Antibiotic Prophylaxis in Gastric, Biliary and Colonic Surgery H. HARLAN STONE, M.D., C. ANN HOOPER, B.S., B.A., LAURA D. KOLB, B.S., CAROL E. GEHEBER, B.S., E. JANELLE DAWKINS, B.S. Antibiotic prophylaxis for surgery has appeared indicated when- From the Joseph B. Whitehead Department of Surgery, ever likelihood of infection is great or consequences of such are Emory University School of Medicine, catastrophic. For better clarification, a prospective, randomized, 69 Butler St., S.E., Atlanta, Georgia 30303 double-blind study was run on 400 patients undergoing elective gastric, biliary, and colonic operations. There were four treat- ment categories, with antibiotic being instituted 12 hours pre- operatively, just prior to operation, after operation, or not at all. were During operation, samples of blood, viscera, muscle, and fat were could then likewise be reduced if less hospital days taken for determination of antibiotic concentration. Both aerobic consumed and if reoperation for some complicating in- and anaerobic cultures were also taken of any viscus entered, fection were not as frequently required; while antibiotic peritoneal cavity, and incision. Similar cultures were run on all use might even be decreased if fewer postoperative postoperative infections. Results demonstrated that the incidence infections developed and, especially, if the duration of of wound infection could be reduced significantly by the preopera- antibiotic prophylaxis was cut to a bare minimum. tive administration ofantibiotic in operations on the stomach (22% to 4%), on the biliary tract (11% to 2%), and large bowel (16% to Nevertheless, potential harm resulting from routine 6%). Less impressive results were obtained for peritoneal sepsis. antibiotic therapy cannot be ignored. Drug toxicity, Initiation of antibiotic postoperatively gave an almost identical allergic reactions, and in particular the evolution of infection rate as if antibiotic had not been given (15% and 16%, resistant bacterial strains certainly appear to be potential respectively). if not actual significant threats. TrHE VALUE as well as dangers of prophylactic anti- biotics has been hotly debated for the past three Clinical Trial decades. Lack of concrete data, as might be derived from To evaluate these several aspects of prophylactic anti- either rigidly controlled laboratory studies or prospective biotic therapy as well as to confirm the already reported randomized clinical trials, has by no means limited these benefits of its application, a prospective randomized and arguments. Only the animal experiments of Burke4 and double-blinded study was carried out on the surgical relatively sophisticated clinical trials by Polk,10, Ledger,7 wards of Grady Memorial Hospital. After 20 months (the and a few others have given any true insight as to the trial period ending February 29, 1976), 400 consecutive benefits of such a program.1 3'4'8 9 All other supportive re- patients admitted for elective operations on the stomach, ports have primarily been emotional claims, based upon biliary tract, and/or colon had been enrolled in the study. either poorly or totally uncontrolled scientific evidence. The only exceptions to inclusion into the study were There are, in addition, other advantages that might be antibiotic therapy with parenteral or orally absorbable gained through the administration of prophylactic anti- agents during the 10 days immediately preceding opera- biotics. Hospital beds possibly could be conserved tion, conditions present that already demanded antibiotic through a shortened average patient stay. Hospital costs prophylaxis (i.e., heart valve disease), known allergy to a cephalosporin, and an age of less than two years. Pa- tients colon surgery, however, did receive 1 Presented at the Annual Meeting of the American Surgical Associa- undergoing tion, New Orleans, Louisiana, April 7-9, 1976. gm of oral neomycin every 4 to 6 hours for two days Supported in part by a grant from Eli Lilly and Company. prior to operation as well as 500 mg of erythromycin 443 444 STONE AND OTHERS Ann. Surg. o October 1976 base every 6 hours for 24 hours preoperatively. Routine of the contents of the organ subjected to operation, attempts were made to preclude any consideration of the peritoneal cavity, and the subcutaneous portion of the antibiotic prophylaxis with respect to decision for incision at the time of closure. Sensitivity testing was operation, procedure performed, and general postoper- subsequently run on all aerobic isolates to the 30 mcg ative care. disc of cefazolin.2 Antibiotic Administration Followup Each patient was given an intramuscular injection of Postoperatively, all patients were carefully followed for either antibiotic (I gm of tefazolin) or placebo (equiv- evidences of infection developing within the abdomen alent volume of diluent) on the evening before opera- and/or surgical incision. In addition, complicating infec- tion, on call to the operating room and on that same tions in other areas were specifically noted. Appropriate evening after return to either the ward or the intensive aerobic and anaerobic cultures were taken from all sites care unit, on the morning of the day following surgery, of known as well as even suspected sepsis. Aerobic and again during the evening of the first postoperative bacterial isolates were also tested for sensitivity to the day (Fig. 1). Scaled down doses were used for children, prophylactic antibiotic, i.e., cefazolin, at a 30 mcg disc with weight being the prime determinant. The solutions size.2 for injection had previously been assembled in patient Complications of drug therapy, other postoperative number packets, so that there were five vials in each pack problems, total as well as postoperative hospital stay, and each vial was coded as to time when it should be all details related to indications for surgery, type of given. Details in randomization were unknown to all con- operation, general status of the patient, and, finally, cerned with patient care, although the master key was eventual outcome were faithfully recorded. These items readily available in the event that a possible drug or were later used to confirm the purity of the randomiza- infectious complication demanded that the code be tion process plus the identification of any significant broken. influence, other than the prophylactic antibiotic, on the Drug dosage had been set up so that equal numbers incidence of subsequent infection. of patients had their prophylactic antibiotic initiated approximately 12 hours preoperatively, one hour prior to Results operation, or within an hour following completion of the operation (Fig. 1). Twenty-five per cent of the patients At the completion of the clinical trial, there were 100 received no antibiotic at all. When given, cefazolin was patients for analysis in each treatment category. Gastric administered in three consecutive injections for a total surgery had been performed on 96, a biliary tract dose of 3 gms over a period of approximately 24 hours. procedure on 131, and colon surgery on 190-thereby No other antimicrobial was given thereafter, that is, giving a total of 417 operations. The extra 17 were ac- unless an established infection could be documented counted for by the fact that these patients had had a or the patient's clinical course became highly suggestive surgical procedure carried out in two, rather thanjust one, of a developing septic complication. area of study. Ages ranged from 2 to 86 years, with an average of47.6. Sampling During Operation There were 179 males and 221 females; 312 were Negro, while 88 were Caucasian. No significant difference At surgery, 9 specific specimens could were taken. An at- be found between the four assigned treatment groups tempt was generally made to obtain all samples within with respect to type of operation, a indication for surgery, few minutes of each other. Once the abdomen had been age, sex, or race. opened, both peripheral as well as portal venous blood There were four postoperative deaths, three of which were drawn for determination of antibiotic blood levels. occurring in patients who had Likewise, liquid had two procedures done contents ofthe organ ofoperation (gastric at the one operation. Otherwise, no major difference was juice, bile, and/or colon contents) were obtained for apparent between the several therapy categories. similar analyses of antibiotic concentration. A modified well-diffusion technique was used for these studies.13 Antibiotic Distribution Biop§ies of viscera resected as well as abdominal wall muscle and subcutaneous fat were also taken. These Concentrations of cefazolin were not significantly specimens were immediately frozen and then sent at inter- different when portal was compared to peripheral venous vals to the Lilly Research Laboratories for determina- blood (Table 1). The average value was 13.7 mcg/ml. tion of antibiotic tissue concentration. Administration of cefazolin 8 to 12 hours prior to Finally, both aerobic and anaerobic cultures were taken operation gave approximately 40% higher tissue levels Vol. 184oNo. 4 ANTIBIOTIC PROPHYLAXIS 445 PRE-OP DAY OF POST-OP GROUP DAY 1 OPERATION DAY A GROU l|AM PM-t AM |PM ||AM |PE FIG. 1. Times of antibiotic administration. Placebo in- jections are indicated by an I x x x 0 0 "O"; cefazolin was given at times marked by an "X." Ii 0 X X X 0 III 0 0 X X X IV 0 0 0 0 0 than if the antibiotic had been started a mere hour pre- lactic antibiotic had been started preoperatively (Table 2). operatively (Table 1). Concentrations of cefazolin in sub- Results were much more impressive with procedures on cutaneous fat were less than half that of the blood when- the colon than for operations on the stomach and biliary ever antibiotic therapy had been instituted only an hour tract. However, no real difference could be discerned before hand. In fact, antibiotic concentrations in fat and in between the two groups receiving preoperative cefazolin, bowel wall were consistently below values discovered in that is, between those patients having such therapy other tissues.