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Efficacy of antibiotic prophylaxis in high risk gastroduodenal operations
Efficacy of Antibiotic Prophylaxis in High Risk Gastroduodenal Operations
Ronald Lee Nichols, MD, New Orleans, Louisiana Watts R. Webb, MD, New Orleans, Louisiana James W. Jones, MD, New Orleans, Louisiana Jeffrey W. Smith, MS, New Orleans, Louisiana Joseph LoCicero III, MD, New Orleans, Louisiana
The use of antibiotic prophylaxis in patients undergoing gastroduodenal operations has generally been recommended only in cases of gastric carcinoma [I ,2]. Recent studies, however, have reported high postoperative infection rates in patients not receiving prophylaxis who underwent operations for other clinical conditions associated with decreased gastric acidity or gastric motility [3-51. These additional categories of high risk patients were also recently shown in a randomized, nonblind, prospective study to benefit from antibiotic prophylaxis [S]. In the present investigation the efficacy of antibiotic prophylaxis in patients with an increased risk of postoperative infection was studied using a randomized, prospective, double-blind design. Material
and Methods
Patient selection and preparation: Between July 1978 and January 1980,43 patients with a high risk of postoperative complications were admitted for gastroduodenal surgery to the Tulane Surgical Service (Charity Hospital of Louisiana at New Orleans and Tulane Medical Center Hospital). The clinical conditions included gastric ulcer, gastric carcinoma, bleeding duodenal or gastric ulcer, and obstructing duodenal ulcer. Patients were excluded from the study population if they were pregnant, had a history of allergy to penicillin or cephalosporins, were under age 12 years or had any significant underlying conditions which would have made evaluation difficult. In addition, any patient who had taken antibiotics during the 72 hours before surgery was not included. Appropriate patients were randomized into treatment From the Department of Sugery, Tulane University School of Medicine. New Orleans, Lobisiana. Requests for reprints should be addressed to Ronald Lee Nichols, MD. Department of Surgery, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112. Presented at the 22nd Annual Meeting of The Society for Surgery of the Alimentary Tract, New York, New York, May 19-20, 1981.
94
or placebo groups. All medication kits were identical in color and size, and no one having patient contact knew which drug regimen the patients were receiving. Treatment patients received a total of 4 g of cefamandole intravenously, 2 g 1 hour before operative incision and 1 g 4 and 8 hours after incision. Control patients received equal volumes of inert placebo intravenously at the same intervals. The operation performed was necessarily individualized according to the clinical situation. No other antibiotic agents were administered to either group. All patients underwent saline irrigation of the peritoneal cavity and subcutaneous tissue before primary wound closure. All patients were observed daily for signs of infection. If a postoperative infectious complication was noted, the patient was considered a treatment failure and subsequent operative and antibiotic therapy was left to the discretion of the treating physician. Sample collection: Needle aspiration of the greater curvature of the stomach using an 18 gauge needle and a 50 cm3 syringe was performed in each patient immediately upon entering the peritoneal cavity. Manual pressure on the anterior surface of the stomach was often necessary to ensure an adequate sample of gastric contents (2 to 3 ml). The major portion of each gastric aspirate was immediately injected into a sterile anaerobic transport bottle, Care was taken to avoid the transfer of air bubbles into this vial. The samples of gastric aspirate were taken directly to the research microbiology laboratory, and processing was begun within 15 minutes of arrival. After the operation, cultures were obtained as necessary from infected sites using similar techniques. Microbiologic techniques: Upon arrival in the laboratory the specimens were immediately passed into an anaerobic glove box. Once the specimen bottle was in the anaerobic environment, most of the contents were removed with a syringe and needle and plated onto blood agar plates with vitamin K and hemin, and blood agar plates with vitamin K, hemin, kanamycin and vancomycin. A portion was also placed into a tube of chopped meat glucose broth for enrichment culturing. Part of the sample was then removed from the anaerobic chamber and inoculated onto
The American Journal of Surgery
Antibiotic
bile esculin azide agar, eosin-methylene blue agar and blood agar plate. A Gram stain was performed at this point and, if large gram-positive bacilli were seen on the stain, a clostrisel agar plate was inoculated anaerobically with the portion of the specimen remaining in the anaerobic chamber. The aerobic plates were incubated at 35OC in a carbon dioxide-enriched environment and the anaerobic plates were incubated at 35’C in the anaerobic glove box (10 percent hydrogen, 10 percent carbon dioxide and 80 percent nitrogen). After 24 hours the plates were observed and representatives of all colony types were picked and Gram-stained. The aerobic coliforms were identified using the Enterotube system and noncoliform aerobes using standard bacteriologic techniques. The colonies from the anaerobic incubation also were subcultured onto blood agar plate for aerobic incubation and onto a peptone-yeast extract glucose broth tube. If the microorganism grew aerobically it was a facultative organism and was identified using standard aerobic bacteriologic techniques. Those bacteria that did not grow outside the glove box were obligate anaerobes and were identified using the techniques described in the VP1 Anaerobe Laboratory Manual. The contents of the peptone-yeast extract glucose broth tube were examined for the presence of metabolic acid end-products using gas chromatography. The original petri dishes were observed daily for 7 days and newly appearing colony types were handled as noted earlier. The chopped meat glucose tube was subcultured at 48 hours and the colony types cultured were compared with those appearing on the original plates. The culture was kept until all bacterial types observed in the original Gram stain were isolated and identified.
Results
The treatment and placebo groups were similar in indications for operation and patient demographic characteristics (Table I). Four of the 43 patienis were excluded from analysis: 2 patients failed to receive all of the three doses, 1 patient never began therapy and 1 received extended antibiotic therapy. None of these patients developed postoperative infectious complications. Seven infections were directly attributed to the gastric surgery in the 20 patients comprising the placebo group, whereas there was only 1 infection in the 19 cefamandole-treated patients (Table II); this difference was statistically significant (p
Volume 143, January 1982
TABLE I
Prophylaxis
in Gastroduodenal
Operations
Comparison of Patient Data in the Two Study Groups Treatment Group ___-
Evaluable patients (n) Indication for operation Gastric cancer Gastric ulcer Chronic Bleeding Duodenal ulcer Bleeding Obstructing Demographic features Sex Male Female Age (yr) Range Under 45 Over 45 Preoperative risk evaluation Good Fair Poor
TABLE II
Placebo Group
19
20
4
4
3 2
5 1
6 4
7 3
12 7
14 6
39-76 5 14
21-78 6 14
4 11 4
3 12 5
Infectious Complications in the Two Study Groups Treatment Group (n = 19) n %
Wound or intraabdominal infections Unrelated infections (urinary or pulmonary) Deaths
Placebo Group (n = 20) n %
1
5
7
35
5
26
3
15
1
5
2
10
Initial gastric aspirate for culture was obtained in 35 of the 39 patients studied. Eleven of these specimens were sterile, while the remaining 24 samples revealed growth of one to six different bacterial species. The nature of the gastric microflora is shown in Table III. In the seven infections related to surgery in the placebo group, four patients had infecting organisms that were found in the stomach at the time of gastric aspiration. These organisms included alpha-hemolytic streptococcus, enterococcus, Streptococcus pneumoniae, peptococcus and Clostridia perfringens. Two other patients had organisms similar to those isolated from the gastric aspirate that could likely have been present at concentrations too low to be isolated with the techniques used. The cause of subhepatic abscess in the one treatment failure was not ascertained before the patient died or by cultures taken at autopsy. The nonrelated infections were due to the usual gram-negative organisms that are the causes of
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Nichols et al
nosocomial infections in the study hospitals. Only one of nine patients had an infecting organism that was also isolated from the initial gastric culture. Comments In 1975 we reported the results of a prospective clinical study on the influence of endogenous gastric microflora on the subsequent development of postoperative wound or intraabdominal infections after gastric resection [5]. This study showed that both gastric acid and normal gastric motility were important in the prevention of gastric bacterial colonization. In the patients with chronic nonobstructing duodenal ulcer, high acid levels and normal gastric motility were noted preoperatively, and few if any
TABLE III
Organisms isolated From lnltial Gastric Aspirate In the Two Study Groups Isolates (n)
Treatment Group
Placebo Group
7 0 3 0 1 4 1
12 3 3 1 2 1 0
0 1 3 2 3 1 0 0 3 1 1
1 0 0 0 0 0 1 2 4 0 2
31
32
1 1 1 1 0 0 1
1 0 0 0 1 1 1
0 0 0 0 0 1
1 1 1 1 2 0
6
10
Aerobic Gram-positive Alpha-hemolytic streptococcus Beta-hemolytic streptococcus Enterococcus Streptococcus pneumoniae Staphylococcus aureus Micrococcus species Bacillus species Gram-negative Enterobacter species Citrobacter species Escherichia coli Proteus mirabilis Klebsiella species Hafnia species Haemophilus species Nonfermentor Neisseria species Eikenella species Yeast Total Anaerobic Gram-positive Lactobacillus species Eubacterium species Eubacterium lentum Sarcina species Peptococcus magnus Peptococcus saccharolyticus Clostridium perfringens Gram-negative Bacteroides saccharolyticus Bacteroides ruminicola Bacteroides melaninogenicus Bacteroides species Fusobacterium nucleatum Veillonella species Total
96
bacteria were isolated from cultures of needle aspirates of stomach contents taken during surgery. The postoperative infection rate in this group of patients was correspondingly low. It was also apparent that gastric bacterial colonization occurred almost uniformly in other patients who had undergone operations for bleeding or obstructing duodenal ulcer, or for gastric ulcer or malignancy. The reason for gastric colonization in these groups of patients was best explained by a compromise of the normal bacterial inhibitory effects of gastric acid or gastric motility. When present, the gastric microflora were usually equally divided between oral or proximal intestinal aerobes and oral (penicillin-sensitive) anaerobes. Patients who had gastric colonization at the time of operation had postoperative infection rates greater than 20 percent. In all but one case, the organisms responsible for the postoperative infections were the same as those isolated from the gastric microflora. At that time it became apparent that carefully designed antibiotic prophylaxis might be beneficial in these high risk patients. Lewis [3] in 1977 reported a 10 year review of wound infections after gastroduodenal operations. His findings were in agreement with our earlier study, indicating that high and low risk patients could be identified during the preoperative period. Further evidence was reported in 1980, showing that 22 of 30 patients who had postoperative infections after gastroduodenal operations had a deficiency of one or both gastric inhibitory factors [4]. The value of antibiotic prophylaxis in gastric surgery has been previously reported [7,8]. However, Lewis et al [S] in 1979 were the first to study only high risk patients. This study of 108 patients undergoing gastroduodenal operations was randomized and prospective but not blinded. The results of the study showed a significantly decreased postoperative infection rate in high risk patients treated with 2 g of cephaloridine intravenously 2 hours before operation and again 5 hours later. Stone et al [S] had previously stressed the importance of beginning antibiotic prophylaxis during the immediate preoperative period for maximal results. The present study confirms the value of short-term antibiotic prophylaxis in high risk patients undergoing gastroduodenal operations. With the use of effective acid-blocking medications for chronic duodenal ulcer disease, it is important to realize that almost all patients needing surgical therapy are at high risk for the development of postoperative infections. The choice to use the second-generation cephalosporin cefamandole rather than more commonly used first-generation agents such as cephalothin was based on the antibiotic susceptibilities reported at the hospitals of this study. Although both generations of cephalosporins have excellent efficacy against the
The American Journal of Surgery
Antibiotic
aerobic and anaerobic oral microorganisms, cefamandole was superior in covering gram-negative coliforms. The choice of which antibiotic agent to use in prophylaxis for gastroduodenal operations should be based on the aerobic coliform susceptibility results at the hospital where the operation is to take place. The importance of covering these organisms as well as gram-positive aerobes and anaerobes has been stressed by Lewis et al [6], who found that the aerobic coliforms, including Escherichia coli, Klebsiella species and Proteus species, were the primary organisms isolated in over 50 percent of wound infections occurring after gastroduodenal operations.
Summary A double-blind, prospective and randomized clinical trial of the efficacy of antibiotic prophylaxis in gastroduodenal operations was studied in 39 patients over an 18 month period. All patients had clinical features that placed them at high risk for the development of postoperative wound or intraabdominal sepsis. In the placebo group of 20 patients seven gastric-related infections developed, while 1 of the 19 patients who received perioperative cefamandole had one gastric-related infection (p
References 1. Antimicrobial prophylaxis: prevention of wound infections and sepsis after surgery. Med Lett Drugs Ther 1979;21:73-6. 2. Veterans Administration Ad Hoc Interdisciplinary Advisory Committee on Antimicrobial Drug Usage. I. Prophylaxis in surgery. JAMA 1977;237:1003-8. 3. Lewis RT. Wound infection after gastroduodenal operations: a 10 year review. Can J Surg 1977;20:435. 4. LoCicero J, Nichols RL. Sepsis after gastroduodenal operations: relationship to gastric acid, motility, and endogenous microflora. South Med J 1980;73:878-80. 5. Nichols RL, Smith JW. lntragastric microbial colonization in common disease states of the stomach and duodenum. Ann Surg 1975;182:557-61. 6. Lewis RT. Allan CM, Goodall RG, Lloyd-Smith WC, Marien B, Wiegand FM. Discriminate use of antibiotic prophylaxis in gastroduodenal surgery. Am J Surg 1979;138:640-3. 7. Polk HC Jr, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66:97. 8. Stone HH, Hooper A, Kolb LD, et al. Antibiotic prophylaxis in gastric. biliary and colonic surgery. Ann Surg 1976;184: 443-52.
Volume 143, January 1982
Prophylaxis
in Gastroduodenal Operations
Discussion Robert E. Condon (Milwaukee, WI): Microbiologic study of the stomach in high risk patients has been done before, but there is not a very broad data base. I was struck by the 35 percent wound infection rate in the placebo-treated group. That is a wound infection risk in the same range as in patients undergoing colon operation who do not receive antibiotic prophylaxis, which emphasizes that this high risk group is at a very high risk indeed. I have a couple of questions. It has always intrigued me that we repeatedly find coliform organisms in these patients with a failed gastric acid barrier. Two of your patients had clostridia-related infectious complications. I am surprised that you found clostridia in the stomach. Where do you think they came from: are they swallowed, or do they come from somewhere else? My second question concerns the incidence of infections not related directly to the operation. Often in studies of surgical prophylaxis both the related and nonrelated infections are decreased by the administration of antibiotic prophylaxis. The nonrelated infections in your study seem not to be affected, and if anything were a little higher in the antibiotic-treated group. Would you comment on that? Would you comment further on the choice of specific antibiotics? In our hospitals, coliforms are still sensitive (more than 85 percent) to E coli. We don’t often see Enterobacter involved in complications after gastric operations, and we are currently using first-generation cephalosporins. Would you comment on that practice? M. D. Ram (Lexington, KY): I have two questions. Is there a difference in the incidence of infection in elective and emergency procedures, and did you separate these in your study group? Second, does leaving the skin wounds open make any difference? When we anticipate wound infection we do leave the wounds open and close them secondarily, and we think it makes a great difference.
Carlos A. Pellegrini (San Francisco, CA): A significant number of patients with obstructing duodenal ulcer and gastric malignancy have positive gastric cultures. I wonder if you would comment on the role of preoperative intraluminal antibiotic and mechanical preparation of the stomach. Second, since in most instances I presume you had to open the stomach, did you use peritoneal lavage with or without antibiotics during surgery?
Ward 0. Griffen (Lexington, KY): I support your use of prophylaxis antibiotics. When we originally set up our prospective study comparing gastric bypass with intestinal bypass, I purposely did not use systemic antibiotics prophylactically in the gastric group. After about 25 patients we had eight wound infections, so we went to first-generation cephalosporins prophylactically, and in the last 500 gastric bypasses we have had only four infections. We did some other things also such as changing the way we closed the wounds. For example, we now use nonabsorbable sutures in closing the wounds. Could you tell us something about the way the wounds in your study were closed? That is, was there a standard wound closure during the study, or were many different types of wound closure used?
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Nichols et al
Simon Wapnick (New York, NY): Did you evaluate the patients who had received cimetidine before surgery? Cimetidine alters gastric flora. We have been impressed by the high incidence of wound infection in patients receiving this drug before gastric operation. Hiram C. Polk, Jr. (Louisville, KY): I think the authors have done us a real service. While there are several similar reports going back over a decade, I believe surgeons, by concentrating on infections in colon surgery, have neglected this subject. Virtually all of the randomized double-blind studies that have included any kind of gastric operations have come to these same conclusions. The second thing the authors have shown that was heretofore unknown is that cefamandole is a wound-active antibiotic. The reason that cephalothin does not work is that it disappears from the wound so quickly as to be worthless. I think the difference between this drug and some other cephalosporins has nothing to do with their anaerobic coverage, because the original agent used, cephaloridine, showed the same kind of control in these high risk patients. I think the specific drug in question needs to be understood by those reading this report, since you may want to use that and not some congener that may not have been studied for its wound protective activity. Ronald Lee Nichols (closing): Regarding Dr. Polk’s comment concerning anaerobic coverage: As occurred in colon surgery, when most surgeons used cephalothin rather than cephaloridine (which Dr. Polk recommended), the results were perhaps different than they would have been with cephaloridine. That remains to be shown. As far as which agent is best in gastric surgery, I don’t know. I don’t know whether cefamandole is better than some of the first-generation cephalosporins. My concern in this study was to get a clear indication for antibiotic prophylaxis in gastric surgery. Not that the studies weren’t done before; they certainly were done, but they had little effect on the editors who in 1979 sent me the galleys to review which suggested that the stomach was sterile and therefore there was no need for prophylaxis. I think sometimes we have to keep trying to get a concept across. I think colon surgery is dangerous, but gastric surgery is equally dangerous in these “high risk” patients. Dr. Wapnick, cimetidine failures are the worst of all possible patients. In some of these cases we have isolated Bacteroides fragilis. As I pointed out, the anaerobes that are important in gastric surgery are generally the oral anaerobes that respond to penicillin. There may be an exception in the patients who fail cimetidine therapy for
98
unknown reasons. They are a very high risk group, and I would consider them at the top of the high risk list. Dr. Pellegrini asked about intraluminal antibiotics. The original studies on inhibition of bacteria in the stomach are not from Dr. Williams’s group or our group. They were from an investigator, Dr. Arnold, who in 1926 reported in the gastroenterology literature on the tremendous inhibitory effect that gastric acid had on bacteria in the stomach. In the last 5 or 6 years we have found that gastric motility is another important inhibitor of bacterial colonization. We toyed with several ideas of putting antibiotics into the stomach, as we advocate in colon surgery. The problem came in the bleeders, who are the largest group in most of these studies. There is no way you can mix whatever you put in the stomach with the gastric clots. The same thing is true with obstructed patients. So we resorted to giving antibiotics that, as Dr. Polk suggested, get to the tissues in the active form. Dr. Ram, I think your comment about emergency procedures is important. There were equal numbers of what we consider emergencies (operated on within 24 hours) in both groups, and I think when we look at the data Dr. LoCicero reported from our institution at the Southern Medical Meeting last year, the most surprising finding was that in gastric surgery the lowest overall infection rate was in perforated duodenal ulcer, considered an emergency situation in all cases. The low infection rate occurred because it is a chemical, not a bacterial, insult in most cases. We close all the wounds routinely after saline irrigation. We do not employ intraperitoneal antibiotics because experimental work from our group shows a lack of convincing data concerning the efficacy of this technique. Dr. Condon, clostridia may be found in the upper gastrointestinal tract. It is not unusual to isolate clostridia from the oral pharynx. There is a wealth of anaerobic bacteria in the mouth, and with poor dental hygiene or in alcoholic patients the anaerobic levels in the mouth approach that in the colon. Concerning nonrelated infections, I think there are other techniques besides antibiotic therapy that decrease atelectosis, pneumonitis and urinary tract infections. Why cefamandole? I chose this agent only because I wanted so deeply to get an answer to this problem. I am well aware of the work of others, and I thought I would choose a product that would work best according to our laboratory sensitivity reports. Dr. Polk once asked me if I pick my antibiotics based on the petri dish or the patient. I think both the clinical and microbiologic data are important in making appropriate antibiotic choices.
The American Journal of Surgery
Ronald Lee Nichols, MD, New Orleans, Louisiana Watts R. Webb, MD, New Orleans, Louisiana James W. Jones, MD, New Orleans, Louisiana Jeffrey W. Smith, MS, New Orleans, Louisiana Joseph LoCicero III, MD, New Orleans, Louisiana
The use of antibiotic prophylaxis in patients undergoing gastroduodenal operations has generally been recommended only in cases of gastric carcinoma [I ,2]. Recent studies, however, have reported high postoperative infection rates in patients not receiving prophylaxis who underwent operations for other clinical conditions associated with decreased gastric acidity or gastric motility [3-51. These additional categories of high risk patients were also recently shown in a randomized, nonblind, prospective study to benefit from antibiotic prophylaxis [S]. In the present investigation the efficacy of antibiotic prophylaxis in patients with an increased risk of postoperative infection was studied using a randomized, prospective, double-blind design. Material
and Methods
Patient selection and preparation: Between July 1978 and January 1980,43 patients with a high risk of postoperative complications were admitted for gastroduodenal surgery to the Tulane Surgical Service (Charity Hospital of Louisiana at New Orleans and Tulane Medical Center Hospital). The clinical conditions included gastric ulcer, gastric carcinoma, bleeding duodenal or gastric ulcer, and obstructing duodenal ulcer. Patients were excluded from the study population if they were pregnant, had a history of allergy to penicillin or cephalosporins, were under age 12 years or had any significant underlying conditions which would have made evaluation difficult. In addition, any patient who had taken antibiotics during the 72 hours before surgery was not included. Appropriate patients were randomized into treatment From the Department of Sugery, Tulane University School of Medicine. New Orleans, Lobisiana. Requests for reprints should be addressed to Ronald Lee Nichols, MD. Department of Surgery, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112. Presented at the 22nd Annual Meeting of The Society for Surgery of the Alimentary Tract, New York, New York, May 19-20, 1981.
94
or placebo groups. All medication kits were identical in color and size, and no one having patient contact knew which drug regimen the patients were receiving. Treatment patients received a total of 4 g of cefamandole intravenously, 2 g 1 hour before operative incision and 1 g 4 and 8 hours after incision. Control patients received equal volumes of inert placebo intravenously at the same intervals. The operation performed was necessarily individualized according to the clinical situation. No other antibiotic agents were administered to either group. All patients underwent saline irrigation of the peritoneal cavity and subcutaneous tissue before primary wound closure. All patients were observed daily for signs of infection. If a postoperative infectious complication was noted, the patient was considered a treatment failure and subsequent operative and antibiotic therapy was left to the discretion of the treating physician. Sample collection: Needle aspiration of the greater curvature of the stomach using an 18 gauge needle and a 50 cm3 syringe was performed in each patient immediately upon entering the peritoneal cavity. Manual pressure on the anterior surface of the stomach was often necessary to ensure an adequate sample of gastric contents (2 to 3 ml). The major portion of each gastric aspirate was immediately injected into a sterile anaerobic transport bottle, Care was taken to avoid the transfer of air bubbles into this vial. The samples of gastric aspirate were taken directly to the research microbiology laboratory, and processing was begun within 15 minutes of arrival. After the operation, cultures were obtained as necessary from infected sites using similar techniques. Microbiologic techniques: Upon arrival in the laboratory the specimens were immediately passed into an anaerobic glove box. Once the specimen bottle was in the anaerobic environment, most of the contents were removed with a syringe and needle and plated onto blood agar plates with vitamin K and hemin, and blood agar plates with vitamin K, hemin, kanamycin and vancomycin. A portion was also placed into a tube of chopped meat glucose broth for enrichment culturing. Part of the sample was then removed from the anaerobic chamber and inoculated onto
The American Journal of Surgery
Antibiotic
bile esculin azide agar, eosin-methylene blue agar and blood agar plate. A Gram stain was performed at this point and, if large gram-positive bacilli were seen on the stain, a clostrisel agar plate was inoculated anaerobically with the portion of the specimen remaining in the anaerobic chamber. The aerobic plates were incubated at 35OC in a carbon dioxide-enriched environment and the anaerobic plates were incubated at 35’C in the anaerobic glove box (10 percent hydrogen, 10 percent carbon dioxide and 80 percent nitrogen). After 24 hours the plates were observed and representatives of all colony types were picked and Gram-stained. The aerobic coliforms were identified using the Enterotube system and noncoliform aerobes using standard bacteriologic techniques. The colonies from the anaerobic incubation also were subcultured onto blood agar plate for aerobic incubation and onto a peptone-yeast extract glucose broth tube. If the microorganism grew aerobically it was a facultative organism and was identified using standard aerobic bacteriologic techniques. Those bacteria that did not grow outside the glove box were obligate anaerobes and were identified using the techniques described in the VP1 Anaerobe Laboratory Manual. The contents of the peptone-yeast extract glucose broth tube were examined for the presence of metabolic acid end-products using gas chromatography. The original petri dishes were observed daily for 7 days and newly appearing colony types were handled as noted earlier. The chopped meat glucose tube was subcultured at 48 hours and the colony types cultured were compared with those appearing on the original plates. The culture was kept until all bacterial types observed in the original Gram stain were isolated and identified.
Results
The treatment and placebo groups were similar in indications for operation and patient demographic characteristics (Table I). Four of the 43 patienis were excluded from analysis: 2 patients failed to receive all of the three doses, 1 patient never began therapy and 1 received extended antibiotic therapy. None of these patients developed postoperative infectious complications. Seven infections were directly attributed to the gastric surgery in the 20 patients comprising the placebo group, whereas there was only 1 infection in the 19 cefamandole-treated patients (Table II); this difference was statistically significant (p
Volume 143, January 1982
TABLE I
Prophylaxis
in Gastroduodenal
Operations
Comparison of Patient Data in the Two Study Groups Treatment Group ___-
Evaluable patients (n) Indication for operation Gastric cancer Gastric ulcer Chronic Bleeding Duodenal ulcer Bleeding Obstructing Demographic features Sex Male Female Age (yr) Range Under 45 Over 45 Preoperative risk evaluation Good Fair Poor
TABLE II
Placebo Group
19
20
4
4
3 2
5 1
6 4
7 3
12 7
14 6
39-76 5 14
21-78 6 14
4 11 4
3 12 5
Infectious Complications in the Two Study Groups Treatment Group (n = 19) n %
Wound or intraabdominal infections Unrelated infections (urinary or pulmonary) Deaths
Placebo Group (n = 20) n %
1
5
7
35
5
26
3
15
1
5
2
10
Initial gastric aspirate for culture was obtained in 35 of the 39 patients studied. Eleven of these specimens were sterile, while the remaining 24 samples revealed growth of one to six different bacterial species. The nature of the gastric microflora is shown in Table III. In the seven infections related to surgery in the placebo group, four patients had infecting organisms that were found in the stomach at the time of gastric aspiration. These organisms included alpha-hemolytic streptococcus, enterococcus, Streptococcus pneumoniae, peptococcus and Clostridia perfringens. Two other patients had organisms similar to those isolated from the gastric aspirate that could likely have been present at concentrations too low to be isolated with the techniques used. The cause of subhepatic abscess in the one treatment failure was not ascertained before the patient died or by cultures taken at autopsy. The nonrelated infections were due to the usual gram-negative organisms that are the causes of
95
Nichols et al
nosocomial infections in the study hospitals. Only one of nine patients had an infecting organism that was also isolated from the initial gastric culture. Comments In 1975 we reported the results of a prospective clinical study on the influence of endogenous gastric microflora on the subsequent development of postoperative wound or intraabdominal infections after gastric resection [5]. This study showed that both gastric acid and normal gastric motility were important in the prevention of gastric bacterial colonization. In the patients with chronic nonobstructing duodenal ulcer, high acid levels and normal gastric motility were noted preoperatively, and few if any
TABLE III
Organisms isolated From lnltial Gastric Aspirate In the Two Study Groups Isolates (n)
Treatment Group
Placebo Group
7 0 3 0 1 4 1
12 3 3 1 2 1 0
0 1 3 2 3 1 0 0 3 1 1
1 0 0 0 0 0 1 2 4 0 2
31
32
1 1 1 1 0 0 1
1 0 0 0 1 1 1
0 0 0 0 0 1
1 1 1 1 2 0
6
10
Aerobic Gram-positive Alpha-hemolytic streptococcus Beta-hemolytic streptococcus Enterococcus Streptococcus pneumoniae Staphylococcus aureus Micrococcus species Bacillus species Gram-negative Enterobacter species Citrobacter species Escherichia coli Proteus mirabilis Klebsiella species Hafnia species Haemophilus species Nonfermentor Neisseria species Eikenella species Yeast Total Anaerobic Gram-positive Lactobacillus species Eubacterium species Eubacterium lentum Sarcina species Peptococcus magnus Peptococcus saccharolyticus Clostridium perfringens Gram-negative Bacteroides saccharolyticus Bacteroides ruminicola Bacteroides melaninogenicus Bacteroides species Fusobacterium nucleatum Veillonella species Total
96
bacteria were isolated from cultures of needle aspirates of stomach contents taken during surgery. The postoperative infection rate in this group of patients was correspondingly low. It was also apparent that gastric bacterial colonization occurred almost uniformly in other patients who had undergone operations for bleeding or obstructing duodenal ulcer, or for gastric ulcer or malignancy. The reason for gastric colonization in these groups of patients was best explained by a compromise of the normal bacterial inhibitory effects of gastric acid or gastric motility. When present, the gastric microflora were usually equally divided between oral or proximal intestinal aerobes and oral (penicillin-sensitive) anaerobes. Patients who had gastric colonization at the time of operation had postoperative infection rates greater than 20 percent. In all but one case, the organisms responsible for the postoperative infections were the same as those isolated from the gastric microflora. At that time it became apparent that carefully designed antibiotic prophylaxis might be beneficial in these high risk patients. Lewis [3] in 1977 reported a 10 year review of wound infections after gastroduodenal operations. His findings were in agreement with our earlier study, indicating that high and low risk patients could be identified during the preoperative period. Further evidence was reported in 1980, showing that 22 of 30 patients who had postoperative infections after gastroduodenal operations had a deficiency of one or both gastric inhibitory factors [4]. The value of antibiotic prophylaxis in gastric surgery has been previously reported [7,8]. However, Lewis et al [S] in 1979 were the first to study only high risk patients. This study of 108 patients undergoing gastroduodenal operations was randomized and prospective but not blinded. The results of the study showed a significantly decreased postoperative infection rate in high risk patients treated with 2 g of cephaloridine intravenously 2 hours before operation and again 5 hours later. Stone et al [S] had previously stressed the importance of beginning antibiotic prophylaxis during the immediate preoperative period for maximal results. The present study confirms the value of short-term antibiotic prophylaxis in high risk patients undergoing gastroduodenal operations. With the use of effective acid-blocking medications for chronic duodenal ulcer disease, it is important to realize that almost all patients needing surgical therapy are at high risk for the development of postoperative infections. The choice to use the second-generation cephalosporin cefamandole rather than more commonly used first-generation agents such as cephalothin was based on the antibiotic susceptibilities reported at the hospitals of this study. Although both generations of cephalosporins have excellent efficacy against the
The American Journal of Surgery
Antibiotic
aerobic and anaerobic oral microorganisms, cefamandole was superior in covering gram-negative coliforms. The choice of which antibiotic agent to use in prophylaxis for gastroduodenal operations should be based on the aerobic coliform susceptibility results at the hospital where the operation is to take place. The importance of covering these organisms as well as gram-positive aerobes and anaerobes has been stressed by Lewis et al [6], who found that the aerobic coliforms, including Escherichia coli, Klebsiella species and Proteus species, were the primary organisms isolated in over 50 percent of wound infections occurring after gastroduodenal operations.
Summary A double-blind, prospective and randomized clinical trial of the efficacy of antibiotic prophylaxis in gastroduodenal operations was studied in 39 patients over an 18 month period. All patients had clinical features that placed them at high risk for the development of postoperative wound or intraabdominal sepsis. In the placebo group of 20 patients seven gastric-related infections developed, while 1 of the 19 patients who received perioperative cefamandole had one gastric-related infection (p
References 1. Antimicrobial prophylaxis: prevention of wound infections and sepsis after surgery. Med Lett Drugs Ther 1979;21:73-6. 2. Veterans Administration Ad Hoc Interdisciplinary Advisory Committee on Antimicrobial Drug Usage. I. Prophylaxis in surgery. JAMA 1977;237:1003-8. 3. Lewis RT. Wound infection after gastroduodenal operations: a 10 year review. Can J Surg 1977;20:435. 4. LoCicero J, Nichols RL. Sepsis after gastroduodenal operations: relationship to gastric acid, motility, and endogenous microflora. South Med J 1980;73:878-80. 5. Nichols RL, Smith JW. lntragastric microbial colonization in common disease states of the stomach and duodenum. Ann Surg 1975;182:557-61. 6. Lewis RT. Allan CM, Goodall RG, Lloyd-Smith WC, Marien B, Wiegand FM. Discriminate use of antibiotic prophylaxis in gastroduodenal surgery. Am J Surg 1979;138:640-3. 7. Polk HC Jr, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66:97. 8. Stone HH, Hooper A, Kolb LD, et al. Antibiotic prophylaxis in gastric. biliary and colonic surgery. Ann Surg 1976;184: 443-52.
Volume 143, January 1982
Prophylaxis
in Gastroduodenal Operations
Discussion Robert E. Condon (Milwaukee, WI): Microbiologic study of the stomach in high risk patients has been done before, but there is not a very broad data base. I was struck by the 35 percent wound infection rate in the placebo-treated group. That is a wound infection risk in the same range as in patients undergoing colon operation who do not receive antibiotic prophylaxis, which emphasizes that this high risk group is at a very high risk indeed. I have a couple of questions. It has always intrigued me that we repeatedly find coliform organisms in these patients with a failed gastric acid barrier. Two of your patients had clostridia-related infectious complications. I am surprised that you found clostridia in the stomach. Where do you think they came from: are they swallowed, or do they come from somewhere else? My second question concerns the incidence of infections not related directly to the operation. Often in studies of surgical prophylaxis both the related and nonrelated infections are decreased by the administration of antibiotic prophylaxis. The nonrelated infections in your study seem not to be affected, and if anything were a little higher in the antibiotic-treated group. Would you comment on that? Would you comment further on the choice of specific antibiotics? In our hospitals, coliforms are still sensitive (more than 85 percent) to E coli. We don’t often see Enterobacter involved in complications after gastric operations, and we are currently using first-generation cephalosporins. Would you comment on that practice? M. D. Ram (Lexington, KY): I have two questions. Is there a difference in the incidence of infection in elective and emergency procedures, and did you separate these in your study group? Second, does leaving the skin wounds open make any difference? When we anticipate wound infection we do leave the wounds open and close them secondarily, and we think it makes a great difference.
Carlos A. Pellegrini (San Francisco, CA): A significant number of patients with obstructing duodenal ulcer and gastric malignancy have positive gastric cultures. I wonder if you would comment on the role of preoperative intraluminal antibiotic and mechanical preparation of the stomach. Second, since in most instances I presume you had to open the stomach, did you use peritoneal lavage with or without antibiotics during surgery?
Ward 0. Griffen (Lexington, KY): I support your use of prophylaxis antibiotics. When we originally set up our prospective study comparing gastric bypass with intestinal bypass, I purposely did not use systemic antibiotics prophylactically in the gastric group. After about 25 patients we had eight wound infections, so we went to first-generation cephalosporins prophylactically, and in the last 500 gastric bypasses we have had only four infections. We did some other things also such as changing the way we closed the wounds. For example, we now use nonabsorbable sutures in closing the wounds. Could you tell us something about the way the wounds in your study were closed? That is, was there a standard wound closure during the study, or were many different types of wound closure used?
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Simon Wapnick (New York, NY): Did you evaluate the patients who had received cimetidine before surgery? Cimetidine alters gastric flora. We have been impressed by the high incidence of wound infection in patients receiving this drug before gastric operation. Hiram C. Polk, Jr. (Louisville, KY): I think the authors have done us a real service. While there are several similar reports going back over a decade, I believe surgeons, by concentrating on infections in colon surgery, have neglected this subject. Virtually all of the randomized double-blind studies that have included any kind of gastric operations have come to these same conclusions. The second thing the authors have shown that was heretofore unknown is that cefamandole is a wound-active antibiotic. The reason that cephalothin does not work is that it disappears from the wound so quickly as to be worthless. I think the difference between this drug and some other cephalosporins has nothing to do with their anaerobic coverage, because the original agent used, cephaloridine, showed the same kind of control in these high risk patients. I think the specific drug in question needs to be understood by those reading this report, since you may want to use that and not some congener that may not have been studied for its wound protective activity. Ronald Lee Nichols (closing): Regarding Dr. Polk’s comment concerning anaerobic coverage: As occurred in colon surgery, when most surgeons used cephalothin rather than cephaloridine (which Dr. Polk recommended), the results were perhaps different than they would have been with cephaloridine. That remains to be shown. As far as which agent is best in gastric surgery, I don’t know. I don’t know whether cefamandole is better than some of the first-generation cephalosporins. My concern in this study was to get a clear indication for antibiotic prophylaxis in gastric surgery. Not that the studies weren’t done before; they certainly were done, but they had little effect on the editors who in 1979 sent me the galleys to review which suggested that the stomach was sterile and therefore there was no need for prophylaxis. I think sometimes we have to keep trying to get a concept across. I think colon surgery is dangerous, but gastric surgery is equally dangerous in these “high risk” patients. Dr. Wapnick, cimetidine failures are the worst of all possible patients. In some of these cases we have isolated Bacteroides fragilis. As I pointed out, the anaerobes that are important in gastric surgery are generally the oral anaerobes that respond to penicillin. There may be an exception in the patients who fail cimetidine therapy for
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unknown reasons. They are a very high risk group, and I would consider them at the top of the high risk list. Dr. Pellegrini asked about intraluminal antibiotics. The original studies on inhibition of bacteria in the stomach are not from Dr. Williams’s group or our group. They were from an investigator, Dr. Arnold, who in 1926 reported in the gastroenterology literature on the tremendous inhibitory effect that gastric acid had on bacteria in the stomach. In the last 5 or 6 years we have found that gastric motility is another important inhibitor of bacterial colonization. We toyed with several ideas of putting antibiotics into the stomach, as we advocate in colon surgery. The problem came in the bleeders, who are the largest group in most of these studies. There is no way you can mix whatever you put in the stomach with the gastric clots. The same thing is true with obstructed patients. So we resorted to giving antibiotics that, as Dr. Polk suggested, get to the tissues in the active form. Dr. Ram, I think your comment about emergency procedures is important. There were equal numbers of what we consider emergencies (operated on within 24 hours) in both groups, and I think when we look at the data Dr. LoCicero reported from our institution at the Southern Medical Meeting last year, the most surprising finding was that in gastric surgery the lowest overall infection rate was in perforated duodenal ulcer, considered an emergency situation in all cases. The low infection rate occurred because it is a chemical, not a bacterial, insult in most cases. We close all the wounds routinely after saline irrigation. We do not employ intraperitoneal antibiotics because experimental work from our group shows a lack of convincing data concerning the efficacy of this technique. Dr. Condon, clostridia may be found in the upper gastrointestinal tract. It is not unusual to isolate clostridia from the oral pharynx. There is a wealth of anaerobic bacteria in the mouth, and with poor dental hygiene or in alcoholic patients the anaerobic levels in the mouth approach that in the colon. Concerning nonrelated infections, I think there are other techniques besides antibiotic therapy that decrease atelectosis, pneumonitis and urinary tract infections. Why cefamandole? I chose this agent only because I wanted so deeply to get an answer to this problem. I am well aware of the work of others, and I thought I would choose a product that would work best according to our laboratory sensitivity reports. Dr. Polk once asked me if I pick my antibiotics based on the petri dish or the patient. I think both the clinical and microbiologic data are important in making appropriate antibiotic choices.
The American Journal of Surgery