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World J Surg (2013) 37:59–66

DOI 10.1007/s00268-012-1816-5

A Randomized, Double-blinded Placebo-controlled Clinical Trial
of the Routine Use of Preoperative Antibiotic Prophylaxis
in Modified Radical Mastectomy
Nelson D. Cabaluna • Gemma B. Uy •
Rommel M. Galicia • Shalimar C. Cortez •

Marc Denver S. Yray • Brian S. Buckley

Published online: 2 October 2012
Ó Socie´te´ Internationale de Chirurgie 2012

Abstract groups in treatments required for SSI, incidence of hema-
Background The effectiveness of antibiotic prophylaxis toma or seroma.
for prevention of surgical site infection (SSI) following Conclusions The findings of this study, alone and when
specific types of breast cancer surgery remains uncertain. meta-analyzed with data from studies in similar surgical
This study assessed the effectiveness of prophylaxis in populations, do not support the use of antibiotic prophy-
modified radical mastectomy (MRM). laxis in MRM.
Methods Women undergoing MRM for breast cancer
were recruited. Women were excluded who had diabetes
mellitus, severe malnutrition or known allergy to cepha- Introduction
losporins; were receiving corticosteroid therapy or were
treated with antibiotics within one week prior to surgery; Surgical site infections (SSI) have been shown to be the
were scheduled for simultaneous breast reconstruction or second most common adverse event in hospitalized
bilateral oophorectomy; had existing local infection. Par- patients [1]. Any surgical procedure carries the risk of SSI
ticipants were randomized to receive either intravenous and although seldom fatal, SSI can cause significant mor-
cefazolin 1 g or placebo within 30 min prior to skin inci- bidity and can delay subsequent adjuvant treatment [2].
sion. Standard skin preparation and operative technique for Postoperative infection rates after surgery for breast cancer
MRM were carried out. Wounds were assessed for SSI and have been estimated to range from 3 to 15 % percent,
other complications weekly for 30 days. higher than the usual rates for clean surgical procedures
Results A total of 254 women were recruited. Age, [3]. Surgery remains the primary and often the first treat-
clinical stage, prior chemotherapy, and operative time were ment for localized breast cancer. Modified radical mas-
similar for antibiotic and placebo groups. The overall tectomy (MRM) and lumpectomy with radiation therapy
incidence of SSI was 14.2 %. There were no significant are the two principal treatment modalities, dependent upon
differences in the infection rate over the 30-day follow-up the stage of the tumor.
period between the placebo and antibiotic groups (15 % vs Systematic reviews of previous clinical trials have
13.4 %; p = 0.719) or at each week. The majority of SSI concluded that antibiotic prophylaxis is associated with
were either cellulitis or superficial infection for both reduced infection rates in breast cancer surgery when
groups. There were no significant differences between trends toward effectiveness that were not statistically sig-
nificant in individual studies have been combined in meta-
analyses [3, 4]. However, these reviews have been affected
by considerable heterogeneity in terms of participants and
N. D. Cabaluna  G. B. Uy  R. M. Galicia  procedures in the included trials, with some including
S. C. Cortez  M. D. S. Yray  B. S. Buckley (&) MRM, lumpectomy, surgery for benign diagnoses and
Department of Surgery, University of the Philippines
axillary lymph node dissections. Individual trials report
Manila-Philippine General Hospital, Taft Avenue,
1000 Manila, Philippines varied results. A nonsignificant trend toward fewer overall
e-mail: briansbuckley@gmail.com infections was observed in patients given prophylactic

123

random numbers was available only to a single nurse inite or probable wound infections in those undergoing research assistant. Patient. dency and by surgical oncology fellows. Morbidities were treated according to standard care. mobi- cancer. Philippines. and 5th years of resi- to IIIC. 11]. Some specifically recommend that antibiotic day of surgery. For example. There remains a need for empirical evidence of the For outcome assessment during follow-up outpatient effectiveness of antibiotic prophylaxis for well-defined visits. there was little difference in operating room staff. The operations were performed by ically diagnosed breast cancer. Internationally. there was a trend toward fewer definite or probable Randomization wound infections in the prophylaxis group compared with placebo. gov- to receive either Augmentin or placebo (17. the outcome evaluator was blinded as to what study surgical procedures and populations. morbidities. Women with recurrent breast technique was uniform with creation of skin flaps. given in the same manner. Materials and methods Surgical procedures Participants All operations were performed under general anesthesia. pro. a tertiary. clinical guidelines reflect All recruited patients underwent skin testing for cefazolin this lack of clarity and are inconsistent in their recom. The [10. A nurse research assistant pre- gery [10.8 %) ernment-funded hospital in Manila. women wounds were drained using 1 closed suction Jackson Pratt scheduled for simultaneous breast reconstruction or drain directed to the axillary area. All surgeons. with a computer-generated randomization list to either the tively. Patients randomized to the treatment arm prophylaxis should be used or considered [8. women who had received previous radiotherapy. A standard skin preparation with povidone iodine scrub then Women aged between 18 and 80 years old with histolog. although the difference was not statistically sig. Others suggest that prophylaxis is indicated where patients in the placebo arm received 10 ml of normal saline implants will be used for simultaneous reconstructive sur. respectively [7]. 4th. ble women were informed of the study and invited to selves been affected by heterogeneity in populations. All eligi- [6].5 %) respec. 606 patients who underwent various types of breast sur- gery. women treated with antibiotics 13 %) in a study on 178 patients who underwent axillary within one week prior to surgery. Individual trials included in the reviews have them.8 %) to allocation. and outcomes.6 %) versus 26/303 (8. antiseptic was used. The table of underwent lumpectomy and 36 % MRM. participate by surgical oncology fellows and general sur- cedures. The operative gible for study participation. Still others specifically recommend that pared the antibiotic and placebo solutions. 9]. blinded as to the treatment allocation. The study was clean elective breast cancer surgery who were randomized conducted in Philippine General Hospital. and women with existing local no difference in infection rates in 334 women undergoing infection were excluded from recruitment. When only def. who were scheduled for elective MRM were eli. sensitivity irrespective of their randomization arm on the mendations. the mastectomy incision 123 . Others are were given intravenous cefazolin 1 g diluted in 10 ml of supportive of prophylaxis in clean surgery generally but sterile water within 30 min prior to skin incision by the offer little clear guidance about breast surgery specifically anesthesiologist who was blinded to the study drug. Another study found virtually allergy to cephalosporins. This study aimed to arm the patient belonged to. After giving informed consent.7 % vs 18. prophylaxis is not indicated for mastectomy without anesthesiologist. patients were randomized nificant: 17/303 (5. lization of the breast from the pectoralis muscle followed women with diabetes mellitus or affected by severe mal. by en bloc axillary dissection using electrocautery. women receiving corticosteroid therapy.60 World J Surg (2013) 37:59–66 cefonicid compared with those given placebo (6 % vs bilateral oophorectomy.9 %) versus 6/126 (4. 12]. and outcome assessors were blinded the incidence of SSI: 6/122 (4. other dissection were considered. surgeon. Thus the evidence base for the effectiveness of antibiotic Intervention and blinding prophylaxis for prevention of SSI in breast cancer surgery is far from clear. in a trial involving gery residents. In the trial 54 % of breast surgery patients treatment arm or the placebo arm of the study. No unblinding took place consider the effectiveness of antibiotic prophylaxis only in during the study period even for patients who developed patients undergoing MRM for breast cancer. who was also responsible for preparing MRM or radical mastectomy combined with axillary node the treatment and placebo solutions. women with known lymph node dissection [5]. clinical stage I surgical residents in their 3rd. and all other operating room staff were implant [12]. ECOG 0-1. All nutrition.

The primary out. with the majority of cases stage IIA or IIB. and all of them received the 123 . 2010. or pre- intention-to-treat basis. and incidence of SSI in routine surgical practice is difficult to previous neoadjuvant chemotherapy.0 % was ative day. 178 min.6 % in the control lated from fluid/tissue of incision site. healthcare systems. sample size was reached. loss rate of 10 %. 2–superficial infection. (4) wound is deliberately opened by the set.0 for statistical (15. the primary outcome measure from 14. 2007 and August 10. Descriptive analysis reported proportions for each cycles of cyclophosphamide. clinical staging. surgeon.7 % in overall surgical practice in the United Kingdom for Disease Control and Prevention. Almost half of the patients in both groups had cant differences between the distribution of baseline char. Ages ranged from 28 to 78 years old. care depending on the severity of the infection: either by drainage.6 % incidence of SSI in breast cancer Data collection and assessment of outcomes surgery without antibiotic prophylaxis was estimated from three previous studies determined as having the most Baseline data were collected from consenting women similar populations to the current trial [6. The relating to age. eligible women admitted for MRM at the the length of operations. seroma. 1–cellulitis. a target sample size of 254 patients was induration).1 % incidence in clean follow-up by the attending surgeons. The level of differences were detected between the treatment and placebo significance was set at p = 0. However. Analysis was done on an arms in terms of age. Secondary outcomes included Results the postoperative presence of hematoma and. (3) at least one sign group to 4. No statistically significant acteristics and outcomes in the two arms. skin test for cefazolin. and 254 women were recruited over 35 months Data handling and analysis between September 11. None declined the invitation to participate.World J Surg (2013) 37:59–66 61 was closed with either a skin stapler or Vicryl absorbable Sample size suture. whichever was ferent surgeons. and means were computed for continuous prior to their operation. and sterile dressings were applied. A 14. SSI was managed according to the standard of Board following technical and ethical reviews. clinical staging of their breast cancer. establish as incidence varies between types of surgery and come was occurrence of SSI within 30 days of MRM. Wounds were eval.0 % in the experimental group. Table 1). To allow for a of inflammation (erythema. Data were collected on All consecutive. 3–infection requiring The study was approved by the University of the Philip- intravenous antibiotics. (2) organism iso. Calculations determined that 228 patients (114 when at least one of the following occurred within per study arm) would be required to have an 80 % chance 30 days after the operative procedure: (1) purulent drainage of detecting. operative time. surgical procedures in the United States of America and uated for the presence of SSI as defined by the Centers 4. and 5-fluorouracil study arm. operative times of more than 3 h. (5) physician declares the wound infected [13]. and t-tests were used to test for signifi. Patients lost to follow-up prior to vious neoadjuvant therapy (Fig.4 %) had undergone neoadjuvant chemotherapy with 4 analysis. For data collection. and 4–necrotizing fasciitis. The mean operative time overall was more appropriate. local warmth of wound. 1. A SSI was recorded [10. laxis to a realistic target SSI incidence in line with the literature. a decrease in (culture documentation not required). Once pines Manila–National Institutes of Health Ethics Review diagnosed.05. Chi square or Fisher’s exact test. for the second half of the study. readmission with intravenous antibiotics. Thirty-nine 2007 and exported to SSPS version 11. the 30th postoperative day were assessed based on the No patient withdrew from the study or had a positive outcome on the last visit. 4. 16. or reoperation. Adriamycin. Drains were removed meaningful target reduction of SSI from current SSI inci- when the drainage from the tube measured less than 50 cc dence in breast cancer surgery without antibiotic prophy- per day. The surgeries were led by forty dif- variables. and long operative time was hospital were invited to join the study until the required defined a priori as greater than 3 h. 14. Clinical stages ranged from I Collected data were encoded in Microsoft Excel version to IIIC. as significant at the 5 % level. the surgical site infection was then Ethical approval graded by the attending surgeon as follows: 0–none. 17]. oral antibiotics. prior to discharge and weekly at the Breast selected as an appropriate estimated target incidence rate Care Center until the fourth week to complete the 30-day for the trial setting based on a 2. because they occur after discharge. 15]. and many infections go unreported Mastectomy wounds were assessed on the first postoper. Patients were instructed on proper care of the drains and were sent home Sample size calculations were based on a clinically one or two days after operation.

Outcomes of all the enrolled patients were included and placebo groups in terms of the treatment required for in the analysis. Only one woman. One patient in the antibiotic patient in the treatment arm had a grade 3 SSI that required group was given one dose of cefazolin by the surgeon prior intravenous antibiotic in addition to drainage of the to evacuation of a hematoma. the other three received abscess. four in each study arm. treatment group and fifteen in the placebo group received There was no statistically significant difference in the oral antibiotics. One woman in the treatment group was incidence of SSI between the intervention and placebo readmitted for treatment with intravenous antibiotics. Fisher’s exact test revealed no statistically signifi. 1 Study flow diagram intended study drug or placebo. There were no significant differences between treatment come. Fourteen in the Overall. in the between study arms. One managed conservatively. SSI grades 2. failed to complete the required 30-day because of empty cells.62 World J Surg (2013) 37:59–66 Fig. and a chi-squared test was used. 3. Two women in the treatment group and three in the complications. At her first week postoperative follow-up visit statistically significant difference was detected between the she had no surgical site infection and outcome assessment groups. even if they developed other postoperative SSI. four required study arms at any of the follow-up time points. Eight women in the study developed postoperative cant differences in the incidence of SSI between the two hematoma. For analysis of the distribution of SSI grades no intravenous or oral antibiotic. SSI occurred in 14. for the intention-to-treat analysis was based on this out. Of these. and 4 were combined treatment group. No SSI were observed on the day of one in the placebo arm who had a grade 2 SSI underwent discharge. Another operative 123 . Those reoperation for control of bleeders (three in the antibiotic already affected by SSI were excluded from each analyses. group and one in the placebo group). period. and the rest were Most SSI were cellulitis or superficial infections. placebo group were treated with drainage. and groups (Table 2).2 % of the patients (36/254). but all occurred during the four-week follow-up reoperation for debridement of concomitant flap necrosis. No follow-up.

3) 0.478a Range 28–78 28–78 28–72 Clinical stage I 14 (5.6) 53.5) 52.3 %) 8 (6.4 %) 0 1 (0.3 %) IIB 81 (31.3 %) mastectomy a 3 Requiring IV antibiotics 1 (0.1 %) 59 (46.3 %) 0.8 %) 41 (32.863). required readmission.8 (9.7 %) Neoadjuvant chemotherapy Yes 39 (15.2) 4 (3.448b n (%) cases [ 3 h 112 (44.5 %) 74 (58.7 %) 0. The mastectomy wound was inspected and study arms in the incidence of seroma: 17 (24.8 %) IIIB 35 (13.5 %) IIIC 3 (1.6 %) 1 (0. ventilator support.0 %) 110 (86.2 %) 2 (1.3 %) MRM Modified radical 2 Superficial infection 16 (6.223b SD Standard deviation a No 215 (84.5 %) 41 (32. Nor was any statistically cefazolin. df 1.4) 1.5 %) 53 (41. None of the women antibiotic group and 18 (23. Data relating to the accumulation of seroma after tomy incision in one patient in the placebo group.8 %) Total 254 (100.6 %) 17 (13. Of these.1) 5 (3.1) 3 (2.5 %) 11 (8.0 %) 21 (16.2) 1.3 (9.0 %) 17 (13.03.0 %) 48 (37.6 %) developed seroma during the follow-up period.1 %) in the placebo group (chi included in the study developed hypersensitivity to square 0.3 %) 8 (6.0 %) Length of operation Mean min (SD) 178 (56) 180 (58) 175 (54) 0.2) 4 (3.4 %) 104 (81.745b IIA 89 (35.9 %) 68 (53.00b At week 4 8 (3.6 %) 111 (87.0 %) 127 (100. 35 who developed pneumonia 10 days postoperatively that (23.457a Range 65–431 65–329 80–431 n (%) cases B 3 h 142 (55. p = 0.6 %) 0.4) 3 (2.719a SSI at each follow-up visit On day of discharge 0 0 0 – At week 1 14 (5.8 %) 108 (85.5) 9 (7.9 %) 40 (31.8 %) 14 (11.8 %) chi square test b 4 Necrotizing fascitis 0 0 0 Fisher’s exact test complication noted was epidermolysis over the mastec.7 %) 8 (6.4 %) No SSI 218 (85.World J Surg (2013) 37:59–66 63 Table 1 Baseline clinical and Total Placebo (n = 127) Antibiotic (n = 127) P value demographic data of study participants for total study Age (years) sample and by study arm Mean (SD) 53.6 %) 23 (18.3 %) IIIA 32 (12.412b At week 2 8 (3.1 %) 0.00b SSI severity grade 1 Cellulitis 19 (7.9) 0.9) 0.9 %) t test b Total 254 (100 %) 127 (100 %) 127 (100 %) chi square test Table 2 Incidence of surgical Total (n = 254) Placebo (n = 127) Antibiotic (n = 127) P value site infection (SSI) in total study sample and by study arm SSI within 30 days of MRM SSI 36 (14.7 %) 8 (6. significant difference detected between the study arms in 123 .4 %) 15 (11.4) 3 (2.5 %) 6 (4. and intravenous There was no statistically significant difference between antibiotics. An removal of the Jackson-Pratt drain was available only for unrelated adverse event was reported in one woman the last 148 patients enrolled in the study.722b At week 3 6 (2.2 %) 19 (15.3 %) in the remained dry without any sign of SSI.9 (9.4 %) 16 (12.0 %) 127 (100.4) 5 (3.

prophylaxis intervention and control arm patient in terms of baseline using cefazolin or a similar agent at the time of anesthesia clinical and demographic characteristics. which we defined as mately 40 % small excisions and 30 % of the cases were more than 3 h. 14. without axillary lymph node dissection for breast cancer. lance system.02).02) [3]. p = 0. all procedures there was considerable heterogeneity in patients and pro- were conducted under the supervision of experienced cedures. the operating None of the studies in the Cochrane review included only room environment is similar to that in many developing this patient group. only mastectomy for breast cancer. 15]. However. increased antibiotic resistance. Figure 2 reports a relatively large. at least for modified radical mastectomy. and all should be discussed. the the wide range of length of operations.53–0. sensitivity [10]. and drug hyper- infection rates between the treatment and placebo groups. axillary lymph node dissections were included—more than 123 . the intervention appears to be ducted in a hospital with a surgical training program. The associated with a significantly reduced risk of SSI (pooled lead surgeons had varying levels of expertise. review’s meta-analysis included data from studies in which less of the experience of the lead surgeon. of course. One was a study that focused on cosmetic The hospital does not have an active infection surveil. 95 % CI. surgery and included paediatric and non-malignant cases. The study has considerable strengths but also some lim. Compared with included eight trials of preoperative prophylaxis deter- many of the previous studies that have considered anti. Other recommendations This study considered the effectiveness of a single dose of have interpreted the evidence base differently and have cefazolin given at anesthesia induction as prophylaxis highlighted the risks of prophylaxis that must be weighed against SI after modified radical mastectomy. as seen in RR 0. regard. and longer operating time. There is little reason to believe that the results Study strengths and limitations are not generalizable to all similar first generation cepha- losporin antibiotics. the meta-analysis that adds the results of this study to the surgeries were led by 40 different surgeons. However.74. benign [18]. 9]. which could assist the interpretation of the [19]. An the study’s homogeneity in both population and proce. Although a single-institution study. Still. influenced our reported outcome. The rationale for this study was to consider the inter- ables in the operating room environment that could have vention’s effectiveness only for MRM for breast cancer.2 % overall incidence of SSI axillary lymph node dissections. p = 0. length of operat. biotic prophylaxis in breast surgery. and in yet another. and one—although would differ between treatment and control groups. updated 2012 Cochrane review of antibiotic prophylaxis dures conducted. very different from the heterogeneity for the prevention of SSI in breast cancer surgery that that has affected many previous studies.95. 0. The 14. and incidence of hematoma or of seroma. A major strength is previous systematic reviews are worth considering. it was not possible included only mastectomy or wide local excision with or to assess postoperative care of drains by the patients. was identical for both the non-reconstructive breast surgery for breast cancer. there is no reason the standards of care one. 7]. there was no significant difference in diarrhea. Two intervention and control arms. the sample size is 95 % CI. The results are in line with and add strength to the findings of a number of previous studies [6. the results of itations. The procedures in one study included approxi- surgeons. However. induction is not effective in preventing postoperative SSI in ing time. a num- ber of clinical guidelines have recommended that antibiotic Discussion prophylaxis should be used or at least considered in breast cancer surgery despite the fact that the evidence base is far Main findings from clear and is affected by heterogeneity in populations and procedures included [8. although. Cochrane review. difficile 30-day follow-up. In the light of the findings of this study. routine clinical practice. That it is at the higher [5. end of the range may indicate that there are other vari.57–0.0 % reported than 40 % of cases were MRM or wide local excisions in the international literature [3]. Although guidance is inconsistent internationally. again. mined that the intervention is effective (pooled RR 0. 0. C. Finally.94. and thus a background infection rate cannot as well as surgical procedures that were not breast surgery be provided. However. In another study nearly 50 % of the procedures were results in this study. did not result in a higher infection rate.64 World J Surg (2013) 37:59–66 the proportions of women with or without seroma who Discussion in the context of existing literature developed a surgical site infection. This study was con. improving pooled data from the studies already included in the the generalizability of the results.71. This study provides good quality evidence No significant differences were recorded between the that.0 to 15. less in this study is within the range of 3. some studies were limited to countries and. After a against uncertain effectiveness: adverse events.

and The findings of this study. However. 95 % CI. no significant association is detec. College of Medicine. those that consider Fig. patient-specific Conclusions characteristics and the use of implants for simultaneous reconstruction may present an increased risk of SSI. the majority mastectomy. do not support the routine use of antibiotic prophylaxis in modified radical mastectomy. It may be appropriate to revisit clinical guidelines that base recommendations about the use of The findings of this study. In addition. 14. whether patient instruction on drain tube maintenance or specific operating room protocols may offer more benefit Implications for surgical practice than prophylaxis. such as lumpectomy.31.17. certain other of SSI (pooled RR 0.World J Surg (2013) 37:59–66 65 Fig. The authors are grateful 123 . The data from these four previous studies that principally selection of antibiotics for use in such research may best be considered mastectomy. or whether an antibiotic prophylaxis is 15. Implications for research Acknowledgments The research on which this article is based was funded by grants from the Research Implementation and Develop- Further well-designed research is necessary to establish ment Office. and the National Institutes of whether alternative antibiotic prophylaxis regimens are Health. 3 Meta-analysis limited to patients having breast surgery for breast cancer without reconstruction. based on sensitivity studies on bacteria isolated from SSI ted between antibiotic prophylaxis and reduced incidence cases in the host institutions. studies may be of value—chiefly. University of the Philippines. alone and when combined with antibiotic prophylaxis on meta-analyses of heterogeneous evidence from other trials in similar populations. 2 Meta-analysis of data from the current study and studies included in the Cochrane review of prophylactic antibiotics to prevent surgical site infection after breast cancer surgery (antibiotics vs placebo or none) Fig. When data from the present study are pooled with effective in other surgeries. more effective. some wide local excision (antibiotics vs placebo or none) 70 % of cases were simple mastectomies or MRM [6. 20]. Manila. 3). suggest research data. alone and when combined in decisions on prophylaxis must take these factors into meta-analysis of results from studies in similar surgical account.61–1. that for clean modified radical mastectomy the routine use of prophylactic cefazolin or a similar agent is not effective in preventing postoperative SSI. p = 0.84. 0. populations.

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