Abstract
Background
Acute calculous cholecystitis (ACC) is the most common complication of cholelithiasis. Laparoscopic cholecystectomy (LC) is the gold standard treatment in mild and moderate forms. Currently there is consensus for the use of antibiotics in the preoperative phase of ACC. However, the need for antibiotic therapy after surgery remains undefined with a low level of scientific evidence.
Methods
The CHART (Cholecystectomy Antibiotic Randomised Trial) study is a single-center, prospective, double blind, and randomized trial. Patients with mild to moderate ACC operated by LC were randomly assigned to receive antibiotic (amoxicillin/clavulanic acid) or placebo treatment for 5 consecutive days. The primary endpoint was postoperative infectious complications. Secondary endpoints were as follows: (1) duration of hospital stay, (2) readmissions, (3) reintervention, and (4) overall mortality.
Results
In the per-protocol analysis, 6 of 104 patients (5.8%) in the placebo arm and 6 of 91 patients (6.6%) in the antibiotic arm developed postoperative infectious complications (absolute difference 0.82 (95% confidence interval, −5.96 to 7.61, P = .81). The median hospital stay was 3 days. There was no mortality. There were no differences regarding readmissions and reoperations between the 2 groups.
Conclusion
Although this trial failed to show noninferiority of postoperative placebo compared to antibiotic treatment after LC for mild and moderate ACC within a noninferiority margin of 5%, the use of antibiotics in the postoperative period does not seem justified, because it was not associated with a decrease in the incidence of infectious and other types of morbidity in the present study.
The incidence of cholelithiasis in the adult population is 10%, and acute calculous cholecystitis (ACC) is the most common complication.
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Diagnosis and management of cholecystitis and cholangitis.
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Acute cholecystitis affects >20 million Americans annually, with costs in excess of $6.3 billon, constituting a major health burden that has increased >20% in the past 3 decades.
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The diagnostic criteria and severity assessment of ACC were well established in the Tokyo guidelines 2007
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According to this expert consensus, ACC is classified into 3 grades: mild, moderate, and severe. Laparoscopic cholecystectomy (LC) is the gold standard treatment in mild and moderate forms.
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TG13 surgical management of acute cholecystitis.
Currently there is consensus for the use of antibiotics in the preoperative phase of ACC, with controversies about its usefulness after the surgical treatment has been completed. Recent guidelines suggest that antibiotics should be administered only up to 24 hours after surgery for mild ACC and 4 to 7 days for moderate or severe forms.
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TG13 antimicrobial therapy for acute cholangitis and cholecystitis.
It has been suggested that a scheme with β-lactam/inhibitor of β-lactamase combinations would be adequate in patients with mild and moderate ACC, according to most frequently isolated germs.
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Despite this, the need for antibiotic therapy after surgery remains ill defined with a lack of high-quality evidence.
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Antibiotic use in acute cholecystitis: practice patterns in the absence of evidence-based guidelines.
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Antibiotic therapy in acute calculous cholecystitis.
Hence, we conducted a randomized controlled trial in patients undergoing LC for mild and moderate ACC, randomizing patients to receive antibiotics or placebo after surgery. The primary objective of the present trial was to assess whether antibiotic treatment after LC in mild or moderate ACC reduces the incidence of postoperative infectious complications. The hypothesis was that postoperative antibiotic treatment has no positive impact on the patient's outcome and therefore should not be indicated in this subset of patients.
Discussion
In this prospective, randomized trial with blinded patients and evaluators, we compared the use of extended antibiotic therapy versus placebo after LC for mild and moderate ACC. The analysis showed that the absence of extended antibiotics treatment was not associated with an increased risk of infectious complications and other types of morbidity. Moreover, both groups had similar results regarding hospital stay, reinterventions, and hospital readmissions.
LC is the gold standard treatment for mild and moderate forms of ACC, with around 120,000 cholecystectomies performed each year in the United States.
2Clinical practice. Acute calculous cholecystitis.
, 7- Yamashita Y.
- Takada T.
- Strasberg S.M.
- et al.
TG13 surgical management of acute cholecystitis.
Even though there is consensus to establish preoperative antimicrobial therapy on suspicion of infection, few studies have assessed the role of antibiotic therapy after LC in ACC. In addition, present guidelines propose to administer antibiotics during the postoperative course with a variable time period.
8- Gomi H.
- Solomkin J.S.
- Takada T.
- et al.
TG13 antimicrobial therapy for acute cholangitis and cholecystitis.
Regarding the type of antibiotic treatment, it has been suggested that a β-lactam/inhibitor of β-lactamase combination monoscheme would be adequate in patients with mild and moderate ACC without intraoperative complications such as bile peritonitis, cholangitis, gallbladder perforation, or abscesses.
8- Gomi H.
- Solomkin J.S.
- Takada T.
- et al.
TG13 antimicrobial therapy for acute cholangitis and cholecystitis.
, 9- Yoshida M.
- Takada T.
- Kawarada Y.
- et al.
Antimicrobial therapy foracute cholecystitis: Tokyo Guidelines.
, 10- Kanafani Z.A.
- Khalifé N.
- Kanj S.S.
- et al.
Antibiotic use in acute cholecystitis: practice patterns in the absence of evidence-based guidelines.
, 11- Fuks D.
- Cossé C.
- Régimbeau J.M.
Antibiotic therapy in acute calculous cholecystitis.
Based on these recommendations, we decided to use an AMC scheme for the group of patients who received postoperative antibiotics treatment, extending it for a period of 5 days. Despite this, we did not observe a reduction in the incidence of postoperative infectious complications. These findings yield similar results to recently published studies.
21- Regimbeau J.M.
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- Pautrat K.
- et al.
Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.
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Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.
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Outcomes of antibiotic prophylaxis in acute cholecystectomy in a population-based gallstone surgery registry.
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Systematic review of antibiotic treatment for acute calculous cholecystitis.
Delivering adequate preoperative antibiotic treatment to a patient with ACC and then removing the septic focus through a cholecystectomy seems to be a sufficient therapeutic strategy to definitively resolve this disease. This change in treatment paradigm leads to a more rational use of antibiotics, reducing bacterial resistance and the incidence of pseudomembranous colitis by
Clostridium difficile.
25Clostridium difficile infection.
Moreover, although the incidence of adverse events caused by medication in the group of patients receiving antibiotics was low, it is well described in the literature.
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Incidence of allergic reactions associated with antibacterial use in a large, managed care organisation.
Laparoscopic cholecystectomy for ACC is a low to medium complexity surgical procedure, with lower morbidity, mortality, and hospital stay rates compared to the open approach.
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Open versus laparoscopic cholecystectomy in acute cholecystitis. Systematic review and meta-analysis.
Several studies have found that early LC in patients with mild and moderate ACC is a safe and effective surgical strategy.
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Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, nct00447304).
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Early versus delayed cholecystectomy for acute cholecystitis, are the 72 hours still the rule? A randomized trial.
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Meta-analysis comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis.
, 31- Cao A.M.
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Early laparoscopic cholecystectomy is superior to delayed acute cholecystitis: a meta-analysis of case-control studies.
Following this therapeutic approach, all the patients in this series were operated within the first 5 days of admission. Early cholecystectomy has been shown to reduce morbidity, hospital stay, and costs with respect to late cholecystectomy (7–45 days) for ACC.
28- Gutt C.N.
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Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, nct00447304).
The surgical quality standards in this series are equal to or higher than those reported in the literature for the treatment of this pathology.
30- Wu X.D.
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- Liu M.M.
- et al.
Meta-analysis comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis.
, 31- Cao A.M.
- Eslick G.D.
- Cox M.R.
Early laparoscopic cholecystectomy is superior to delayed acute cholecystitis: a meta-analysis of case-control studies.
In all cases, an intraoperative cholangiography could be performed, without bile duct injuries. The mean duration of the surgeries was 90 minutes, with a 3-day hospital stay, without mortality, and with a very low reoperation and readmission rate.
The overall morbidity reported in the literature ranges from 15% to 30%, and surgical site infection is the most frequent complication.
32- Cao A.M.
- Eslick G.D.
- Cox M.R.
Early cholecystectomy is superior to delayed cholecystectomy for acute cholecystitis: a meta-analysis.
In our study, this incidence was around 5% and was higher than those reported in the literature. A recent meta-analysis reported an incidence of wound infection of 2.7% for early cholecystectomy and 4.1% for late cholecystectomy in acute cholecystitis.
31- Cao A.M.
- Eslick G.D.
- Cox M.R.
Early laparoscopic cholecystectomy is superior to delayed acute cholecystitis: a meta-analysis of case-control studies.
This fact could be explained by the strict follow-up of the patients in the present study. In spite of this, the use of antibiotics did not reduce the incidence of surgical site infections, as other studies have shown.
21- Regimbeau J.M.
- Fuks D.
- Pautrat K.
- et al.
Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.
, 22- Loozen C.S.
- Kortram K.
- Kornmann V.N.
- et al.
Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.
In a recent study, Regimbeau et al
21- Regimbeau J.M.
- Fuks D.
- Pautrat K.
- et al.
Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.
analyzed a total of 414 patients treated with 2 g of AMC in the postoperative period of cholecystectomies due to acute cholecystitis, without a decrease in the incidence of infectious complications. Although the study was randomized and included 17 medical centers in France, its main limitations were that there was no comparison with a placebo or a strictly blinded analysis of the results. In addition, the course of antibiotic therapy was nonstandardized, with a variable number of treatment days. There were also problems in the postoperative follow-up of patients, with a high proportion of protocol violations. On the other hand, both patients operated with conventional surgery (15%) and laparoscopic surgery (with a conversion rate of 10%) were included in the same analysis. These situations could generate doubts in the interpretation of results. Loozen et al
22- Loozen C.S.
- Kortram K.
- Kornmann V.N.
- et al.
Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.
randomized 156 patients to receive a single preoperative dose of cefazolin (2,000 mg) versus antibiotic prophylaxis for 3 days after cholecystectomy (intravenous Cefuroxima 750 mg plus metronidazole 500 mg 3 times daily). The main conclusion was that standard single-dose antibiotic prophylaxis did not lead to an increase in postoperative infectious complications. However, to demonstrate the noninferiority of this treatment, a sample size of almost 600 patients would have been necessary. Given the low rate of infection in LC it would be questionable if such a study were necessary. From a methodologic point of view, our study solves many of the problems previously discussed. First, our antibiotic treatment with AMC was compared with a placebo, and both the patient and the investigators were blinded until the end of the study. The duration of the antibiotic treatment was set for 5 consecutive days for both branches, with a high adherence to the protocol. At the same time, patients were strictly scheduled for clinical controls at 7 and 30 postoperative days, with a complete follow-up of all patients recruited.
The main limitation of this trial is that although we found no differences between the results of the primary and secondary endpoints raised for the study, the noninferiority of the placebo compared with antibiotics for development of infectious complications could not be proven because the noninferiority margin of 5% lay within the 95% confidence interval. Therefore, our study was finally underpowered to demonstrate noninferiority, which would have required a sample size of 682 patients. Wound infection was the most frequent complication of the present series, with the same distribution in both arms of treatment. The clinical relevance of this type of complication for a LC would be debatable because it is an infection in a small wound, which had no impact on the postoperative evolution of the patients. On the other hand, we estimated the probabilities of including the noninferiority limits in the confidence intervals of the risk difference, which ranged between 52.5% and 73.8%. The first scenario is reasonably optimistic for its effect on the standard errors of the difference, while the second scenario is more conservative in the same sense and probably looks more realistic. Finally, other studies used a noninferiority margin of 11%, and the associated wide confidence intervals could have masked a possible difference in postoperative infections between the compared groups.
21- Regimbeau J.M.
- Fuks D.
- Pautrat K.
- et al.
Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.
Since the noninferiority margin is arbitrarily set, if we had applied a larger margin for our study (eg, ≥7), based on our results we would have concluded noninferiority in our final analysis.
In conclusion, although this trial failed to show noninferiority of postoperative placebo compared to antibiotic treatment after LC for mild and moderate acute cholecystitis within a noninferiority margin of 5%, the use of antibiotics in the postoperative period does not seem justified because it was not associated with an increased risk of infectious complications and other types of morbidity in the present study. Moreover, both groups compared had similar results regarding hospital stay.
Article info
Publication history
Published online: March 02, 2018
Accepted:
January 22,
2018
Received in revised form:
January 8,
2018
Received:
November 22,
2017
Footnotes
Author Statement: The concept of the study was derived from MDS. This study was designed by PP, JG, FA, DG, CE, VA, LB, LS, NC, EDS, JP, RSC, OM AND MDS. The article was written by PP, JG, FA, VA, DG, CE AND MDS. DG, VA, CE, and MDS performed the sample size calculation and planned the statistical analyses. PP, JG, FA, DG, CE, VA, LB, LS, NC, EDS, JP, RSC, OM AND MDS were involved in trial implementation and critically revised the manuscript. PP, JG, FA, DG, CE, VA, LB, LS, NC, EDS, JP, RSC, OM AND MDS, give final approval of the version to be published.
Copyright
© 2018 Elsevier Inc. All rights reserved.