Surgical Infection Society Guidelines for Antibiotic Use in Patients Undergoing Cholecystectomy for Gallbladder Disease

Abstract

Background:

Manifestations of gallbladder disease range from intermittent abdominal pain (symptomatic cholelithiasis) to potentially life-threatening illness (gangrenous cholecystitis). Although surgical intervention to treat acute cholecystitis is well defined, the role of antibiotic administration before or after cholecystectomy to decrease morbidity or mortality is less clear.

Methods:

The Surgical Infection Society's Therapeutics and Guidelines Committee convened to develop guidelines for antibiotic use in patients undergoing cholecystectomy for gallbladder disease to prevent surgical site infection, other infection, hospital length of stay, or mortality. PubMed, Embase, and the Cochrane Database were searched for relevant studies. Evaluation of the published evidence was performed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system. Using a process of iterative consensus, all authors voted to accept or reject each recommendation.

Results:

We recommend against routine use of peri-operative antibiotic agents in low-risk patients undergoing elective laparoscopic cholecystectomy. We recommend use of peri-operative antibiotic agents for patients undergoing laparoscopic cholecystectomy for acute cholecystitis. We recommend against use of post-operative antibiotic agents after elective laparoscopic cholecystectomy for symptomatic cholelithiasis. We recommend against use of post-operative antibiotic agents in patients undergoing laparoscopic cholecystectomy for mild or moderate acute cholecystitis. We recommend a maximum of four days of antibiotic agents, and perhaps a shorter duration in patients undergoing cholecystectomy for severe (Tokyo Guidelines grade III) cholecystitis.

Conclusions:

This guideline summarizes the current Surgical Infection Society recommendations for antibiotic use in patients undergoing cholecystectomy for gallbladder disease.

In the United States, approximately 6% of men and 9% of women have gallstones [1]. Severity of gallbladder disease is highly variable and ranges from intermittent, self-limited abdominal pain (symptomatic cholelithiasis) to more severe, unremitting pain with signs of systemic inflammation (acute cholecystitis), to gangrenous or perforated cholecystitis necessitating admission to an intensive care unit. For the majority of patients with symptomatic disease, there is consensus that laparoscopic cholecystectomy is the gold standard therapy to manage this common condition, because it results in less post-operative pain, shorter hospital length of stay, and fewer surgical site infections (SSIs) than open surgery [2,3]. However, the role of antibiotic agents in the management of the spectrum of gallbladder disease is less clear. As the negative consequences of widespread antibiotic use and overuse become more evident, it is imperative that clinicians prescribe antibiotic therapy judiciously. The purpose of this review is to develop evidence-based guidelines for appropriate antibiotic use in patients undergoing cholecystectomy (Table 1).

Table 1.

Surgical Infection Society Recommendations for Antibiotic Use in Cholecystectomy

PICO question	Recommendation	Grade of evidence
In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of peri-operative antibiotic agents versus no antibiotic agents decrease morbidity or mortality?	We recommend against routine use of peri-operative antibiotic agents in low-risk patients undergoing elective laparoscopic cholecystectomy.	1A
In adult patients undergoing laparoscopic cholecystectomy for acute cholecystitis, does administration of peri-operative antibiotic agents versus no antibiotic agents decrease morbidity or mortality?	We recommend use of peri-operative antibiotic agents for patients undergoing laparoscopic cholecystectomy for acute cholecystitis.	2C
In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of post-operative antibiotic agents versus no post-operative antibiotic agents decrease morbidity or mortality?	We recommend against use of post-operative antibiotic agents after elective laparoscopic cholecystectomy for symptomatic cholelithiasis.	2C
In adult patients undergoing laparoscopic cholecystectomy for mild or moderate (Tokyo Guidelines grade I or II) cholecystitis, does administration of post-operative antibiotic agents versus no post-operative antibiotic agents decrease morbidity or mortality?	We recommend against use of post-operative antibiotic agents in patients undergoing laparoscopic cholecystectomy for mild or moderate acute cholecystitis.	1B
In adult patients undergoing cholecystectomy for severe (Tokyo Guidelines grade III) cholecystitis, what is the appropriate duration of post-operative antibiotic agents to decrease morbidity or mortality?	We recommend that patients with severe (Tokyo Guidelines grade III) cholecystitis undergoing cholecystectomy should receive a maximum of four days of antibiotic agents, although a shorter duration may also be safe.	1B

Objectives

Our population, intervention, comparator, and outcome (PICO) questions are as follows:

Population: Adult patients (>18 years of age) with gallstone disease undergoing cholecystectomy

Intervention: Administration of antibiotic agents

Comparators: No administration of antibiotic agents peri-operatively, administration of antibiotic agents peri-operatively but not post-operatively, and duration of post-operative antibiotic use

Outcomes: Surgical site infection (superficial, deep), hospital length of stay, other infectious complications including organ/space infection or intra-abdominal infections, and mortality

In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of peri-operative antibiotic agents compared with no antibiotic agents decrease morbidity (hospital length of stay [LOS], SSI, and rates of other infections including organ/space infection or intra-abdominal infections) or mortality?

In adult patients undergoing laparoscopic cholecystectomy for acute cholecystitis, does administration of peri-operative antibiotic agents compared with no antibiotic agents decrease morbidity (hospital LOS, SSI, other infections including organ/space infection or intra-abdominal infections) or mortality?

In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of post-operative antibiotic agents compared with no antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

In adult patients undergoing laparoscopic cholecystectomy for mild or moderate acute cholecystitis, does administration of post-operative antibiotic agents compared with no post-operative antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

In adult patients undergoing cholecystectomy for severe (Tokyo Guidelines grade III) cholecystitis, what is the appropriate duration of post-operative antibiotic agents to decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

Identification of References

PubMed, Embase, and the Cochrane Database were all queried by a professional librarian and two authors (K.P.C. and J.M.H.) to identify all appropriate studies pertaining to the PICO questions. The medical subject heading (MeSH) terms of symptomatic cholelithiasis, biliary colic, acute cholecystitis, antibacterial agent, antibiotic agents, cefazolin, ancef, kefzol, cefoxitin, mefoxin, cefotetan, cefotan, ceftriaxone, rocephin, piperacillin-tazobactam, zosyn, clindamycin, cleocin, aztreonam, azactam, metronidazole, flagyl, prophylaxis, SSI, wound infection, English, human, were used in varying combinations. After electronic literature search, all titles and abstracts were reviewed by two authors (K.P.C. and J.M.H.), to identify those studies relevant to each PICO question. Case studies, animal studies, pediatric studies, and commentaries were excluded. Additional studies that would be relevant were sought by reviewing each of the bibliographies of the studies for any missing relevant articles. In total, 153 studies were identified. After careful review and selection, a total of 24 articles are included in this review. For PICO questions 1, only meta-analyses were included in the review, although the individual studies were reviewed by the authors for context and adequate inclusion criteria. For the remaining PICO questions, the highest quality articles were included in the review (Fig. 1).

FIG. 1.

Flow diagram showing selection process for included articles. PICO = population, intervention, comparator, and outcome.

Data Extraction and Methodology

Grading of Recommendations, Assessment, Development and Evaluations (GRADE) definitions were used to evaluate the quality and certainty of all reviewed studies. The GRADE framework was applied to all outcomes to assess for risk of bias, publication inconsistency, imprecision and indirectness [4].

To allow for accurate terminology, efforts were made to adhere to the following definitions in our study. As most studies used the term SSI to encompass only superficial and deep SSIs, organ/space or intra-abdominal infections are discussed separately in each PICO question when the data are available. No study specifically defined SSI (superficial or deep) and number of trocar site affected. It is presumed by the authors that an SSI was at a trocar site for laparoscopic surgery and that one or more trocar infections constituted an SSI. When available, the specific definitions used in each study are presented. Using a process of iterative consensus, all authors voted to accept or reject the recommendations.

Results

1. In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of peri-operative antibiotic agents versus no antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

In the past decade, numerous studies have evaluated use of peri-operative antibiotic agents on post-operative infections in elective laparoscopic cholecystectomies for symptomatic cholelithiasis. Unfortunately, these studies suffer from small sample sizes and are underpowered to detect differences in infectious complications, as the rate of infections following these clean-contaminated procedures is quite low, ranging between 0% and 10%. To address this, meta-analyses have been undertaken. Each meta-analysis has used slightly different inclusion and exclusion criteria and need to be interpreted with these in mind. The first large meta-analysis was performed in 2008 by Choudhary et al. [5]. This review included only randomized controlled trials (RCTs) evaluating peri-operative antibiotic agents versus no antibiotic agents or placebo for laparoscopic cholecystectomy with any infection complication as an end point. Studies that compared two antibiotic agents that did not evaluate infection as the outcome or were not controlled were excluded. A total of nine RCTs published between 1997 and 2006 were included in the analysis, for a total of 1,437 patients. No significant publication bias was identified. One study compared antibiotic prophylaxis to no antibiotic and use of bag extraction of the gallbladder. However, this meta-analysis did not truly evaluate peri-operative antibiotic agents, because three of the nine studies used peri-operative and post-operative antibiotic therapy.

The composite infection rate was 2.4% in patients treated with prophylactic antibiotic agents compared with 3.6% without antibiotic agents (odds ratio [OR] 0.66; 95% confidence interval [CI], 0.35–1.24). The location of the infection site was clearly delineated in this meta-analysis. Rates of superficial site infections (1.6% compared with 2.3%; OR, 0.71; 95% CI, 0.34–1.48) and rate of intra-abdominal infections (0.3% vs. 0.4%; OR, 1.03; 95% CI, 0.25–4.2) were not statistically different between patients who received prophylactic antibiotic agents and those who did not, respectively. Distant infections (defined as infections not associated with the abdomen or wounds, such as pneumonia or urinary tract infections) were also not statistically different between antibiotic agents or no antibiotic groups (0.8% vs. 2%; OR, 0.49; 95% CI, 0.13–1.81). This meta-analysis did include one article that included patients with cholecystitis [6], and no articles further defined groups at higher risk for infection.

Zhou et al. [7] next synthesized data on elective laparoscopic cholecystectomy and antibiotic prophylaxis in 2009. This analysis included 15 RCTs evaluating elective cases, identifying 2,961 patients. Exclusion criteria included studies that were comparisons between two antibiotic agents without a no-antibiotic agents arm, patients with cholecystitis, pancreatitis, jaundice, or concurrent antibiotic use for a separate infection. Some studies included in the meta-analysis excluded patients converted to open whereas others included them in their analysis. Eight of the 15 studies included antibiotic use both peri-operatively and post-operatively. This review found no difference in the rates of superficial or deep wound infections (22/1,494 [1.47%] vs. 26/1,467 (1.77%); OR, 0.79; 95% CI, 0.44–1.41), intra-abdominal or organ/space infections (0.2% vs. 0.07%; OR, 2.51; 95% CI, 0.35–17.84), or distant infections (0.4% compared with 0.6%; OR, 0.53; 95% CI, 0.41–1.27) with and without the use of prophylactic antibiotic agents, respectively.

The only Cochrane Review addressing this PICO was performed by Sanabria et al. [8] in 2010. This review included 11 RCTs and 1,664 patients. Articles including patients with cholecystitis were excluded, but three RCTs that gave antibiotic agents both pre-operatively and post-operatively were included. Risk of bias was high in many studies (allocation concealment high in seven trials, high risk of bias in allocation sequence in eight trials, blinded assessment was at high risk of bias in three trials, one study had no blinding, and all trials were found to have high risk of vested interest bias. Only one study was performed with intention to treat analysis. No studies reported on mortality, and there were no differences between a composite variable of superficial SSI, deep SSI, and organ/space infections (2.7% with antibiotic agents vs. 3.3% with no antibiotic agents; OR, 0.87; 95% CI, 0.49–1.54), or extra-abdominal infections (1.0% with antibiotic prophylaxis and 1.8% without; OR, 0.77; 95% CI, 0.41–1.46).

In recent years, multiple meta-analyses have been performed, each again with varying inclusion and exclusion criteria. In 2016, Liang et al. [9] conducted a meta-analysis of 21 RCTs. This group included only RCTs that compared antibiotic agents with no antibiotic agents, but again included a number of studies (6/21) that included both pre- and post-operative antibiotic administration. This analysis found that antibiotic prophylaxis was associated with a decreased incidence of the composite variable of superficial SSI, deep SSI, and organ/space infections (2 [2.7%] compared with no antibiotic [4.1%]; OR, 0.55; 95% CI, 0.38–0.79). This meta-analysis also reported a decrease in all infection types with antibiotic prophylaxis in elective laparoscopic cholecystectomy compared with no antibiotic (2.4% and 4.3%, respectively; mean difference, −0.16; 95% CI, −0.28 to −0.04). They found low rates of heterogeneity between trials for these outcomes. However, the majority of the reduction in risk of infection with antibiotic prophylaxis was from a single study by Matsui et al. [13] (weighted at 44%, the next highest weight was 8.4%). If this study was removed, the SSI rates were 3.1% with antibiotic prophylaxis and 4.2% without antibiotic prophylaxis, and the global infection rate was 2.9% and 3.0%. They did not report odds ratios with this study removed, but state the difference between groups is no longer significant. Hospital LOS was reported in nine RCTs, and antibiotic prophylaxis was associated with a decreased hospital LOS (mean difference, −0.16; 95% CI, −0.28 to −0.04). However, all studies were conducted prior to 2014, and mean hospital stay ranged from 1.03–3.69 days in the antibiotic group and 0.7–3 days in the no antibiotic group. There was significant heterogeneity in the studies evaluating LOS. In current practice, most elective laparoscopic cholecystectomies for symptomatic gallstones are performed as outpatient surgery, potentially minimizing clinical significance of this finding.

In 2018 three different meta-analyses were performed to evaluate whether antibiotic prophylaxis prior to elective laparoscopic cholecystectomy is beneficial. Kim et al. [10] performed a meta-analysis of 25 RCTs, as well as three prospective studies and three retrospective studies. They reasoned that including prospective and retrospective studies that were high quality would increase power of the analysis. This meta-analysis included six studies that evaluated both pre- and post-operative use of antibiotic agents in elective cholecystectomy, which would not be used in the standard definition of prophylaxis in clean-contaminated cases. The authors reported risk reduction analyses for RCTs, prospective and retrospective studies separately and as a pooled analysis. This group found that there was a slight, but significant benefit to antibiotic use in decreasing overall SSI in RCTs (relative risk [RR], 0.70; 95% CI, 0.53–0.94), with wide variation in risk ratios in prospective (RR, 0.12; 95% CI, 0.04–0.37) and retrospective studies (RR, 1.59; 95% CI, 0.30–8.32). Pooled analysis favored antibiotic use for reduction in SSI (RR, 0.67; 95% CI, 0.51–0.88). This effect was mostly related to superficial SSI, as when deep SSI were evaluated separately, there was no benefit for antibiotic use (RR, 1.0; 95% CI, 0.46–2.21). This group did not report on the effect of antibiotic prophylaxis on intra-abdominal or organ/space infections after laparoscopic cholecystectomy.

Matsui et al. [11] also conducted a meta-analysis in 2018, with similar findings to those of Kim et al. [10]. This group analyzed seven previous meta-analyses and included 22 separate RCTs. Again, this group included at least four studies with pre- and post-operative antibiotic administration, two studies could not be reviewed by the guideline authors because they were only available in the Chinese language. This group used both fixed and random effects modeling to calculate risk ratios for antibiotic agents compared with no antibiotic agents. The risk ratio for SSI in a fixed-effects model just reached statistical significance for slight benefit of antibiotic use (RR, 0.71; 95% CI, 0.51–0.99), but in random effect modeling this significance was no longer apparent (RR, 0.75; 95% CI, 0.53–1.07). Distant infection (defined as pneumonia, urinary tract infections, or other infection far from the surgical area) were also evaluated, and the authors found a lower risk ratio for antibiotic use compared with no antibiotic agents (fixed effects model: RR, 0.37; 95% CI, 0.19–0.73; random effects model: RR, 0.45; 95% CI, 0.22–0.92). The effect on intra-abdominal or organ/space infections was not reported.

Gomez-Ospina et al. [12] included RCTs that evaluated elective laparoscopic cholecystectomies comparing antibiotic agents to no antibiotic agents or placebo, but differed from previous studies as it specifically excluded studies that used antibiotic agents both pre- and post-operatively, in addition to excluding any studies that included patients with cholecystitis, were not randomized, and did not have an appropriate comparator. A total of 18 studies were included in the meta-analysis with 4,087 patients. For most studies, the authors concluded there was a low risk of bias but did give the caveat that many studies did not have enough information reported in their methods to assess fully for allocation, concealment, blinding, random sequence generation, performance, or detection bias. This group found that there were no differences for the risk of developing a SSI (superficial or deep) (risk difference [RD], −0.0; 95% CI, −0.01 to 0.01), intra-abdominal infection (RD for cefazolin, −0.0; 95% CI, −0.01 to 0.01; and ceftriaxone RD, 0.00; 95% CI, −0.04 to 0.04), or distant infections (cefazolin RD, 0.0; 95% CI, −0.01 to 0.01) for antibiotic prophylaxis versus no treatment.

The RCT conducted by Matsui et al. [13] requires further analysis, because it is the largest RCT and its inclusion leads to large effects in many meta-analyses. This study is an RCT that is further reviewed in PICO question 3, as it compares patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis who were randomized to one of two groups. Group 1 received three doses of 1 g of intravenous cefazolin, the first prior to surgical incision, and the second and third doses at 12 and 24 hours after surgery. Group 2 did not receive any antibiotic agents (pre-operatively or post-operatively). This was a relatively large RCT, with 504 patients in the antibiotic group and 505 patients in the no-antibiotic group. The number of SSIs in the no antibiotic group was quite high (14/505; 2.8%) compared with those who received antibiotic agents (4/505; 0.8%). The mean hospital stay was quite long in both groups: 3.6 days for the antibiotic group and 3.8 days in the no-antibiotic group. This study was included in the meta-analyses performed by Liang et al. [9], Kim et al. [10], and Matsui et al. [11] and accounted for the greatest weight in all these studies. As this study used prolonged antibiotic course, its inclusion in analyses evaluating prophylactic antibiotic treatment in outpatient, elective gallbladder surgery is questionable.

The most recent U.S. Centers for Disease Control and Prevention (CDC) guidelines recommend that additional antibiotic agents should not be administered after the surgical incision is closed in clean and clean-contaminated procedures, such as laparoscopic cholecystectomies. Many RCTs and meta-analyses reviewed here, however, include post-operative antibiotic agents in their definition of prophylaxis. In addition, many studies include distant infections in their analysis, which although important to evaluate, are not the indication for administration of prophylactic antibiotic agents. It raises the question about how these numbers would change in present day evaluations, where elective cholecystectomy is performed as an outpatient procedure, most often without urethral catheter drainage lowering risk for urinary tract infections and quick return to normal activities, which may decrease the rate of pneumonia. To best answer this question, a large multicenter, ideally multinational RCT with large number of patients needs to be performed using modern day practices.

Recommendation

We recommend against routine use of peri-operative antibiotic agents in low-risk patients undergoing elective laparoscopic cholecystectomy—Level 1A.

2. In adult patients undergoing laparoscopic cholecystectomy for acute cholecystitis, does administration of peri-operative antibiotic agents versus no antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

In current practice, the majority of patients admitted with acute cholecystitis are started on antibiotic agents at admission and continued until surgical intervention, with plans for an urgent cholecystectomy for definitive treatment of their cholecystitis. However, no large RCTs have been performed to evaluate benefit the of antibiotic agents or appropriate pre-operative duration in mild acute cholecystitis. Jaafar et al. [14] evaluated the use of pre-operative antibiotic agents on patient morbidity in acute cholecystitis, conducting a retrospective cohort analysis to assess the effect of antibiotic prophylaxis on post-operative infections using a large Swedish national registry of patients undergoing acute cholecystectomy between January 20016 and December 2010. All patients admitted to a hospital who underwent cholecystectomy prior to discharge for gallstone-related pathology were included. Pathologies were classified as complicated (pancreatitis, jaundice, and cholecystitis) and uncomplicated. Of a total of 13,911 procedures were included, 8,205 were for patients with acute cholecystitis. Of patients with acute cholecystitis, 82% received some form of pre-operative antibiotic agents (2,264 as prophylaxis given only one hour prior to operation, 4,469 pre-operatively on a scheduled bases). Sixty-three percent of all cases were completed laparoscopically, however, the rate of conversion specifically within the cholecystitis cohort was not reported.

Two primary outcomes of interest were likelihood of post-operative infections requiring antibiotic treatment (superficial SSI) and post-operative abscess (deep SSI or intra-abdominal infection) within 30 days of index operation. Using stepwise regression to control for patient and procedure related variables (patient gender, age, American Society of Anesthesiologists [ASA] grade, indication for operation, laparoscopic vs. open approach, length of operation, iatrogenic gallbladder perforation) they found there was no difference in rates of superficial SSI (adjusted odd ratio [OR], 0.84; 95% CI, 0.67–1.06) or post-operative abscess development (adjusted OR, 0.72; 95% CI, 0.47–1.11) with pre-operative antibiotic use or no-antibiotic use in patient with cholecystitis. The authors concluded pre-operative antibiotic agents offer no benefit in acute cholecystectomy. This study was limited by inherent bias from its retrospective review of a national registry. Study cohorts were heterogenous in patient comorbidity, disease severity, antibiotic use criteria, and regimen as well as procedure approach between groups.

This same group recently conducted a small RCT evaluating antibiotic treatment with piperacillin/tazobactam pre-operatively compared with placebo [15]. Seventy-nine percent of patients in the antibiotic group only received one dose just prior to operation, the remaining received more than one dose pre-operatively, with treatment varying from one hour to 72 hours. The primary outcome was post-operative infection, including superficial, deep SSI, intra-abdominal abscess, sepsis, or distant infection site. This was only reported as a composite variable in this study, not as individual infection sites, so no data regarding rates of SSI or intra-abdominal infection can be reported. The authors did not identify a difference in the rate of post-operative infections (including pneumonia, urinary tract infections, as well as SSIs) for the antibiotic group compared with the placebo group. Infectious complications were relatively high (9%) in the antibiotic group and 16% in the placebo group (p = 0.19). This study has flaws, in that 17 patients were lost to follow-up, five patients in the antibiotic group did not follow protocol (had continued prolonged antibiotic treatment), and 10 patients in the placebo group received antibiotic agents pre-operatively. The authors attempted to compensate for these issues with both an intention-to-treat and per-protocol analysis, but the results must be interpreted cautiously.

In an interesting study by Mazeh et al. [16], acute cholecystitis was treated medically, randomly assigning 84 patients to receive intravenous antibiotic agents or supportive care only, with planned elective cholecystectomy in six to eight weeks. Although this would no longer be the recommended treatment, the study does raise interesting questions about the benefit of antibiotic treatment in mild acute calculous cholecystitis (ACC). Patients were included if they met diagnostic criteria based on 2018 Tokyo Guidelines for grade I ACC and included the following: sonographic findings of cholecystolithiasis/sludge with at least 4 mm of wall thickening [17]. All patients were also required to have one of the following clinical criteria as well: epigastric or right upper quadrant pain, temperature higher than 38.0°C, or a white blood cell (WBC) count greater than 10,000/mm³. Patients were block randomized to either receive scheduled intravenous antibiotic agents until discharge (amoxicillin/clavulanate or ciprofloxacin/metronidazole for penicillin allergy) or supportive therapy alone. Any patient who failed to improve after 72 hours in the non-antibiotic group was prescribed antibiotic agents and any patient who decompensated in either group was sent for percutaneous cholecystostomy tube placement. Eight patients crossed over from the supportive group to antibiotic treatment but were analyzed with intention-to-treat.

There were no differences in recovery from cholecystitis, with no difference in LOS between patients who received antibiotic agents or supportive care only during the index admissions (3.9 vs. 3.8 days, respectively; p = 0.89) or any re-admissions (3.8 vs. 4.5 days, respectively; p = 0.67). Patients in the antibiotic group resumed a liquid diet earlier (1.7 vs. 2.2 days; p = 0.02) but resumption of regular diet was similar (2.8 vs. 3.2 days; p = 0.16). There was no difference in hospital re-admission rates between the antibiotic arm and the supportive arm (19% vs. 13%, respectively; p = 0.73,) cholecystostomy tube placement (12% vs. 5%, respectively; p = 0.43), or complications from surgery (0% vs. 7.7%, respectively; p = 0.16). These results must be interpreted with caution, as it is a single study with small numbers and did not address antibiotic agents around the time of cholecystectomy but does raise the question about the necessity for prolonged pre-operative antibiotic agents prior to cholecystectomy.

Currently, there is still no clear answer to the appropriate timing or need for antibiotic agents pre-operatively for patients undergoing laparoscopic cholecystectomy for acute cholecystitis. This is an area that future research should focus on. Currently, Loozen et al. [18] is hoping to address this through a multi-center randomized control non-inferiority trial that is finishing recruitment. The Perioperative Antibiotic Use in the Treatment of Acute Inflammation of the Gallbladder (PEANUTS II) trial was designed to assess whether peri-operative antibiotic prophylaxis is indicated to prevent post-operative infectious complications in patients undergoing emergency cholecystectomy for ACC. Planned enrollment includes up to 484 patients presenting with mild to moderate (Tokyo Guidelines grade I/II) ACC diagnosed on ultrasound or computed tomography. All patients will undergo standardized four-port laparoscopic cholecystectomy within 24 hours of enrollment. The treatment arm will receive 2 g of cefazolin 15 to 30 minutes prior to surgery. The primary end point is a composite of infectious complications including surgical site and deep organ/space infection, urinary tract infection, pneumonia, and bacteremia. Secondary end points include all individual elements of the primary end point and, in addition, all other complications, total hospital LOS, and total costs. Results from this trial should help close the knowledge gap surrounding role of antibiotic prophylaxis in emergent laparoscopic intervention for mild to moderate ACC.

Recommendation

As current practice and 2018 Tokyo Guidelines [15] recommend treatment with antibiotic agents upon admission, we recommend use of peri-operative antibiotic agents for patients undergoing laparoscopic cholecystectomy for acute cholecystitis—Level 2C.

3. In adult patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis, does administration of post-operative antibiotic agents versus no post-operative antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

We were only able to identify one study that specifically evaluated the effect of post-operative antibiotic agents compared with only prophylactic antibiotic (one dose before surgery) on outcomes in laparoscopic cholecystectomy. Chauhan et al. [19] performed a randomized trial comparing patients undergoing elective laparoscopic cholecystectomy who either received pre-operative ceftriaxone (112 patients) and no post-operative antibiotic agents, with a group that received pre-operative ceftriaxone followed by ceftriaxone for two days post-operatively (98 patients). Patients with cholangitis, obstructive jaundice, or biliary pancreatitis were excluded. In addition, patients who received antibiotic agents within two weeks prior to surgery, underwent recent endoscopy, or endoscopic retrograde cholangiopancreatography in the past month were excluded. This study found that post-operative antibiotic agents were not associated with a decrease in SSIs (1.8% in patients receiving only pre-operative antibiotic agents, compared with 3.0% receiving post-operatively as well; p = 0.66). Bile spillage rates were similar between groups, as were patient's ages, body mass indexes, and rates of diabetes mellitus.

Other studies have compared no antibiotic agents to longer duration of peri-operative antibiotic agents. Koc et al. [20] conducted a prospective, double-blind, randomized analysis of 92 patients undergoing elective laparoscopic cholecystectomy at a single center in Ankara, Turkey, from February 2001 to March 2002. Patients were excluded if they had an allergy to β-lactam/cephalosporin, recent antibiotic use, leukocytosis, obstructive jaundice, pancreatitis, hepatic disease, prosthetic valves, or were deemed high risk for infection. Patients were randomly assigned to peri-operative antibiotic agents (2 g cefotaxime prior to incision and an additional intravenous dose at 24 hours) compared with no peri-operative antibiotic agents (normal saline). Baseline characteristics were similar between groups (mean age, 47–50; >50% male; operating room time (∼70 min); ASA scores; bile spillage (∼20%); hospital LOS (average 5 days); diabetes mellitus; and infected bile). Biliary aerobic and anaerobic cultures were obtained by needle aspiration prior to gallbladder dissection on all cases.

Patients were evaluated by a surgeon at seven to 10 days post-operatively and followed for one month after surgery. The overall rate of post-operative SSI was 2.1% (2/92 total analyzed patients). There was no difference in SSI rates between the no antibiotic and the peri-operative antibiotic groups, each group 1 patient develop a SSI (2%), no data were reported for rates of intra-abdominal infections. The average hospital LOS was five days, longer than the majority of laparoscopic cholecystectomies performed for symptomatic cholelithiasis. There were no deaths. Biliary cultures were positive in 10% of patients, most commonly growing Pseudomonas, Klebsiella, and Escherichia coli.

Multivariable analysis demonstrated increased age, diabetes mellitus, and colic within 30 days of surgery were independent factors associated with infectious complications. Authors also noted bile microbiology did not predict post-operative infectious complications. This was a small study with potential for selection bias, as 112 patients were initially randomized, 20 of whom were excluded from analysis for protocol violations.

The largest study was performed by Matsui et al. [13] and was an RCT of 1,037 patients undergoing elective laparoscopic cholecystectomy for gallstones or polyps at Kansai Medical University in Japan from March 2007 to May 2013. Patients >18 years old were excluded if were undergoing concurrent surgery, had an antibiotic allergy, or had severe comorbidities. Patients were randomized to receive no antibiotic agents versus pre-operative and post-operative antibiotic agents (1 g intravenous cefazolin just prior to skin incision and two additional doses at 12 and 24 hours post-operative). Baseline characteristics of both groups were similar in regard to age, gender, presence of gallstones, operative time >60 minutes (>50%), and rates of biliary spillage (∼20%). All patients underwent urine catheterization during surgery, had specimens removed with a plastic bag, and skin closed with staples.

Primary outcome included operative infections (further broken into subgroups of wound infections (superficial or deep SSIs) and subhepatic abscesses) or distant infection with secondary end points of hospital LOS and post-operative costs. All patients were evaluated for follow-up of at least eight days. There were no deaths reported. Overall rate of infection was lower for the peri-operative antibiotic group (1.2%) compared with the no antibiotic group (6.7%) in the intention to treat analysis. The no antibiotic group had higher rates of superficial and deep SSIs (2.6% vs. 0.8%; p = 0.02), and distant infections (3.2% vs. 0.2%). The rate of subhepatic abscesses did not differ between groups (0.2% in no antibiotic agents vs. 0% antibiotic group; p = 1). Mean hospital LOS was statistically longer in the no antibiotic group (3.81 days compared with 3.55 days; p = 0.009). As discussed in PICO 1, this study must be interpreted with the caveats of the long stays, as the long hospital stay may have affected the risk of infection post-operatively, compared with the outpatient setting.

Darzi et al. [21] conducted a double-blind, placebo-controlled randomized trial of 429 patients undergoing elective laparoscopic cholecystectomy from March 2012 through 2015 at four hospitals in Babol, Iran. Patients aged 18–75 with no history of abdominal surgery and who did not have evidence of choledocholithiasis, cholangitis, pancreatitis, diabetes mellitus, antibiotic allergy, and had not received antibiotic agents in the past seven days were randomized to no antibiotic agents (normal saline) or to receive peri-operative antibiotic agents (intravenous cephazolin) 30 minutes prior to anesthesia and subsequently at six and 12 hours post-operatively.

Baseline characteristics were similar between groups (approximately 90% female; average age early 40s; 7% gallbladder rupture; average operating room time approximately 35 minutes). Patients underwent weekly post-operative clinical follow-up for one month. Overall SSI rate was 1.9% with no statistical difference between the groups (2.0% placebo vs. 1.7% peri-operative antibiotic agents). There was an eight-fold increase in risk of developing an SSI if there was noted to be bile spillage during the case. Average LOS was one day for both groups. There were no recorded deaths. The authors concluded that use of peri-operative cefazolin does not lower rate of SSI.

Recommendation

We recommend against use of post-operative antibiotic agents after elective laparoscopic cholecystectomy for symptomatic cholelithiasis—Grade 2C.

4. In adult patients undergoing laparoscopic cholecystectomy for mild or moderate (Tokyo Guidelines grade I or II) cholecystitis, does administration of post-operative antibiotic agents versus no post-operative antibiotic agents decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

In 2013, Rodríguez-Sanjuán et al. [22] performed a prospective, observational study of 287 consecutive patients (60.6% male; mean age 67.8 years) meeting criteria for Tokyo Guidelines grade II cholecystitis operated on within 72 hours at a single center in Spain. Additional inclusion criteria were at least 30-day follow-up, no biliary leaks or requirement for radiologic or operative intervention for biliary collections of peritonitis, and no pre-existing SSI. Laparoscopic cholecystectomy occurred in 73.9% of cases. Empiric antibiotic therapy was started before surgery and continued post-operatively. The most common antibiotic used was piperacillin/tazobactam (56.1%), followed by amoxicillin/clavulanate (20.9%). The attending surgeon selected the antibiotic and duration of therapy. Infection risk was assessed using the National Nosocomial Infections Surveillance (NNIS) score. Surgical site infection definitions were based on CDC/NHSN criteria. Patients were classified into three groups according to duration of therapy: group 1 (0–4 days; 15.7%); group 2 (5–7 days; 26.1%); and group 3 (>7 days; 58.2%).

Analysis of baseline demographics and comorbidities found lower age, NNIS scores, use of an open approach, conversions to open surgery, and use of piperacillin/tazobactam versus amoxicillin/clavulanate in group 1. Positive cultures were found in 98 of 152 available patients (64.5%). Overall morbidity, including infections, bleeding, hernias, and nonsurgical (cardiac, pulmonary) complications occurred in 16.4%. There were no cases of Clostridium difficile infection. Multivariable analysis of infection risk did not find differences between treatment groups. The authors concluded there is no benefit of continuing post-operative antibiotic treatment beyond four days and questioned the utility of post-operative antibiotic agents in mild cases of cholecystitis. Limitations include a non-prospective design, heterogeneity in antibiotic selection, and single center experience.

In 2014, Regimbeau et al. [23] published the results of an open-label, non-inferiority, randomized clinical trial of 414 adult patients meeting Tokyo Guidelines grade I or II criteria for ACC treated with cholecystectomy at 17 French medical centers between 2010 and 2012. Exclusion criteria included acalculous or grade III cholecystitis, choledocholithiasis, cholangitis, peritonitis, pancreatitis, cirrhosis, suspected biliary cancer, pregnancy or breast feeding, or a β-lactam allergy. All patients received amoxicillin/clavulanate at the time of diagnosis and until surgery.

Choice between laparoscopic or open cholecystectomy, with or without intra-operative cholangiography or abdominal drainage was dictated by the surgeon. Patients were randomly assigned via computer-generated code to no post-operative antibiotic agents or continuation of the amoxicillin (oral or intravenous depending on diet) regimen three times daily for five days. Primary outcome was risk of infection (which was defined by clinical, biochemical, morphologic features, possible bacteriologic data) either at the surgical site (inclusive of SSI and organ/space or intra-abdominal abscess) or at a distant site within four weeks. Secondary outcomes assessed included post-operative morbidity, re-admission rate, LOS, and mortality. A power analysis determined a sample size of 196 patients per group with a noninferiority margin of 11% with an expected infection rate of 18.5% in the antibiotic group.

The treatment groups were well-balanced in terms of baseline demographic and clinical characteristics. Fifty percent of the nontreatment group and 47% of the treatment group had grade I cholecystitis. Bile cultures were negative in 60.9% of patients. The intention-to-treat analysis showed that the infection rates were 17% (35/207) and 15% (31/207) in the antibiotic and non-treatment groups, respectively. The per-protocol analysis showed infection rates of 13% for both groups. Based on the non-inferiority margin of 11%, the authors concluded lack of post-operative antibiotic agents is not associated with greater risk of infections. Limitations of this study included absence of placebo and blinding, high proportion of protocol violations, and potential underestimation of the true duration of antibiotic agents as the majority of patients were sent home with non-standardized prescriptions.

In 2017, Loozen et al. [24] reported the results of a randomized, controlled, non-inferiority trial of 150 adult patients meeting Tokyo Guidelines grade I criteria for acute cholecystitis treated with cholecystectomy at six major teaching hospitals in The Netherlands between 2012 and 2014. Additional inclusion criteria included Acute Physiology and Chronic Health Evaluation (APACHE) II score between one and six on enrollment and performance of a laparoscopic cholecystectomy within 24 hours after randomization. Exclusion criteria included age younger than 18 years, pregnancy, antibiotic administration before cholecystitis diagnosis, allergy to study antibiotic agents, need for endoscopic retrograde cholangiopancreatograph (ERCP) at admission, or abnormal liver function tests with suspicion of acute cholangitis. All patients received a single prophylactic dose of cefazolin (2 g, intravenous) 15–20 minutes before surgery. After surgery, patients were block randomlys assigned using an online generator to receive either no post-operative antibiotic agents (standard group) or three days of cefuroxime (750 mg, intravenous) and metronidazole (500 mg, intravenous) three times daily for three days.

The primary end point was a composite of all infections (SSI, intra-abdominal abscess, and distant infections) and complications within 30 days of surgery. Secondary end points included hospital LOS and all other complications as assessed by Dindo-Clavien grades. A power analysis determined a sample size of 78 per group with a non-inferiority margin of 5%.

Baseline characteristics were similar between groups. A total of 2.7% of laparoscopic procedures were converted to open (p = NS). Seven standard group patients had gallbladder empyema versus 10 patients in the extended group (p = NS). There were no differences between groups in terms of bile spillage, stone loss, or rates of positive bile cultures. The intention-to-treat analysis showed that 4% (3/77) of patients in the extended group and 4% (3/73) developed post-operative complications. The per-protocol analysis revealed a 4% complication rate in both groups. Non-inferiority of the standard prophylaxis treatment could not be proven because the margin of 5% fell within the confidence interval. None of the secondary outcome differences achieved significance except hospital LOS, which was longer in the extended group (3 vs. 1 day; p < 0.001). The authors concluded that considering the low overall infection rate, extended antibiotic prophylaxis seems clinically irrelevant. Future studies would likely require approximately 600 patients to show non-inferiority. Limitations included lack of blinding and restricted antibiotic choice and route of administration.

Kim et al. [25] published a prospective, double-blind RCT of 188 adult patients (50.5% male; mean age 52) meeting Tokyo Guidelines grade I or II criteria for acute cholecystitis treated with cholecystectomy at five hospitals in Korea between 2015 and 2016. Exclusion criteria included immunodeficiency, concurrent operation on other organs, suspicion of cancer or hollow organ injury, previous upper abdominal surgery, exploration of the common bile duct, biliary peritonitis, gallbladder perforation, peri-cholecystic abscess, or conversion to laparotomy. All patients received pre-operative cefoxitin (1 g, three tims per day, intravenous) beginning at diagnosis, 30 minutes before surgery, and once intra-operatively.

After surgery, patients were randomly assigned 1:1 via computer generated random numbers to either a placebo of normal saline (10 mL, three times per day, intravenous) followed by ascorbic acid (1,000 mg, twice daily, orally) for up to three days after discharge or cefoxitin (1 g, three times per day, intravenous) followed by cefaclor (250 mg, twice daily, orally) upon starting diet and continuing for three days after discharge. Patients were assessed for SSI up to four weeks after discharge. The primary end point was incidence of SSI and other infectious morbidities (again as a composite outcome variable), whereas secondary end points were hospital LOS, post-operative pain score, non-infectious morbidities, and re-admission. A power analysis determined a sample size of 100 per group to show significance with an expected incidence of SSI of 18.5%.

Baseline demographics and characteristics, duration of pre-operative antibiotic agents, acute cholecystitis grade, and pre-operative inflammatory markers were similar between groups. Mean operative time, blood loss, type of surgery, LOS, and pain scores were also similar between groups. Overall infectious complications occurred in 7.4% of placebo patients and 8.6% of antibiotic patients (p = 0.79). Each group had four cases of SSI (p = 1). Non-infectious complications were similar between groups, as were re-admissions. There was a nonsignificant trend in longer hospital LOS in the antibiotic group (p = 0.074). More than 90% of patients in each group completed the study without having to cross-over because of fever or SSI. The authors concluded absence of post-operative antibiotic agents in patients undergoing cholecystectomy for mild or moderate acute cholecystitis does not increase the incidence of infections. Limitations included non-standardization of the pre-operative period and no analysis of the cost of hospitalization.

In 2018, de Santibañes et al. [26] reported results of a prospective, double-blind, randomized controlled, non-inferiority trial of 195 patients meeting revised Tokyo Guidelines grade I or II criteria for ACC treated with laparoscopic cholecystectomy plus intra-operative cholangiogram at a single center in Argentina between 2014 and 2017. Other inclusion criteria included age between 18 and 85 years old, and non-pregnant and non-lactating females. Exclusion criteria included hypersensitivity to study antibiotic agent or placebo, grade III cholecystitis, liver or gallbladder abscess, cholangitis, biliary peritonitis, cancer, common bile duct stones, conversion to laparotomy, acquired immune deficiency syndrome (AIDS), patients who had undergone transplantation, and previous treatment with antibiotic agents for more than five days. All patients received hydration, proton pump inhibitors, analgesics, and ampicillin/sulbactam intravenously every six hours until surgery, which occurred within five days after admission. Using a statistical randomizer, consecutive patients were assigned to receive amoxicillin/clavulanate (1 g orally every eight hours) for five days after surgery (experimental group) or lactose placebo (1 g orally every eight hours) for five days after surgery (control group).

Patients were monitored at an outpatient clinic between seven and 30 days after surgery. The primary end point was any infection occurring within 30 days after surgery. Secondary end points included hospital LOS, re-admissions, re-interventions, and overall mortality. A power analysis determined a sample size of 150 per group with a non-inferiority margin of 5% and an expected infection rate of 3% in the antibiotic group.

Baseline demographics and characteristics, ultrasound results, length of surgery, and number of intra-operative complications were similar between groups. More patients in the experimental group presented with fever and a Murphy sign, this group also had a higher mean baseline platelet count. The per-protocol analysis revealed infectious complications in 5.8% of placebo patients and 6.6% of antibiotic patients (p = 0.81). The confidence interval included the 5% non-inferiority margin set during study design. The intention-to-treat analysis also did not find differences in the primary end point between groups. Neither the per-protocol nor intention-to-treat analyses revealed differences in any of the secondary end points between experimental groups. The authors concluded that use of post-operative antibiotic agents appears unjustified and does not result in fewer infectious complications or other morbidities. The main limitation was that the study was underpowered to prove non-inferiority.

Recommendation

We recommend against use of post-operative antibiotic agents in patients undergoing laparoscopic cholecystectomy for mild or moderate acute cholecystitis—Level 1B.

5. In adult patients undergoing cholecystectomy for severe (Tokyo Guidelines grade III) cholecystitis, what is the appropriate duration of post-operative antibiotic agents to decrease morbidity (hospital LOS, SSI, other infection including organ/space infection or intra-abdominal infections) or mortality?

High-quality evidence specifically evaluating optimal duration of antibiotic therapy to reduce morbidity and mortality in adults with severe acute cholecystitis undergoing cholecystectomy is limited. As discussed, two RCTs evaluated post-operative antibiotic administration versus no administration for patients undergoing cholecystectomy for mild (grade I) or moderate (grade II) acute cholecystitis [23,24]. All patients received pre-operative or peri-operative antibiotic agents. Neither study demonstrated clinically significant differences in infection rates. Based on these findings and a lack of data for severe cholecystitis, expert opinion suggests continuing antimicrobial therapy for four to seven days after source control of the infection (Tokyo Guidelines 2018) [17].

In 2015, Sawyer et al. [27] published the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial that included patients with acute cholecystitis. In this prospective, multi-center trial, the authors randomly assigned patients with complicated intra-abdominal infection and adequate source control to receive either antibiotic agents until two days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or a fixed course of antibiotic agents for four ± one days (experimental group). The primary outcome was a composite of SSI, recurrent intra-abdominal infection, or death within 30 days after the source control procedure. Secondary outcomes included duration of therapy and rates of subsequent infections.

The baseline patient and index infection characteristics show that 31 of 260 subjects (11.9%) in the control group and 25 of 258 subjects (9.7%) in the experimental group had their index infection in the biliary tree, including the gallbladder. Although there are no additional details regarding the severity of the biliary infections, mean APACHE II scores for the control and experimental groups were not significantly different at 9.9 ± 0.4 and 10.3 ± 0.4, respectively. It should be noted that the range of APACHE II scores extended from 0 to 71, so patients with severe cholecystitis may be included in the analysis. Additionally, the mean maximum WBC counts per cubic millimeter for the control and experimental groups were not significantly different at 15,600 ± 0.4 and 17,100 ± 0.7, respectively.

In terms of outcome measures, the authors reported no between-group differences in the composite primary end point, or individual primary end points. Diagnosis of SSI and recurrent intra-abdominal infection occurred significantly later in the control group. The median duration of antibiotic therapy was significantly shorter in the experimental group (4.0 days) versus the control group (8.0 days; 95% CI, −4.7 to −3.3; p < 0.001). No differences between groups were identified with rates of extra-abdominal infections or secondary infections with resistant pathogens.

Results of the STOP-IT trial are consistent with the Tokyo Guidelines 2018, in that patients with intra-abdominal infections (including severe acute cholecystitis) who can achieve source control derive no additional benefits from prolonged courses of post-operative antibiotic agents. When evaluating these data in the context of data for mild or moderate acute cholecystitis, it stands to reason that for adult patients undergoing source control with cholecystectomy for severe cholecystitis, the optimal duration of post-operative antibiotic therapy falls somewhere between no additional treatment and a maximum duration of four days. Further studies are warranted to better define the risks and benefits of post-operative antibiotic therapy for patients with this specific disease process.

Recommendation

Patients with severe (Tokyo Guidlelines grade III) cholecystitis undergoing cholecystectomy should receive a maximum of four days of antibiotic agents, although a shorter duration may also be safe—Level 1B.

Antibiotic Prophylaxis in Special Circumstances

Gallbladder disease has many nuances that are difficult to account for in research studies. We briefly discuss some of these special circumstances for completeness, including antibiotic prophylaxis when conversion to open procedure is required, in the setting of ERCP is performed, and when cholecystostomy tube is placed.

Conversion to open

Converting to an open cholecystectomy is occasionally required because of patient anatomy or underlying pathology. Given the larger surface area of the wound and higher reported rates of SSI, infection risk may differ for open versus laparoscopic cases. Unfortunately, conversion to open surgery was often an exclusion criterion for the studies included in our review or not reported in analysis. Many older studies reported the lower risk of SSI with laparoscopic cholecystectomy [28 –31]. More recent data regarding SSI in open cholecystectomy are limited given the low rates of conversion. Warren et al. [3] performed one of the largest more recent reviews, retrospectively evaluating 66,566 cholecystectomies performed between 2003 and 2014. Two percent of cholecystectomies in their study were performed open, with half converted to open after attempted laparoscopic procedure, and half performed as a planned open procedure. The risk of SSI was higher after open procedures, 4.7% compared with 0.6% in laparoscopic procedure, but was not different between planned open procedures and converted procedures.

In our review, we could not identify any studies specifically addressing antibiotic prophylaxis for conversion to open cholecystectomy. When open cholecystectomy was standard of care, recommendations for antibiotic prophylaxis remained similar to current recommendations for open, clean-contaminated procedures. In guidelines published in 1993 and 1998 guideline, biliary procedures were recommended to have antibiotic prophylaxis appropriately timed prior to the procedure, with re-administration as needed during the procedure without continuation after procedure completion [32,33].

When conversion to open occurs because of more severe infection such as grade II or III cholecystitis or associated abscess, surgeons may prolong antibiotic courses, fearing increased risk of infection. This situation was addressed by the STOP IT trial [27], which found that prolonged antibiotic agents after contaminated or dirty procedures does not lead to improvement in post-operative infectious complications.

Surgeons should follow standard antibiotic prophylactic guidelines for open procedures and not prolong antibiotic duration simply because of conversion to open procedure. The 2017 CDC guidelines for prevention of SSI recommends that for clean and clean-contaminated procedures, additional prophylactic antimicrobial agent doses should not be administered after the surgical incision is closed in the operating room irrespective of the presence of a drain [34]. If conversion occurs in treatment of symptomatic cholelithiasis, or grade I or II cholecystitis, pre-operative and intra-operative prophylaxis should be given for the clean-contaminated case and no post-operative antibiotic agents given. If conversion to open occurs for grade III cholecystitis, we recommend not continuing post-operative antibiotic agents more than four days.

Antibiotic prophylaxis when performing cholecystectomy with cholecystostomy tube in place

Insertion of percutaneous cholecystostomy tube (PCT) remains the recommended treatment for patients who are not surgical candidates because of comorbidities (ASA 3 or greater, or Charlson comorbidity index 4 or greater) or with organ dysfunction because of cholecystitis that is too severe to allow surgical intervention as recommended in the Tokyo Guidelines 2018 [35]. Lu et al. [36] conducted a large review of patients with acute cholecystitis treated with either cholecystectomy or PCT. A total of 4.7% of patients were treated with PCT, the remaining underent cholecystectomy. Patients treated with PCT were older, more likely to be male, and had higher comorbidity scores. A PCT was associated with 25% rate of recurrence, higher rate of mortality, and longer hospital stays, however, it also was associated with lower rate of in-hospital complications. Once a PCT is in place, optimal antibiotic duration has only limited data, but two studies have compared antibiotic duration of short duration (7 days or less) and long duration (more than 7 days) [37,38]. These studies found no significant difference in length of drainage, hospital LOS, rates of interval cholecystectomy, recurrent cholecystitis, or mortality. Both groups concluded that shorter courses of antibiotic agents for treatment of cholecystitis with PTC was safe.

Unfortunately, we were unable to identify any study evaluating use of antibiotic agents at the time of interval cholecystectomy if the PTC is still in place. Because no data are available and a foreign body is present, we would recommend the use of appropriate pre-operative antibiotic agent for clean-contaminated biliary procedure, without continuing antibiotic agents post-operatively unless an abscess or grade III cholecystitis.

Antibiotic agents and ERCP

Pre-operative ERCP has been reported to be a risk factor for SSI after laparoscopic cholecystectomy [3]. However, reasons for this observation have not been definec clearly. The different patient population (those with pancreatitis or cholangitis) who undergo ERCP around the time of their cholecystectomy may select for patients at greater risk of infection or higher rates of bacteremia. Loor et al. [39] reported a higher rate of SSI in patients undergoing cholecystectomy after ERCP, but no difference in SSI when ERCP was performed under the same anesthestic. Currently, the Tokyo Guidelines recommend four to seven days of antibiotic agents after ERCP for cholangitis. However, the 2018 guidelines no longer recommend prophylactic antimicrobial use for elective ERCP [17]. Newer literature shorten the duration of post-ERCP antibiotic agents, with recent studies publishing no difference in outcomes with three days of antibiotic agents [40,41]. When cholangitis is not present but ERCP is performed around the time of cholecystectomy there is no study specifically evaluating antibiotic use. Current guidelines from the European Society of Gastrointestinal Endoscopy and American Society for Gastrointestinal Endoscopy recommend against antibiotic prophylaxis for ERCP performed for bile duct obstruction in the absence of cholangitis unless there is incomplete drainage [42 –44]. We would recommend, conditionally, given the low grade of evidence in regards to ERCP and cholecystectomy, that no change in antibiotic prophylaxis be undertaken around the time of cholecystectomy, unless cholangitis is present, and that the surgeon should use prophylaxis based on the grade of cholecystitis.

Conclusions

Cholecystectomy is one of the most common general surgery procedures and is utilized to treat a wide range of gallbladder disease. Given the high frequency of this procedure, it is somewhat surprising that better data are not available for evidence-based guidelines on appropriate antibiotic use in patients undergoing cholecystectomy. Additional studies with clearly defined patient populations and comparable outcomes are needed to better evaluate the most appropriate timing and duration of antibiotic use in patients undergoing cholecystectomy.

Footnotes

Funding Information

No funding source was used for this body of work.

Author Disclosure Statement

All authors have no conflicts of interests or financial disclosures. All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.

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