Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy

Antibiotic prophylaxis for patients undergoing elective

laparoscopic cholecystectomy (Review)

Sanabria A, Dominguez LC, Valdivieso E, Gomez G

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 12

http://www.thecochranelibrary.com

Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 1 Surgical site infection. 28

Analysis 1.2. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 2 Extra-abdominal

infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.3. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 3 Surgical site infection

(Intention-to-treat analysis worst-best case scenario). . . . . . . . . . . . . . . . . . . . . 30

Analysis 1.4. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 4 Surgical site infection

(Intention-to-treat analysis best-worst case scenario). . . . . . . . . . . . . . . . . . . . . 31

31APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iAntibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy (Review)


[Intervention Review]

Antibiotic prophylaxis for patients undergoing electivelaparoscopic cholecystectomy

Alvaro Sanabria1 , Luis C Dominguez2 , Eduardo Valdivieso3 , Gabriel Gomez3

1Department of Surgery, School of Medicine-Universidad de La Sabana, Fundación Abood Shaio, Chia, Colombia. 2Department of

Surgery, Hospital Universitario San Ignacio - Pontificia Universidad Javeriana, Bogota, Colombia. 3Department of Surgery, School of

Medicine-Pontificia Universidad Javeriana, Bogota, Colombia

Contact address: Alvaro Sanabria, Department of Surgery, School of Medicine-Universidad de La Sabana, Fundación Abood Shaio,

Campus Puente del Comun km 21 via Chia, Chia, Cundinamarca, Colombia. [email protected].

Editorial group: Cochrane Hepato-Biliary Group.

Publication status and date: New, published in Issue 12, 2010.

Review content assessed as up-to-date: 19 August 2010.

Citation: Sanabria A, Dominguez LC, Valdivieso E, Gomez G. Antibiotic prophylaxis for patients undergoing elec-

tive laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD005265. DOI:

10.1002/14651858.CD005265.pub2.


A B S T R A C T

Background

Cholecystectomy is a common surgical procedure. In the open cholecystectomy area, antibiotic prophylaxis showed beneficial effects,

but it is not known if its benefits and harms are similar in laparoscopic cholecystectomy. Some clinical trials suggest that antibiotic

prophylaxis may not be necessary in laparoscopic cholecystectomy.

Objectives

To assess the beneficial and harmful effects of antibiotic prophylaxis versus placebo or no prophylaxis for patients undergoing elective

laparoscopic cholecystectomy.

Search strategy

We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CEN-

TRAL) in The Cochrane Library (Issue 3, 2010), MEDLINE (1985 to August 2010), EMBASE (1985 to August 2010), SCI-EXPANDED(1985 to August 2010), LILACS (1988 to August 2010) as well as reference lists of relevant articles.

Selection criteria

Randomised clinical trials comparing antibiotic prophylaxis versus placebo or no prophylaxis in patients undergoing elective laparoscopic

cholecystectomy.

Data collection and analysis

Our outcome measures were all-cause mortality, surgical site infections, extra-abdominal infections, adverse events, and quality of life.

All outcome measures were confined to within hospitalisation or 30 days after discharge. We summarised the outcome measures by

reporting odds ratios and 95% confidence intervals (CI), using both the fixed-effect and the random-effects models.

1Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy (Review)


mailto:[email protected]

Main results

We included eleven randomised clinical trials with 1664 participants who were mostly at low anaesthetic risk, low frequency of co-

morbidities, low risk of conversion to open surgery, and low risk of infectious complications. None of the trials had low risk of bias.

We found no statistically significant differences between antibiotic prophylaxis and no prophylaxis in the proportion of surgical site

infections (odds ratio (OR) 0.87, 95% CI 0.49 to 1.54) or extra-abdominal infections (OR 0.77, 95% CI 0.41 to 1.46). Heterogeneity

was not statistically significant.

Authors’ conclusions

This systematic review shows that there is not sufficient evidence to support or refute the use of antibiotic prophylaxis to reduce surgical

site infection and global infections in patients with low risk of anaesthetic complications, co-morbidities, conversion to open surgery,

and infectious complications, and undergoing elective laparoscopic cholecystectomy. Larger randomised clinical trials with intention-

to-treat analysis and patients also at high risk of conversion to open surgery are needed.

P L A I N L A N G U A G E S U M M A R Y

Antibiotic prophylaxis for elective gallbladder surgery

Elective gallbladder surgery is the most common elective surgical procedure in the abdomen. Antibiotic prophylaxis is a common conduct

in open cholecystectomy, and it is also applied to patients undergoing laparoscopic cholecystectomy without any proof of effectiveness.

Laparoscopic surgery offers some advantages related to less manipulation and shorter length of surgical wound, so antibiotic prophylaxis

effect could be lower than in open surgery. This meta-analysis of eleven randomised clinical trials could not find sufficient evidence to

support or refute the use of antibiotic prophylaxis to reduce surgical site infection or global infections in patients with low anaesthetic

risk, low co-morbidities, and low-risk of conversion to open surgery, and undergoing elective laparoscopic cholecystectomy. This is

why large and well-designed randomised trials including patients with high-risk of conversion to open surgery should be conducted in

order to define the beneficial or harmful effects of the antibiotics when given as a prophylaxis.

B A C K G R O U N D

Cholecystectomy is the universally accepted method to man-

age symptomatic uncomplicated cholelithiasis and other benign

gallbladder diseases because it can cure the disease and has low

morbidity and mortality (Keus 2010). Cholelithiasis is one of

the most common abdominal diseases of adults (Bowen 1992;

Angelico 1997). Although many patients are not symptomatic

and gallbladder stones are an incidental finding during ultra-

sonography (Wenckert 1966; Gracie 1982), 1% to 4% of pa-

tients have digestive complaints that compel a treatment (NIH

1993). Furthermore, biliary dyskinesia and gallbladder polyps, al-

though less frequent, are also indications of elective cholecystec-

tomy (Schwesinger 1996; Mainprize 2000).

The most frequent complication in patients undergoing chole-

cystectomy is surgical site infection (Henry 1983). Surgical site

infection was reported in 10% to 23% of the patients who had

been operated on before the routine use of antibiotic prophy-

laxis was introduced in 1960 (Kaufman 1986; Chandrashekhar

1996). The surgical site infection increases length of stay and costs

and decreases the quality of life (Strachan 1977; Morran 1978;

Lykkegaard 1981; Strubbs 1983).

Since 1960, antibiotic prophylaxis has been considered as the

best intervention to prevent surgical site infection in elective

surgery (Strachan 1977; Morran 1978; Morran 1984; Sykes 1984;

Harnoss 1985; Kaufman 1986). Antibiotic prophylaxis includes

preoperative administration of wide-spectrum antibiotics against

the most frequent bacteria involved in surgical site infection, trying

to get high tissue levels of the antibiotic at the surgical wound in

order to avoid colonisation and growth of microorganisms (Barie

2000; Weed 2003). It is accepted that antibiotic prophylaxis must

be administered in all surgical procedures classified as clean-con-

taminated or in selected patients undergoing clean procedures

(Bratzler 2004). Cholecystectomy is considered clean-contami-

nated on the basis that the biliary tract is entered without signifi-

cant spillage during the procedure. Some randomised clinical tri-

als have confirmed that antibiotic prophylaxis in open cholecys-

tectomy is decreasing the risk of surgical site infection (Jewesson



1996; Lippert 1998; Agrawal 1999).

Since 1986, with the original description of laparoscopic chole-

cystectomy, surgical treatment of benign gallbladder diseases, es-

pecially cholelithiasis, has undergone a dramatic change. Devel-

opment of minimally invasive surgery for cholelithiasis showed a

decrease in length of stay (Berggren 1994), costs (Srivastava 2001),

postoperative pain (McMahon 1994), and an increase in quality of

life of patients operated on (Barkun 1992; Keus 2006). Although

this surgical method diminished the length and manipulation of

the surgical wound, antibiotic prophylaxis use did not change.

Recent clinical trials have re-evaluated the usefulness of antibiotic

prophylaxis in laparoscopic cholecystectomy (Illig 1997; Higgins

1999; Harling 2000; Tocchi 2000; Mahatharadol 2001). In la-

paroscopic cholecystectomy the incisions are smaller than in open

cholecystectomy, and the laparoscopic technique is likely associ-

ated with less risk of microbiological contamination because all

manipulations of the excised organ are made through a trocar that

isolates the surgical wound from the gallbladder and decreases the

contact of the wound with the external environment. Nonethe-

less, there is no consensus about these considerations, and many

surgeons still use antibiotic prophylaxis in laparoscopic cholecys-

tectomy.

We found two meta-analyses investigating the beneficial and harm-

ful effects of antibiotics when used as prophylaxis of surgical site

infection in patients undergoing elective laparoscopic cholecystec-

tomy (Al-Ghnaniem 2003; Catarci 2004). The authors concluded

that antibiotic prophylaxis do not seem to offer advantages, but

the meta-analyses have methodological flaws that make their con-

clusions prone to bias such as poor reporting of methods and in-

clusion of retrospective studies.

O B J E C T I V E S

To assess the beneficial or harmful effects of antibiotic prophylaxis

in patients undergoing elective laparoscopic cholecystectomy.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised clinical trials comparing prophylactic antibiotics

versus no antibiotics or placebo before laparoscopic cholecystec-

tomy. Trials were included, irrespective of number of patients ran-

domised, database registry, and language of the publication. Quasi-

randomised trials were excluded, but data on adverse events, if

available, were to be recorded.

Types of participants

Adult patients (more than 17 years old) undergoing laparoscopic

cholecystectomy with preoperative clinical diagnosis of cholelithi-

asis without acute cholecystitis or other benign non-acute inflam-

matory disease of the gallbladder. Jaundiced patients were ex-

cluded.

Types of interventions

Antibiotic prophylaxis versus placebo or no antibiotic, adminis-

tered intravenously or orally, prior to elective laparoscopic surgery.

Types of outcome measures

Primary outcomes

1. All-cause mortality.

2. Surgical site infection defined according to the Centre of Disease

Control (CDC) classification (Mangram 1999), recorded as ’yes’

or ’no’.

3. Extra-abdominal infections defined according to the CDC clas-

sification (Garner 1996), recorded as ’yes’ or ’no’.

4. Adverse events, defined as allergic reactions to antibiotics (ICH-

GCP 1997).

5. Quality of life.

All outcome measures were confined to within hospitalisation or

30 days after discharge.

Search methods for identification of studies

Electronic searches

We searched The Cochrane Hepato-Biliary Group Controlled Tri-als Register (Gluud 2010), the Cochrane Central Register of Con-trolled Trials (CENTRAL) in The Cochrane Library, MEDLINE,

EMBASE, Science Citation Index Expanded (SCI-EXPANDED),and LILACS (Royle 2003). Searches were not performed before

1985, as laparoscopic cholecystectomy was not used before 1985.

Search strategies with the time span of the searches are given in

Appendix 1.



Searching other resources

We wrote to authors of included trials for information on any

published, unpublished, and ongoing trials. We also checked the

reference lists of all the identified trials for relevant trials. Published

abstracts from the conference proceedings from the American Di-

gestive Disease Week (DDW) published in Gastroenterology and

the United European Gastroenterology Week (UEGW) published

in Gut were also handsearched. In addition, we contacted experts

in the field and pharmaceutical companies and asked them to

provide details of pertinent clinical trials or any relevant unpub-

lished materials. The international societies of minimally invasive

surgery (European and American Laparoscopic Surgery Society)

and the international gastrointestinal surgery societies (Gastroin-

testinal Surgery Society) were also contacted and asked to provide

information on any unpublished studies.

Data collection and analysis

We conducted the review according to our protocol (Sanabria

2004), the recommendations of the Cochrane Handbook for Sys-tematic Reviews of Interventions (Higgins 2009), and The CochraneHepato-Biliary Group Module (Gluud 2010).

Selection of studies

Alvaro Sanabria (AS), Eduardo Valdivieso (EV), and Luis

Dominguez (LD) extracted the data, and a consensus was sought

in case of disagreement. AS and Gabriel Gomez (GG) performed

the statistical analysis. We listed identified trials and made an eval-

uation whether the trials fulfilled the inclusion criteria. We also

listed the excluded trials with the reasons for exclusion. We re-

solved differences among us through discussion until consensus

was reached.

Data extraction and management

The following information was extracted for each trial included

in this review:

1. Inclusion and exclusion criteria for patients being

considered.

2. Use of prophylactic antibiotics: prophylaxis is defined as the

use of antibiotic before the infection occurs and prior to surgery.

3. Number of randomised patients.

4. Number and reason of patients not randomised.

5. Exclusion after randomisation.

6. Drop-outs.

7. Intention-to-treat analysis.

8. Number of laparoscopic cholecystectomies converted to

open cholecystectomies.

9. Adverse events.

Data on septic and non-septic abdominal complications (surgical

site infections, biliary tract injury, biliary leakage), extra-abdom-

inal complications, and number of deaths were extracted when

present.

The statistical package Review Manager 5 (RevMan 2008) pro-

vided by The Cochrane Collaboration was used. For dichotomous

outcomes, the impact of the intervention was expressed as an odds

ratio (OR) together with 95% confidence interval (CI). We did not

have continuous variables in this review. We used a random-effects

(DerSimonian 1986) model and a fixed-effect model (DeMets

1987). In case of discrepancy between the two models (eg, one

giving a significant intervention effect and the other giving no sig-

nificant intervention effect), we reported both results; otherwise,

we reported only the results from the fixed-effect model.

Assessment of risk of bias in included studies

Methodological quality is defined as the confidence that the design

and report will restrict bias in the intervention comparison (Moher

1998). According to empirical evidence (Schulz 1995; Moher

1998; Jüni 2001; Kjaergard 2001; Wood 2008), the evaluation of

the risk of bias could be achieved through assessing the following

domains:

Allocation sequence generation

• Low risk of bias: sequence generation was achieved using

computer random number generation or a random number

table. Drawing lots, tossing a coin, shuffling cards, and throwing

dice are adequate if performed by an independent adjudicator.

• Uncertain risk of bias: the trial is described as randomised,

but the method of sequence generation was not specified.

• High risk of bias: the sequence generation method is not, or

may not be, random. Quasi-randomised studies, those using

dates, names, or admittance numbers in order to allocate patients

are inadequate and will be excluded for the assessment of benefits

but not for harms.

Allocation concealment

• Low risk of bias: allocation was controlled by a central and

independent randomisation unit, sequentially numbered,

opaque and sealed envelopes or similar, so that intervention

allocations could not have been foreseen in advance of, or

during, enrolment.

• Uncertain risk of bias: the trial was described as randomised

but the method used to conceal the allocation was not described,

so that intervention allocations may have been foreseen in

advance of, or during, enrolment.

• High risk of bias: if the allocation sequence was known to

the investigators who assigned participants or if the study was

quasi-randomised. Quasi-randomised studies will be excluded

for the assessment of benefits but not for harms.

Blinding



• Low risk of bias: the trial was described as blinded, the

parties that were blinded, and the method of blinding was

described, so that knowledge of allocation was adequately

prevented during the trial.

• Uncertain risk of bias: the trial was described as blind, but

the method of blinding was not described, so that knowledge of

allocation was possible during the trial.

• High risk of bias, the trial was not blinded, so that the

allocation was known during the trial.

Incomplete outcome data

• Low risk of bias: the numbers and reasons for dropouts and

withdrawals in all intervention groups were described or if it was

specified that there were no dropouts or withdrawals.

• Uncertain risk of bias: the report gave the impression that

there had been no dropouts or withdrawals, but this was not

specifically stated.

• High risk of bias: the number or reasons for dropouts and

withdrawals were not described.

Selective outcome reporting

• Low risk of bias: pre-defined, or clinically relevant and

reasonably expected outcomes are reported on.

• Uncertain risk of bias: not all pre-defined, or clinically

relevant and reasonably expected outcomes are reported on or are

not reported fully, or it is unclear whether data on these

outcomes were recorded or not.

• High risk of bias: one or more clinically relevant and

reasonably expected outcomes were not reported on; data on

these outcomes were likely to have been recorded.

Vested interest bias

• Low risk of bias: if there was no risk of vested interests on

the side of researchers, manufacturers, or funding bodies; or any

personal conflicts by the authors of the trial publication that

might have unduly influenced judgements were disclosed in an

honest and upright manner.

• Uncertain risk of bias: if it is not possible to say that there

were or there were not any financial interests on the side of

researchers, manufacturers, or funding bodies reported in the

trial publications.

• High risk of bias: if there was risk for vested interests, eg,

the trial was funded by a drug manufacturer, or researches had

received money for the performance of the trial, and interests

like these could have influenced the results of the trial report.

Trials with low risk of bias were considered trials that were judged as

trials having ’low risk of bias’ in all of the above specified individual

domains. Trials with high risk of bias were considered those trials

that were judged as trials having ’uncertain risk of bias’ or ’high risk

of bias’ in one or more of the above specified individual domains.

Measures of treatment effect

Dichotomous data were analysed calculating the odds ratio (OR)

for each trial, expressing the uncertainty with 95% confidence

intervals (CI). Comparisons were made between trials evaluating

antibiotic prophylaxis against no intervention or placebo adminis-

tered intravenously or orally, prior to elective laparoscopic surgery.

Unit of analysis issues

Groups within the randomised clinical trial.

Dealing with missing data

Regarding the surgical site infection, we included patients with

incomplete or missing data in the sensitivity analyses by imputing

them according to the following scenario.

• Available case analysis: data on only those whose results are

known, using as denominator the total number of patients who

completed the trial. This meta-analysis was done per-protocol.

• Sensitivity analysis using worst-best case analysis (Analysis

1.3) and best-worst case analysis (Analysis 1.4).

Assessment of heterogeneity

The chi-squared test for heterogeneity was used to provide an in-

dication of between-study heterogeneity (Higgins 2002). In addi-

tion, the degree of heterogeneity observed in the results was quan-

tified using the I2 statistic, which can be interpreted as the per-

centage of variation observed between the studies attributable to

between-study differences rather than sampling error (chance).

Assessment of reporting biases

We used a funnel plot to provide a visual assessment of whether

treatment estimates are associated with trial size. The detection

of biases varies with the magnitude of the treatment effect (Egger

1997; Macaskill 2001), the distribution of study size, and whether

a one- or two-tailed test is used (Macaskill 2001). We used two

tests to assess funnel plot asymmetry, adjusted rank correlation test

(Begg 1994), and regression asymmetry test (Egger 1997).

Subgroup analysis and investigation of heterogeneity

We had planned a subgroup analysis in order to compare the in-

tervention effect in trials with low risk of bias to that of trials with

high risk of bias. Furthermore, we had planned to explore causes of

heterogeneity (defined as the presence of statistical heterogeneity

by chi-squared test with significance set at P value less than 0.10

and measure the quantities of heterogeneity by I2 (Higgins 2002))

by comparing different groups of trials stratified according to pa-

tient risk factors, level of experience of the surgeon, and other fac-

tors that may explain heterogeneity. Values of I2 were categorised



according to Higgins (Higgins 2003): low, up to 25%; moderate,

from 25 to 50% and high, higher than 75%.

Funnel plot

Funnel plot for selected trials is shown in Figure 1 and Figure 2.

The adjusted rank correlation test and the regression asymmetry

test were not statistically significant (intercept P value 0.42), which

does not suggest bias.

Figure 1. Funnel plot of comparison: 1 Antibiotic prophylaxis versus no-prophylaxis, outcome: 1.1 Surgical

site infection.



Figure 2. Funnel plot of comparison: 1 Antibiotic prophylaxis versus no-prophylaxis, outcome: 1.2 Global

infections.

Sensitivity analysis

• A sensitivity analysis using worst-best case and best-worst

case analyses.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Results of the search

Our searches provided fifteen studies, four of which we had to ex-

clude. Three did not fulfil our inclusion criteria: Anselmi 1995 was

a quasi-randomised trial since the generation of the allocation se-

quence was based on dates; Uchiyama 2003 was not a randomised

trial; and Chang 2006 included patients with acute cholecystitis.

The fourth, Gonzales 1996, was a thesis that we were unable to

obtain. All the remaining eleven trials were randomised clinical

trials with parallel designs. Ten of these trials were identified in

MEDLINE and one in LILACS. Those from MEDLINE were in

English, and the one from LILACS in Spanish. Authors and other

sources of information did not provide further trials.

The inclusion criteria were similar for the selected trials: adult

patients scheduled for elective laparoscopic cholecystectomy, with

preoperative diagnosis of benign condition (gallbladder stones,

chronic cholecystitis, cholesterolosis, or gallbladder polyps).

The exclusion criteria were also similar for the included trials: (a)

pregnant or lactating women; (b) antibiotic allergy; (c) antibiotic

therapy within 48 hours to 7 days prior to surgery; (d) clinically

active infection at the moment of surgery; (e) evidence or sus-

picion of common bile duct stones; (f ) contraindications for la-

paroscopic cholecystectomy; (g) indication of obligatory antibi-

otic prophylaxis because the medical condition was different from

biliary disease (immunosuppression, corticoid use, etc). Csendes

1995, Tocchi 2000, Kuthe 2006, Uludag 2009, Yildiz 2009, and

Sharma 2010 excluded patients converted to open cholecystec-

tomy; Harling 2000 excluded those who had an operative cholan-

giogram performed; and Uludag 2009 excluded patients older

than 60 years and with American Society of Anaesthesiology (ASA)



classification higher than II.

At the entry into the trials, participants were not reported to be

different regarding age, sex, severity (measured with ASA classifica-

tion), and concomitant diseases. Csendes 1995, Illig 1997, Tocchi

2000, Mahatharadol 2001, Koc 2003, Uludag 2009, and Sharma

2010 reported bile spillage or intraoperative gallbladder rupture

without statistically significant differences, but Yildiz 2009 found

differences in this variable. Trials that reported ASA classification

included mainly low-risk patients.

Interventions were prophylactic antibiotics with one preoperative

dose in eight trials (Csendes 1995; Higgins 1999; Harling 2000;

Mahatharadol 2001; Kuthe 2006; Uludag 2009; Yildiz 2009;

Sharma 2010), or preoperative and postoperative administration

less than 24 hours in three trials (Illig 1997; Tocchi 2000; Koc

2003). We considered these differences to be clinically not rele-

vant, because there is a policy accepting that antibiotic prophylaxis

is extended up to 24 hours. The control group was given either

placebo of saline solution (Higgins 1999; Tocchi 2000; Koc 2003;

Kuthe 2006; Uludag 2009; Yildiz 2009; Sharma 2010) or no an-

tibiotic (Csendes 1995; Illig 1997; Harling 2000; Mahatharadol

2001). Harling 2000 used a plastic bag to remove the gallblad-

der from the abdomen in all patients in the ’no antibiotic’ group,

Tocchi 2000 and Uludag 2009 in all patients, and Sharma 2010

used it only in patients with perforated gallbladder. The antibiotics

used in the trials were cefuroxime (Harling 2000; Kuthe 2006),

cefazolin (Csendes 1995; Illig 1997; Higgins 1999; Mahatharadol

2001; Uludag 2009; Yildiz 2009), cefotetan (Higgins 1999), cefo-

taxime (Tocchi 2000; Koc 2003) and ceftriaxone (Sharma 2010).

In the Illig 1997 trial, seven patients in the control group received

antibiotics against the protocol, and antibiotics were provided to

patients with higher risk of infection (inflammation and conver-

sion to open surgery). This violation could influence the results of

the trial, with a bias acting as a measure that artificially decreases

the difference of surgical site infection. The Higgins 1999 trial had

two antibiotic groups, one with cefazolin and one with cefotetan,

which were pooled together for analysis, because both antibiotics

belong to the same pharmacological family.

Laparoscopic surgery included skin preparation with povidone-

iodine solution, use of three or four ports, creation of pneumoperi-

toneum, and extraction of gallbladder through the operating port,

always using a bag (Tocchi 2000; Uludag 2009) or at the surgeon’s

preference as Sharma 2010 in cases of perforated gallbladder. In-

cisions were closed at the end of the operation with absorbable

or non-absorbable suture. Illig 1997, Harling 2000, Tocchi 2000,

Koc 2003, Kuthe 2006, Uludag 2009, Yildiz 2009, and Sharma

2010 took a sample of bile for culture. Tocchi 2000 drained always

the subhepatic region through the opening of a 5 mm trocar with

a silicone tube, which was removed on the first postoperative day

and Sharma 2010 only used a drain in cases of perforated gallblad-

der.

Infectious complications were defined clinically as fever with a

clinical focus and culture positives from infectious sites, as recom-

mended by the The Centers for Disease Control and Prevention

(CDC) criteria for surgical site infection (Mangram 1999). Illig

1997, Harling 2000 and Uludag 2009 reported isolated microor-

ganisms from each surgical site infection (SSI), without differences

between groups.

Risk of bias in included studies

Generation of the allocation sequence was considered of low risk

of bias in three trials (Tocchi 2000; Kuthe 2006; Uludag 2009)

and high in the remaining eight. Allocation concealment was of

low risk of bias in four trials (Higgins 1999; Harling 2000; Uludag

2009; Sharma 2010) and high in the remaining seven trials. Seven

trials (Higgins 1999; Tocchi 2000; Koc 2003; Kuthe 2006; Uludag

2009; Yildiz 2009; Sharma 2010) used placebo. Blinded assess-

ment was performed in seven trials classified as low risk of bias

(Higgins 1999; Harling 2000; Tocchi 2000; Koc 2003; Kuthe

2006; Yildiz 2009; Sharma 2010) and three trials had high risk of

bias regarding this component (Illig 1997; Mahatharadol 2001;

Uludag 2009). Csendes 1995 did not perform blinding. All trials

had a low risk of bias regarding incomplete outcome data and se-

lective outcome reporting. All trials had a high risk of bias regard-

ing vested interest bias.

Follow-up was adequate in all trials, except in Illig 1997, who

reported six losses to follow-up in 250 patients, and Mahatharadol

2001, who reported one loss to follow-up in 101 patients (Figure

3; Figure 4).



Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Intention-to-treat analysis for primary outcomes was made only

in Illig 1997. Other trials excluded patients after randomisation,

especially patients with non-specified protocol violations and pa-

tients who underwent conversion to open surgery, which has a

higher risk of surgical site infection. We have tried to contact the

authors of original trials to get information about reasons for exclu-

sion, number and distribution of patients excluded, and outcomes

of these patients. As we could not obtain more information, we

made a sensitivity analysis for surgical site infection, using worst-

best and best-worst scenarios for those trials reporting number of

patients excluded by group. This analysis showed a high sensitivity

to post-randomisation exclusions (Analysis 1.3 and Analysis 1.4).

Finally, all trials were of high risk of bias.

Sample-size estimation was only clearly described in Higgins 1999

and Illig 1997. The other trials did not report on any form of

sample size calculation.

Effects of interventions

In total, 1664 patients were recruited in the eleven trials; 900 in the

prophylaxis group and 764 in the no-prophylaxis group. The rate

of conversion to open surgery was 2.4% in Higgins 1999, 8.4% in

Illig 1997, 3.8% in Harling 2000, and 4.1% in Uludag 2009. Koc

2003 excluded 20 of the 112 (17.8%) patients originally included

in the trial because of protocol violations. Higgins 1999 excluded

38 of 450 (8.4%) patients because of protocol violations. Harling

2000 excluded 30 of 106 (28.3%) patients because of the need

of cholangiography, concomitant antibiotic usage, spillage of bile

from gallbladder, and conversion to open surgery. Mahatharadol

2001 excluded two of 102 (1.9%) patients because of lost to fol-

low-up and protocol violation. Kuthe 2006 excluded 11 of 104

(1.5%) patients because of intra-operative spillage, conversion to

open cholecystectomy, and refusal to continue in the trial, and

Uludag 2009 excluded 6 of 144 (4.1%) patients because of con-

version to open surgery. Tocchi 2000 excluded 6 of 90 (6.6%)

patients, but he did not state the reasons. The other trials did

not report the number of patients that were lost to follow-up. As

only one trial had an intention-to-treat analysis, we performed

two sensitivity analyses, using a worst-best case (a poor outcome

is assigned to each treated patient for whom data were missing)

and a best-worst case (a good outcome is assigned to each treated

patient for whom data were missing) scenarios.

All-cause mortality

Mortality was not reported in any of the trials.

Surgical site infection

The number of surgical site infections was similar in the two

groups: 24 of 900 (2.7%) patients in the prophylaxis group had

a surgical site infection against 25 of 764 (3.3%) in the no-pro-

phylaxis group. The OR was 0.87, 95% CI (0.49 to 1.54). No

statistically significant differences or heterogeneity were observed

(Analysis 1.1). As I2 values were lower than 2%, the planned anal-

yses for heterogeneity were not necessary. The sensitivity analy-

sis with the worst-best case scenario yields an OR of 2.80, 95%

CI 1.75, 4.46, and the best-worst case scenario yields an OR of

0.34, 95% CI (0.21 to 0.54), showing a high sensitivity to post-

randomisation exclusions.

Extra-abdominal infections

Seven trials reported infectious events that are different from surgi-

cal site infections (Csendes 1995; Illig 1997; Higgins 1999; Tocchi

2000; Kuthe 2006; Uludag 2009; Sharma 2010), and these oc-

curred in 7 of 657 (1.0%) patients in the prophylaxis group and

22 of 531 (1.8%) patients in the no-prophylaxis group. For the

Tocchi 2000 trial, we counted only four complications, although

the trial refers to five events. This is because a subhepatic collection

secondary to technical defect cannot be assumed as a direct out-

come for antibiotic prophylaxis. The OR was 0.66 (95% CI 0.25

to 1.74). No statistically significant differences or heterogeneity

were observed (Analysis 1.2). As I2 values were lower than 2%,

the planned analyses for heterogeneity were not necessary.

Adverse events

Information about adverse events was not given in any of the trials.

Quality of life

None of the trials reported on the quality of life.

D I S C U S S I O N

Our systematic review could not find evidence to support or re-

fute the use of antibiotic prophylaxis for reduction of surgical site

infections in patients at low risk of acquiring infections or com-

plications when undergoing elective laparoscopic cholecystectomy

when prophylactic antibiotics were administered.

Preliminary observations showed a decrease in surgical site infec-

tion after beginning of laparoscopic cholecystectomy when antibi-

otic prophylaxis was applied. So, some randomised clinical trials

were designed to assess the effectiveness of antibiotic prophylaxis

(Anselmi 1995; Csendes 1995; Illig 1997; Higgins 1999; Harling

2000; Tocchi 2000; Mahatharadol 2001; Koc 2003). However,

because of the low frequency of surgical site infections and com-

plications, each one of the trials had a small sample size to defi-

nitely probe a positive effect. Previously, Al-Ghnaniem 2003 and

Catarci 2004 reported meta-analyses on this topic, but the first

was published only as an abstract and did not allow an adequate



quality assessment to be made, and the second included a retro-

spective study and did not include other relevant trials.

Our systematic review that includes eleven randomised clinical

trials was not able to find significant statistical differences in the

occurrence of surgical site infection and global infections between

patients undergoing laparoscopic cholecystectomy who received

and those who did not receive prophylactic antibiotics. However,

it must be highlighted that the number of participants included

in this systematic review is lower than those needed to show a real

equivalence between treatments because of the low rate of out-

comes. Another fact that must be realised is the lack of intention-

to-treat analysis in all but one of the analysed trials. This is im-

portant to stress because trials with no intention-to- treat analyses

tend to produce misleading results (Moher 1998). Most of the

trials analysed included only patients with no protocol violations

and without conversion to open surgery. This has created a selec-

tion of patients with a very low risk of surgical site infection - a

reason that can explain the results for no difference between treat-

ments. The sensitivity analysis showed a high dependence of re-

sults related with post-randomisation exclusions, which supports

even more the potential risk of bias of our finding. If one shall ap-

ply these findings to all patients who are going to undergo elective

laparoscopic cholecystectomy is still a matter of personal judge-

ment until a definite recommendation could be given.

Conductance of more clinical trials with low risk of bias must

be considered in order to increase the sample size and to surpass

methodological weaknesses found in this review. A future ran-

domised trial will need a sample size of approximately 3500 pa-

tients by intervention group. Neither clinical heterogeneity nor

statistical heterogeneity were identified in the relevant clinical vari-

ables of the trials included, so it could be that the compared pa-

tients were similar. Since many of the risk of bias criteria were

not clearly reported, we cannot be sure that bias did not have an

effect in the trials. We believe that lost to follow-up, found in Illig

1997 and Mahatharadol 2001, was minimal and do not introduce

important bias to the results, but as previously commented, the

lack of intention-to-treat analysis makes this conclusion difficult

to apply to all candidates to laparoscopic cholecystectomy.

Another important point to discuss is the individual risk of the

patients. The included trials had selected mainly patients at low

risk of acquiring an infection, making its management reasonably

simple, and the life of the patient was not compromised. How-

ever, this statement cannot be applied to high-risk patients as those

prone to conversion to open surgery, those with co-morbidities

and those with high anaesthetic risk scores as ASA, for whom these

conditions are not accomplished, and an infection could cause the

death of the patient. In relation to the generalisability of the re-

sults, it is important to highlight this concern. New trials including

patients at high risk of acquiring infections from the laparoscopic

cholecystectomy intervention are necessary to confirm the finding

of no difference in effect. The existing clinical trials suggest that

antibiotic prophylaxis in laparoscopic cholecystectomy may not

be needed for patients at low risk of acquiring infections or com-

plications and with low risk of conversion to open surgery, and

that each patient undergoing surgery must be assessed carefully

when selecting the therapy.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

With the present data, the evidence does not support or refute the

use of antibiotic prophylaxis to reduce surgical site infection in

low-risk patients undergoing laparoscopic cholecystectomy. The

use of prophylactic antibiotics administration must be selected

individually in those patients with medium or high risk.

Implications for research

It is necessary to conduct randomised clinical trials with large sam-

ple sizes to get enough number of patients and outcomes to probe

the equivalence between treatments. Moreover, it is also neces-

sary to asses this assumption in high-risk patients. Reporting re-

quirements of randomised clinical trials as suggested by the CON-

SORT statement (www.consort-statement.org) should be strictly

applied, since lack of good reporting could wrongly decrease the

methodological quality of surgical randomised clinical trials.

A C K N O W L E D G E M E N T S

To Dimitrinka Nikolova, Managing Editor, Cochrane Hepato-

Biliary Group for help in the development of this review.

Peer Reviewers: Tahany Awad, Denmark; Kurinchi Gurusamy,

UK; Frederik Keus, The Netherlands.

Contact Editor: Christian Gluud, Denmark.



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Csendes 1995

Methods Randomised clinical trial with a parallel design.

Generation of the allocation sequence: unclear.

Allocation concealment: unclear.

Blinding: not performed. Outcome assessment was made by surgeons of the treatment

group, but it was not stated if they were blinded.

Follow-up: adequate; without lost to follow-up at 15 days.

Intention-to-treat analysis: no.

Sample size calculations: no.

Participants 105 patients randomised (50 for antibiotic group and 55 for no-antibiotic group).

Sex: 32 men/73 women.

Mean age 48.1 to 49.3. Age of inclusion not reported.

Inclusion criteria: clinical diagnosis of chronic cholecystitis undergoing elective chole-

cystectomy.

Exclusions criteria: conversion to open surgery and acute cholecystitis.

Trial duration: 14 months.

Interventions Intravenous single cefazolin dose, 1 g given at the time of induction compared with no

antibiotic in the control group.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections.

Notes Contacted authors April 9/2007. It was impossible to get more information about ex-

cluded patients because data were not available.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Unclear. “Randomly distributed into two

groups”, “Se dividieron en dos grupos al

azar”.

Allocation concealment? Unclear Unclear. “Randomly distributed into two

groups”, “Se dividieron en dos grupos al

azar”.

Blinding?

All outcomes

No “Patients were controlled during hospi-

tal stay and then, 15 days after discharge

in an out-patient setting, recording data

about infection”, “Los pacientes fueron

controlados en su estadia intrahospitalaria

y luego hasta 15 dias en forma ambulatoria

consignando la presencia de cualquier in-

feccion”



Csendes 1995 (Continued)

Incomplete outcome data addressed?

All outcomes

No Per protocol analysis.

Vested interest bias? Unclear It is not possible to say if there were or there

were not any financial interests.

Harling 2000



Allocation concealment: adequate; sealed envelopes.

Blinding: single-blind. Outcome assessment was made by surgeons of the treatment

group blind to intervention.

Follow-up: adequate: without lost to follow-up (time not stated).



Participants 76 patients (39 for antibiotic group and 37 for no-antibiotic group).

Sex distribution not reported.

Mean age not reported. Age of inclusion not reported.

Inclusion criteria: patients undergoing elective cholecystectomy.

Exclusions criteria: need to carry out cholangiography, concomitant usage of antibiotics,

spillage of gallbladder content, and conversion to open surgery.


Interventions Intravenous single cefuroxime dose, 750 mg given at the time of induction compared

with removing of the gallbladder with a plastic bag.

Outcomes Surgical site infection determined by pus drainage.

Notes

Risk of bias


Adequate sequence generation? Unclear Unclear.“Patients ... were randomised to re-

ceive...”.

Allocation concealment? Yes “Randomisation ... was done using a sealed

envelope technique”.

Blinding?

All outcomes

Yes “An infection control sister followed up the

patients”.


All outcomes




Harling 2000 (Continued)


were not financial interests.

Higgins 1999



Allocation concealment: adequate; sealed envelopes.

Blinding: double-blind. Use of placebo. Outcome assessment was made by surgeons of

the treatment group blind to intervention.

Follow-up: adequate: without lost to follow-up at 30 days.


Sample size calculations: yes. Power of 80%, alfa error of 5%.

Participants 412 patients (277 for antibiotics groups and 135 for placebo).

Sex distribution not reported.

Mean age: 47.1 to 48.2. Age of inclusion 18 to 80.

Inclusion criteria: patients scheduled to elective cholecystectomy.

Exclusions criteria: pregnant or lactating women, antibiotic allergy, previous antibiotic

therapy, acute cholecystitis or cholangitis, jaundice, previous biliary surgery, choledo-

cholithiasis, prosthetic valves, contraindication to laparoscopy.


Interventions Intravenous single cefotetan and cefazolin dose, 1 g each one given at the time of induc-

tion compared with placebo.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections “any

infection remote to the surgical site”.

Notes

Risk of bias


Adequate sequence generation? Unclear Unclear.

Allocation concealment? Yes Sealed envelopes.

Blinding?

All outcomes

Yes Outcome assessment was made by surgeons

of the treatment group blind to interven-

tion.


All outcomes

Yes Per protocol analysis.



Higgins 1999 (Continued)



Illig 1997




Blinding: not performed. Outcome assessment was made by surgeons of the treatment

group, but it was not stated whether they were blinded.

Follow-up: adequate. Lost to follow-up of 2.4% at 30 days.

Intention-to-treat analysis: yes.

Sample size calculations: yes. Power of 80%, alfa error of 5%, absolute difference to

identify of 4%.



Mean age: 46.5 to 47.3. Age of inclusion not reported.


Exclusions criteria: acute cholecystitis, obstructive jaundice, immunosuppression, preg-

nancy, artificial device or graft in place, use of antibiotics 7 days prior to surgery.


Interventions Intravenous preoperative dose of cefazolin, 1 g given at the time of induction and followed

by two doses at 8 and 16 hours postoperatively compared with no antibiotic in the

control group.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections “Lower

urinary tract infection (UTIs, with symptomatic bacteriuria)...and any other problem

with local effects only ...”.

Notes

Risk of bias


Adequate sequence generation? Unclear Patients were randomised to receive pro-

phylactic antibiotics.

Allocation concealment? Unclear Patients were randomised to receive pro-

phylactic antibiotics.

Blinding?

All outcomes

No Complications were reported to the inves-

tigators as they occurred.


All outcomes

Yes Intention to treat analysis.



Illig 1997 (Continued)



Koc 2003




Blinding: yes. Use of placebo. Outcome assessment was made by surgeons of the treat-

ment group, blinded to the interventions.

Follow-up: adequate. No losses to follow up.





Mean age: 47.5 to 50.1. Age of inclusion reported as adults.


Exclusions criteria: antibiotic allergy, acute cholecystitis, previous biliary surgery, ob-

structive jaundice, immunosuppression, artificial device or graft in place, use of antibi-

otics 7 days prior to surgery.


Interventions Intravenous preoperative dose of cefotaxime, 2 g given at the time of induction and

followed by a dose at 24 hours postoperatively compared with placebo in the control

group.


Notes

Risk of bias


Adequate sequence generation? Unclear After the patients were confirmed for the

study, they were randomised....

Allocation concealment? Unclear After the patients were confirmed for the

study, they were randomised... .

Blinding?

All outcomes

Yes Both the surgical team and the patients

were blinded to the groups.


All outcomes




Koc 2003 (Continued)



Kuthe 2006


Generation of the allocation sequence: Random number table.


Blinding: yes. Use of placebo. Outcome assessment was made by residents of the treat-



Intention-to-treat analysis: No.

Sample size calculations: reported, but not clear.



Mean age: 42.04 to 42.38. Age of inclusion reported as adults.


Exclusions criteria: antibiotic allergy, acute cholecystitis, previous biliary surgery, ob-

structive jaundice, immunosuppression, artificial device or graft in place, use of antibi-

otics 7 days prior to surgery, conversion to open surgery.


Interventions Intravenous preoperative dose of cefotaxime, 1.5 g given at the time of induction com-

pared with placebo in the control group.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections

(pyrexia of more than 38 C (excluding the first postoperative day), positive bacterio-

logical culture from possible infection sites such as wounds, the urinary or respiratory

tract...”

Notes

Risk of bias


Adequate sequence generation? Yes Random number table.

Allocation concealment? Unclear Unclear.

Blinding?

All outcomes

Yes Outcome assessment was made by residents

of the treatment group, blinded to the in-

terventions.


All outcomes




Kuthe 2006 (Continued)

Vested interest bias? Unclear It is not possible to say that there were or

there were not financial interests.

Mahatharadol 2001


Generation of the allocation sequence: adequate.


Blinding: no. Outcome assessment was made by surgeons of the treatment group, but it

was not stated if they were blinded.

Follow-up: adequate. Lost to follow-up of 0.9%.

Intention-to-treat analysis: no. One patient who was lost to follow-up was excluded from

the analysis.




Mean age: 51 to 52.2.

Age of inclusion: 15 to 80 years old.


Exclusions criteria: antibiotic allergy, acute cholecystitis, obstructive jaundice, immuno-

suppression, artificial device or graft in place, use of antibiotics 48 hours prior to surgery.

Duration of treatment: 7 months.

Interventions Intravenous preoperative dose of cefazolin, 1 g given at the time of induction compared

with no antibiotic in the control group.


Notes

Risk of bias


Adequate sequence generation? Unclear By block randomisation.

Allocation concealment? Unclear By block randomisation.

Blinding?

All outcomes

No All patients were followed-up for 30 days

after the procedure at the out-patient clinic

or by telephone contact.


All outcomes




Mahatharadol 2001 (Continued)



Sharma 2010


Generation of the allocation sequence: adequate.

Allocation concealment: adequate.

Blinding: yes. Use of placebo. Outcome assessment was made by residents of the treat-


Follow-up: adequate. Lost to follow-up of 0%.





Mean age: 39 to 39.

Age of inclusion: Older than 18 years old.

Inclusion criteria: patients undergoing elective cholecystectomy for symptomatic gall-

stone disease.

Exclusions criteria: jaundice, acute cholecystitis, cholangitis, acute pancreatitis or other

acute inflammation, conversion to open cholecystectomy, immunosuppressive therapy,

cardiac disorders mandating prophylactic use of antibiotics, or antibiotic use in the

preceding seven days.

Duration of treatment: not reported.

Interventions Intravenous preoperative dose of ceftriaxone, 1 g given at the time of induction compared

with physiologic saline as placebo in the control group.

Outcomes “Superficial SSI was defined as erythema or purulent discharge at the surgical site above

the deep fascia. A deep infection was defined as purulent material deep to the fascia or

near the gallbladder fossa. A distant infection was defined as any infection remote from

the surgical site.”

Notes

Risk of bias


Adequate sequence generation? Unclear “Anesthetist randomly opened one of a col-

lection of sealed envelopes”

Allocation concealment? Yes “Anesthetist randomly opened one of a col-

lection of sealed envelopes”, “The surgeon

and medical staff were unaware of which

treatment the patient received.”



Sharma 2010 (Continued)

Blinding?

All outcomes

Yes “The surgeon and medical staff were un-

aware of which treatment the patient re-

ceived.”


All outcomes




Tocchi 2000


Generation of the allocation sequence: adequate. Computer randomisation.



ment group who were blinded to the intervention.



the analysis.




Mean age: 49.5 to 53.6. Age of inclusion not stated.


Exclusions criteria: antibiotic allergy, acute cholecystitis, obstructive jaundice or chole-

docholithiasis, previous ERCP, corticosteroid therapy, use of antibiotics 7 days prior to

surgery, conversion to open surgery.

Trial duration: 2 years.

Interventions Intravenous preoperative dose of cefotaxime, 2 g given at the time of induction and

followed by a dose at 24 hours postoperatively compared with placebo in the control

group.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections “in-

fectious complications were defined as pyrexia with a body temperature higher than 380 C twice a day (excluding the first postoperative day) and culture findings positive for

pathogens from infectious sites such as wounds, the urinary or respiratory tract...”.

Notes

Risk of bias


Adequate sequence generation? Yes Compute-matrix randomisation.



Tocchi 2000 (Continued)

Allocation concealment? Unclear Compute-matrix randomisation.

Blinding?

All outcomes

Yes Patients were followed postoperatively.


All outcomes




Uludag 2009


Generation of the allocation sequence: adequate. Random selection.

Allocation concealment: Closed envelopes.

Blinding: No. Use of placebo. Outcome assessment was made by surgeons of the treat-

ment group who were not blinded to the intervention.


Intention-to-treat analysis: no. Patients converted to open cholecystectomy were ex-

cluded




Mean age: 42.5 to 44.6. Age of inclusion not stated. Excluded patients older than 60

years


Exclusions criteria: patients older than 60 years; antibiotic intake in the 7 days prior to

surgery; acute cholecystitis in the 6 months prior to the procedure; evidence of cholan-

gitis and/or obstructive jaundice and biliary pancreatitis; regular corticosteroid therapy;

pregnancy or lactation; previous biliary tract surgery or previous endoscopic retrograde

cholangiopancreatography; presence of American Society of Anesthesiologists classifica-

tion (ASA) higher than score II; evidence of diabetes mellitus; body mass index higher

than 30; and conversion to open cholecystectomy.



with placebo in the control group.

Outcomes Surgical site infection determined by pus drainage and extra-abdominal infections “num-

ber of septic complications”.

Notes

Risk of bias




Uludag 2009 (Continued)

Adequate sequence generation? Yes Random selection “One of 2 packages con-

taining either cefazolin or placebo was cho-

sen randomly by the anaesthesiologist for

each patient.”

Allocation concealment? Yes Closed envelope method “The package was

opened by the anaesthesiologist, and the

type of solution administered (cefazolin or

placebo) was recorded. The medical staff

and the patient were unaware of the content

of the solution.”

Blinding?

All outcomes

Unclear Patients were followed postoperatively by

the same surgical group.


All outcomes




Yildiz 2009


Generation of the allocation sequence: adequate. Unclear.



ment group who were blinded to the intervention.



the analysis.




Mean age: 49.9 to 51.3. Age of inclusion not stated.


Exclusions criteria: conversion to laparotomy, acute cholecystitis, evidence of obstructive

jaundice, history of biliary tract surgery, prosthetic valves, chronic hepatic diseases, acute

pancreatitis, immunosuppression, steroid therapy, chronic systemic infections, allergy to

β-lactam antibiotics.



with placebo in the control group.

Outcomes Surgical site infection determined by body temperature higher than 38°C, purulent

discharge from the incisions, and any abdominal signs of infection.



Yildiz 2009 (Continued)

Notes

Risk of bias


Adequate sequence generation? Unclear Unclear.

Allocation concealment? Unclear Unclear.

Blinding?

All outcomes

Yes “The patients were followed up regularly

until the day of discharge and on 7th and

30th days postoperatively by the same sur-

gical team (Dr. OA and Dr. EH) who were

blind to AP.”


All outcomes




Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Anselmi 1995 Quasi-randomised trial. Randomisation was performed after date of birth.

Chang 2006 Included patients with acute cholecystitis.

Gonzales 1996 Published as a theses. We could not obtain copy of the thesis.

Uchiyama 2003 Comparative, not randomised trial.



D A T A A N D A N A L Y S E S

Comparison 1. Antibiotic prophylaxis versus placebo or no-prophylaxis

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Surgical site infection 11 1664 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.49, 1.54]

1.1 Per protocol analysis

(Intention-to-treat analysis not

performed)

11 1664 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.49, 1.54]

2 Extra-abdominal infections 7 1188 Odds Ratio (M-H, Fixed, 95% CI) 0.66 [0.25, 1.74]

3 Surgical site infection

(Intention-to-treat analysis

worst-best case scenario)


4 Surgical site infection

(Intention-to-treat analysis

best-worst case scenario)


Analysis 1.1. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 1 Surgical

site infection.

Review: Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy

Comparison: 1 Antibiotic prophylaxis versus placebo or no-prophylaxis

Outcome: 1 Surgical site infection

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Per protocol analysis (Intention-to-treat analysis not performed)

Csendes 1995 2/50 2/55 7.2 % 1.10 [ 0.15, 8.15 ]

Harling 2000 3/39 3/37 11.1 % 0.94 [ 0.18, 5.00 ]

Higgins 1999 5/277 2/135 10.4 % 1.22 [ 0.23, 6.38 ]

Illig 1997 0/128 1/122 6.0 % 0.32 [ 0.01, 7.81 ]

Koc 2003 1/49 1/43 4.1 % 0.88 [ 0.05, 14.43 ]

Kuthe 2006 1/40 2/53 6.6 % 0.65 [ 0.06, 7.47 ]

Mahatharadol 2001 0/50 1/50 5.8 % 0.33 [ 0.01, 8.21 ]

Sharma 2010 2/50 4/50 15.1 % 0.48 [ 0.08, 2.74 ]

0.01 0.1 1 10 100

Favours treatment Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio


Tocchi 2000 3/44 4/40 15.3 % 0.66 [ 0.14, 3.14 ]

Uludag 2009 3/68 2/76 7.1 % 1.71 [ 0.28, 10.54 ]

Yildiz 2009 4/105 3/103 11.4 % 1.32 [ 0.29, 6.05 ]

Total (95% CI) 900 764 100.0 % 0.87 [ 0.49, 1.54 ]

Total events: 24 (Treatment), 25 (Control)

Heterogeneity: Chi2 = 2.40, df = 10 (P = 0.99); I2 =0.0%

Test for overall effect: Z = 0.47 (P = 0.64)

0.01 0.1 1 10 100


Analysis 1.2. Comparison 1 Antibiotic prophylaxis versus placebo or no-prophylaxis, Outcome 2 Extra-

abdominal infections.



Outcome: 2 Extra-abdominal infections

Study or subgroup Treatment Control Odds Ratio Odds Ratio


Csendes 1995 0/50 0/55 0.0 [ 0.0, 0.0 ]

Higgins 1999 1/277 0/135 1.47 [ 0.06, 36.33 ]

Illig 1997 1/128 2/122 0.47 [ 0.04, 5.28 ]

Kuthe 2006 0/40 0/53 0.0 [ 0.0, 0.0 ]

Sharma 2010 0/50 0/50 0.0 [ 0.0, 0.0 ]

Tocchi 2000 1/44 3/40 0.29 [ 0.03, 2.88 ]

Uludag 2009 4/68 5/76 0.89 [ 0.23, 3.45 ]

Total (95% CI) 657 531 0.66 [ 0.25, 1.74 ]


Heterogeneity: Chi2 = 1.00, df = 3 (P = 0.80); I2 =0.0%


0.05 0.2 1 5 20





site infection (Intention-to-treat analysis worst-best case scenario).



Outcome: 3 Surgical site infection (Intention-to-treat analysis worst-best case scenario)



Csendes 1995 2/50 2/55 7.7 % 1.10 [ 0.15, 8.15 ]

Harling 2000 8/44 3/41 10.7 % 2.81 [ 0.69, 11.45 ]

Higgins 1999 29/300 2/150 10.1 % 7.92 [ 1.86, 33.65 ]

Illig 1997 0/128 1/122 6.4 % 0.32 [ 0.01, 7.81 ]

Koc 2003 11/59 1/53 3.6 % 11.92 [ 1.48, 95.80 ]

Kuthe 2006 7/46 2/58 6.3 % 5.03 [ 0.99, 25.49 ]

Mahatharadol 2001 2/51 1/51 4.0 % 2.04 [ 0.18, 23.24 ]

Sharma 2010 2/50 4/50 16.2 % 0.48 [ 0.08, 2.74 ]

Tocchi 2000 6/47 4/43 15.3 % 1.43 [ 0.37, 5.44 ]

Uludag 2009 7/72 2/78 7.3 % 4.09 [ 0.82, 20.39 ]

Yildiz 2009 4/105 3/103 12.3 % 1.32 [ 0.29, 6.05 ]

Total (95% CI) 952 804 100.0 % 2.80 [ 1.75, 4.46 ]


Heterogeneity: Chi2 = 13.06, df = 10 (P = 0.22); I2 =23%


0.01 0.1 1 10 100

Favours experimental Favours control




site infection (Intention-to-treat analysis best-worst case scenario).



Outcome: 4 Surgical site infection (Intention-to-treat analysis best-worst case scenario)



Csendes 1995 2/50 2/55 2.9 % 1.10 [ 0.15, 8.15 ]

Harling 2000 3/44 7/41 10.6 % 0.36 [ 0.09, 1.48 ]

Higgins 1999 5/300 13/150 26.7 % 0.18 [ 0.06, 0.51 ]

Illig 1997 0/128 1/122 2.4 % 0.32 [ 0.01, 7.81 ]

Koc 2003 1/59 11/53 17.8 % 0.07 [ 0.01, 0.53 ]

Kuthe 2006 1/46 7/58 9.5 % 0.16 [ 0.02, 1.37 ]

Mahatharadol 2001 1/51 2/51 3.1 % 0.49 [ 0.04, 5.58 ]

Sharma 2010 2/50 4/50 6.0 % 0.48 [ 0.08, 2.74 ]

Tocchi 2000 3/47 7/43 10.7 % 0.35 [ 0.08, 1.45 ]

Uludag 2009 3/72 4/78 5.8 % 0.80 [ 0.17, 3.72 ]

Yildiz 2009 4/105 3/103 4.6 % 1.32 [ 0.29, 6.05 ]

Total (95% CI) 952 804 100.0 % 0.34 [ 0.21, 0.54 ]


Heterogeneity: Chi2 = 10.13, df = 10 (P = 0.43); I2 =1%

Test for overall effect: Z = 4.49 (P < 0.00001)

0.005 0.1 1 10 200

Favours experimental Favours control



A P P E N D I C E S

Appendix 1. Search Strategies

Database Period Search strategy

The Cochrane Hepato-Biliary Group Con-

trolled Trials Register

August 2010 ((antibiotic* OR prophyla*) AND (laparoscop* AND cholecys-

tectom*)) AND #20 >=1985

The Cochrane Central Register of Con-

trolled Trials in The Cochrane Library

Issue 3, 2010 #1 MeSH descriptor Antibiotic Prophylaxis explode all trees

#2 antibiotic* OR prophyla*

#3 (#1 OR #2)

#4 MeSH descriptor Laparoscopy explode all trees

#5 laparoscop* AND cholecystectom*

#6 (#4 OR #5)

#7 (#3 AND #6), from 1985 to 2010

MEDLINE (Ovid SP) 1985 to August 2010 1. exp Antibiotic Prophylaxis/

2. (antibiotic* or prophyla*).mp. [mp=title, original title, ab-

stract, name of substance word, subject heading word, unique

identifier]

3. 1 or 2

4. exp Laparoscopy/

5. (laparoscop* and cholecystectom*).mp. [mp=title, original

title, abstract, name of substance word, subject heading word,

unique identifier]

6. 4 or 5

7. 3 and 6

8. (random* or blind* or placebo* or meta-analysis).mp. [mp=

title, original title, abstract, name of substance word, subject

heading word, unique identifier]

9. 7 and 8

10. limit 9 to yr=“1985 -Current”

EMBASE (Ovid SP) 1985 to August 2010 1. exp antibiotic prophylaxis/

2. (antibiotic* or prophyla*).mp. [mp=title, abstract, subject

headings, heading word, drug trade name, original title, device

manufacturer, drug manufacturer]

3. 1 or 2

4. exp LAPAROSCOPY/

5. (laparoscop* and cholecystectom*).mp. [mp=title, abstract,

subject headings, heading word, drug trade name, original title,

device manufacturer, drug manufacturer]

6. 4 or 5

7. 3 and 6

8. (random* or blind* or placebo* or meta-analysis).mp. [mp=

title, abstract, subject headings, heading word, drug trade name,

original title, device manufacturer, drug manufacturer]

9. 7 and 8

10. limit 9 to yr=“1985 -Current”



(Continued)

LILACS 1985 to August 2010 #1 “COLECISTECTOMIA”

#2 “LAPAROSCOPIA”

#3 “ANTIBIOTICOS”

#4 “PROFILAXIS”

#5 #1 OR #2

#6 #3 OR #4

#7 #5 AND #6

Science Citation Index Expanded (http://

apps.isiknowledge.com)

1985 to August 2010 # 5 #4 AND #3

# 4 TS=(random* or blind* or placebo* or meta-analysis)

# 3 #2 AND #1

# 2 TS=(laparoscop* and cholecystectom*)

# 1 TS=(antibiotic* or prophyla*)

H I S T O R Y

Protocol first published: Issue 2, 2005

Review first published: Issue 12, 2010

C O N T R I B U T I O N S O F A U T H O R S

AE Sanabria: conceiving, designing, and co-ordination of the review.

AE Sanabria, E Valdivieso, and G Gomez: developing of search strategy; undertaking searches; screening search results; management

of papers retrieval; screening of retrieved papers against inclusion criteria; writing to authors of papers for additional information;

collecting data for the review; providing of additional data about papers; management of data for the review; appraising quality of

papers; abstracting data from papers; analysing of data; interpreting data; providing a methodological perspective; providing a clinical

perspective; and writing the review.

L Dominguez: undertaking searches; screening search results; screening of retrieved papers against inclusion criteria; collecting data

for the review; providing of additional data about papers; appraising quality of papers; abstracting data from papers; interpreting data;

providing a clinical perspective; and writing the review.

D E C L A R A T I O N S O F I N T E R E S T

None known.



S O U R C E S O F S U P P O R T

Internal sources

• Pontificia Universidad Javeriana-Hospital Universitario San Ignacio, Colombia.

• Universidad de La Sabana, Colombia.

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

As the protocol for this review was published in 2004, we had to update it following the guidelines in the Reviewer’s Handbook (Higgins

2009) before starting our work on the review. The changes we have made refer to the risk of bias and order of the outcomes.



Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy

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