Antibiotic Prophylaxis in Gastric, Biliary and Colonic Surgery H. HARLAN STONE, M.D., C. ANN HOOPER, B.S., B.A., LAURA D. KOLB, B.S., CAROL E. GEHEBER, B.S., E. JANELLE DAWKINS, B.S.
Antibiotic prophylaxis for surgery has appeared indicated whenever likelihood of infection is great or consequences of such are catastrophic. For better clarification, a prospective, randomized, double-blind study was run on 400 patients undergoing elective gastric, biliary, and colonic operations. There were four treatment categories, with antibiotic being instituted 12 hours preoperatively, just prior to operation, after operation, or not at all. During operation, samples of blood, viscera, muscle, and fat were taken for determination of antibiotic concentration. Both aerobic and anaerobic cultures were also taken of any viscus entered, peritoneal cavity, and incision. Similar cultures were run on all postoperative infections. Results demonstrated that the incidence of wound infection could be reduced significantly by the preoperative administration of antibiotic in operations on the stomach (22% to 4%), on the biliary tract (11% to 2%), and large bowel (16% to 6%). Less impressive results were obtained for peritoneal sepsis. Initiation of antibiotic postoperatively gave an almost identical infection rate as if antibiotic had not been given (15% and 16%, respectively).
TrHE VALUE as well as dangers of prophylactic antibiotics has been hotly debated for the past three decades. Lack of concrete data, as might be derived from either rigidly controlled laboratory studies or prospective randomized clinical trials, has by no means limited these arguments. Only the animal experiments of Burke4 and relatively sophisticated clinical trials by Polk,10, Ledger,7 and a few others have given any true insight as to the benefits of such a program.1 3'4'8 9 All other supportive reports have primarily been emotional claims, based upon either poorly or totally uncontrolled scientific evidence. There are, in addition, other advantages that might be gained through the administration of prophylactic antibiotics. Hospital beds possibly could be conserved through a shortened average patient stay. Hospital costs Presented at the Annual Meeting of the American Surgical Association, New Orleans, Louisiana, April 7-9, 1976. Supported in part by a grant from Eli Lilly and Company.
From the Joseph B. Whitehead Department of Surgery, Emory University School of Medicine, 69 Butler St., S.E., Atlanta, Georgia 30303
could then likewise be reduced if less hospital days were consumed and if reoperation for some complicating infection were not as frequently required; while antibiotic use might even be decreased if fewer postoperative infections developed and, especially, if the duration of antibiotic prophylaxis was cut to a bare minimum. Nevertheless, potential harm resulting from routine antibiotic therapy cannot be ignored. Drug toxicity, allergic reactions, and in particular the evolution of resistant bacterial strains certainly appear to be potential if not actual significant threats. Clinical Trial
To evaluate these several aspects of prophylactic antibiotic therapy as well as to confirm the already reported benefits of its application, a prospective randomized and double-blinded study was carried out on the surgical wards of Grady Memorial Hospital. After 20 months (the trial period ending February 29, 1976), 400 consecutive patients admitted for elective operations on the stomach, biliary tract, and/or colon had been enrolled in the study. The only exceptions to inclusion into the study were antibiotic therapy with parenteral or orally absorbable agents during the 10 days immediately preceding operation, conditions present that already demanded antibiotic prophylaxis (i.e., heart valve disease), known allergy to a cephalosporin, and an age of less than two years. Patients undergoing colon surgery, however, did receive 1 gm of oral neomycin every 4 to 6 hours for two days prior to operation as well as 500 mg of erythromycin
443
Ann. Surg. October 1976 STONE AND OTHERS 444 base every 6 hours for 24 hours preoperatively. Routine of the contents of the organ subjected to operation, attempts were made to preclude any consideration of the peritoneal cavity, and the subcutaneous portion of the antibiotic prophylaxis with respect to decision for incision at the time of closure. Sensitivity testing was operation, procedure performed, and general postoper- subsequently run on all aerobic isolates to the 30 mcg ative care. disc of cefazolin.2 o
Antibiotic Administration Each patient was given an intramuscular injection of either antibiotic (I gm of tefazolin) or placebo (equivalent volume of diluent) on the evening before operation, on call to the operating room and on that same evening after return to either the ward or the intensive care unit, on the morning of the day following surgery, and again during the evening of the first postoperative day (Fig. 1). Scaled down doses were used for children, with weight being the prime determinant. The solutions for injection had previously been assembled in patient number packets, so that there were five vials in each pack and each vial was coded as to time when it should be given. Details in randomization were unknown to all concerned with patient care, although the master key was readily available in the event that a possible drug or infectious complication demanded that the code be broken. Drug dosage had been set up so that equal numbers of patients had their prophylactic antibiotic initiated approximately 12 hours preoperatively, one hour prior to operation, or within an hour following completion of the operation (Fig. 1). Twenty-five per cent of the patients received no antibiotic at all. When given, cefazolin was administered in three consecutive injections for a total dose of 3 gms over a period of approximately 24 hours. No other antimicrobial was given thereafter, that is, unless an established infection could be documented or the patient's clinical course became highly suggestive of a developing septic complication.
Sampling During Operation At surgery, 9 specific specimens were taken. An attempt was generally made to obtain all samples within a few minutes of each other. Once the abdomen had been opened, both peripheral as well as portal venous blood were drawn for determination of antibiotic blood levels. Likewise, liquid contents of the organ of operation (gastric juice, bile, and/or colon contents) were obtained for similar analyses of antibiotic concentration. A modified well-diffusion technique was used for these studies.13 Biop§ies of viscera resected as well as abdominal wall muscle and subcutaneous fat were also taken. These specimens were immediately frozen and then sent at intervals to the Lilly Research Laboratories for determination of antibiotic tissue concentration. Finally, both aerobic and anaerobic cultures were taken
Followup Postoperatively, all patients were carefully followed for evidences of infection developing within the abdomen and/or surgical incision. In addition, complicating infections in other areas were specifically noted. Appropriate aerobic and anaerobic cultures were taken from all sites of known as well as even suspected sepsis. Aerobic bacterial isolates were also tested for sensitivity to the prophylactic antibiotic, i.e., cefazolin, at a 30 mcg disc size.2 Complications of drug therapy, other postoperative problems, total as well as postoperative hospital stay, all details related to indications for surgery, type of operation, general status of the patient, and, finally, eventual outcome were faithfully recorded. These items were later used to confirm the purity of the randomization process plus the identification of any significant influence, other than the prophylactic antibiotic, on the incidence of subsequent infection. Results At the completion of the clinical trial, there were 100 patients for analysis in each treatment category. Gastric surgery had been performed on 96, a biliary tract procedure on 131, and colon surgery on 190-thereby giving a total of 417 operations. The extra 17 were accounted for by the fact that these patients had had a surgical procedure carried out in two, rather than just one, area of study. Ages ranged from 2 to 86 years, with an average of 47.6. There were 179 males and 221 females; 312 were Negro, while 88 were Caucasian. No significant difference could be found between the four assigned treatment groups with respect to type of operation, indication for surgery, age, sex, or race. There were four postoperative deaths, three of which occurring in patients who had had two procedures done at the one operation. Otherwise, no major difference was apparent between the several therapy categories.
Antibiotic Distribution
Concentrations of cefazolin were not significantly different when portal was compared to peripheral venous blood (Table 1). The average value was 13.7 mcg/ml. Administration of cefazolin 8 to 12 hours prior to operation gave approximately 40% higher tissue levels
GROUP
GROU
FIG. 1. Times of antibiotic administration. Placebo injections are indicated by an "O"; cefazolin was given at times marked by an "X."
445
ANTIBIOTIC PROPHYLAXIS
Vol. 184oNo. 4
PRE-OP DAY 1
PM-t
l |AM
||AM
x X X 0
0 X X 0
x X 0 0
x 0 0 0
I Ii III IV
POST-OP DAY A
DAY OF OPERATION AM |PM
|PE 0 0 X 0
lactic antibiotic had been started preoperatively (Table 2). Results were much more impressive with procedures on the colon than for operations on the stomach and biliary tract. However, no real difference could be discerned between the two groups receiving preoperative cefazolin, that is, between those patients having such therapy instituted 8 to 12 hours prior to operation and those whose antibiotic was not begun until just an hour before surgery. By contrast, the incidence of peritoneal sepsis was essentially the same as if no antibiotic had been given whenever cefazolin administration had been put off until after operation. Differences in wound infection rate were much more dramatic than were those for intraperitoneal sepsis (Table 3). Overall, there was an almost four-fold greater incidence of infection within the incision when antibiotic was withheld than when such had been given preoperatively. Initiating cefazolin therapy after operation gave approximately the same results as if the parenteral antibiotic had been completely withheld. All of these figures were highly significant (P = .01). As with intraIncidence of Infection peritoneal infection, results obtained in the two preoperThe reduction in incidence of intraperitoneal sepsis ative treatment groups were almost identical. was relatively significant (P = 0.05) whenever prophy-
than if the antibiotic had been started a mere hour preoperatively (Table 1). Concentrations of cefazolin in subcutaneous fat were less than half that of the blood whenever antibiotic therapy had been instituted only an hour before hand. In fact, antibiotic concentrations in fat and in bowel wall were consistently below values discovered in other tissues. Stomach and gallbladder had biologically measurable concentrations of cefazolin in their walls that even surpassed concomitant blood levels, yet such may well have been due to the additive bacteriocidal effect of acid and bile, respectively. Analyses of bile and gastric juice for cefazolin concentrations were undoubtedly spurious because of their already known antimicrobial actions (Table 1). Similarly, the preoperative administration of oral neomycin and erythromycin base may well have accounted for the apparent presence of study antibiotic in colon contents, irrespective as to whether cefazolin had been administered preoperatively or not.
Table 2. Peritoneal Infection Table 1. Distribution of Chefazolin at Operation: Antibiotic Administered Preoperatively Antibiotic Begun
Preoperatively
Operation
8-12 Hours
Peripheral venous blood mcg/ml Portal venous blood mcg/ml Abdominal muscle mcg/gm Subcutaneous fat mcg/gm Gastric secretions mcg/ml Bile mcg/ml Colon contents mcg/ml Stomach wall mcg/gm Gall bladder wall mcg/gm Colon wall mcg/gm
Antibiotic Begun Area of
1
Hour
14.1 13.8 14.0 9.8 14.3 22.5 22.3
13.5 13.4 9.3 6.3 11.2 21.4 20.4
15.9 21.3 11.0
12.9 14.9 9.8
Gastric Infected Incidence Biliary Infected Incidence Colonic Infected Incidence Totals Infected Incidence
8-12 hr Preop
I hr Preop
1-4 hr
Never
Postop
Given
Totals
22
27
24
23
96
1
1
1
2
4%
4%
9%o 38 1 3%
5 5% 131 3 2%
43 3
190 8
5% 29 1
3% 54 1
2% 100 2
2%
31
33
0
1 3% 46 3 7% 100 5 5%
-
47 1 2% 100 2 2%
7% 100 6 5%
4% 400 15 4%
Ann. Surg. E October 1976
STONE AND OTHERS
446
Table 4. Bacterial Contamination and Wound Infection
Table 3. Wound Infection
Operative Culture of Wound
Antibiotic Begun Area of Operation
8-12 hr Preop
Gastric Infected Incidence Biliary Infected Incidence Colonic Infected Incidence Totals Infected Incidence
I hr
Preop 27 1 4% 31 0
22 1 5% 29 1 3% 54 3 6% 100 4 4%
47 3 6% 100 3 3%
1-4 hr Postop
24 4 17% 33 3 9% 46 7 15% 100 14 14%
and Peritoneum
Never Given
23 5 22% 38 4 11% 43 7 16%c 100 15
15%
Totals 96 11 11% 131 8
6% 190 20 11% 400 36 9%
Bacterial Contamination
Exactly half of the patients had positive cultures of the wound and/or peritoneum at the time of operation; and, of these, 35 or 17.5% had Staphylococcus aureus as one of the bacterial contaminants (Table 4). Preoperative antibiotic prophylaxis gave a wound infection rate of only 7% in those patients with culture proven contamination; while postoperative cefazolin administration or no antibiotic treatment at all produced infection rates of 24% and 29%, respectively, for the same degree of bacterial contamination. The incidence of wound infection due to Staphylococcus aureus was similarly affected in both treatment groups by the action of preoperative prophylactic therapy. A striking contrast to this increased incidence of infection was the exceedingly rare development of inci-
Antibiotic Begun
Positive Culture
Preoperative Infected
96 7 7% 55 13
10 3
24%
30%W
49 14
12 3 25%
Incidence
Postoperative Infected Incidence Never given Infected Incidence
Negative
Positive
Culture
Staph.
104 0 0% 45 1
13 1
8%
29%
2% 51 1
2%
sional sepsis when all intraoperative wound as well as peritoneal cultures had been negative (Table 4). Although the majority of bacterial isolates recovered from organs of operation could be classified as gramnegative rods, such species were even more predominant in operations on the colon (Table 5). In addition, anaerobes and Enterococcus were also plentiful in the colonic flora. Antimicrobial sensitivity of the 790 aerobic isolates obtained at operation was 74.8% to the 30 mcg cefazolin disc. On the other hand, the actual and not just potential contaminants (i.e., isolates from the wound and/or peritoneum alone) had a much greater susceptibility to cefazolin (91.2%) (Fig. 2). Aerobic bacteria cultured from all complicating wound and peritoneal infections, however, had sensitivities that averaged only 39% (Table 5 and Fig. 2). The total number of bacteria contaminating the wound also appeared to influence the likelihood of subsequent
TABLE 5. Bacterial Sensitivities to Cefazolin: Testing to 30 mcg Antibiotic Disc. Gastric Isolates Species Isolated
E. coli E. species
Klebsiella-Enterobacter Klebsiella species Proteus mirablis Proteus species Pseudomonas Other G-neg rods
Staph
aureus
B. Streptococcus Enterococcus Misc. aerobes Bacteroides Eubacteria Pepto & Peptostrepto Clostridia Misc. anaerobes
C. albicans *
Sensitivities not
run.
Biliary Isolates
Number
Per cent Sensitive
Number
49 4 6 32 13 8 6 13 24 3 43 4 23 13 17 10 79 3
47 2 5 31 12 1 0 13 24 3 22 4 * * * * * *
31 2 2 13 3 2 0 8 36 1 18 0 6 4 3 5 27 0
Per Cent Sensitive 30 2 2 12 3 0 4 34 1 4
* * * * * *
Colon Isolates
Total Initial
Number
Per Cent Sensitive
Number
159 8 16 58 17 38 21 7 33 2 205 5 52 32 16 21 69 6
137 6 15 54 16 10 0 6 32 2 54 3 * * * * * *
239 14 24 103 33 48 27 28 93 6 266 9 81 49 36 36 175 9
Per Cent Sensitive
90%G 71%
92% 94% 94% 23%
O% 82%
Infection Isolates
Number
Per Cent Sensitive
18 8 8 4 12 7 10 11
61% 38% 75% 50%c 68% 0% 10% 64%o
97% 10%-
22 30%o 78%-
* * * * * *
2 I 1 18 0
9W * * * * * *
447
ANTIBIOTIC PROPHYLAXIS
Vol. 184 a No. 4
no way altered the infection rate when the contaminating bacteria were already resistant to the antimicrobial agent given, i.e., cefazolin. This relationship of number of bacterial species to incidence of complicating infection was dramatically reflected in the culture data as well as the disease process for which gastric operations were done (Table 6). Hyperacidity was associated with a relatively sterile stomach lumen and accordingly resulted in only a single postoperative infection. Such contrasted strikingly to the 30%o average infection rate when surgery was performed for gastric cancer or a benign gastric ulcer.
100 C')
z
cog~ u)E
0
(02 -o 0= L)0020
z
0
0
Cause of Infection
.
1%1*1
Pm-operativ
Post-0pative
Never Given
TIME OF BEGINNING ANTIBIOIlC FIG. 2. Antibiotic sensitivities of the bacterial isolates. Bacterial susceptibility to 30 mcg discs of cefazolin is charted according to time of initiating antibiotic therapy. Shaded bars represent results obtained from taking initial isolates, while the clear bars reflect sensitivities of bacteria cultured from subsequent wound and/or peritoneal infections.
infection (Fig. 3). This was especially true in patients not given preoperative antibiotic or in whom cefazolin administration was delayed until the patient had reached the recovery room. Nevertheless, antibiotic therapy in
All seven of the wound infections occurring in patients who received preoperative antibiotic could be explained, at least on theoretical grounds, by a wound and/or peritoneal contamination by cefazolin-resistant bacteria (Table 7). One of the patients, in addition, had an antibiotic concentration in his subcutaneous fat which might well be deemed insufficient for the control of an inoculum containing otherwise susceptible pathogens. Patients who never received preventative antibiotic or whose antimicrobial therapy was begun in the postoperative phase had infection rates, specifically due to cefazolin-resistant bacteria, that were almost identical to what had been noted for the preoperative treatment groups (Table 7). However, none of the tissues of the late or not-treated patients contained antibiotic-a
80
PREIOPE.pATIV/E CEFA2ZOLIN
I
CEFAZOLIN NEVER OR POST- OPERATIVELY
06O
60 z FIG. 3. Relationship of the number of bacterial species contaminating the incision at the time of wound closure and incidence of subsequent wound infection.
Z 40 0
/
IL
0 0 Z 20 b
o- -o Cefozwin ms=stant
Ir I
I
I
2
I
I
I,
I
sC,n
. I
I
4 5 5+ 4 2 3 1 3 NUMBER OF BACTERIAL SPECIES ISOLATED (from incision at time of closu)
5
5+
Ann.
STONE AND OTHERS
448
TABLE 6. Wound Infection After Gastric Surgery: Influence of Indication for Operation
Duodenal ulcer Gastric ulcer Gastric cancer Pancreatic pseudocyst Other
Number
Infected
Incidence
48 14 13 17 4
1 4 4 1 1
2% 29%o 31% 6% 25%
situation to be expected when cefazolin was not circulating in the blood-and thus provided a plausible explanation for subsequent infection due to cefazolin-susceptible microbes.
Antibiotic Resistance Although 75% of aerobic bacteria colonizing the visceral contents (Table 5) and 91% of aerobic isolates initially obtained from the incision and/or peritoneum (Fig. 2) were sensitive to the action of cefazolin, antibiotic therapy reduced this rate of drug susceptibility to 39o for those bacteria responsible for subsequent wound infection. This was true for all patients receiving preventive therapy, irrespective as to whether the antimicrobial had been started before or after surgery. However, if cefazolin had never been given, the percentage of antibiotic sensitive isolates was approximately the same as had been noted from bacteria initially cultured from the incision and/or abdominal cavity at the time of operation (Fig. 2).
Surg. v October 1976
such infectious complications developing was least for the receiving antibiotic just an hour prior to operation
group
(Table 8). No adverse reactions were noted, either locally or systemically, from the use of cefazolin. Likewise, there was not a single case of drug allergy.
Financial Considerations
Tabulation of the average number of postoperative days required by all patients revealed that an incisional infection was associated with an extra 15.6 hospital days (Table 9). At a per diem rate of $80.00 a day, the minimal additional expenditure for a single wound infection was $12,048.00 per patient, exclusive of all supplemental laboratory tests, drug therapy, and second
operations. If financial considerations were, instead, analyzed according to therapy group, a significantly different pattern became apparent (Table 10). The average excess postoperative stay was 1.5 days for patients beginning cefazolin postoperatively and 2.9 days for those never receiving the antibiotic in comparison to the two preoperative treatment groups. Such additional hospital days increased the total hospital cost by $120.00 and $232.00 per patient, respectively. By contrast, the cost of preventive antibiotic therapy was negligible, that is, only $13.47 per patient.
Discussion Three basic factors, acting singly or in combination, Other Infections appear to be responsible for the development of a The likelihood of infection developing in areas outside postoperative wound infection. These are: 1) a bacterial the wound and peritoneum was not significantly altered inoculum of sufficient numbers as well as of necessary by antibiotic administration, even though the number of virulence; 2) a local substrate upon which the conTABLE 7. Reasons for Postoperative Wound Infection
Antibiotic Begun
Cause/relationships Total number of infections Bacteria resistant to antibiotic Isolates from organ Isolates from peritoneum Isolates from wound Insufficient antibiotic concentration In tissue
Organ Muscle Fat In fluid Juice In blood
Peripheral Portal Other or unknown
8-12 hr
I hr
1-4 hr
Preop
Preop
Postop
Never Given
Totals
4
3
14
15
36
4 4 3
2 3 2
4 3 3
5 6 7
15 16 15
0 0 0
1 0 1
14 14 14
15 15 15
30 29 30
1
1
11
11
24
0 0 1
0 0 1
14 14 2
15 15 1
29 29 5
VOl. 184 . NO. 4
ANTIBIOTIC PROPHYLAXIS
TABLE 8. Infections Outside the Area of Operation
449 TABLE 9. Hospital Economics
Antibiotic Begun
Wound Infection
Area
of Infection
Patients Urinary Pulmonary Bacteremia Other Totals
8-12 hr 1 hr 1-4 hr Never Preop Preop Postop Given 100 10 4 2 I 17
100 12 0 0 1 13
100 7 3 4 4 18
100 7 3 2 5 17
Totals
Incidence
400 36 10 8 11 65
9%O 3% 2% 3% 16%O
taminating microbes can live as well as propagate; and 3) some impairment, be it local or systemic, in host resistance. Preoperative measures, such as intestinal cleansing, antiseptic skin preparation, and operation within a relatively sterile environment represent attempts at reducing the absolute quantity of the bacterial inoculum. However, once contamination has occurred, the size of the inoculum still can be diminished by a careful wound toilet with removal of all gross material and then the selective application of some topical antibiotic."1 On the other hand, creating a wound that is less hospitable to bacterial colonization and thus to subsequent infection is primarily a product of the dedication and ability of the surgeon. It is his technical skill, meticulous attention to detail, and gentle handling of tissues that curbs the amount of clot and cellular necrosis and thus the ready availability of nutrition to any bacterial inoculum. In this setting, the prophylactic role of a parenterally administered antibiotic is merely to increase local tissue resistance against the majority, if not all, of the invading pathogens. This it appears to do quite effectively, even though certain limitations are to be expected and specific requirements must be met. 1'3-5'7-10 Prophylactic antibiotics have been documented to be of considerable value in reducing the incidence of wound infection in several areas of surgery.13'57-10 Many of these claims have true scientific merit and are based upon prospective, randomized trials of antibiotic versus a placebo. Unfortunately, however, there are approximately 50 poorly-founded and retrospectively reviewed "testimonials" for every one controlled and statistically significant study. Without doubt, the hallmark is the report by Polk and Lopez-Mayor.10 Their studies on elective colon surgery demonstrated a highly significant reduction in wound infection rate whenever cephaloridine was given just prior to operation. Later investigators have followed suit and, using the same or entirely different antibiotics, have shown remarkably good results in more distant anatomical areas, such as with operations on the biliary tract,5 hysterectomy,1'7 compound fractures,8 and clean orthopedic surgery.3'9 The one consideration that all
Patients Postop hospital days Average postop days Average excess days Minimal excess cost ($80.00 per diem)
No wound Infection
36 931 25.9 15.6 $1248.00 per patient
364 3736 10.3
authors have stressed, without exception, is that the antimicrobial agent must be started prior to operation. Postoperative initiation of antibiotic therapy has appeared to be of no true benefit in reducing the incidence of wound sepsis, only in making such infectious complications less lethal and perhaps more confined to a given region or compartment.11 At present, prophylactic antibiotic therapy seems indicated whenever: 1) the consequences of wound infection are uniformly disastrous, even though the occurrence of this sepsis is uncommon; 2) the incidence of wound infection is great, yet seldom does it ever threaten life or limb; and 3) the patient has such an extreme impairment in host defense mechanisms that any infection, no matter how minor, has a propensity for becoming systemic and thereby fatal. Accordingly, the benefits to be accrued from a preventive antibiotic program include reductions in both morbidity and mortality. Additional and certainly less humane-sounding advantages are a conservation of hospital bed space and the potential for great savings in moneys to be expended for individual patient care. The application of prophylactic antibiotics to clinical practice should be based solely on need. This can be identified only through an effective hospital surveillance program, whereby operative cases are followed and the incidence of postoperative sepsis for a given surgical procedure is then calculated at relatively frequent intervals.6 However, it must be emphasized that preventive antibiotics can never substitute for excellence in operative skills, patient and procedure selection, thoroughness of postoperative care, and, most important of all, operating room hygiene. TABLE 10. Cost Comparisons
Patients Postop hospital days Average postop days Average excess days Minimal excess cost ($80.00 per diem) Cost of antibiotic Excess expenditure per patient
Preop Antibiotic
Postop Antibiotic
No Antibiotic
200 2113 10.6 Per patient Per patient
100 1208 12.1
1.5 $120.00
100 1346 13.5 2.9 $232.00
$13.47
$13.47
Per patient
$13.47
$133.47
$232.00
450
Ann.
STONE AND OTHERS
Once the need for prophylactic antibiotic has been justified because of a proven significant incidence of wound infection after surgery in a certain area or operation for a specific patient condition, the responsible bacteria must then be tabulated as a part of the same surveillance procedure.6 From such data, plus information available from both the literature as well as the hospital laboratory on antimicrobial sensitivities of these responsible pathogens, several antibiotics can be intelligently evaluated for possible use in a preventive program. Prime considerations are: 1) a reported as well as the individual hospital experience confirming specific antibiotic effectiveness against the anticipated pathogens; 2) lack of toxicity and rare allergic reactions; 3) a tissue distribution that will permit the antimicrobial agent to reach those body areas with a known predilection for postoperative infection and in concentrations known to be effective; 4) an established time/dose/route relationship that will assure antibiotic tissue levels at the time of anticipated contamination4; 5) elimination of all antimicrobial agents which presently serve (or have no immediately available substitute) as first choice antibiotics for the more usual postoperative infections, such as those of the wound or peritoneum; and 6) expected cost of preventive drug therapy for each individual antibiotic under consideration. From such information, a practical selection as to specific antibiotic for a given operation can then be made. In the future, cephalosporins will probably be the single group of drugs most commonly employed, although requirements will indeed vary from hospital to hospital because of entirely different infectious problems to be overcome. Thus, considerable variation in the exact prophylactic antibiotic program should be expected and even encouraged. Nevertheless, it is extremely important that preventive treatment not be abused. Otherwise, surgical skills will deteriorate; and antibiotic-resistant microbes may then become even more dominant in the standard hospital flora than they now are.12
Conclusions Antibiotic prophylaxis against sepsis following elective surgery has appeared indicated whenever likelihood of infection is great or consequences of such, though rare, are catastrophic. For better clarification, the value of preventive antimicrobials was assessed in a prospective, randomized, double-blind study of 400 patients undergoing elective gastric, biliary, and colonic operations. There were four treatment categories, with antibiotic (cefazolin) being instituted: 1) 12 hours preoperatively; 2) just prior to operation; 3) just after operation; or 4) never. The placebo could be distinguished only by breaking the numbered code. During operation, samples of peripheral and portal venous blood, visceral secretions,
Surg. * October 1976
organ resected, abdominal muscle and subcutaneous fat were taken for determination of antibiotic concentration. Both aerobic and anaerobic cultures were also taken of any hollow viscus entered, peritoneal cavity, and abdominal incision at closure. Similar cultures were run on all postoperative infections. Results demonstrated that the incidence of wound infection could be cut significantly by timely administration of prophylactic antibiotic in operations on the stomach (22% to 4%), on the biliary tract (11% to 2%) and large bowel (16% to 6%), all with P values of .01. Less impressive results, though almost as significant (P = 0.05), were obtained for peritoneal sepsis. However, for prophylaxis to be successful, the antibiotic had not only to be effective against anticipated bacterial contaminants, but present in the circulating blood and, more especially, in local tissues at the time of contamination. Indeed, initiation of antibiotic postoperatively gave almost the same wound infection rate as if antibiotic had not been given at all (15% and 16%, respectively). Evolution of antibiotic resistant bacterial strains and greater hospital economy in beds and money were additional important considerations.
References 1. Allen, J. L., Rampone, J. F., and Wheeless, C. R.: Use of a Prophylactic Antibiotic in Elective Major Gynologic Operations. Obstet. Gynecol., 39:218, 1972. 2. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., and Turk, M.: Antibiotic Susceptibility Testing by a Standardized Single Disc Method. Am. J. Clin. Pathol., 45:493, 1966. 3. Boyd, R. J., Burke, J. F., and Colton, T.: A Double-Blind Clinical Trial of Prophylactic Antibiotics in Hip Fractures. J. Bone Joint Surg., 55-A:1251, 1973. 4. Burke, J. F.: The Effective Period of Preventive Antibiotic Action in Experimental Incisions and Dermal Lesions. Surgery, 50:161, 1961. 5. Chetlin, S. H., and Elliott, D. W.: Preoperative Antibiotics in Biliary Surgery. Arch. Surg., 107:319, 1973. 6. Cruse, P. J. E., and Foord, R.: A Five-Year Prospective Study of 23,649 Surgical Wounds. Arch Surg., 107:206, 1973. 7. Ledger, W. J., Sweet, R. L., and Headington, J. T.: Prophylactic
8.
9.
10. 11.
12.
13.
Cephaloridine in the Prevention of Postoperative Pelvic Infections in Premenopausal Women Undergoing Vaginal Hysterectomy. Am. J. Obstet. Gynecol., 115:766, 1973. Patzakis, M. J., Harvey, J. P. and Ivler, D.: The Role of Antibiotics in the Management of Open Fractures. J. Bone Joint Surg., 56-A:532, 1974. Pavel, A., Smith, R. L., Ballard, A., and Larsen, I. J.: Prophylactic Antibiotics in Clean Orthopaedic Surgery. J. Bone Joint Surg., 56-A: 777, 1974. Polk, H. C., Jr., and Lopez-Mayor, J. F.: Postoperative Wound Infection: A Prospective Study of Determinant Factors and Prevention. Surgery, 66:97, 1969. Stone, H. H., and Hester, T. R., Jr.: Incisional and Peritoneal Infection After Emergency Celiotomy. Ann. Surg., 177:669, 1973. Stone, H. H., and Kolb, L. D.: The Evolution and Spread of Gentamicin-Resistant Pseudomonads. J. Trauma, 11:586, 1971. Winters, R. E., Litwack, K. D., and Hewitt, W. L.: Relation Between Dose and Levels of Gentamicin in Blood. J. Infect. Dis., 124; Supplement: 590, 1971.
Antibiotic prophylaxis for surgery has appeared indicated whenever likelihood of infection is great or consequences of such are catastrophic. For better clarification, a prospective, randomized, double-blind study was run on 400 patients undergoing elective gastric, biliary, and colonic operations. There were four treatment categories, with antibiotic being instituted 12 hours preoperatively, just prior to operation, after operation, or not at all. During operation, samples of blood, viscera, muscle, and fat were taken for determination of antibiotic concentration. Both aerobic and anaerobic cultures were also taken of any viscus entered, peritoneal cavity, and incision. Similar cultures were run on all postoperative infections. Results demonstrated that the incidence of wound infection could be reduced significantly by the preoperative administration of antibiotic in operations on the stomach (22% to 4%), on the biliary tract (11% to 2%), and large bowel (16% to 6%). Less impressive results were obtained for peritoneal sepsis. Initiation of antibiotic postoperatively gave an almost identical infection rate as if antibiotic had not been given (15% and 16%, respectively).
TrHE VALUE as well as dangers of prophylactic antibiotics has been hotly debated for the past three decades. Lack of concrete data, as might be derived from either rigidly controlled laboratory studies or prospective randomized clinical trials, has by no means limited these arguments. Only the animal experiments of Burke4 and relatively sophisticated clinical trials by Polk,10, Ledger,7 and a few others have given any true insight as to the benefits of such a program.1 3'4'8 9 All other supportive reports have primarily been emotional claims, based upon either poorly or totally uncontrolled scientific evidence. There are, in addition, other advantages that might be gained through the administration of prophylactic antibiotics. Hospital beds possibly could be conserved through a shortened average patient stay. Hospital costs Presented at the Annual Meeting of the American Surgical Association, New Orleans, Louisiana, April 7-9, 1976. Supported in part by a grant from Eli Lilly and Company.
From the Joseph B. Whitehead Department of Surgery, Emory University School of Medicine, 69 Butler St., S.E., Atlanta, Georgia 30303
could then likewise be reduced if less hospital days were consumed and if reoperation for some complicating infection were not as frequently required; while antibiotic use might even be decreased if fewer postoperative infections developed and, especially, if the duration of antibiotic prophylaxis was cut to a bare minimum. Nevertheless, potential harm resulting from routine antibiotic therapy cannot be ignored. Drug toxicity, allergic reactions, and in particular the evolution of resistant bacterial strains certainly appear to be potential if not actual significant threats. Clinical Trial
To evaluate these several aspects of prophylactic antibiotic therapy as well as to confirm the already reported benefits of its application, a prospective randomized and double-blinded study was carried out on the surgical wards of Grady Memorial Hospital. After 20 months (the trial period ending February 29, 1976), 400 consecutive patients admitted for elective operations on the stomach, biliary tract, and/or colon had been enrolled in the study. The only exceptions to inclusion into the study were antibiotic therapy with parenteral or orally absorbable agents during the 10 days immediately preceding operation, conditions present that already demanded antibiotic prophylaxis (i.e., heart valve disease), known allergy to a cephalosporin, and an age of less than two years. Patients undergoing colon surgery, however, did receive 1 gm of oral neomycin every 4 to 6 hours for two days prior to operation as well as 500 mg of erythromycin
443
Ann. Surg. October 1976 STONE AND OTHERS 444 base every 6 hours for 24 hours preoperatively. Routine of the contents of the organ subjected to operation, attempts were made to preclude any consideration of the peritoneal cavity, and the subcutaneous portion of the antibiotic prophylaxis with respect to decision for incision at the time of closure. Sensitivity testing was operation, procedure performed, and general postoper- subsequently run on all aerobic isolates to the 30 mcg ative care. disc of cefazolin.2 o
Antibiotic Administration Each patient was given an intramuscular injection of either antibiotic (I gm of tefazolin) or placebo (equivalent volume of diluent) on the evening before operation, on call to the operating room and on that same evening after return to either the ward or the intensive care unit, on the morning of the day following surgery, and again during the evening of the first postoperative day (Fig. 1). Scaled down doses were used for children, with weight being the prime determinant. The solutions for injection had previously been assembled in patient number packets, so that there were five vials in each pack and each vial was coded as to time when it should be given. Details in randomization were unknown to all concerned with patient care, although the master key was readily available in the event that a possible drug or infectious complication demanded that the code be broken. Drug dosage had been set up so that equal numbers of patients had their prophylactic antibiotic initiated approximately 12 hours preoperatively, one hour prior to operation, or within an hour following completion of the operation (Fig. 1). Twenty-five per cent of the patients received no antibiotic at all. When given, cefazolin was administered in three consecutive injections for a total dose of 3 gms over a period of approximately 24 hours. No other antimicrobial was given thereafter, that is, unless an established infection could be documented or the patient's clinical course became highly suggestive of a developing septic complication.
Sampling During Operation At surgery, 9 specific specimens were taken. An attempt was generally made to obtain all samples within a few minutes of each other. Once the abdomen had been opened, both peripheral as well as portal venous blood were drawn for determination of antibiotic blood levels. Likewise, liquid contents of the organ of operation (gastric juice, bile, and/or colon contents) were obtained for similar analyses of antibiotic concentration. A modified well-diffusion technique was used for these studies.13 Biop§ies of viscera resected as well as abdominal wall muscle and subcutaneous fat were also taken. These specimens were immediately frozen and then sent at intervals to the Lilly Research Laboratories for determination of antibiotic tissue concentration. Finally, both aerobic and anaerobic cultures were taken
Followup Postoperatively, all patients were carefully followed for evidences of infection developing within the abdomen and/or surgical incision. In addition, complicating infections in other areas were specifically noted. Appropriate aerobic and anaerobic cultures were taken from all sites of known as well as even suspected sepsis. Aerobic bacterial isolates were also tested for sensitivity to the prophylactic antibiotic, i.e., cefazolin, at a 30 mcg disc size.2 Complications of drug therapy, other postoperative problems, total as well as postoperative hospital stay, all details related to indications for surgery, type of operation, general status of the patient, and, finally, eventual outcome were faithfully recorded. These items were later used to confirm the purity of the randomization process plus the identification of any significant influence, other than the prophylactic antibiotic, on the incidence of subsequent infection. Results At the completion of the clinical trial, there were 100 patients for analysis in each treatment category. Gastric surgery had been performed on 96, a biliary tract procedure on 131, and colon surgery on 190-thereby giving a total of 417 operations. The extra 17 were accounted for by the fact that these patients had had a surgical procedure carried out in two, rather than just one, area of study. Ages ranged from 2 to 86 years, with an average of 47.6. There were 179 males and 221 females; 312 were Negro, while 88 were Caucasian. No significant difference could be found between the four assigned treatment groups with respect to type of operation, indication for surgery, age, sex, or race. There were four postoperative deaths, three of which occurring in patients who had had two procedures done at the one operation. Otherwise, no major difference was apparent between the several therapy categories.
Antibiotic Distribution
Concentrations of cefazolin were not significantly different when portal was compared to peripheral venous blood (Table 1). The average value was 13.7 mcg/ml. Administration of cefazolin 8 to 12 hours prior to operation gave approximately 40% higher tissue levels
GROUP
GROU
FIG. 1. Times of antibiotic administration. Placebo injections are indicated by an "O"; cefazolin was given at times marked by an "X."
445
ANTIBIOTIC PROPHYLAXIS
Vol. 184oNo. 4
PRE-OP DAY 1
PM-t
l |AM
||AM
x X X 0
0 X X 0
x X 0 0
x 0 0 0
I Ii III IV
POST-OP DAY A
DAY OF OPERATION AM |PM
|PE 0 0 X 0
lactic antibiotic had been started preoperatively (Table 2). Results were much more impressive with procedures on the colon than for operations on the stomach and biliary tract. However, no real difference could be discerned between the two groups receiving preoperative cefazolin, that is, between those patients having such therapy instituted 8 to 12 hours prior to operation and those whose antibiotic was not begun until just an hour before surgery. By contrast, the incidence of peritoneal sepsis was essentially the same as if no antibiotic had been given whenever cefazolin administration had been put off until after operation. Differences in wound infection rate were much more dramatic than were those for intraperitoneal sepsis (Table 3). Overall, there was an almost four-fold greater incidence of infection within the incision when antibiotic was withheld than when such had been given preoperatively. Initiating cefazolin therapy after operation gave approximately the same results as if the parenteral antibiotic had been completely withheld. All of these figures were highly significant (P = .01). As with intraIncidence of Infection peritoneal infection, results obtained in the two preoperThe reduction in incidence of intraperitoneal sepsis ative treatment groups were almost identical. was relatively significant (P = 0.05) whenever prophy-
than if the antibiotic had been started a mere hour preoperatively (Table 1). Concentrations of cefazolin in subcutaneous fat were less than half that of the blood whenever antibiotic therapy had been instituted only an hour before hand. In fact, antibiotic concentrations in fat and in bowel wall were consistently below values discovered in other tissues. Stomach and gallbladder had biologically measurable concentrations of cefazolin in their walls that even surpassed concomitant blood levels, yet such may well have been due to the additive bacteriocidal effect of acid and bile, respectively. Analyses of bile and gastric juice for cefazolin concentrations were undoubtedly spurious because of their already known antimicrobial actions (Table 1). Similarly, the preoperative administration of oral neomycin and erythromycin base may well have accounted for the apparent presence of study antibiotic in colon contents, irrespective as to whether cefazolin had been administered preoperatively or not.
Table 2. Peritoneal Infection Table 1. Distribution of Chefazolin at Operation: Antibiotic Administered Preoperatively Antibiotic Begun
Preoperatively
Operation
8-12 Hours
Peripheral venous blood mcg/ml Portal venous blood mcg/ml Abdominal muscle mcg/gm Subcutaneous fat mcg/gm Gastric secretions mcg/ml Bile mcg/ml Colon contents mcg/ml Stomach wall mcg/gm Gall bladder wall mcg/gm Colon wall mcg/gm
Antibiotic Begun Area of
1
Hour
14.1 13.8 14.0 9.8 14.3 22.5 22.3
13.5 13.4 9.3 6.3 11.2 21.4 20.4
15.9 21.3 11.0
12.9 14.9 9.8
Gastric Infected Incidence Biliary Infected Incidence Colonic Infected Incidence Totals Infected Incidence
8-12 hr Preop
I hr Preop
1-4 hr
Never
Postop
Given
Totals
22
27
24
23
96
1
1
1
2
4%
4%
9%o 38 1 3%
5 5% 131 3 2%
43 3
190 8
5% 29 1
3% 54 1
2% 100 2
2%
31
33
0
1 3% 46 3 7% 100 5 5%
-
47 1 2% 100 2 2%
7% 100 6 5%
4% 400 15 4%
Ann. Surg. E October 1976
STONE AND OTHERS
446
Table 4. Bacterial Contamination and Wound Infection
Table 3. Wound Infection
Operative Culture of Wound
Antibiotic Begun Area of Operation
8-12 hr Preop
Gastric Infected Incidence Biliary Infected Incidence Colonic Infected Incidence Totals Infected Incidence
I hr
Preop 27 1 4% 31 0
22 1 5% 29 1 3% 54 3 6% 100 4 4%
47 3 6% 100 3 3%
1-4 hr Postop
24 4 17% 33 3 9% 46 7 15% 100 14 14%
and Peritoneum
Never Given
23 5 22% 38 4 11% 43 7 16%c 100 15
15%
Totals 96 11 11% 131 8
6% 190 20 11% 400 36 9%
Bacterial Contamination
Exactly half of the patients had positive cultures of the wound and/or peritoneum at the time of operation; and, of these, 35 or 17.5% had Staphylococcus aureus as one of the bacterial contaminants (Table 4). Preoperative antibiotic prophylaxis gave a wound infection rate of only 7% in those patients with culture proven contamination; while postoperative cefazolin administration or no antibiotic treatment at all produced infection rates of 24% and 29%, respectively, for the same degree of bacterial contamination. The incidence of wound infection due to Staphylococcus aureus was similarly affected in both treatment groups by the action of preoperative prophylactic therapy. A striking contrast to this increased incidence of infection was the exceedingly rare development of inci-
Antibiotic Begun
Positive Culture
Preoperative Infected
96 7 7% 55 13
10 3
24%
30%W
49 14
12 3 25%
Incidence
Postoperative Infected Incidence Never given Infected Incidence
Negative
Positive
Culture
Staph.
104 0 0% 45 1
13 1
8%
29%
2% 51 1
2%
sional sepsis when all intraoperative wound as well as peritoneal cultures had been negative (Table 4). Although the majority of bacterial isolates recovered from organs of operation could be classified as gramnegative rods, such species were even more predominant in operations on the colon (Table 5). In addition, anaerobes and Enterococcus were also plentiful in the colonic flora. Antimicrobial sensitivity of the 790 aerobic isolates obtained at operation was 74.8% to the 30 mcg cefazolin disc. On the other hand, the actual and not just potential contaminants (i.e., isolates from the wound and/or peritoneum alone) had a much greater susceptibility to cefazolin (91.2%) (Fig. 2). Aerobic bacteria cultured from all complicating wound and peritoneal infections, however, had sensitivities that averaged only 39% (Table 5 and Fig. 2). The total number of bacteria contaminating the wound also appeared to influence the likelihood of subsequent
TABLE 5. Bacterial Sensitivities to Cefazolin: Testing to 30 mcg Antibiotic Disc. Gastric Isolates Species Isolated
E. coli E. species
Klebsiella-Enterobacter Klebsiella species Proteus mirablis Proteus species Pseudomonas Other G-neg rods
Staph
aureus
B. Streptococcus Enterococcus Misc. aerobes Bacteroides Eubacteria Pepto & Peptostrepto Clostridia Misc. anaerobes
C. albicans *
Sensitivities not
run.
Biliary Isolates
Number
Per cent Sensitive
Number
49 4 6 32 13 8 6 13 24 3 43 4 23 13 17 10 79 3
47 2 5 31 12 1 0 13 24 3 22 4 * * * * * *
31 2 2 13 3 2 0 8 36 1 18 0 6 4 3 5 27 0
Per Cent Sensitive 30 2 2 12 3 0 4 34 1 4
* * * * * *
Colon Isolates
Total Initial
Number
Per Cent Sensitive
Number
159 8 16 58 17 38 21 7 33 2 205 5 52 32 16 21 69 6
137 6 15 54 16 10 0 6 32 2 54 3 * * * * * *
239 14 24 103 33 48 27 28 93 6 266 9 81 49 36 36 175 9
Per Cent Sensitive
90%G 71%
92% 94% 94% 23%
O% 82%
Infection Isolates
Number
Per Cent Sensitive
18 8 8 4 12 7 10 11
61% 38% 75% 50%c 68% 0% 10% 64%o
97% 10%-
22 30%o 78%-
* * * * * *
2 I 1 18 0
9W * * * * * *
447
ANTIBIOTIC PROPHYLAXIS
Vol. 184 a No. 4
no way altered the infection rate when the contaminating bacteria were already resistant to the antimicrobial agent given, i.e., cefazolin. This relationship of number of bacterial species to incidence of complicating infection was dramatically reflected in the culture data as well as the disease process for which gastric operations were done (Table 6). Hyperacidity was associated with a relatively sterile stomach lumen and accordingly resulted in only a single postoperative infection. Such contrasted strikingly to the 30%o average infection rate when surgery was performed for gastric cancer or a benign gastric ulcer.
100 C')
z
cog~ u)E
0
(02 -o 0= L)0020
z
0
0
Cause of Infection
.
1%1*1
Pm-operativ
Post-0pative
Never Given
TIME OF BEGINNING ANTIBIOIlC FIG. 2. Antibiotic sensitivities of the bacterial isolates. Bacterial susceptibility to 30 mcg discs of cefazolin is charted according to time of initiating antibiotic therapy. Shaded bars represent results obtained from taking initial isolates, while the clear bars reflect sensitivities of bacteria cultured from subsequent wound and/or peritoneal infections.
infection (Fig. 3). This was especially true in patients not given preoperative antibiotic or in whom cefazolin administration was delayed until the patient had reached the recovery room. Nevertheless, antibiotic therapy in
All seven of the wound infections occurring in patients who received preoperative antibiotic could be explained, at least on theoretical grounds, by a wound and/or peritoneal contamination by cefazolin-resistant bacteria (Table 7). One of the patients, in addition, had an antibiotic concentration in his subcutaneous fat which might well be deemed insufficient for the control of an inoculum containing otherwise susceptible pathogens. Patients who never received preventative antibiotic or whose antimicrobial therapy was begun in the postoperative phase had infection rates, specifically due to cefazolin-resistant bacteria, that were almost identical to what had been noted for the preoperative treatment groups (Table 7). However, none of the tissues of the late or not-treated patients contained antibiotic-a
80
PREIOPE.pATIV/E CEFA2ZOLIN
I
CEFAZOLIN NEVER OR POST- OPERATIVELY
06O
60 z FIG. 3. Relationship of the number of bacterial species contaminating the incision at the time of wound closure and incidence of subsequent wound infection.
Z 40 0
/
IL
0 0 Z 20 b
o- -o Cefozwin ms=stant
Ir I
I
I
2
I
I
I,
I
sC,n
. I
I
4 5 5+ 4 2 3 1 3 NUMBER OF BACTERIAL SPECIES ISOLATED (from incision at time of closu)
5
5+
Ann.
STONE AND OTHERS
448
TABLE 6. Wound Infection After Gastric Surgery: Influence of Indication for Operation
Duodenal ulcer Gastric ulcer Gastric cancer Pancreatic pseudocyst Other
Number
Infected
Incidence
48 14 13 17 4
1 4 4 1 1
2% 29%o 31% 6% 25%
situation to be expected when cefazolin was not circulating in the blood-and thus provided a plausible explanation for subsequent infection due to cefazolin-susceptible microbes.
Antibiotic Resistance Although 75% of aerobic bacteria colonizing the visceral contents (Table 5) and 91% of aerobic isolates initially obtained from the incision and/or peritoneum (Fig. 2) were sensitive to the action of cefazolin, antibiotic therapy reduced this rate of drug susceptibility to 39o for those bacteria responsible for subsequent wound infection. This was true for all patients receiving preventive therapy, irrespective as to whether the antimicrobial had been started before or after surgery. However, if cefazolin had never been given, the percentage of antibiotic sensitive isolates was approximately the same as had been noted from bacteria initially cultured from the incision and/or abdominal cavity at the time of operation (Fig. 2).
Surg. v October 1976
such infectious complications developing was least for the receiving antibiotic just an hour prior to operation
group
(Table 8). No adverse reactions were noted, either locally or systemically, from the use of cefazolin. Likewise, there was not a single case of drug allergy.
Financial Considerations
Tabulation of the average number of postoperative days required by all patients revealed that an incisional infection was associated with an extra 15.6 hospital days (Table 9). At a per diem rate of $80.00 a day, the minimal additional expenditure for a single wound infection was $12,048.00 per patient, exclusive of all supplemental laboratory tests, drug therapy, and second
operations. If financial considerations were, instead, analyzed according to therapy group, a significantly different pattern became apparent (Table 10). The average excess postoperative stay was 1.5 days for patients beginning cefazolin postoperatively and 2.9 days for those never receiving the antibiotic in comparison to the two preoperative treatment groups. Such additional hospital days increased the total hospital cost by $120.00 and $232.00 per patient, respectively. By contrast, the cost of preventive antibiotic therapy was negligible, that is, only $13.47 per patient.
Discussion Three basic factors, acting singly or in combination, Other Infections appear to be responsible for the development of a The likelihood of infection developing in areas outside postoperative wound infection. These are: 1) a bacterial the wound and peritoneum was not significantly altered inoculum of sufficient numbers as well as of necessary by antibiotic administration, even though the number of virulence; 2) a local substrate upon which the conTABLE 7. Reasons for Postoperative Wound Infection
Antibiotic Begun
Cause/relationships Total number of infections Bacteria resistant to antibiotic Isolates from organ Isolates from peritoneum Isolates from wound Insufficient antibiotic concentration In tissue
Organ Muscle Fat In fluid Juice In blood
Peripheral Portal Other or unknown
8-12 hr
I hr
1-4 hr
Preop
Preop
Postop
Never Given
Totals
4
3
14
15
36
4 4 3
2 3 2
4 3 3
5 6 7
15 16 15
0 0 0
1 0 1
14 14 14
15 15 15
30 29 30
1
1
11
11
24
0 0 1
0 0 1
14 14 2
15 15 1
29 29 5
VOl. 184 . NO. 4
ANTIBIOTIC PROPHYLAXIS
TABLE 8. Infections Outside the Area of Operation
449 TABLE 9. Hospital Economics
Antibiotic Begun
Wound Infection
Area
of Infection
Patients Urinary Pulmonary Bacteremia Other Totals
8-12 hr 1 hr 1-4 hr Never Preop Preop Postop Given 100 10 4 2 I 17
100 12 0 0 1 13
100 7 3 4 4 18
100 7 3 2 5 17
Totals
Incidence
400 36 10 8 11 65
9%O 3% 2% 3% 16%O
taminating microbes can live as well as propagate; and 3) some impairment, be it local or systemic, in host resistance. Preoperative measures, such as intestinal cleansing, antiseptic skin preparation, and operation within a relatively sterile environment represent attempts at reducing the absolute quantity of the bacterial inoculum. However, once contamination has occurred, the size of the inoculum still can be diminished by a careful wound toilet with removal of all gross material and then the selective application of some topical antibiotic."1 On the other hand, creating a wound that is less hospitable to bacterial colonization and thus to subsequent infection is primarily a product of the dedication and ability of the surgeon. It is his technical skill, meticulous attention to detail, and gentle handling of tissues that curbs the amount of clot and cellular necrosis and thus the ready availability of nutrition to any bacterial inoculum. In this setting, the prophylactic role of a parenterally administered antibiotic is merely to increase local tissue resistance against the majority, if not all, of the invading pathogens. This it appears to do quite effectively, even though certain limitations are to be expected and specific requirements must be met. 1'3-5'7-10 Prophylactic antibiotics have been documented to be of considerable value in reducing the incidence of wound infection in several areas of surgery.13'57-10 Many of these claims have true scientific merit and are based upon prospective, randomized trials of antibiotic versus a placebo. Unfortunately, however, there are approximately 50 poorly-founded and retrospectively reviewed "testimonials" for every one controlled and statistically significant study. Without doubt, the hallmark is the report by Polk and Lopez-Mayor.10 Their studies on elective colon surgery demonstrated a highly significant reduction in wound infection rate whenever cephaloridine was given just prior to operation. Later investigators have followed suit and, using the same or entirely different antibiotics, have shown remarkably good results in more distant anatomical areas, such as with operations on the biliary tract,5 hysterectomy,1'7 compound fractures,8 and clean orthopedic surgery.3'9 The one consideration that all
Patients Postop hospital days Average postop days Average excess days Minimal excess cost ($80.00 per diem)
No wound Infection
36 931 25.9 15.6 $1248.00 per patient
364 3736 10.3
authors have stressed, without exception, is that the antimicrobial agent must be started prior to operation. Postoperative initiation of antibiotic therapy has appeared to be of no true benefit in reducing the incidence of wound sepsis, only in making such infectious complications less lethal and perhaps more confined to a given region or compartment.11 At present, prophylactic antibiotic therapy seems indicated whenever: 1) the consequences of wound infection are uniformly disastrous, even though the occurrence of this sepsis is uncommon; 2) the incidence of wound infection is great, yet seldom does it ever threaten life or limb; and 3) the patient has such an extreme impairment in host defense mechanisms that any infection, no matter how minor, has a propensity for becoming systemic and thereby fatal. Accordingly, the benefits to be accrued from a preventive antibiotic program include reductions in both morbidity and mortality. Additional and certainly less humane-sounding advantages are a conservation of hospital bed space and the potential for great savings in moneys to be expended for individual patient care. The application of prophylactic antibiotics to clinical practice should be based solely on need. This can be identified only through an effective hospital surveillance program, whereby operative cases are followed and the incidence of postoperative sepsis for a given surgical procedure is then calculated at relatively frequent intervals.6 However, it must be emphasized that preventive antibiotics can never substitute for excellence in operative skills, patient and procedure selection, thoroughness of postoperative care, and, most important of all, operating room hygiene. TABLE 10. Cost Comparisons
Patients Postop hospital days Average postop days Average excess days Minimal excess cost ($80.00 per diem) Cost of antibiotic Excess expenditure per patient
Preop Antibiotic
Postop Antibiotic
No Antibiotic
200 2113 10.6 Per patient Per patient
100 1208 12.1
1.5 $120.00
100 1346 13.5 2.9 $232.00
$13.47
$13.47
Per patient
$13.47
$133.47
$232.00
450
Ann.
STONE AND OTHERS
Once the need for prophylactic antibiotic has been justified because of a proven significant incidence of wound infection after surgery in a certain area or operation for a specific patient condition, the responsible bacteria must then be tabulated as a part of the same surveillance procedure.6 From such data, plus information available from both the literature as well as the hospital laboratory on antimicrobial sensitivities of these responsible pathogens, several antibiotics can be intelligently evaluated for possible use in a preventive program. Prime considerations are: 1) a reported as well as the individual hospital experience confirming specific antibiotic effectiveness against the anticipated pathogens; 2) lack of toxicity and rare allergic reactions; 3) a tissue distribution that will permit the antimicrobial agent to reach those body areas with a known predilection for postoperative infection and in concentrations known to be effective; 4) an established time/dose/route relationship that will assure antibiotic tissue levels at the time of anticipated contamination4; 5) elimination of all antimicrobial agents which presently serve (or have no immediately available substitute) as first choice antibiotics for the more usual postoperative infections, such as those of the wound or peritoneum; and 6) expected cost of preventive drug therapy for each individual antibiotic under consideration. From such information, a practical selection as to specific antibiotic for a given operation can then be made. In the future, cephalosporins will probably be the single group of drugs most commonly employed, although requirements will indeed vary from hospital to hospital because of entirely different infectious problems to be overcome. Thus, considerable variation in the exact prophylactic antibiotic program should be expected and even encouraged. Nevertheless, it is extremely important that preventive treatment not be abused. Otherwise, surgical skills will deteriorate; and antibiotic-resistant microbes may then become even more dominant in the standard hospital flora than they now are.12
Conclusions Antibiotic prophylaxis against sepsis following elective surgery has appeared indicated whenever likelihood of infection is great or consequences of such, though rare, are catastrophic. For better clarification, the value of preventive antimicrobials was assessed in a prospective, randomized, double-blind study of 400 patients undergoing elective gastric, biliary, and colonic operations. There were four treatment categories, with antibiotic (cefazolin) being instituted: 1) 12 hours preoperatively; 2) just prior to operation; 3) just after operation; or 4) never. The placebo could be distinguished only by breaking the numbered code. During operation, samples of peripheral and portal venous blood, visceral secretions,
Surg. * October 1976
organ resected, abdominal muscle and subcutaneous fat were taken for determination of antibiotic concentration. Both aerobic and anaerobic cultures were also taken of any hollow viscus entered, peritoneal cavity, and abdominal incision at closure. Similar cultures were run on all postoperative infections. Results demonstrated that the incidence of wound infection could be cut significantly by timely administration of prophylactic antibiotic in operations on the stomach (22% to 4%), on the biliary tract (11% to 2%) and large bowel (16% to 6%), all with P values of .01. Less impressive results, though almost as significant (P = 0.05), were obtained for peritoneal sepsis. However, for prophylaxis to be successful, the antibiotic had not only to be effective against anticipated bacterial contaminants, but present in the circulating blood and, more especially, in local tissues at the time of contamination. Indeed, initiation of antibiotic postoperatively gave almost the same wound infection rate as if antibiotic had not been given at all (15% and 16%, respectively). Evolution of antibiotic resistant bacterial strains and greater hospital economy in beds and money were additional important considerations.
References 1. Allen, J. L., Rampone, J. F., and Wheeless, C. R.: Use of a Prophylactic Antibiotic in Elective Major Gynologic Operations. Obstet. Gynecol., 39:218, 1972. 2. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., and Turk, M.: Antibiotic Susceptibility Testing by a Standardized Single Disc Method. Am. J. Clin. Pathol., 45:493, 1966. 3. Boyd, R. J., Burke, J. F., and Colton, T.: A Double-Blind Clinical Trial of Prophylactic Antibiotics in Hip Fractures. J. Bone Joint Surg., 55-A:1251, 1973. 4. Burke, J. F.: The Effective Period of Preventive Antibiotic Action in Experimental Incisions and Dermal Lesions. Surgery, 50:161, 1961. 5. Chetlin, S. H., and Elliott, D. W.: Preoperative Antibiotics in Biliary Surgery. Arch. Surg., 107:319, 1973. 6. Cruse, P. J. E., and Foord, R.: A Five-Year Prospective Study of 23,649 Surgical Wounds. Arch Surg., 107:206, 1973. 7. Ledger, W. J., Sweet, R. L., and Headington, J. T.: Prophylactic
8.
9.
10. 11.
12.
13.
Cephaloridine in the Prevention of Postoperative Pelvic Infections in Premenopausal Women Undergoing Vaginal Hysterectomy. Am. J. Obstet. Gynecol., 115:766, 1973. Patzakis, M. J., Harvey, J. P. and Ivler, D.: The Role of Antibiotics in the Management of Open Fractures. J. Bone Joint Surg., 56-A:532, 1974. Pavel, A., Smith, R. L., Ballard, A., and Larsen, I. J.: Prophylactic Antibiotics in Clean Orthopaedic Surgery. J. Bone Joint Surg., 56-A: 777, 1974. Polk, H. C., Jr., and Lopez-Mayor, J. F.: Postoperative Wound Infection: A Prospective Study of Determinant Factors and Prevention. Surgery, 66:97, 1969. Stone, H. H., and Hester, T. R., Jr.: Incisional and Peritoneal Infection After Emergency Celiotomy. Ann. Surg., 177:669, 1973. Stone, H. H., and Kolb, L. D.: The Evolution and Spread of Gentamicin-Resistant Pseudomonads. J. Trauma, 11:586, 1971. Winters, R. E., Litwack, K. D., and Hewitt, W. L.: Relation Between Dose and Levels of Gentamicin in Blood. J. Infect. Dis., 124; Supplement: 590, 1971.
