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Prospective, randomized, controlled trial of ticarcillin and cephalothin as prophylactic antibiotics for gastrointestinal operations
Prospective, Randomized, Controlled Trial of Ticarcillin And Cephalothin as Prophylactic Antibiotics For Gastrointestinal Operations
J. Jeffrey Brown, MD, Columbia, South Carolina Thomas P. Mutton, MD, Winston-Salem,
North Carolina
Benedict L. Wasilauskas, MD, Winston-Salem, Richard T. Myers, MD, Winston-Salem, Jesse H. Meredith, MD, Winston-Salem,
North Carolina
North Carolina North Carolina
Many surgeons agree that the judicious use of prophylactic antibiotics reduces the incidence of infection after gastrointestinal operations. However, the ideal antibiotic and the optimal duration of its administration have not been determined. Polk and Lopez-Mayor [I] originally advocated a three dose, 12 hour regimen of cephaloridine. Stone [2,3] and Strachan [4] and their colleagues subsequently demonstrated the efficacy of cephazolin and cephamandole in patients at increased risk of infection. Certain other drugs have been shown effective in controlled clinical trials: penicillin [5], metronidazole [6-81, and combinations of lincomycin and an aminoglycoside [9,10]. This prospective, randomized, blind study was undertaken in 190 patients to investigate the effectiveness of ticarcillin and cephalothin as prophylactic antibiotics for operations on the colon, stomach, small bowel or obstructed biliary tract. Methods All patients entering North Carolina Baptist Hospital and scheduled for elective operations involving transection of the obstructed biliary tract (serum bilirubin 3.0 mg/dl or greater), stomach, small bowel or colon, but not appendectomy or routine cholecystectomy, were screened for inclusion in the study. All patients were included except those excluded because of a history of allergy to penicillin, cephalothin or related drugs; pregnancy; history of bleeding From the Departments of Surgery and Pathology, Bowman Gray School of Medicine of Wake Forest University. Winston-Salem, North Carolina. Requests for reprints should be addressed to Richard T. Myers, MD, Department of Surgery, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103.
Volume 143, March 1992
disorders; abnormal preoperative bleeding time; need for postoperative antibiotics determined by the surgeon before operation; probable need for delayed primary closure of the wound; antibiotics having been taken within 7 days before operation, excepting oral antibiotics for colon preparation; impaired renal function; age less than 1 year; or inability or refusal of the patient to give written informed consent. The 190 qualifying patients were randomized into one of three groups. Group I patients were given a single, intravenous, 6 g dose of ticarcillin within 15 minutes of the induction of anesthesia (children were given 1.0 g/10 kg body weight). Group II patients were given a 2 g dose of cephalothin intravenously at the time of induction of anesthesia and subsequent 2 g doses 4 and 8 hours after the initial dose (children were given 30 mg/kg body weight). Group III patients were given 10 to 20 ml of 5 percent dextrose in water intravenously within 15 minutes of induction of anesthesia. The respective medications were sent to the operating room in a sealed envelope and were administered by the anesthesiologist. Thus, although the surgeon and the patient did not know which drug was used, the anesthesiologist did know, so that the study was not double-blind. All patients undergoing operation on the colon had an identical mechanical and neomycin-erythromycin bowel preparation as described by Vargish et al [II] and currently practiced in this hospital. At the end of the operation, after closure of the peritoneum, a swab of the superficial surgical wound was taken for aerobic and anaerobic cultures by routine methods. Drug sensitivities on cultures grown were determined by the Kirby-Bauer disk-diffusion method. Throughout their hospital stay, patients were followed by a registered nurse and a consultant surgeon, neither of whom knew to which group a patient had been assigned and neither of whom was directly responsible for the pa-
343
Brown et al
TABLE I
Patient Profile (Determinate)
Treatment Groups
Total
I: Ticarcillin II: Cephalothin Ill: Placebo Totals
Patients (n) Male Female
59
Age (yr) Average Range
Diabetes
Patients (n) With PI DM Obesity*
Operative Time (hr) Average Range
f:
26 22 15
33 35 21
7-64 17-67 24-86
53.5 47.5 54.4
4 4 4
4 2 0
3 2 2
17 21 12
0.9-6.0 0.6-4.7 0.6-4.3
2.6 2.6 2.4
152
63
a9
7-87
51.5
12
6
7
50
0.8-6.0
2.6
Defined as more than 30 pounds over ideal body weight. DM = disseminated malignancy (carcinomatosis); PI = pharmacologic immunosuppression. l
tient’s care. The attending surgeon examined the patients
during their outpatient follow-up visits during the first 3 to 5 weeks after discharge. Infections and other postoperative complications were monitored continuously throughout the study. When the results were tabulated, 13 patients who had received other antibiotics within 48 hours of operation, 12 patients who had not had an intraabdominal viscus opened, 8 patients who had had delayed primary closure of their wound, 2 patients who had had technical complications making wound evaluation impossible, and 3 patients who had had less than 3 weeks of outpatient follow-up observation were excluded from the definitive (determinate) study group and were placed in an indeterminate group (38 patients). Sixteen of the 38 patients were from the ticarcillin group, 18 from the cephalothin group, and 4 from the placebo group. Data from this indeterminate group were examined separately. All data were analyzed by either the chi-square test or Fisher’s exact probability test.
Results Patient profile: Of the 190 patients enrolled in the
study, 152 were in the determinate group. For those patients, clinical factors that might have influenced the rate of postoperative infection are compared in Table I. The differences between the therapy groups were not significant for any of those factors. Comparisons of the same factors were made between the determinate and the indeterminate patient groups, and again no significant differences were noted. Infectious complications: Surgical infection was defined as the discharge of purulent or culture-positive drainage from the wound or the presence of any intraabdominal pus or abscess. TABLE II
The data were continuously monitored for infection rates. After 120 patients had been included in the study, 10 of 38 patients in the placebo group had developed infections, whereas only 2 of 32 patients in the ticarcillin group and 1 of 29 patients in the cephalothin group had developed infections. Those differences were statistically significant (p 10.05), and the placebo limb of the study was discontinued. At the conclusion of the study, infections had developed in 2 of 59 determinate-group patients and 2 of 16 indeterminate-group patients in the ticarcillin group (5 percent overall), in 3 of 57 determinategroup patients and 2 of 18 indeterminate-group patients in the cephalothin group (7 percent overall), and in 10 of 36 determinate-group patients and 2 of 4 indeterminate-group patients in the placebo group (30 percent overall). Infection rates for all determinate patients were then examined according to the type of operation performed, and those results are presented in Table II. Comparisons of infection rates in patients undergoing gastric segmentation (Roux-Y gastrojejunostomy in morbidly obese patients) and those undergoing colon resection were also made. Infection rates were significantly reduced (p <0.05) when placebo-treated patients (2 of 8) were compared with all antibiotic-treated gastric segmentation patients (0 of 28). In patients who underwent a left colon resection, there was significant reduction (p <0.05) of wound infections in those who received one of the study antibiotics (1 of 34) versus those who were given placebo (2 of 9). When all patients undergoing
Infection Rates for Determinate Patients Group I: Ticarcillin
Gastric segmentation Other gastric operation Right colon Left colon Ostomy closure or revision Small bowel resection Biliary operation Totals
344
Group II: Cephalothin
Group Ill: Placebo
n
00
n
%
n
0111 O/6 o/a 0121 o/5 215 o/3
. ... .. ..
o/17 O/16 O/6 l/l3 l/3 O/l l/l
. . ... . .
218 l/6 l/5 219 415 o/2 O/l
2159 p 10.01
46.
., 3.4
...
3157 p 50.05
a 33 lbb’ 5.3
1O/36
% 25 17 20 22 80
.. .. 27.8
The American Journal of Surgery
Prophylactic
colon resection were examined, there was a similar reduction in wound infections in the placebo-treated patients (3 of 14) and both the cephalothin-treated (1 of 19) and the ticarcillin-treated (0 of 29) patients. A detailed presentation of the 15 patients who developed infection is given in Table III. Of those 15 patients, both operative and postoperative cultures were not available for 4. For six, there was close cor-
TABLE 111 Detailed
Patient
Antibiotics
for Gastrointestinal
Operations
relation between bacteria on the two cultures; for the other five, there was no correlation. Other complications: A total of 35 complications other than wound and peritoneal infections were observed in the determinate group of patients: urinary tract infections (eight patients); atelectasis and pneumonia (seven patients); phlebitis (three patients); gastrointestinal obstruction (four patients, one death); gastrointestinal bleeding (three patients);
Analysis of Infections in Determinate Patients by Treatment Groups
Diagnosis
Operation
Infection (Day First Noted)
Operating Room Culture
Infection Culture
Comments
Group I (Ticarcillin) 1
2
Megaduodenum, chronic bowel obstruction Radiation enteritis
Duodenal resection
Septic shock
Small bowel resection
Peritoneal abscess (23)
(1)
Klebsiella pneumoniae, B. fragilis E. coli, B. fragilis
Klebsiella pneumoniae E. coli, 8. fragilis. Klebsiella pneumoniae
Died (sepsis) 36 hours postoperatively Postoperative short bowel syndrome
Group II (Cephalothin) 3
4
5
Spasm of sphincter of Oddi Ulcerative colitis
Malfunctioning Koch ileostomy
Sphincteroplasty
‘Stitch abscess” (17)
Total proctocolectomy
Pelvic abscess (31)
Revision of ileostomy
Wound and peritoneal abscess (18)
Alpha streptococcus S. epidermidis
B. fragilis, fusobacterium
Not done
Not available
Abscess drained per perineum at another hospital onday
8. fragilis, fusobacterium
Group Ill (Placebo) Proteus mirabilis
Developed ventral hernia
Wound (8)
S. epidermidis, B. fragilis, enterococci No growth
S. aureus, Streptococcus
Wound evisceration
Colostomy closure
Wound (4)
Not done
Right colectomy
wound (20)
Gastric segmentation Closure of colostomy Gastric segmentation
Wound (28)
E. coli, enterococci No growth
E. coli, Proteus mirabilis, enterococci S. epidermidis
6
Diverticulitis
Total abdominal colectomy
Wound (19)
7
Duodenal web
Gastrojejunostomy
8
Colostomy
9 10
Malignant neoplasm Morbid obesity
11
Colostomy
12
Morbid obesity
13
Diverticulitis
14
Colostomy
15
Colostomy
Wound (14) Wound (10)
S. aureus
E. coli, bacillus species S. aureus, alpha and gamma streptococcus S. epidermidis
Not done
S. aureus, B. fragilis, enterococci, clostridia Proteus mirabilis, E. coli, S. aureus,
Total abdominal colectomy Colostomy revision
Wound (5) Wound (3)
B. fragilis, S. epidermidis, enterococci
Colostomy closure
Wound (3)
Enterococci, Proteus mirabilis, E. coli,
S. aureus
S. aureus,
S. aureus
Volume 143. March 1992
345
Brown et al
TABLE IV
Organismsisolated in 72 Positive Operating Room Wound Cultures Ticarcillin
Staphylococcus epidermidis Staphylococcus aureus Alpha streptococcus Gamma streptococcus Enterococci E. coli Bacillus species Proteus mirabilis Pseudomonas Klebsiella pneumoniae Enterobacter Diphtheroides Bacteroides fragilis Clostridium Other Totals
Resistant
Sensitive
Resistant
z 4 7 7 1 1 2 0 1 1 5 1 5
3 0 0 0 1 1 0 0 0 2 0 1 2 0 1
4 0 1 0 1 1 0 0 0 1 0 0 1 0 3
47 5 9 4 1 5 1 1 0 3 0 0 2 1 3
1 0 0 0 7 d
90
11
12
82
23
Sensitive
49
42
9” 4 9” 1 1 2 3 1 2 8 1 9 113
pulmonary embolism, gangrenous foot, short bowel syndrome and enterocutaneous fistula (one patient each); and miscellaneous (six patients). Seventeen of those complications occurred in the ticarcillin group, 9 in the cephalothin group and 9 in the placebo group. One patient in the ticarcillin group and one patient in the cephalothin group had two complications each. Deaths: Two patients in the determinate group died, one being the only patient (Case 1, Table III) to die as a result of surgically related sepsis. He was a 63 year old man who had chronic, high grade, partial small bowel obstruction and secondary megaduodenum due to massive adhesions. He was chronically malnourished, and probably had immunosuppression for that reason, although preoperative skin tests had not been done to confirm immunosuppression. The operative time required for lysis of adhesions and duodenal resection was 6 hours, and shortly after completion of the operation disseminated Klebsiella sepsis and shock developed. He died within 36 hours. The second death occurred in a patient in the cephalothin group who underwent right colectomy and required exploration for intestinal obstruction 22 days later. The second operation was performed through the original abdominal wound and there was no evidence of wound or peritoneal infection. The interval between operations was considered to represent a postoperative follow-up sufficient to allow his inclusion in the determinate group, although he died from complications after his second laparotomy. Six of 190 patients died (3.7 percent). In addition to the two determinate-group deaths, four indeterminate-group deaths occurred, one each caused by perioperative myocardial infarction, upper gastrointestinal tract hemorrhage, respiratory insufficiency and aspiration pneumonia.
346
Cephalothin Not Tested
Isolates (n)
0 2 0 1 2 5 0
1
Not Tested
1 0 0 0 1 0 0 0 0 0 0 0 1 0
5 8
Bacteriology: One hundred forty of the 152 determinate patients in the study had a swab of their superficial operative wound taken in the operating room just after closure of the peritoneum or fascia. Of the 54 cultures from the ticarcillin group, 24 (44 percent) were positive for one or more organisms; of the 54 cultures from the cephalothin group, 27 (50 percent) were positive; of the 32 cultures from the placebo group, 21 (66 percent) were positive. Thus, the prophylactic use of broad-spectrum antibiotics reduced the rate of recovery of wound contaminants at the end of the operation, but there was no difference between the two antibiotics tested. Table IV itemizes the organisms isolated in the 72 positive operative wound cultures and the in vitro sensitivities of those organisms to the two antibiotics used in the study. The organisms isolated are those that might be expected after major gastrointestinal procedures, and the in vitro sensitivities closely paralleled those that would be predicted from the known spectra of activities of the drugs. Both of the antibiotics used demonstrated in vitro effectiveness against a majority of the organisms isolated. Results of postoperative cultures of wound, urine, sputum and blood revealed no emergence of strains of bacteria resistant to either ticarcillin or cephalothin. Comments The indications for the use of prophylactic antibiotics have been well documented by Chetlin and Elliott [12], Polk and Lopez-Mayor [I], Stone et al [3] and Griffiths et al [13]. The ideal prophylactic antibiotic would be one that is active against all pathogens that might be anticipated, is incapable of causing the emergence of resistant bacterial strains, and has negligible toxicity to the patient. Obviously, the drug with all of those characteristics does not
TheAmerkan
Journal of Surgery
Prophylactic
exist at present, so the search continues for the best alternatives. Although the spectrum of antibacterial activity remains constant for any given antibiotic, theoretically one can reduce the risks of patient toxicity and the emergence of resistant organisms by shortening the interval over which the antibiotic is given. Stone et al [2] recently reported that cephamandole was as effective in preventing peritoneal and surgical wound infections when it was given in a three dose perioperative prophylactic regimen as it was when given over 3 days; the hospital costs were considerably lower with the shorter course. Our study investigated the ultimate short-term prophylactic administration of a drug: a single dose regimen. Ticarcillin has a very attractive in vitro spectrum of activity for prophylactic use as a single antimicrobial agent in gastrointestinal surgery, and for that reason was chosen for this study. It is effective against most aerobic gram-negative pathogens encountered in bowel surgery and against many strains of Bacteroides fragilis. Klebsiella is probably the most significant fecal pathogen against which ticarcillin is ineffective, and that organism was responsible for the septic complications and death of a high risk patient treated with ticarcillin. Another factor that might have contributed to that death was the combination of a lengthy operation without a second dose of antibiotic being given in a patient who was chronically ill and malnourished. Although the value of cephalothin as a prophylactic antibiotic in gastrointestinal surgery has been questioned by Burdon [5] and Condon [6] and their colleagues, we selected it for use in this study because it was being used extensively for that purpose at the North Carolina Baptist Hospital as well as at many other medical centers [6]. Its use in a three dose regimen was based on the same consideration, as well as on the findings of Polk and Lopez-Mayor [I] and Stone et al [2,3]. Because of the short half-life of this drug, we believe that the use of a large dose at short intervals is an important consideration if cephalothin is used as a prophylactic agent. Both of the drugs chosen were superior to a placebo in the prevention of postoperative wound and peritoneal infections. There was no significant difference in infection rates between the cephalothin-treated and ticarcillin-treated patients. It is noteworthy that ticarcillin exhibited in vitro activity against a slightly higher percentage of the bacterial contaminants isolated from the operative wound at the time of operation (80 versus 73 percent). Of particular interest is the absence of infection in the 34 patients in the ticarcillin group undergoing operation on the colon or closure or revision of a colostomy or ileostomy. The combination of systemic ticarcillin with oral neomycin and erythromycin appears very effective in colon operations and warrants further investigation.
Volume 143, March 1962
Antibiotics
for Gastrointestinal
Operations
Comparison of the drug sensitivities of the organisms isolated from the operating room wound cultures with those isolated from the postoperative infection cultures revealed no evidence of the emergence of resistant bacterial strains. Furthermore, analysis of the sensitivities of the organisms recovered on postoperative cultures of sputum, urine and blood in those patients treated prophylactically with ticarcillin and cephalothin revealed no discernible variations from the expected sensitivities. Thus, neither of the prophylactic treatment regimens appears to predispose to the development of bacterial resistance. Fifteen of the 152 determinate patients developed postoperative wound or peritoneal infections, and an additional 25 patients had a major or minor postoperative surgical complication. Thus, in the determinate patients, the overall rate of infectious complications was 10 percent (15 of 152) and the overall complication rate was 26 percent (40 of 152). No definite conclusions can be drawn from the bacteriologic data from the patients who became infected. It is interesting, however, that in 6 of the 11 patients for whom both organisms from the intraoperative cultures and organisms from the cultures of the subsequent infections can be compared, the results of the wound contaminants present at the end of the procedures would have provided an excellent basis for appropriate antibiotic selection while the final results of the cultures of the infected wounds were awaited. It should also be noted that 8 of the 15 surgical infections were diagnosed between the 14th and the 31st postoperative days, emphasizing the need for an adequate follow-up period in a study of this nature. Summary The effectiveness of ticarcillin (one 6 g dose at the start of the operation) and cephalothin (three 2 g doses given at 4 hour intervals from the start of the operation) as prophylactic antibiotics in operations on the colon, stomach, small bowel or obstructed biliary tract was determined in a prospective, randomized, blind study of 190 patients. Data from the 152 patients forming the definitive study revealed a significant reduction in the rate of wound and peritoneal infections with the use of ticarcillin (3.4 percent) and cephalothin (5.3 percent) over that with the use of a placebo (27.8 percent). Cultures showed no evidence of antibiotic resistance in the contaminant organisms of patients who later developed infections. Both antibiotic regimens offered excellent protection against infection after gastrointestinal operations; neither produced untoward side effects. The very short duration of treatment, particularly with ticarcillin, conferred the additional benefits of low cost, simplicity of drug administration, and negligible risk of the emergence of resistant bacterial strains.
347
Brown et al
References 1. Polk HC Jr, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66:97-103. 2. Stone HH, Haney BB, Kolb LD, Geheber CE, Hooper CA. Prophylactic and preventive antibiotic therapy. Timing, duration and economics. Ann Surg 1979;169:691-9. 3. Stone HH, Hooper CA, Kolb LD, Geheber CE, Dawkins EJ. Antibiotic prophylaxis in gastric, biliary and colonic surgery. Ann Surg 1976;164:443-52. 4. Strachan CJL, Black J, Powis SJA, et al. Prophylactic use of cephazolln against wound sepsis after cholecystectomy. Br Med J 1977;1:1254-6. 5. Burdon JGW, Morris PJ, Hunt P, Watts MI. A trial of cephalothin sodium in colon surgery to prevent wound infection. Arch Surg 1977;112:1169-73. 6. Condon RE, Bartlett JG, Nichols RL, Schulte WJ, Gorbach SL, Dchi S. Preoperative prophylactic oephalothin fails to control septic complications of colorectal operations: results of controlled clinical trial. Am J Surg 1979;137:66-74. 7. Rodgers J, Ross D, f&Naught W, Gillespie G. lntrarectal me-
34s
6.
9.
10.
11.
12. 13.
tronidazole in the prevention of anaerobic infections after emergency appendicectomy: a controlled clinical trial. Br J Surg 1979;66:425-7. Hughes ESR, Hardy KJ, Cuthbertson AM, Rubbo SD. Chemoprophylaxis in large bowel surgery. 1. Effect of intravenous administration of penicillin in incidence of postoperative infection. Med J Aust 1970;1:305-6. Greenall MJ, Bakran A, Pickford IR, et al. A double-blind trial of a single intravenous dose of metronldazole as prophylaxis against wound infection following appendicectomy. Br J Surg 1979;66:426-9. Feathers RS, Lewis AAM, Sagor GR, Amirak ID, Noone P. Prophylactic systemic antibiotics in colorectal surgery. Lancet 1977;2:4-6. Vargish T, Crawford LC, Stallings RA, Wasilauskas BL, Myers RT. A randomized prospective evaluation of orally administered antibiotics in operations on the colon. Surg Gynecol Obstet 1976;146:193-6. Chetlin SH, Elliott DW. Preoperative antibiotics in biliary surgery. Arch Surg 1973;107:319-23. Griffiths DA, Shorey BA, Simpson RA, Speller DCE, Williams NB. Single-dose peroperative antibiotic prophylaxis in gastrointestinal surgery. Lancet 1976;2:325-6.
The American Journal of Surgery
J. Jeffrey Brown, MD, Columbia, South Carolina Thomas P. Mutton, MD, Winston-Salem,
North Carolina
Benedict L. Wasilauskas, MD, Winston-Salem, Richard T. Myers, MD, Winston-Salem, Jesse H. Meredith, MD, Winston-Salem,
North Carolina
North Carolina North Carolina
Many surgeons agree that the judicious use of prophylactic antibiotics reduces the incidence of infection after gastrointestinal operations. However, the ideal antibiotic and the optimal duration of its administration have not been determined. Polk and Lopez-Mayor [I] originally advocated a three dose, 12 hour regimen of cephaloridine. Stone [2,3] and Strachan [4] and their colleagues subsequently demonstrated the efficacy of cephazolin and cephamandole in patients at increased risk of infection. Certain other drugs have been shown effective in controlled clinical trials: penicillin [5], metronidazole [6-81, and combinations of lincomycin and an aminoglycoside [9,10]. This prospective, randomized, blind study was undertaken in 190 patients to investigate the effectiveness of ticarcillin and cephalothin as prophylactic antibiotics for operations on the colon, stomach, small bowel or obstructed biliary tract. Methods All patients entering North Carolina Baptist Hospital and scheduled for elective operations involving transection of the obstructed biliary tract (serum bilirubin 3.0 mg/dl or greater), stomach, small bowel or colon, but not appendectomy or routine cholecystectomy, were screened for inclusion in the study. All patients were included except those excluded because of a history of allergy to penicillin, cephalothin or related drugs; pregnancy; history of bleeding From the Departments of Surgery and Pathology, Bowman Gray School of Medicine of Wake Forest University. Winston-Salem, North Carolina. Requests for reprints should be addressed to Richard T. Myers, MD, Department of Surgery, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103.
Volume 143, March 1992
disorders; abnormal preoperative bleeding time; need for postoperative antibiotics determined by the surgeon before operation; probable need for delayed primary closure of the wound; antibiotics having been taken within 7 days before operation, excepting oral antibiotics for colon preparation; impaired renal function; age less than 1 year; or inability or refusal of the patient to give written informed consent. The 190 qualifying patients were randomized into one of three groups. Group I patients were given a single, intravenous, 6 g dose of ticarcillin within 15 minutes of the induction of anesthesia (children were given 1.0 g/10 kg body weight). Group II patients were given a 2 g dose of cephalothin intravenously at the time of induction of anesthesia and subsequent 2 g doses 4 and 8 hours after the initial dose (children were given 30 mg/kg body weight). Group III patients were given 10 to 20 ml of 5 percent dextrose in water intravenously within 15 minutes of induction of anesthesia. The respective medications were sent to the operating room in a sealed envelope and were administered by the anesthesiologist. Thus, although the surgeon and the patient did not know which drug was used, the anesthesiologist did know, so that the study was not double-blind. All patients undergoing operation on the colon had an identical mechanical and neomycin-erythromycin bowel preparation as described by Vargish et al [II] and currently practiced in this hospital. At the end of the operation, after closure of the peritoneum, a swab of the superficial surgical wound was taken for aerobic and anaerobic cultures by routine methods. Drug sensitivities on cultures grown were determined by the Kirby-Bauer disk-diffusion method. Throughout their hospital stay, patients were followed by a registered nurse and a consultant surgeon, neither of whom knew to which group a patient had been assigned and neither of whom was directly responsible for the pa-
343
Brown et al
TABLE I
Patient Profile (Determinate)
Treatment Groups
Total
I: Ticarcillin II: Cephalothin Ill: Placebo Totals
Patients (n) Male Female
59
Age (yr) Average Range
Diabetes
Patients (n) With PI DM Obesity*
Operative Time (hr) Average Range
f:
26 22 15
33 35 21
7-64 17-67 24-86
53.5 47.5 54.4
4 4 4
4 2 0
3 2 2
17 21 12
0.9-6.0 0.6-4.7 0.6-4.3
2.6 2.6 2.4
152
63
a9
7-87
51.5
12
6
7
50
0.8-6.0
2.6
Defined as more than 30 pounds over ideal body weight. DM = disseminated malignancy (carcinomatosis); PI = pharmacologic immunosuppression. l
tient’s care. The attending surgeon examined the patients
during their outpatient follow-up visits during the first 3 to 5 weeks after discharge. Infections and other postoperative complications were monitored continuously throughout the study. When the results were tabulated, 13 patients who had received other antibiotics within 48 hours of operation, 12 patients who had not had an intraabdominal viscus opened, 8 patients who had had delayed primary closure of their wound, 2 patients who had had technical complications making wound evaluation impossible, and 3 patients who had had less than 3 weeks of outpatient follow-up observation were excluded from the definitive (determinate) study group and were placed in an indeterminate group (38 patients). Sixteen of the 38 patients were from the ticarcillin group, 18 from the cephalothin group, and 4 from the placebo group. Data from this indeterminate group were examined separately. All data were analyzed by either the chi-square test or Fisher’s exact probability test.
Results Patient profile: Of the 190 patients enrolled in the
study, 152 were in the determinate group. For those patients, clinical factors that might have influenced the rate of postoperative infection are compared in Table I. The differences between the therapy groups were not significant for any of those factors. Comparisons of the same factors were made between the determinate and the indeterminate patient groups, and again no significant differences were noted. Infectious complications: Surgical infection was defined as the discharge of purulent or culture-positive drainage from the wound or the presence of any intraabdominal pus or abscess. TABLE II
The data were continuously monitored for infection rates. After 120 patients had been included in the study, 10 of 38 patients in the placebo group had developed infections, whereas only 2 of 32 patients in the ticarcillin group and 1 of 29 patients in the cephalothin group had developed infections. Those differences were statistically significant (p 10.05), and the placebo limb of the study was discontinued. At the conclusion of the study, infections had developed in 2 of 59 determinate-group patients and 2 of 16 indeterminate-group patients in the ticarcillin group (5 percent overall), in 3 of 57 determinategroup patients and 2 of 18 indeterminate-group patients in the cephalothin group (7 percent overall), and in 10 of 36 determinate-group patients and 2 of 4 indeterminate-group patients in the placebo group (30 percent overall). Infection rates for all determinate patients were then examined according to the type of operation performed, and those results are presented in Table II. Comparisons of infection rates in patients undergoing gastric segmentation (Roux-Y gastrojejunostomy in morbidly obese patients) and those undergoing colon resection were also made. Infection rates were significantly reduced (p <0.05) when placebo-treated patients (2 of 8) were compared with all antibiotic-treated gastric segmentation patients (0 of 28). In patients who underwent a left colon resection, there was significant reduction (p <0.05) of wound infections in those who received one of the study antibiotics (1 of 34) versus those who were given placebo (2 of 9). When all patients undergoing
Infection Rates for Determinate Patients Group I: Ticarcillin
Gastric segmentation Other gastric operation Right colon Left colon Ostomy closure or revision Small bowel resection Biliary operation Totals
344
Group II: Cephalothin
Group Ill: Placebo
n
00
n
%
n
0111 O/6 o/a 0121 o/5 215 o/3
. ... .. ..
o/17 O/16 O/6 l/l3 l/3 O/l l/l
. . ... . .
218 l/6 l/5 219 415 o/2 O/l
2159 p 10.01
46.
., 3.4
...
3157 p 50.05
a 33 lbb’ 5.3
1O/36
% 25 17 20 22 80
.. .. 27.8
The American Journal of Surgery
Prophylactic
colon resection were examined, there was a similar reduction in wound infections in the placebo-treated patients (3 of 14) and both the cephalothin-treated (1 of 19) and the ticarcillin-treated (0 of 29) patients. A detailed presentation of the 15 patients who developed infection is given in Table III. Of those 15 patients, both operative and postoperative cultures were not available for 4. For six, there was close cor-
TABLE 111 Detailed
Patient
Antibiotics
for Gastrointestinal
Operations
relation between bacteria on the two cultures; for the other five, there was no correlation. Other complications: A total of 35 complications other than wound and peritoneal infections were observed in the determinate group of patients: urinary tract infections (eight patients); atelectasis and pneumonia (seven patients); phlebitis (three patients); gastrointestinal obstruction (four patients, one death); gastrointestinal bleeding (three patients);
Analysis of Infections in Determinate Patients by Treatment Groups
Diagnosis
Operation
Infection (Day First Noted)
Operating Room Culture
Infection Culture
Comments
Group I (Ticarcillin) 1
2
Megaduodenum, chronic bowel obstruction Radiation enteritis
Duodenal resection
Septic shock
Small bowel resection
Peritoneal abscess (23)
(1)
Klebsiella pneumoniae, B. fragilis E. coli, B. fragilis
Klebsiella pneumoniae E. coli, 8. fragilis. Klebsiella pneumoniae
Died (sepsis) 36 hours postoperatively Postoperative short bowel syndrome
Group II (Cephalothin) 3
4
5
Spasm of sphincter of Oddi Ulcerative colitis
Malfunctioning Koch ileostomy
Sphincteroplasty
‘Stitch abscess” (17)
Total proctocolectomy
Pelvic abscess (31)
Revision of ileostomy
Wound and peritoneal abscess (18)
Alpha streptococcus S. epidermidis
B. fragilis, fusobacterium
Not done
Not available
Abscess drained per perineum at another hospital onday
8. fragilis, fusobacterium
Group Ill (Placebo) Proteus mirabilis
Developed ventral hernia
Wound (8)
S. epidermidis, B. fragilis, enterococci No growth
S. aureus, Streptococcus
Wound evisceration
Colostomy closure
Wound (4)
Not done
Right colectomy
wound (20)
Gastric segmentation Closure of colostomy Gastric segmentation
Wound (28)
E. coli, enterococci No growth
E. coli, Proteus mirabilis, enterococci S. epidermidis
6
Diverticulitis
Total abdominal colectomy
Wound (19)
7
Duodenal web
Gastrojejunostomy
8
Colostomy
9 10
Malignant neoplasm Morbid obesity
11
Colostomy
12
Morbid obesity
13
Diverticulitis
14
Colostomy
15
Colostomy
Wound (14) Wound (10)
S. aureus
E. coli, bacillus species S. aureus, alpha and gamma streptococcus S. epidermidis
Not done
S. aureus, B. fragilis, enterococci, clostridia Proteus mirabilis, E. coli, S. aureus,
Total abdominal colectomy Colostomy revision
Wound (5) Wound (3)
B. fragilis, S. epidermidis, enterococci
Colostomy closure
Wound (3)
Enterococci, Proteus mirabilis, E. coli,
S. aureus
S. aureus,
S. aureus
Volume 143. March 1992
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Brown et al
TABLE IV
Organismsisolated in 72 Positive Operating Room Wound Cultures Ticarcillin
Staphylococcus epidermidis Staphylococcus aureus Alpha streptococcus Gamma streptococcus Enterococci E. coli Bacillus species Proteus mirabilis Pseudomonas Klebsiella pneumoniae Enterobacter Diphtheroides Bacteroides fragilis Clostridium Other Totals
Resistant
Sensitive
Resistant
z 4 7 7 1 1 2 0 1 1 5 1 5
3 0 0 0 1 1 0 0 0 2 0 1 2 0 1
4 0 1 0 1 1 0 0 0 1 0 0 1 0 3
47 5 9 4 1 5 1 1 0 3 0 0 2 1 3
1 0 0 0 7 d
90
11
12
82
23
Sensitive
49
42
9” 4 9” 1 1 2 3 1 2 8 1 9 113
pulmonary embolism, gangrenous foot, short bowel syndrome and enterocutaneous fistula (one patient each); and miscellaneous (six patients). Seventeen of those complications occurred in the ticarcillin group, 9 in the cephalothin group and 9 in the placebo group. One patient in the ticarcillin group and one patient in the cephalothin group had two complications each. Deaths: Two patients in the determinate group died, one being the only patient (Case 1, Table III) to die as a result of surgically related sepsis. He was a 63 year old man who had chronic, high grade, partial small bowel obstruction and secondary megaduodenum due to massive adhesions. He was chronically malnourished, and probably had immunosuppression for that reason, although preoperative skin tests had not been done to confirm immunosuppression. The operative time required for lysis of adhesions and duodenal resection was 6 hours, and shortly after completion of the operation disseminated Klebsiella sepsis and shock developed. He died within 36 hours. The second death occurred in a patient in the cephalothin group who underwent right colectomy and required exploration for intestinal obstruction 22 days later. The second operation was performed through the original abdominal wound and there was no evidence of wound or peritoneal infection. The interval between operations was considered to represent a postoperative follow-up sufficient to allow his inclusion in the determinate group, although he died from complications after his second laparotomy. Six of 190 patients died (3.7 percent). In addition to the two determinate-group deaths, four indeterminate-group deaths occurred, one each caused by perioperative myocardial infarction, upper gastrointestinal tract hemorrhage, respiratory insufficiency and aspiration pneumonia.
346
Cephalothin Not Tested
Isolates (n)
0 2 0 1 2 5 0
1
Not Tested
1 0 0 0 1 0 0 0 0 0 0 0 1 0
5 8
Bacteriology: One hundred forty of the 152 determinate patients in the study had a swab of their superficial operative wound taken in the operating room just after closure of the peritoneum or fascia. Of the 54 cultures from the ticarcillin group, 24 (44 percent) were positive for one or more organisms; of the 54 cultures from the cephalothin group, 27 (50 percent) were positive; of the 32 cultures from the placebo group, 21 (66 percent) were positive. Thus, the prophylactic use of broad-spectrum antibiotics reduced the rate of recovery of wound contaminants at the end of the operation, but there was no difference between the two antibiotics tested. Table IV itemizes the organisms isolated in the 72 positive operative wound cultures and the in vitro sensitivities of those organisms to the two antibiotics used in the study. The organisms isolated are those that might be expected after major gastrointestinal procedures, and the in vitro sensitivities closely paralleled those that would be predicted from the known spectra of activities of the drugs. Both of the antibiotics used demonstrated in vitro effectiveness against a majority of the organisms isolated. Results of postoperative cultures of wound, urine, sputum and blood revealed no emergence of strains of bacteria resistant to either ticarcillin or cephalothin. Comments The indications for the use of prophylactic antibiotics have been well documented by Chetlin and Elliott [12], Polk and Lopez-Mayor [I], Stone et al [3] and Griffiths et al [13]. The ideal prophylactic antibiotic would be one that is active against all pathogens that might be anticipated, is incapable of causing the emergence of resistant bacterial strains, and has negligible toxicity to the patient. Obviously, the drug with all of those characteristics does not
TheAmerkan
Journal of Surgery
Prophylactic
exist at present, so the search continues for the best alternatives. Although the spectrum of antibacterial activity remains constant for any given antibiotic, theoretically one can reduce the risks of patient toxicity and the emergence of resistant organisms by shortening the interval over which the antibiotic is given. Stone et al [2] recently reported that cephamandole was as effective in preventing peritoneal and surgical wound infections when it was given in a three dose perioperative prophylactic regimen as it was when given over 3 days; the hospital costs were considerably lower with the shorter course. Our study investigated the ultimate short-term prophylactic administration of a drug: a single dose regimen. Ticarcillin has a very attractive in vitro spectrum of activity for prophylactic use as a single antimicrobial agent in gastrointestinal surgery, and for that reason was chosen for this study. It is effective against most aerobic gram-negative pathogens encountered in bowel surgery and against many strains of Bacteroides fragilis. Klebsiella is probably the most significant fecal pathogen against which ticarcillin is ineffective, and that organism was responsible for the septic complications and death of a high risk patient treated with ticarcillin. Another factor that might have contributed to that death was the combination of a lengthy operation without a second dose of antibiotic being given in a patient who was chronically ill and malnourished. Although the value of cephalothin as a prophylactic antibiotic in gastrointestinal surgery has been questioned by Burdon [5] and Condon [6] and their colleagues, we selected it for use in this study because it was being used extensively for that purpose at the North Carolina Baptist Hospital as well as at many other medical centers [6]. Its use in a three dose regimen was based on the same consideration, as well as on the findings of Polk and Lopez-Mayor [I] and Stone et al [2,3]. Because of the short half-life of this drug, we believe that the use of a large dose at short intervals is an important consideration if cephalothin is used as a prophylactic agent. Both of the drugs chosen were superior to a placebo in the prevention of postoperative wound and peritoneal infections. There was no significant difference in infection rates between the cephalothin-treated and ticarcillin-treated patients. It is noteworthy that ticarcillin exhibited in vitro activity against a slightly higher percentage of the bacterial contaminants isolated from the operative wound at the time of operation (80 versus 73 percent). Of particular interest is the absence of infection in the 34 patients in the ticarcillin group undergoing operation on the colon or closure or revision of a colostomy or ileostomy. The combination of systemic ticarcillin with oral neomycin and erythromycin appears very effective in colon operations and warrants further investigation.
Volume 143, March 1962
Antibiotics
for Gastrointestinal
Operations
Comparison of the drug sensitivities of the organisms isolated from the operating room wound cultures with those isolated from the postoperative infection cultures revealed no evidence of the emergence of resistant bacterial strains. Furthermore, analysis of the sensitivities of the organisms recovered on postoperative cultures of sputum, urine and blood in those patients treated prophylactically with ticarcillin and cephalothin revealed no discernible variations from the expected sensitivities. Thus, neither of the prophylactic treatment regimens appears to predispose to the development of bacterial resistance. Fifteen of the 152 determinate patients developed postoperative wound or peritoneal infections, and an additional 25 patients had a major or minor postoperative surgical complication. Thus, in the determinate patients, the overall rate of infectious complications was 10 percent (15 of 152) and the overall complication rate was 26 percent (40 of 152). No definite conclusions can be drawn from the bacteriologic data from the patients who became infected. It is interesting, however, that in 6 of the 11 patients for whom both organisms from the intraoperative cultures and organisms from the cultures of the subsequent infections can be compared, the results of the wound contaminants present at the end of the procedures would have provided an excellent basis for appropriate antibiotic selection while the final results of the cultures of the infected wounds were awaited. It should also be noted that 8 of the 15 surgical infections were diagnosed between the 14th and the 31st postoperative days, emphasizing the need for an adequate follow-up period in a study of this nature. Summary The effectiveness of ticarcillin (one 6 g dose at the start of the operation) and cephalothin (three 2 g doses given at 4 hour intervals from the start of the operation) as prophylactic antibiotics in operations on the colon, stomach, small bowel or obstructed biliary tract was determined in a prospective, randomized, blind study of 190 patients. Data from the 152 patients forming the definitive study revealed a significant reduction in the rate of wound and peritoneal infections with the use of ticarcillin (3.4 percent) and cephalothin (5.3 percent) over that with the use of a placebo (27.8 percent). Cultures showed no evidence of antibiotic resistance in the contaminant organisms of patients who later developed infections. Both antibiotic regimens offered excellent protection against infection after gastrointestinal operations; neither produced untoward side effects. The very short duration of treatment, particularly with ticarcillin, conferred the additional benefits of low cost, simplicity of drug administration, and negligible risk of the emergence of resistant bacterial strains.
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Brown et al
References 1. Polk HC Jr, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66:97-103. 2. Stone HH, Haney BB, Kolb LD, Geheber CE, Hooper CA. Prophylactic and preventive antibiotic therapy. Timing, duration and economics. Ann Surg 1979;169:691-9. 3. Stone HH, Hooper CA, Kolb LD, Geheber CE, Dawkins EJ. Antibiotic prophylaxis in gastric, biliary and colonic surgery. Ann Surg 1976;164:443-52. 4. Strachan CJL, Black J, Powis SJA, et al. Prophylactic use of cephazolln against wound sepsis after cholecystectomy. Br Med J 1977;1:1254-6. 5. Burdon JGW, Morris PJ, Hunt P, Watts MI. A trial of cephalothin sodium in colon surgery to prevent wound infection. Arch Surg 1977;112:1169-73. 6. Condon RE, Bartlett JG, Nichols RL, Schulte WJ, Gorbach SL, Dchi S. Preoperative prophylactic oephalothin fails to control septic complications of colorectal operations: results of controlled clinical trial. Am J Surg 1979;137:66-74. 7. Rodgers J, Ross D, f&Naught W, Gillespie G. lntrarectal me-
34s
6.
9.
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12. 13.
tronidazole in the prevention of anaerobic infections after emergency appendicectomy: a controlled clinical trial. Br J Surg 1979;66:425-7. Hughes ESR, Hardy KJ, Cuthbertson AM, Rubbo SD. Chemoprophylaxis in large bowel surgery. 1. Effect of intravenous administration of penicillin in incidence of postoperative infection. Med J Aust 1970;1:305-6. Greenall MJ, Bakran A, Pickford IR, et al. A double-blind trial of a single intravenous dose of metronldazole as prophylaxis against wound infection following appendicectomy. Br J Surg 1979;66:426-9. Feathers RS, Lewis AAM, Sagor GR, Amirak ID, Noone P. Prophylactic systemic antibiotics in colorectal surgery. Lancet 1977;2:4-6. Vargish T, Crawford LC, Stallings RA, Wasilauskas BL, Myers RT. A randomized prospective evaluation of orally administered antibiotics in operations on the colon. Surg Gynecol Obstet 1976;146:193-6. Chetlin SH, Elliott DW. Preoperative antibiotics in biliary surgery. Arch Surg 1973;107:319-23. Griffiths DA, Shorey BA, Simpson RA, Speller DCE, Williams NB. Single-dose peroperative antibiotic prophylaxis in gastrointestinal surgery. Lancet 1976;2:325-6.
The American Journal of Surgery