Randomized clinical trial

Randomized clinical trial of oral and intravenous versus

intravenous antibiotic prophylaxis for laparoscopic colorectal
resection
A. Ikeda, T. Konishi, M. Ueno, Y. Fukunaga, S. Nagayama, Y. Fujimoto, T. Akiyoshi
and T. Yamaguchi
Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake Koto-ku, Tokyo,
135-8550, Japan
Correspondence to: Dr T. Konishi (e-mail: tkonishi-tky@umin.ac.jp)

Background: The use of oral prophylactic antibiotics for the prevention of surgical-site infection (SSI)
in patients undergoing laparoscopic surgery for colorectal cancer is controversial. The aim of this RCT
was to evaluate whether intravenous perioperative antibiotics are inferior to combined preoperative oral
and perioperative intravenous antibiotics in this setting.
Methods: Patients undergoing elective laparoscopic colorectal resection in a single cancer centre were
assigned randomly to combined preoperative oral antibiotics (metronidazole and kanamycin) and periop-
erative intravenous antibiotics (cefmetazole) (oral/IV group) or to perioperative intravenous antibiotics
(cefmetazole) alone (IV-only group). Patients were stratified for the analyses based on type of opera-
tion (colonic surgery, anterior resection or abdominoperineal resection), preoperative use of mechanical
bowel preparation, preoperative chemoradiotherapy and the presence of diabetes mellitus. The primary
endpoint was the overall rate of SSI. Secondary endpoints were the rates of incisional site infection,
organ/space infection, anastomotic leakage, intra-abdominal abscess, adverse events and postoperative
complications.
Results: Of 540 patients offered participation in the trial in 2013–2014, 515 agreed to take part and
were randomized. Some 256 patients in the IV-only group and 255 in the oral/IV group completed the
treatment per protocol. The overall rate of SSI was 7⋅8 per cent (20 of 256) in the IV-only group and
7⋅8 per cent (20 of 255) in the oral/IV group, confirming that perioperative administration of intravenous
antibiotics alone was not inferior to the combined regimen (P = 0⋅017). There were no differences in rates
of incisional site infection (5⋅5 versus 5⋅9 per cent respectively), organ/space infection (2⋅3 versus 2⋅0 per
cent) or other secondary endpoints between the two groups.
Conclusion: Intravenous perioperative antimicrobial prophylaxis alone is not inferior to combined pre-
operative oral and intravenous perioperative prophylaxis with regard to SSI in patients with colo-
rectal cancer undergoing elective laparoscopic resection. Registration number: UMIN000019339
(http://www.umin.ac.jp/ctr/).

Paper accepted 27 June 2016

Published online 23 August 2016 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10281

Introduction investigating the effects of bowel preparation. Despite

Antimicrobial prophylaxis has become the standard means
of preventing surgical-site infection (SSI) in patients
undergoing elective colorectal cancer surgery. SSI leads
to worse quality of life, longer hospital stay and increased
cost. It is well established that perioperative parenteral
antibiotics reduce SSI and that systemic antimicrobial
prophylaxis should be a standard component of studies
some guidelines recommending administration of a
combination of preoperative non-absorbable oral and peri-
operative intravenous antibiotics to prevent SSI in patients
undergoing colorectal surgery1 , the use of oral antibiotics
has declined. Previous RCTs and meta-analyses2 – 6 have
reported conflicting findings regarding the impact of oral
and parenteral antimicrobial prophylaxis on the incidence
of SSI in patients undergoing gastrointestinal surgery.

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Prophylaxis of surgical-site infection in laparoscopic colorectal resection
Most studies were heterogeneous and were not focused
on laparoscopic surgery, where the incidence of SSI may
be reduced. The aim of this trial was to evaluate the
non-inferiority of intravenous perioperative antimicrobial
prophylaxis alone versus combined oral preoperative and
intravenous perioperative antimicrobial prophylaxis in
patients undergoing laparoscopic surgery for colorectal
cancer.
Methods
The study was conducted with the approval of the ethics
committee of the Cancer Institute Hospital of the Japanese
Foundation for Cancer Research, Tokyo, Japan. Written
informed consent was obtained from all participants. This
trial is registered with the UMIN Clinical Trials Registry
(UMIN000019339).
Study design
This prospective RCT was designed to evaluate the
non-inferiority of intravenous antimicrobial prophylaxis
alone versus combined oral and intravenous antimicrobial
prophylaxis in patients undergoing laparoscopic colorectal
surgery. The primary endpoint was the overall rate of
SSI. Secondary endpoints were the rates of incisional
site infection, organ/space infection, anastomotic leakage,
intra-abdominal abscess, adverse events and postoperative
complications.
Inclusion and exclusion criteria
All consecutive patients with colorectal cancer undergoing
elective laparoscopic colorectal resection from June 2013
to April 2014 in the Cancer Institute Hospital of the
Japanese Foundation for Cancer Research were enrolled.
The following exclusion criteria were applied: age less than
20 years; patients with bowel obstruction and who could
not tolerate liquid intake; pregnancy; history of allergy
to the drugs in the protocol; administration of antibiotics
in the 2 weeks before surgery; severe dysfunction of liver,
kidney, heart or lung; and synchronous resection of other
major organs such as the stomach, liver or uterus. Patients
undergoing synchronous resection of the gallbladder or
ovary were not excluded. Patients with incomplete bowel
obstruction tolerating liquid intake were included in the
study.
Patient randomization
Eligible patients were assigned randomly to one of the
two groups. Patients in the intravenous (IV)-only group
© 2016 BJS Society Ltd
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1609
received 1 g cefmetazole intravenously at least 30 min
before skin incision, then every 3 h during surgery until
skin closure. After completion of surgery, two additional
doses of intravenous prophylaxis were given within 24 h.
Patients in the combined oral/intravenous (oral/IV) group
received two oral doses of 750 mg metronidazole with
1000 mg kanamycin at 15.00 and 21.00 hours on the day
before the surgery in addition to the same intravenous
antibiotic regimen as patients in the IV-only group.
The sequentially numbered, opaque, sealed envelopes
system was used for patient randomization. At random-
ization, patients were stratified according to planned
type of surgery (colonic surgery, anterior resection
or abdominoperineal resection), preoperative use of
mechanical bowel preparation with magnesium citrate,
preoperative chemoradiotherapy, and the presence of
diabetes mellitus with a haemoglobin A1c level above
7⋅0 mg/dl or requiring medical therapy. The sets of
envelopes were prepared for each combination of the
stratification categories, and patients were randomized
using the corresponding sets of envelopes. Randomization
was done in the trial centre. After obtaining the patient’s
informed consent before surgery for participation in the
trial, an envelope was opened by an independent clinician.
The results of the allocations were not informed to the
infection control doctors or nurses who determined SSI,
but neither patients nor surgeons were masked to the
assignment. All antibiotics in the protocol regimen were
prescribed according to standard clinical and compliance
protocols.
Perioperative protocols and surgical procedures
All patients, except those with bowel obstruction, under-
went mechanical bowel preparation with magnesium cit-
rate at 08.00 hours and sodium picosulfate at 11.00 hours
on the day before surgery. Patients had all hair within the
proposed surgical field shaved using electrical hair-clippers
after induction of anaesthesia, and the skin was prepared
with povidone–iodine. Mobilization of the bowel, liga-
tion of vessels and lymph node dissection were performed
intracorporeally. In patients undergoing colonic surgery
an extracorporeal functional end-to-end anastomosis or
intracorporeal anastomosis with a double-stapling tech-
nique was employed depending on the anastomosis loca-
tion, whereas in those undergoing anterior resection an
intracorporeal double-stapled or hand-sewn coloanal anas-
tomosis was employed. Surgical wounds were covered with
disposable wound protectors during the extracorporeal part
of the procedure. In some patients undergoing anterior
resection, closed drains were placed behind the anasto-
motic site. After all gloves had been changed, the fascia
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1610 A. Ikeda, T. Konishi, M. Ueno, Y. Fukunaga, S. Nagayama, Y. Fujimoto et al.

Assessed for eligibility n = 554

Excluded n = 39
Exclusion criteria met n = 12
Preoperative use of other antibiotics n = 8
Enrolment

Planned synchronous liver resection n = 1

Severe renal failure n = 1
Allergy to kanamycin n = 2
Declined participation n = 25
Other reason n = 2

Randomized n = 515
Allocation

Allocated to IV-only group n = 257 Allocated to oral/IV group n = 258

Received allocated treatment n = 257
Converted to open surgery n = 1
Follow-up
Received allocated treatment n = 256
Did not receive allocated treatment n = 2
Oral intake not tolerated owing to obstruction n = 2
Converted to open surgery n = 1

Lost to follow-up n = 0 Lost to follow-up n = 0

Analysis

Analysed n = 256 Analysed n = 255

Fig. 1 CONSORT diagram for the study. IV, intravenous

Table 1 Patient characteristics Table 2 Operations and pathology

IV-only group Oral/IV group IV-only group Oral/IV group
(n = 256) (n = 255) (n = 256) (n = 255)
Age (years)* 62 (29–86) 65 (27–93) Surgical procedure
Sex ratio (M : F) 141 : 115 142 : 114
Colonic surgery† 155 (60⋅5) 154 (60⋅4)
BMI (kg/m2 )* 22⋅8 (14⋅8–35⋅2) 22⋅4 (15⋅3–37⋅4)
Anterior resection‡ 89 (34⋅8) 88 (34⋅5)
ASA fitness grade
I 86 (33⋅6) 68 (26⋅7) APR§ 12 (4⋅7) 13 (5⋅1)
II 165 (64⋅5) 180 (70⋅6) Stoma creation 57 (22⋅3) 63 (24⋅7)
III 5 (2⋅0) 7 (2⋅7) Duration of surgery* 232 (102–701) 227 (100–686)
Smoker 104 (40⋅6) 106 (41⋅6) Blood loss* 15 (0–1200) 15 (0–620)
Diabetes mellitus 31 (12⋅1) 37 (14⋅5) Blood transfusion 0 (0) 0 (0)
Previous history of 75 (29⋅3) 85 (33⋅3) Abdominal drain 124 (48⋅4) 119 (46⋅7)
abdominal surgery
pTNM stage
Preoperative 40 (15⋅6) 31 (12⋅2)
0 14 (5⋅5) 11 (4⋅3)
radiotherapy
Mechanical bowel 216 (84⋅4) 223 (87⋅5) I 71 (27⋅7) 77 (30⋅2)
preparation II 61 (23⋅8) 72 (28⋅2)
III 72 (28⋅1) 66 (25⋅9)
Values in parentheses are percentages unless indicated otherwise; *values IV 29 (11⋅3) 19 (7⋅5)
are median (range). IV, intravenous.
Other tumour¶ 9 (3⋅5) 10 (3⋅9)

was closed with monofilament absorbable sutures. Inci-
sion sites were washed with saline, and subcuticular sutures
were placed for skin closure. Subcutaneous drains were not
used. The incisional sites were covered with sterile dress-
ings that were removed within 48 h. Intra-abdominal drains
were removed 5–7 days after the operation. All proce-
dures were performed or supervised by six expert colorectal
Values in parentheses are percentages unless indicated otherwise; *values
are median (range). †Three and one total abdominal colectomy
operations are included in the intravenous (IV)-only group and
oral/intravenous (oral/IV) group respectively. ‡One total
proctocolectomy is included in the oral/IV group. §One total
proctocolectomy is included in the IV-only group. ¶Includes 12
neuroendocrine tumours, two gastrointestinal stromal tumours, four
recurrent adenocarcinomas and one adenoma with severe dysplasia. APR,
abdominoperineal resection.

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Prophylaxis of surgical-site infection in laparoscopic colorectal resection 1611

Table 3 Surgical-site infections

IV-only group (n = 256)* Oral/IV group (n = 255)* Absolute difference (%)† Odds ratio‡ P

Overall SSI 20 (7⋅8) 20 (7⋅8) −0⋅03 (−4⋅00, 3⋅94) – 0⋅017#

Incisional site infection 14 (5⋅5) 15 (5⋅9) 0⋅93 (0⋅44, 1⋅96) 0⋅840**
Perineal incisional site§ 3 of 12 (25) 2 of 13 (15) 1⋅83 (0⋅25, 13⋅47) 0⋅645**
Abdominal incisional site 11 (4⋅3) 13 (5⋅1) 0⋅84 (0⋅37, 1⋅90) 0⋅669**
Organ/space infection 6 (2⋅3) 5 (2⋅0) 1⋅20 (0⋅36, 3⋅98) 1⋅000**
Intra-abdominal abscess 0 (0) 2 (0⋅8) – 0⋅249**
Anastomotic leak¶ 6 of 244 (2⋅5) 3 of 242 (1⋅2) 2⋅01 (0⋅50, 8⋅12) 0⋅504**

Values in parentheses are *percentages, †90 per cent c.i. for non-inferiority and ‡95 per cent c.i. §Analysis performed in the patients who had an
abdominoperineal resection. ¶Analysis performed in patients with an anastomosis. IV, intravenous; SSI, surgical-site infection. #One-sided P value for
non-inferiority of the primary endpoint (Dunnett–Gent test). **Two-sided P value for the secondary endpoint (Pearson’s χ2 or Fisher’s exact test).

Table 4 Surgical-site infections according to surgical procedure

IV-only group (n = 256) Oral/IV group (n = 255) Odds ratio* P

Overall SSIs
All procedures 20 (7⋅8) 20 (7⋅8) 1⋅00 (0⋅52, 1⋅90) 0⋅990
Right colectomy 6 of 70 (9) 2 of 77 (3) 3⋅52 (0⋅69, 18⋅03) 0⋅152
Left colectomy 6 of 85 (7) 6 of 77 (8) 0⋅90 (0⋅28, 2⋅91) 1⋅000
Anterior resection 5 of 89 (6) 8 of 88 (9) 0⋅60 (0⋅19, 1⋅90) 0⋅405
APR 3 of 12 (25) 4 of 13 (31) 0⋅75 (0⋅13, 4⋅36) 1⋅000
Incisional site infections
All procedures 14 (5⋅5) 15 (5⋅9) 0⋅93 (0⋅44, 1⋅96) 0⋅840
Right colectomy 6 of 70 (9) 2 of 77 (3) 3⋅52 (0⋅69, 18⋅03) 0⋅152
Left colectomy 4 of 85 (5) 5 of 77 (6) 0⋅71 (0⋅18, 2⋅75) 0⋅737
Anterior resection 1 of 89 (1) 5 of 88 (6) 0⋅19 (0⋅02, 1⋅65) 0⋅118
APR 3 of 12 (25) 3 of 13 (23) 1⋅11 (0⋅18, 6⋅97) 1⋅000
Organ/space infections
All procedures 6 (2⋅3) 5 (2⋅0) 1⋅20 (0⋅36, 3⋅98) 1⋅000
Right colectomy 0 of 70 (0) 0 of 77 (0) – –
Left colectomy 2 of 85 (2) 1 of 77 (1) 1⋅83 (0⋅16, 20⋅61) 1⋅000
Anterior resection 4 of 89 (5) 3 of 88 (3) 1⋅33 (0⋅29, 6⋅14) 1⋅000
APR 0 of 12 (0) 1 of 13 (8) – 1⋅000

Values in parentheses are percentages unless indicated otherwise; *values in parentheses are 95 per cent confidence intervals; IV, intravenous;
SSI, surgical-site infection; APR, abdominoperineal resection.

surgeons, each of whom had performed more than 500
laparoscopic colorectal operations and had a board certi-
fication in laparoscopic surgery from the Japan Society for
Endoscopic Surgery.
Determination of surgical-site infection
SSI was defined according to the guidelines issued by
the Centers for Disease Control and Prevention1 . Briefly,
the criteria for incisional SSI were infections occurring at
the incisional site within 30 days after the procedure and
involving the skin, subcutaneous tissue, muscle and fas-
cia but not the organ/space, together with at least one
of the following: purulent drainage from the incision; an
organism isolated from a culture of fluid from the inci-
sion; incisional pain, tenderness, localized swelling, redness
or heat; an incision that dehisced spontaneously or was
opened deliberately by a surgeon in the presence of the
signs and symptoms of infection described above. Super-
ficial and deep incisional SSIs were evaluated together
under the umbrella term of incisional SSI. The criteria for
organ/space SSI were infections occurring within 30 days
of the procedure in any part of the anatomy that was
opened or manipulated during the operation other than the
incisional site, together with at least one of the following:
purulent fluid from a drain placed into the organ/space;
an organism isolated from a culture of fluid from the
organ/space; abscess or other evidence of infection involv-
ing the organ/space found on direct examination, during
reoperation, or by histopathological or radiological exam-
ination; diagnosis of an organ/space SSI by an attending
physician. Patients were inspected daily for SSI until dis-
charge by attending physicians and nurses, with follow-up
for at least 30 days after surgery in the outpatient clinic.
Final decisions concerning SSI were made by independent
SSI surveillance doctors and infection control nurses.

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1612 A. Ikeda, T. Konishi, M. Ueno, Y. Fukunaga, S. Nagayama, Y. Fujimoto et al.

No. of
patients Odds ratio P

Colon 309 1·53 (0·61, 3·86) 0·489

Surgery type AR 177 0·60 (0·19, 1·90) 0·405
APR 25 0·75 (0·13, 4·36) 1·000
Yes 439 0·97 (0·48, 1·97) 0·932
Mechanical BP
No 72 1·07 (0·22, 5·19) 1·000
Yes 71 0·35 (0·10, 1·18) 0·132
CRT
No 440 1·45 (0·65, 3·22) 0·366
Yes 68 0·38 (0·04, 3·83) 0·620
Diabetes mellitus
No 443 1·09 (0·55, 2·16) 0·804
≥ 64 261 0·78 (0·31, 1·98) 0·647
Age (years)
< 64 250 1·26 (0·50, 3·20) 0·649
M 275 0·86 (0·41, 1·82) 0·701
Sex
F 236 1·35 (0·35, 5·17) 0·742
Yes 210 0·60 (0·24, 1·51) 0·270
Smoker
No 301 1·74 (0·67, 4·55) 0·344
≥ 25 134 1·78 (0·50, 6·39) 0·532
BMI (kg/m2) < 25 377 0·80 (0·38, 1·72) 0·572
0–II 306 0·74 (0·31, 1·79) 0·503
pTNM stage
III–IV 186 1·61 (0·57, 4·55) 0·623
≥ 240 234 0·94 (0·42, 2·13) 0·890
Duration of surgery (min)
< 240 277 1·04 (0·35, 3·04) 1·000
≥ 100 52 0·72 (0·19, 2·74) 0·734
Blood loss (ml)
< 100 459 1·08 (0·51, 2·23) 0·838
Yes 243 0·61 (0·26, 1·41) 0·244
Abdominal drain
No 268 2·15 (0·71, 6·46) 0·192
Yes 120 0·32 (0·10, 1·06) 0·063
Ostomy creation
No 391 2·01 (0·84, 4·81) 0·111
0·01 0·1 1 10
Favours IV-only group Favours oral/IV group

Fig. 2Forest plot of the treatment effect of oral antimicrobial prophylaxis in the subgroups. Odds ratios are shown with 95 per cent
confidence intervals, calculated by logistic regression. AR, anterior resection; APR, abdominoperineal resection; BP, bowel preparation;
CRT, chemoradiotherapy; IV, intravenous

Sample size Fisher’s exact test, as appropriate. Subgroups were anal-

ysed by logistic regression to assess the treatment effects
The predetermined non-inferiority margin δ was an abso-
of oral prophylaxis in various subgroups. Because of the
lute 5 per cent increase in overall SSI in the IV-only group
exploratory nature of subgroup comparisons, test results
compared with the oral/IV group. Assuming a one-sided
were reported without multiplicity adjustments for type I
α of 0⋅05, a power of 80 per cent and a 5 per cent inci-
error. Statistical analysis was performed using JMP® soft-
dence of overall SSI in both groups, 235 patients per group
ware version 9⋅0 and SAS® software version 9⋅4 (both from
were needed (Dunnett–Gent test)7 . Assuming an 8 per cent
SAS Institute, Cary, North Carolina, USA). P < 0⋅050 was
drop-out rate, the planned required sample size was 253
considered statistically significant.
patients. The non-inferiority margin of 5 per cent was set
only for the primary endpoint. Non-inferiority was to be
judged when the upper limit of the 90 per cent confidence
Results
interval of the absolute difference between the incidences
of SSI was lower than δ = 5 per cent. Among a total of 554 patients with colorectal cancer under-
going elective laparoscopic colorectal resection from June
Statistical analysis
2013 to April 2014, 540 were eligible for the study and 515
Continuous variables were analysed using Student’s t agreed to participate (Fig. 1). These 515 patients were ran-
test, and categorical valuables with Pearson’s χ2 test or domly assigned: 257 patients were allocated to receive only

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Prophylaxis of surgical-site infection in laparoscopic colorectal resection 1613

Table 5 Surgical complications

IV-only group (n = 256) Oral/IV group (n = 255) Odds ratio* P

MI/arrhythmia 1 (0⋅4) 1 (0⋅4) 1⋅00 (0⋅06, 16⋅01) 1⋅000

DVT/PE 0 (0) 0 (0) – –
Small bowel obstruction 14 (5⋅5) 9 (3⋅5) 1⋅58 (0⋅67, 3⋅72) 0⋅290
Anastomotic haemorrhage 3 of 244 (1⋅2) 3 of 242 (1⋅2) 0⋅99 (0⋅20, 4⋅96) 1⋅000
Anastomotic leak 6 of 244 (2⋅5) 3 of 242 (1⋅2) 2⋅01 (0⋅50, 8⋅12) 0⋅504
Bleeding requiring transfusion 0 (0) 0 (0) – –
Enterocolitis 4 (1⋅6) 1 (0⋅4) 4⋅03 (0⋅45, 36⋅32) 0⋅373
CD pseudomembranous colitis 1 (0⋅4) 0 (0) – 1⋅000
Urinary tract disorder 7 (2⋅7) 6 (2⋅4) 1⋅17 (0⋅39, 3⋅52) 1⋅000
Stoma-related problem 2 (0⋅8) 1 (0⋅4) 2⋅00 (0⋅18, 22⋅20) 1⋅000
Other complication 11 (4⋅3) 7 (2⋅8) 1⋅59 (0⋅61, 4⋅17) 0⋅473
Readmission within 30 days 1 (0⋅4) 0 (0) – 1⋅000
Perioperative death 0 (0) 0 (0) – –

Values in parentheses are percentages unless indicated otherwise; *values in parentheses are 95 per cent c.i. IV, intravenous; MI, myocardial infarction;
DVT, deep vein thrombosis; PE, pulmonary embolism; CD, Clostridium difficile.

intravenous antibiotics (IV-only group) and 258 to receive
combined oral/intravenous antibiotics (oral/IV group). All
patients except for two received the planned antimicrobial
doses and were followed up for 30 days after surgery. One
patient in each group had a conversion to open operation.
Finally, 511 patients were analysed.
Table 1 shows the patient characteristics of the two
groups, which were well balanced at baseline. Forty
patients in the IV-only group and 32 in the oral/IV group
did not receive mechanical bowel preparation because of
tumour-related bowel obstruction. Operative and patho-
logical backgrounds were also well balanced between the
two groups (Table 2). Median (range) blood loss was 15
(0–1200) ml and median (range) duration of surgery was
230 (100–701) min.
The rates of overall, incisional and organ/space SSI in
the two groups combined were 7⋅8, 5⋅7 and 2⋅2 per cent
respectively (Table 3). The overall rate of SSI was 7⋅8 per
cent in both the IV-only and oral/IV group. The absolute
difference was −0⋅03 (90 per cent c.i. −4⋅00 to 3⋅94, 95 per
cent c.i. −4⋅76 to 4⋅70) per cent. The upper limit of the
90 per cent c.i. for the absolute difference (3⋅94) was lower
than the preset 5 per cent margin specified in the protocol
(P = 0⋅017, Dunnett–Gent test). The results confirmed the
non-inferiority of intravenous antibiotics alone compared
with combined oral/intravenous antibiotics.
Anastomotic leakage was observed in 2⋅5 per cent of the
IV-only group and in 1⋅2 per cent of the oral/IV group
(P = 0⋅504) (Table 3). Additionally, there were no significant
differences between the two groups in the rates of all types
of SSI, including perineal and abdominal incisional site
infections, and intra-abdominal abscess.
The rates of SSI according to surgical procedure are
summarized in Table 4. The proportions of each procedure
were well balanced between the two groups. There were
no significant differences between the groups in overall
SSI, incisional site infections or organ/space infections for
all types of procedure. When the treatment effects of oral
microbial prophylaxis in various subgroups were assessed,
no subgroup showed an increased incidence of overall SSI
with omission of oral antimicrobial prophylaxis, including
the subgroups stratified in randomization (Fig. 2).
No significant differences were found between the
groups in surgical complications other than SSI (Table 5).
Enterocolitis occurred at a low rate: in only four patients in
the IV-only group (1⋅6 per cent) and in one patient in the
oral/IV group (0⋅4 per cent). One patient in the IV-only
group developed Clostridium difficile pseudomembranous
colitis. There were no perioperative deaths.
Discussion
This study found that use of intravenous antibiotics alone
was not inferior to the combined administration of oral
and intravenous antibiotics with regard to SSI in patients
with colorectal cancer undergoing elective laparoscopic
resection. The rates of overall, incisional and organ/space
infection were similar in the two groups.
Recent RCTs and meta-analyses have reported conflict-
ing results concerning the benefit of oral non-absorbable
antibiotics in reducing SSI in patients undergoing colo-
rectal surgery. In an RCT in 2002, Lewis6 found that a
combination of oral and systemic antibiotics was supe-
rior to systemic antibiotics alone for the prevention of SSI
in patients undergoing elective colonic surgery. However,
in 2005, Espin-Basany and colleagues3 drew the oppo-
site conclusion: their RCT showed that adding oral to
systemic antibiotics conferred no advantage over systemic

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1614
antibiotics alone. Kobayashi and co-workers4 , in the largest
reported RCT of the three, found that combined oral
and intravenous antibiotics did not reduce the incidence
of SSI compared with intravenous antibiotics alone. A
meta-analysis8 of 16 RCTs published from 1979 to 2007
reported that a combination of oral and intravenous antibi-
otics achieved a lower incidence of wound infection than
intravenous antibiotics alone. These contradictory out-
comes could be attributable to the heterogeneity of the
study populations, which included cancer and benign dis-
ease, open and laparoscopic surgery, and elective and emer-
gency operations.
The present findings suggest that administration of oral
antibiotics may be redundant in laparoscopic colorectal
resection. Their omission would reduce healthcare costs9 ,
if these results were valid in other hands – note that the
overall SSI rate in the present study was lower than
that reported from other centres3 – 6,10 – 16 . Rates of other
complications were also low in this trial, indicating good
surgical quality. It is unlikely that morbidity was under-
estimated because prospective surveillance was performed
for 30 days, including outpatient clinics.
Previous studies have employed a variety of regimens
for oral antibiotic prophylaxis6,9 . In this study, kanamycin
plus metronidazole was chosen. Kanamycin, an oral
non-absorbable aminoglycoside, has a broad spectrum of
activity against aerobic flora. Metronidazole is a nitroim-
idazole with a spectrum of activity against anaerobic
bacteria. In the protocol, patients received two doses of oral
antibiotics the day before operation, in contrast to most
previous studies, which provided at least three doses3,4,17 .
With regard to this point, Espin-Basany et al.3 demon-
strated no significant differences in the incidence of wound
infection among patients receiving either three doses, one
dose, or no dose of oral antibiotics. Song and Glenny9 also
demonstrated no significant differences in the incidence
of wound infection among many different regimens, as
long as the regimen covered both aerobic and anaerobic
bacteria.
Basic scientific observations of antimicrobial prophylaxis
and the faecal flora have shown that production of colla-
genase and matrix metalloproteinase 9 by Pseudomonas
aeruginosa and Enterococcus faecalis is enhanced in the
inflammatory milieu of an anastomosis18,19 . These findings
suggest a possible impact of these microorganisms on
promoting anastomotic leakage, and thus oral microbial
prophylaxis might reduce leakage by eradicating these
microorganisms9,18,19 . The present study is evidently
underpowered to provide any conclusions regarding the
contribution of oral microbial prophylaxis in reducing
anastomotic leakage.
© 2016 BJS Society Ltd
Published by John Wiley & Sons Ltd
A. Ikeda, T. Konishi, M. Ueno, Y. Fukunaga, S. Nagayama, Y. Fujimoto et al.
In the subset analyses, no subgroup showed an increase in
SSI with omission of oral antimicrobial prophylaxis. The
findings are consistent with the primary outcome of the
study, although these subset analyses were exploratory in
nature and not powered for differences. Other limitations
include that this was a single-centre rather than a multi-
centre RCT, and that it was not double-blinded. The infec-
tion control doctors and nurses who determined SSIs were
blinded to the assignment, thus reducing bias in assess-
ment of the primary endpoint. Randomization was per-
formed using the opaque envelopes system, which may
have a potential risk of subversion compared with random-
ization by a computer program. This trial was conducted
in a specialized high-volume centre with a low conversion
rate, and the majority of patients were non-obese with ASA
grade I or II. In these respects, characteristics of the present
patients may differ from those of patients cared for in other
settings, such that the results may not be generalizable.
Acknowledgements
The authors thank the infection control nurses (K. Ida
and T. Akatsuchi) and surgeons (T. Nagasaki, J. Nagata,
T. Mukai, R. Ohno, K. Tomori, A. Murata, M. Takeda, Y.
Takeda, E. Kusumoto) who participated in the surveillance
programme for SSI implemented at the Cancer Institute
Hospital of the Japanese Foundation for Cancer Research.
The authors also thank N. Ishizuka from the clinical trial
department for the statistical analysis.
Disclosure: The authors declare no conflict of interest.
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