148
Aurora Pop-Vicas et al We found no significant difference in the SSI relative risk
when cefazolin was compared with penicillin-based β-lactam antibiotics (penicillin G, ampicillin, amoxicillin-clavulanate) or with second- or third-generation cephalosporins that lacked antianaerobic spectrum. Any conclusions regarding optimal surgical antibiotic pro-
Fig. 3. Forest plot, meta-analysis of relative risk for SSI with cefazolin versus other cephalosporin antimicrobials with antianaerobic activity (cefotetan, cefoxitin) among women undergoing abdominal or vaginal hysterectomy. Fixed effects model. Heterogeneity I2=0, P value=.623.
Fig. 4. Forest plot, meta-analysis of relative risk for surgical site infection (SSI) with cefazolin versus β-lactam with antianaerobic activity (cefoxitin, cefotetan, or amoxicillin-clavulanate) among women undergoing abdominal or vaginal hyster- ectomy. Fixed effects model. Heterogeneity I2=0; P value=.756.
cephalosporins with broader antianaerobic activity, namely cefoxitin or cefotetan. Although not statistically significant, the trend toward lower efficacy was still present when we added amoxicillin-clavulanate, another β-lactam antibiotic with sig- nificant antianaerobic spectrum, into the meta-analysis. Our findings are plausible considering the pathophysiology and microbiology underlying SSI in gynecological surgery. Post- operative infections after gynecological surgery are primarily polymicrobial, with enterococci, aerobic-gram-negative bacilli, and anaerobic bacteria, including Bacteroides spp frequently isolated. In addition to the skin as the usual site of contamina- tion for gram-positive pathogens, endogenous bacteria migrating from the vagina and endocervix can gain access to the operative sites. The endogenous flora of the lower reproductive tract in women includes facultative and obligate anaerobic species. Anaerobes are particularly predominant in bacterial vaginosis, long recognized as an SSI risk factor in women undergoing hysterectomy.26–30 The recent clinical study by Till et al,31 not included in our meta-analysis as it is an observational trial, provides further support for the consideration of agents with good antianaerobic spectrum to antimicrobial prophylaxis in hysterectomy. In a large retrospective cohort study including 18,255 hysterectomies in 73 hospitals during 2012–2015, com- bination prophylaxis with cefazolin plus metronidazole resulted in significantly lower SSI rates than cefazolin alone.31 Addi- tionally, a recent retrospective cohort study by Uppal et al32 of 21,358 patients fromtheMichigan Surgical Quality Collaborative undergoing hysterectomy between 2012 and 2015 reported that the rate of SSI was significantly higher in patients receiving non-β-lactam antimicrobials than in those receiving β-lactam antimicrobials.
phylaxis in hysterectomy are tempered by the significant lim- itations of the literature in this field. First, most cefazolin trials are old, with no representation of laparoscopic procedures and with only 1 RCT published within the last decade.25 Variations in antibiotic dosing and perioperative duration, lack of stan- dardized weight-based dosing, and lack of information regard- ing antimicrobial redosing in relation to duration of surgery introduce significant clinical heterogeneity and make compar- isons with contemporary standard of practice difficult. Second, most hysterectomies performed in these studies were due to benign surgical indications. The exclusion of patients with underlying gynecological malignancies, especially ovarian can- cers that are usually clinically advanced at presentation and require complex debulking procedures, renders the choice of optimal surgical antibiotic prophylaxis uncertain in these cases. Third, the methodological rigor is low or indeterminate in many of the older studies; we identified a high potential for bias in more than half of the studies. Lastly, most studies reported “postoperative fever” as a major clinical outcome for antibiotic prophylaxis. Although some cases of postoperative fever may be due to SSI, this is a nonspecific outcome, potentially attributable to a variety of other infectious or noninfectious processes. Its exclusion from our analysis may have underestimated the true incidence of SSI. To our knowledge, this is the first meta-analysis that frames
the question of surgical antibiotic prophylaxis in terms of com- parative efficacy for cefazolin versus antimicrobials with broader antianaerobic spectrum—a clinically relevant question for con- temporary surgery. Previous meta-analyses in the field have focused on the preventive benefits of antibiotic prophylaxis in general and have included antimicrobials that are no longer used for this clinical purpose.9,33–35 Due to the antiquated nature of the published RCT on this topic, and their inherent limitations stated above, the question cannot be answered conclusively from the evidence-based literature available at this time. In conclusion, the question of optimal antimicrobial prophy-
laxis for SSI prevention in contemporary hysterectomy deserves further study, and RCTs are needed to assess the efficacy of cefazolin versus other antimicrobials with broader antianaerobic spectrum. The enrollment of patients undergoing complex sur- gical procedures due to underlying gynecological malignancies, and the inclusion of laparoscopic as well as open surgical approaches should be prioritized for future trials. In addition, given the known deleterious effects of broad-spectrum anti- microbials on the gut microbiome, future studies of comparative efficacy should also explore the adverse effects of broader anti- anaerobic spectrum on gut microbiota, in addition to the effects on SSI prevention. (Table 3)
Financial support. None provided.
Conflicts of interest. All authors report no conflicts of interest relevant to this article.
Supplementary materials. To view supplementary material for this article, please visit
https://doi.org/10.1017/ice.2018.286
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