [UTIs] and sepsis following TRPB) for the 4 index procedures. For the 3 surgical procedures, SSIs include superficial, deep incisional, and organ- space infections. We included RCTs published through October 31, 2017, with no limit on the year of publication; 2 authors (A.T. and S.G.) independently screened titles and abstracts to identify relevant studies. We used the term for the “surgical procedure AND the recommended prophylactic antibiotics” AND the term “prophylaxis” for both the PubMed and Cochrane databases (Supplementary Table 1). For example, for colorectal surgery, we used the following terms: “colorectal surgery AND prophylaxis AND cefoxitin,”“colorectal surgery AND prophylaxis AND cefotetan,” and “colorectal surgery AND prophylaxis AND cefa- zolin AND metronidazole.” A list of search terms for each pro- cedure is provided in Supplementary Table 1. Recommended antibiotic prophylactic agents for the index procedures were chosen based on published guidelines.7 In addition, Cochrane reviews on the efficacy of antibiotic prophylaxis for each procedure were reviewed, and data from relevant studies were extracted.8–10 No restriction on language was imposed, and we did not attempt to identify unpublished articles or contact study authors.
Study selection
Studies were considered eligible if they included recommended antibiotics for surgical prophylaxis and reported extractable data on the proportion of postoperative infections. Because our objective was to examine changes in the efficacy of prophylactic antibiotics over time, we extracted data from all study arms of RCTs that included the currently recommended prophylactic antibiotics for the 4 procedures. For example, in the case of placebo control RCTs, we extracted data only from the antibiotic study arm, and for RCTs comparing the efficacy of 2 different kinds of antibiotics, we extracted data only from the study arm that included the current recommended prophylactic antibiotics. For cesarean section, we excluded RCTs in which antibiotics
were administered post–umbilical cord clamping, as the efficacy of antibiotic prophylaxis post–cord clamping was found to be inferior compared with prophylaxis prior to skin incision.11 For appendectomy and colorectal surgery, the antibiotics recom- mended for prophylaxis include cefotetan, cefoxitin, or a com- bination of cefazolin with metronidazole. Given the similar spectrum of activity of these 3 agents, they are expected to demonstrate similar efficacy and thus are recommended by the published guidelines. For colorectal surgery, a combination of ceftriaxone plus metronidazole and ertapenem alone were also listed as conditionally recommended agents. However, we did not consider these regimens because they have broad-spectrum activity and routine use is discouraged due to concern that it may lead to an increase in resistant organisms. Cefazolin is the recommended prophylactic antibiotic for cesarean section, whereas fluoroquinolones are recommended for TRPB prophy- laxis. Although trimethoprim-sulfamethoxazole is the recom- mended prophylactic agent for TRPB, we could find only 2 studies meeting our inclusion criteria, limiting us to examine long-term trends to this antibiotic and thus we excluded them.
Sumanth Gandra et al
Studies in which prophylactic antibiotics were administered for more than 24 hours were excluded because current guidelines recommend that the duration of surgical prophylaxis is less than 24 hours.7 For colorectal surgery and TRPB, studies in which antibiotics were administered as part of bowel preparation were excluded, although studies with only mechanical bowel prepara- tion were included. For colorectal surgery, elective and emergency surgeries were included. For appendectomy, only simple appen- dicitis cases were included because antibiotics are usually con- tinued postsurgery for complicated appendicitis cases. We included all cesarean section procedure RCTs involving elective and nonelective cases and women in labor.
Data extraction and quality assessment
The primary outcome was the change in the proportion of postoperative infections over time associated with the recom- mended prophylactic antibiotic agents for the 4 procedures. The denominator of this proportion for each trial was the number of participants randomized minus participants whose outcomes were missing, and the numerator was the number of participants with postoperative infections. Also, 2 authors (A.T. and S.G.) independently extracted data from eligible studies, and any dis- crepancies were resolved by consensus. The definition of SSI varied among studies for the 3 surgical procedures. To overcome this inconsistency, we extracted information from each study on superficial and deep incisional wound infections, intra-abdominal abscess, peritonitis and sepsis related to surgery following color- ectal surgery and appendectomy. For cesarean section, we extracted information from each study on superficial and deep incisional wound infections and endometritis. For TRPB, we extracted information on symptomatic UTIs and sepsis (Supple- mentary Material 2). The methodological quality of included studies was assessed
using the Cochrane Collaboration tool for assessing risk of bias,12 implemented by 2 reviewers (A.T. and S.G.). The quality of each study was judged by evaluating the following sources of bias: selection bias (random sequence generation, allocation conceal- ment), attrition bias (incomplete data outcomes), detection bias (blinding of participants, blinding of outcome assessment), selective outcome reporting, and other bias. Bias assessments of studies identified from Cochrane reviews were extracted from reviews where available.
Data synthesis and analysis
For each index procedure, information including the antibiotic name, year of publication, year of actual study where available, country of study, author name, type of surgery (elective or nonelective), SSI reported, timing of antibiotic prophylaxis, follow up duration, number of infected patients, and total number of patients for eligible studies was recorded in a database. A separate database of excluded studies was maintained, along with reasons for exclusion. Data from included studies were imported into STATA version 14.2 software (StataCorp, College Station, TX) for analysis. We performed a random effects meta-analysis to esti- mate the overall proportion of postoperative infection using the metaprop command in Stata software.13 The pooled proportions were calculated using the approach of DerSimonian and Laird,14 with stabilized variance using the Freeman-Tukey double arcsine methodology, allowing us the inclusion of studies with 0% post- operative infection.13 The τ2 statistic was used to estimate the
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