European Journal of Surgical Oncology 2000; 26: 363366

doi:10.1053/ejso.1999.0899, available online at http://www.idealibrary.com on

Antibiotic prophylaxis for post-operative wound infection in clean

elective breast surgery

R. Gupta, D. Sinnett, R. Carpenter, P. E. Preece and G. T. Royle

Department of Surgery, Royal South Hants Hospital, Southampton, Department of Surgery,

Charing Cross Hospital, London, Department of Surgery, St Bartholomews Hospital, London and
Department of Surgery, Ninewells Hospital & Medical School, Dundee, UK

Antibiotic prophylaxis has been used to good effect in the prevention of post-operative wound infections in patients
undergoing gastrointestinal operations. We have assessed the use of a single dose of intravenous antibiotic (Augmentin
1.2 g), given with induction of anaesthesia as prophylaxis, against post-operative wound infection in women undergoing
clean, elective breast surgery. Three hundred and thirty-four patients were recruited. Of the 164 receiving antibiotic
prophylaxis 29 (17.7%) had wound infections compared with 32 (18.8%) in the placebo group (P=0.79). There were no
significant differences in any other post-operative infective complications. Antibiotic prophylaxis is probably not required
in clean, elective breast surgery. 2000 Harcourt Publishers Ltd
Key words: antibiotic prophylaxis; post-operative infections.

Introduction ecacy in other elective operations in order to reduce

Carcinoma of the breast aects one in 12 women in the
UK. Surgery, in the form of mastectomy or local excision
with or without axillary clearance, remains the primary
treatment of choice, as the majority are locally invasive at
the time of presentation. Patients will often require adjuvant
therapy in the form of chemotherapy or radiotherapy.
Overall these treatment regimes result in a local recurrence
rate of less than 10%.1 Non-invasive breast carcinoma is
usually treated with wide local excision, without the need
for axillary clearance.2,3
Wound infection occurs in approximately 10% of women
undergoing curative surgery for breast carcinoma, and seems
to be particularly common following axillary clearance.
Wound infection is also common where definitive surgery
follows a recent open biopsy. Despite the risk of morbidity
the need for staging means that axillary clearance remains
part of the management protocol for breast cancer.
Wound infection usually occurs between 5 and 21 days
following surgery in approximately 10% of patients. The
causative organism is often Staphylococcus aureus although
Staphylococcus albus and coliforms or bacteroides may be
the cause. The presence of mammary duct ectasia is
associated with an increased risk of wound infection. It is
often not possible to make this diagnosis, however, until
after surgery has been performed. The occurrence of wound
infection can have an adverse impact on the psychological
welfare of the patient and her subsequent management.
Prophylactic antibiotics have been used with considerable
Correspondence to: Mr G. T. Royle.
infective complications. Our study was conducted to assess
whether prophylactic antibiotics would reduce the rate of
post-operative infection.
Methods
We have performed a prospective, randomized, observer
blind, placebo-controlled study in four dierent centres in
order to assess the ecacy of a single dose of antibiotic
(1.2 g Augmentin200 mg clavulanic acid and 1000 mg
amoxycillin), in women undergoing definitive surgery for
malignant breast disease. This study was granted ethical
approval by the local hospital ethics committees of all
four participating centres (Royal South Hants Hospital,
Southampton; Charing Cross Hospital, London; St
Bartholomews Hospital, London and Ninewells Hospital,
Dundee, UK). All patients gave written, informed consent
prior to inclusion in this study. Patients were randomized
to receive the antibiotic or placebo (20 ml 0.9% sterile saline)
by reference to a computer generated list. Where the study
agent was administered the anaesthetist was instructed to
reconstitute the antibiotic from vials of sterile powder. It
was then administered to the patients as a single intravenous
bolus injection through a peripherally placed 22 gauge
intravenous cannula, shortly after the induction of
anaesthesia but before the first incision was made. The
placebo was administered in the same way as a single bolus
injection of sterile saline. At no time until the breaking of
the code was the investigator made aware of whether the
active agent or the placebo was administered, so making
this study observer blind.

07487983/00/040363+04 $35.00/0 2000 Harcourt Publishers Ltd

364
Table 1. Number of patients recruited and suitable for final analysis
Treatment group
Augmentin Placebo Total
Randomized 177 180 357
Screened 177 180 357
Completed study 156 157 313
Valid for ecacy analysis 174 177 351
Table 2. Demographic details of study patients (meanSD)
Augmentin Placebo
(n=174) (n=177)
Age (years) 5611.7 5811.1
Height (cm) 1626.4 1626.0
Weight (kg) 63.6 (43.6108.1) 64.5 (44.7104.7)
Median (range).
The randomization list was generated by computer. The
randomization codes were kept in sealed envelopes. Codes
were sequentially allocated to randomized patients. Neither
the patient nor any of the sta involved with this study
were aware of the allocation of treatment until after the
study had been completed.
The patients who were included in this study were 18
years of age or over. There was no upper age limit. All
patients had a diagnosis of breast cancer, based on previous
histological evidence or from a combination of cytology
and mammography. All patients had either a mastectomy
or a wide local excision, with or without axillary clearance,
as definitive treatment for their disease. No patient was
entered into the study more than once. Patients known to
have a hypersensitivity to penicillin were excluded from
this study, as were patients who were taking concurrent
antimicrobial therapy at the time, or within 72 hours of
planned surgery for any reason. Pregnant patients, or those
known to be suering from renal impairment (serum
creatinine >200
mol/l) or liver failure (liver function tests
greater than twice the upper limit of normal), were also
excluded.
The primary end point was the incidence of wound
infection. This was defined as discharge from the wound or
erythema indicative of cellulitis (>5 mm from the wound)
at any time during the study period, either before or after
discharge from hospital. The wound characteristics were
assessed in terms of the presence of healing, marked
echymosis, lymphocoele, erythema, serous exudate, purulent
exudate, abscess and wound breakdown. Secondary
endpoints included febrile morbidity. These included
duration of post-operative hospital stay, delay in progressing
to chemotherapy radiotherapy or surgical cosmesis due to
wound infection and the incidence of chest or urinary
infection, septicaemia or other infections. Febrile morbidity
was defined as an increase in the patients temperature to
above 38.0C on two separate occasions (excluding the
24 hours in the immediate post-operative period). Post-
operative hospital stay was defined as (date of
dischargedate of operation) +1. The wound was assessed
and further progress monitored at a routine outpatient clinic
attendance 1014 days following discharge.
The tolerability of the study agent was also assessed by
R. Gupta et al.
recording the incidence of adverse events. An adverse event
was defined as one where patients answered positively to
the question Do you feel dierently in any way since the
last visit? If the patient responded yes details of the
treatment emergent adverse event and its severity, including
its relationship to the study agent, were documented in the
relevant case report forms. The relationship to the study
agent was judged by the investigator to be unassessable,
unrelated, probably unrelated or probably related. All
adverse experiences were coded from the verbatim term
according to the World Health Organization adverse
reaction terminology dictionary by body system and
preferred term. This method of detecting adverse events was
in accordance with the Good Clinical Practice Guidelines of
the time.
The incidence of wound infection was compared between
treatment groups using the chi-squared test. A two-tailed
test with significance level of 5% was performed. The main
analysis was performed on the control population, which
excluded patients who did not receive the injection of the
study agent and those who had no follow-up assessments.
We aimed to recruit 500 patients over a 2 year period,
allocating 250 to each of the study arms. Allowing for
withdrawals it was estimated that 200 patients in each
treatment group would be required to detect a dierence of
7% in the wound infection rate. This calculation was based
on the assumption that the infection rate would be 3% in
the Augmentin group and 10% in the placebo group, with
a significance level of 0.05 and 80% power.
Results
In total 357 patients were recruited from all of the four
centres. The period of the study was from 13 January 1992
until 4 January 1994. Table 1 shows details of these patients.
Although 357 patients were recruited, a total of 351
produced data suitable for ecacy analysis. Of the patients
in the Augmentin group five (3.1%) were withdrawn due to
a violation of the protocol. One patient (0.6%) in this group
was withdrawn for an unspecified reason. In the placebo
group eight patients (4.8%) were withdrawn due to protocol
violation and one (0.6 %) due to the existence of concurrent
disease. Protocol violations resulted in six patients being
excluded from the intention-to-treat group. In two,
prophylaxis was given, in three no operation was performed
and in one no post-treatment assessment were recorded.
These rules were not specified in the protocol. Patients who
could be evaluated regarding the ecacy of treatment were
defined as those who received at least one dose of the study
agent or placebo.
Table 2 gives demographic details of the patients in the
study. It can be seen that the patients were similar in this
respect. It can be seen that patients in both groups were
similar in terms of age, height and weight. Table 3 gives
pre-operative and operative details of these patients and
Table 4 gives their staging details: again it can be seen that
patients in both groups had similar numbers of operative
procedures.
Table 5 gives details of wound swabs. Seventeen swabs
were taken from the wounds of 14 patients in the Augmentin
 Antibiotic prophylaxis for post-operative wound infection 365

Table 3. Pre-operative and operative details of study patients

Augmentin Placebo

Open biopsy in previous 4 weeks 53 (30.6%) 43 (24.4%)

Days prior to definitive surgery 25 (1160) 25 (447)
WLE following previous open biopsy 1 (0.6%) 5 (2.8%)
WLE with axillary clearance 65 (37.4%) 56 (31.6%)
Mastectomy alone 11 (6.3%) 14 (7.9%)
Axillary clearance alone 19 (9.2%) 18 (10.2%)
Mastectomy with axillary clearance 71 (40.8%) 76 (42.9%)
Duration of operation (minutes) 50 (15180) 50 (15180)
Drain insertion 171 (98.3%) 172 (97.7%)

Median (range). WLE: wide local incision.

Table 4. Staging details of study patients in the placebo group had signs of a chest infection during
the course of this study. Three patients in the Augmentin
Augmentin Placebo
group and one in the placebo group had a urinary tract
Tumour score 1 63 (41.7%) 73 (48.3%) infection. Two patients in the Augmentin group and one in
Tumour score 2 77 (51.0%) 69 (45.7%) the placebo group had other infections during the course
Nodal involvement 61 (38.1%) 62 (39.5%) of the study. There were no cases of septicaemia in this
Distant metastases 0 2 (1.2%)
study.
The median duration of hospital stay in both groups was
5 days; the overall duration of hospital stay was 172 days.
Table 5. Details of wound swabs of study patients A delay in the clinical management of the patients with
regard to chemotherapy, radiotherapy or surgical cosmesis
Augmentin Placebo as a result of wound infection was reported in 17 (10.2%)
n=164 n=170 cases in the Augmentin group compared with nine (5.4%)
Number of patients (swabs) 14 (17) 20 (30) in the placebo group.
Number of bacteriologically A total of 74 adverse events were reported by 59 (17.2%)
positive swabs 11 21 patients during the course of this study. Thirty-one (18.2%)
patients were in the Augmentin group who reported a total
of 41 such events, compared with 28 (16.2%) patients in the
placebo group who reported 33. The dierence between the
Table 6. Incidence of wound infection in study patients
two groups in the number of patients reporting at least one
Augmentin Placebo adverse event was not statistically significant (P=0.62).
n=164 n=170

Wound infection (%) 29 (17.7) 32 (18.8)

Dierence between groups 1.1%
95% confidence interval 9.4%, 7.1%
P-value 0.79
Day on which infection first observed 12 11
Range 324 625
group, of which 11 were bacteriologically positive. In the
placebo group 30 swabs were taken from 20 patients: of
these 21 were bacteriologically positive. Table 6 gives the
incidence of wound infection in patients. The wound
infection rate was similar in both groups, but was not
statistically significantly dierent. Furthermore, four
patients in each group were reported to have wound
infections during their hospital stay whilst 28 (17.1%) in the
Augmentin group and 29 (17.1%) in the placebo group had
wound infections following their discharge from hospital.
An episode of febrile morbidity was experienced at least
once by five (2.9%) patients in the Augmentin group and
six (3.5%) in the placebo group. Two patients experienced
two episodes each. The incidence of febrile morbidity was
not statistically significantly dierent.
One patient in the Augmentin group and three patients
Discussion
Amoxycillinclavulanic acid has been a popular and eective
antibiotic in comparative trials of antibiotics. In a series of
non-contaminated operations dierent doses of this agent
were found to be equally eective in preventing infective
complications.4 In another trail of non-contaminated intra-
abdominal operations it was compard with the combination
of cefuroxime and metroniodazole. Again, similar rates
of infective complications were found.5 Comparison with
cephradine/metronidazole,6 mezlocillin7 and gentamicin8
produced similar results.
Patients with appendicitis undergoing operative treatment
have been studied. Comparison of amoxycillinclavulanic
acid with metronidazole9 demonstrated similar post-
operative infective complication rates even in those patients
who had gangrenous appendicitis. Elderly patients
undergoing elective colorectal operations are at high risk
of post-operative infective complications. In a study of such
operations amoxycillinclavulanic acid was compared with a
combination of gentamicin and metronidazole.10 The overall
rates of abdominal or perineal wound infection, intra-
abdominal abscess and systemic sepsis were similar in the
366 R. Gupta et al.
two groups. Another study of these patients comparing
amoxycillinclavulanic acid with gentamicin and
clindamycin demonstrated a lower rate if intra-abdominal
septic complications required reoperation.11
Similar rates of post-operative infective complications
were reported in a study comparing amoxycillinclavulanic
acid with cefotaxime or cefamandole1214 in patients
undergoing biliary operations. Amoxycillinclavulanic acid
was found to be better than the combination of cephalothin
and clindamycin when given as three peri-operative doses
in patients having biliary and gallbladder operations.
Our study has examined the use of a single dose of
intravenous Augmentin given at induction as prophylaxis
against wound infection in women undergoing breast
surgery. The results indicate that such a practice does not
influence the incidence of this or any other infective
complication in these patients. In this respect this study
supports the findings of a previous study in which cephazolin
was assessed in a similar context. However, the study agent,
Augmentin, was well tolerated with no adverse events being
suciently serious to warrant withdrawal of patients from
the study. Further research is now required to identify breast
patients at risk of infective complications who might benefit
from prophylactic antibiotic therapy.
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Accepted for publication 20 October 1999