- Email: [email protected]
Antibiotic prophylaxis with cefotaxime in gastroduodenal and biliary surgery
Antibiotic Prophylaxis with Cefotaxime in Castroduodenal and Biliary Surgery Jose Angel Garcia-Rodriguez, MD, Salamanca,Spain, Jorge Puig-LaCalle, MD, Catalina Arnau, PIID, Miquel Porta, MD, Carlos Vallve, MD, Barcelona,Spain
In a multicenter prospective, randomized study, the efficacy of a single preoperative dose of 1 g of cefotaxime for avoiding wound infections was compared with four 2-g doses of cefoxitin. In the study, 1,451 patients with infection risk factors who underwent gastroduodenal or biliary surgery were included, of whom 722 received cefotaxime and 729 cefoxitin. The characteristics of both groups were comparable. The frequency of wound infectious in the cefotaxime group was 3.3 percent and in the cefoxitin group, 7.6 percent. The difference was statistically significant. The lowest rate of wound infection (0.63 percent) was achieved when cefotaxime was administered during the last hour before surgery. In both groups, the frequency of infections was directly related to the duration of operation. Hospital stay was, on average, 3 days longer in patients with wound infections. After cost-benefit analysis, we have concluded that cefotaxime treatment results in substantial reduction of costs derived from antibiotic prophylaxis.
I
n a recent prospective study, surgical wound infections accounted for 3.2 percent of clean wounds; the incidence increased to 5.1 percent in patients requiring emergency operations and to 7.8 percent in conditions thought to predispose to infection [I]. In gastroduodenal and biliary surgery, the prophylactic administration of a betalactam antibiotic is considered adequate when infection risk factors are present. Cefoxitin is the most widely used cefalosporin for this indication. Nevertheless, since after the National Nosocomial Infection Study [2], gram-negative organisms and anaerobes now constitute 70 percent of the pathogens responsible for this complications, the From the Department of Microbiology, University of Salamanca, Salamanna, Spain, the Department of General Surgery, Hospital de San Pablo, Barcelona, Spain; and the Institut Municipal d’Investigaci6 MMica, Universitat Aut6noma de Barcelona, Barcelona, Spain. Requests for reprints should be addressed to CarlcxsVallv6, MD, Travessera de Gracia, 47-49,08021-Barcelona, Spain. Partially presented at the 17th National Congress of Surgery, Madrid, Spain, November 6-9, 1988. Supported in part by Hoe&t Ib& ica, S.A., Barcelona and Roussel Ib&ica, S.A., Madrid, Spain.
428
THE AMERICAN JOURNAL OF SURGERY
application of cefalosporin derivatives with a wider spectrum of activity may yield more favorable results. The findings of Louie et al [3] and Tasker et al [4] suggest that a preoperative single dose of cefotaxime reduces the incidence of wound infections after gastroduodenal surgery and after cholecystectomy to very low levels. We determined that in order to obtain significant results in a comparative study, a larger number of patients than those included in the aforementioned trials was needed; this goal could best be achieved in a multicenter trial. In addition, since wound infections are directly responsible for an increase in length of hospitalization, the economic benefits associated with the use of newer cephalosporins are worth considering. PATIENTS
AND METHODS
The study was a prospective, nonblinded, randomized comparison of the prophylactic administration of cefotaxime and cefoxitin for the prevention of postoperative infections. Cefotaxime was administered as a 1 g single dose before beginning operation. Cefoxitin was given in four doses of 2 g each, the first one before the operation and subsequent ones 6,12, and 18 hours postoperatively. Both antibiotics were administered intravenously. Patients of both genders aged 18 years or over undergoing gastroduodenal or biliary surgery were eligible for the study if they presented with at least one of the risk factors detailed in Table I. Concomitant administration of other antibiotics was not allowed. Other exclusion criteria were pregnancy or lactation, hypersensitivity to beta-lactams, renal or hepatic insufficiency, and terminal illness. The following variables were recorded for each patient: duration of hospital stay, date and duration of intervention, time of administration of the first dose of the antibiotic, date of onset and remission of wound infection and fever, and measures adopted for treatment of wound infection, According to the proposal of the National Research Council [5], surgical wound infection was defined as cellulitis with purulent secretion, with or without dehisccnce. Whenever wound infection occurred, a bacteriologic study and an antimicrobial susceptibility test were performed. Fever during the first 24 hours after operation was evaluated in all cases. Information on all adverse events was recorded, including onset, intensity, evolution, and possible causality relationship. In order to perform a cost-benefit analysis, the annual number of abdominal surgical interventions, the average hospital stay of these patients, and the daily hospitalization costs in the participating centers were requested. The infection rates in both groups were compared by the Fisher exact test. Differences in mean postoperative
VOLUME 158 NOVEMBER 1989
TABLE I Mstrtbutlon ot Risk Factors In 1,451 Patients
Risk Factors Age over 60 years Obesity or rnalnutrlt~n Diabetes Treatment wlth cortioosteroids Previous bile duct surgery Emergency surgery Bile duct exploration Bile duct stones Acute cholecystltis Obstrwtlve jaundice Prevlous gastrectoiny
Cefotaxima
Procedures
Cefotaxima
C+foxitin
Operation on esophagus Incision and excision of stomach Othw operation on stomach Incision, excision, 8 anastomosis of intestine Operatkm on liver Operation on gallbladder 8. biliary tract Operation on pancreas other operation on abdominal region No information available
2 08 96 2 5 512 2 6 16
2 03 104 0 3 514 2 9 5
Total
729
722
P Value
Cefoxitin
404 274 70 5 21 101 310 126 104 89 2
TABLE II Surgical Procedures in 1,451 Pathmts
417 234 79 4 14 136 291 90 132 73 ..
NS <0.05 NS NS NS <0.02 NS <0.07 <0.05 NS NS
NS = not significant.
defined according to the classification of the United States Department of Health [6’J. In seven of the patients treated with cefotaxime and in six of the patients treated with cefoxitin, there was no information available about infection of the surgical wound. Among the remaining 722 patients treated with cefotaxime, wound infection was verified in 24 (3.3 percent) during a follow-up period of 16 days. Fifty-four of 716 patients treated prophylactically with cefoxitin (7.5 percent) developed wound infection during the ldday follow-up period. The difference between percentages was statistically significant (p <0.002). As shown in Figure 1 (cumulative percentages), 90 percent of the infections appeared between the second and seventh days after surgery. One hundred sixty-nine patients in the cefotaxime group (23.4 percent) and 204 in the cefoxitin group (28.5 percent) developed fever after surgery. The most frequent reasons for fever were wound infections (23 cases in the cefotaxime group, 51 cases in the cefoxitin group), and respiratory tract infections (36 cases in the cefotaxime group, 40 cases in the cefoxitin group). Bacterial growth was achieved in 17 of 19 culture specimens from cefotaxime patients and in 42 of the 48 specimens
hospital stay were assessed with the Student’s t test. For the cost-benefit analysis, 95 percent confidence intervals were estimated
RESULTS The study was performed between March 1987 and March 1988. A total of 1,45 1 patients who underwent abdominal surgery at 41 hospitals participated. Among those patients, 729 were treated prophylactically with cefotaxime and 722 with cefoxitin. The patients were an average of 6 1 years of age in the cefotaxime group and 62 years of age in the cefoxitin group. Sex distribution was the same in both groups: 57 percent were female and 43 percent were male. The distribution of risk factors is detailed in Table I. The cefotaxime group included more patients who were obese or had bile duct stones than the cefoxitin group; the latter group included more patients who had emergency surgery or had acute cholecystitis. Overall, risk factors were evenly distributed among both study groups. Table II displays the surgical procedures,
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THE AMERICAN JOURNAL OF SURGERY
VOLUME 158 NOVEMBER 1989
429
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121-240 m
Time of administration before beginning surgery (minutes) I-
from the cefoxitin patients. The influence of time of onset of prophylactic treatment on wound infection frequency is shown in Figure 2. In the cefotaxime group, wound infections were less frequent when prophylaxis administration took place during the last hour before operation (0.63 percent when the antibiotic was administered less than 60 minutes before onset of surgery and 4 percent when time elapsed was over 2 hours). This relationship was not observed in the cefoxitin group. The duration of surgery was evenly distributed among both groups of
patients. As expected I, infections were more frequent in patients who underwent longer operations (Figure 3). Treatment of wound infections consisted of debridement and administration of antibiotics. Patients received one to three antibiotics during 2 to 10 days in both study groups. In patients without wound infection, the hospital stay was 10.2 f 0.3 days. When wound infection developed, this figure increased to 13.7 f 1.3 days. The difference was statistically significant (p
430
158
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
NOVEMBER
1989
CEFOTAXIME
TABLE III
TABLE IV
Protoaol (kvuons Cefotaxima Cefoxitln
DOV&tbllS
No infurmatbn abcut time of adrninktration of annblotic A&nhWraUon of antibiotic with Wterap6utlc
7
2
7
4
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9
5
17 1 7
14 3 6
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40
34
SURGERY
Cost-Banefll AnriysW
l-bspitalizatlon for woundInfection Incre8w of ho@tal stay in cases of wound infection (d) Hospitallurtlon cosvd Cost of ho8pitalization in cases ofwoundhlfecth Antibiotic treatment of wound infection Average cost of antiblotlcld Number of antibiotics per patient Duration of treatment (d) Cost of antibiotic treatment
3.4 $144.43 $491
$22.16 1.4 6 $186.15
Cverall cost of wound infection
‘Thetotalisqrwtathanthenlmberofpati~wlthdrawnfromthe study (cefotnxlma 39 pmtkMs, cefoxltin 32 patients) because some patients were wmawn for moTe than one mason.
Cefoxitin prophylaxis Cost of cefoxltin Probability of wound Infection Cost of treatment of wound infection (0.077 X $677.15) Cost of proptlylaxis per patient
11 adverse drug reactions were recorded, 3 of which were associated with cefotaxime and 8 with cefoxitin. Cefotaxime events were locahzed to the skin. In the cefoxitin group, three events were skin reactions, three were cases of gastrointestinal intolerance, and one event was related to the central nervous system. The intensity of the reaction was mild to moderate, and causality was rated between “possible” and “probable.” All reactions resolved spontaneously; in one only case was administration of cefoxitin interrupted. Eleven patients (4 in the cefotaxime group, 7 in the cefoxitin group) died during the immediate postoperative period, in no case was a relationship with the antibiotic employed established. Thirty-nine patients in the cefotaxime group (5.4 percent) and 32 in the cefoxitin group (4.5 percent) did not meet all the protocol specifications (Table III). The characteristics (age, sex distribution, risk factors, and surgical procedures) of the patients fulfii the protocol speci& cations were identical to the characteristics of the patient population included in the trial. The frequency of wound infection in these patients was 3.3 percent in the cefotaxime group (690 patients) and 7.7 percent in the cefoxitin group (690 patients). The difference was statistically significant (p
Cefomxime prophylaxis Cefotaxime cost Probability of wouxi InfectIon Cost of treatment of wound infection (0.033 x $677.15) Cost of prophylaxis per patient Reduction of prophylaxis costs per patkNIt by cefotaxime instead of cefoxltin
$677.15
$52.29 0.077 $52.14 $104.43 $6.29 0.033 $22.35 $26.64 $75.71
Costs in U.S. dollars were calculatedtakln9 into accountthe averexchangerate In 1987 (one U.S. dollar = 123.46 pesetaa) l
95 percent confidence intervals for the frequency of wound infection, the lower limit of savings was $59.87/ patient and the upper limit, $91 A/patient. Data provided by 12 hospitals led us to conclude that in the 41 participating hospitals, the total number of gastroduode nal and biliary operations in which antibiotic prophylaxis was indicated amounted to 2,019 cases in 1987; therefore, the total savings could be estimated as being between $121,439 and $184,529. COMMENTS The method followed in this study combined the advantages of a controlled clinical trial with the practical approach of clinical observation. The random allocation of both prophylactic measures and the high number of patients included allowed a high degree of generalization concerning the results obtained. The evaluation of the results achieved after both the “intention-to-treat” analysis and the “explanatory” analysis (patients fulfilling the inclusion and exclusion criteria) shows that the frequency of wound infections with the prophylactic administration of cefotaxime is about two times lower than when using cefoxitin for the same purpose. In a study that was published when our study was beiig conducted, Jones et al [ 7], for the same type of surgery, reported a frequency of wound infection of 0 in 60 patients treated with cefotaxime and 1.7 percent in 60 patients treated with cefoxitin. Taking into account the corresponding confidence intervals (0 to 6 percent for cefotaxime, 0 to 9 percent for cefoxitin), we concluded
THE AMERICAN JOURNAL OF SURGERY
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that the present study broadly corroborates the results of that study. The bacteriologic findings coincide qualitatively and quantitatively with the broad analysis conducted by Gugliehno et al [S] in 1983, with Escherichia coli and Staphylococcus aureus being the most frequent isolates; therefore, the results achieved in the present study could be applied to the general circumstances regarding gastroduodenal and biliary surgery. The importance of the timing of initiation of antibiotic prophylaxis has been recognized previously [9]. When cefotaxime was administered up to 1 hour before operation, the frequency of wound infections was up to three times lower than when administration took place earlier. Prophylactic administration of cefotaxime during the last hour before operation ensures optimal results. This observation is in agreement with the kinetic characteristics of this cefalosporin derivative [IO,1I 1. Cruse and Foord [12] have described the direct relationship between length of operation and wound infection rate. Our results agree with this observation and may lead to the practice of administering a second dose of cefotaxime when the duration of surgery exceeds two hours. Although clearly requested on case report forms, under-reporting of adverse drug reactions occurred in our study. Jones et al [7] recorded 3.8 percent adverse reactions for cefotaxime and 7 percent for cefoxitin in a series of 1,036 patients. Our percenta es were less. On the other hand, data from the literature B131 confirm the observation of Jones and co-workers. Our cost-benefit analysis must be considered a lessthan-perfect approach to the real situation. For example, the costs related to the administration of an antibiotic or to the surgical treatment of an infection, as well as the indirect costs, could not be addressed. Nevertheless, the economic importance of surgical wound infections has already been emphasized by Terry [14]. In the study by Jones et al [7], a saving of $90.30/patient was calculated when using cefotaxime instead of cefoxitin. Thii figure surprisingly coincides with our own calculations. From this study it may be concluded that (1) cefotaxime is more effective than cefoxitin in the prophylaxis of wound infections in high-risk patients submitted to gastroduodenal and biliary surgery; (2) optimal results are achieved when cefotaxime is administered immediately before operation; (3) in cases of prolonged operation (more than 2 hours), it may be advisable to administer a second dose of 1 g of cefotaxime intravenously; and (4) the use of cefotaxime as a standard agent for wound infection prophylaxis in patients with risk factors may lead to an important reduction in the costs involved in gastroduodenal and biliary surgery.
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THE AMERICAN JOURNAL OF SURGERY
It is difficult to justify publishing the horde of submittedpapers dealing with one more antibioticapplied to mainstreamgeneral surgicalprocedures. On the other hand, this study, by virtueof the large number of seemingly similar patients admitted to the trial, discloses differences that most workers in the field may have doubted exist. Whether this is of real value and can be confirmed in broad practice remains to be seen.
REFERENCES 1. Gil-Egea MJ, Pi-Sunyer MT, Verdaguer A, Sanz F, SitgesSerra A, Torre Eleizegui L. Surgical wound infections: prospective study of 4,468 clean wounds. Infect Control 1987; 8: 277-280. 2. US. Centers for Disease Control. Nosocomial infection surveillance, 1983. MMWR CDC Surveill Summ 1985; 33: 9-21. 3. Lottie TJ, Blanchard R, Yaffe C, Lertzman J, McLeod J. Randomized, double-blind comparison of cefotaxime, cefoxitin, cefazolin or placebo as prophylaxis during gastric, small bowel or complicated biliary surgery. J Antimicrob Chemother 1984; 14 (suppl B): 255-62. 4. Tasker DG, G’Maley V, Lewis P, Karran SJ. Cefotaxime in the prophylaxis of wound infection following cholecystectomy. In: Spitzy KI-I, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. Viemta: International Congress of Chemotherapy, 1983: 22-25. 5. National Academy of Sciences-National Research Council. Postoperative wound infections: the influence of ultraviolet irradiations of the operating room and of various other factors. Ann Surg 1964; 160 (suppl 2): 1-192. 6. International Classification of Diseases. Clinical classification. Vol. 3. U.S. Department of Health and Human Services publication no. (PHS) 80-1260. 2nd ed., 1980. 7. Jones RN, Wojeski W, Bakke J, Porter C, Searles M. Antibiotic prophylaxis of 1036 patients undergoing elective surgical proce dures. A prospective, randomized comparative trial of cefazolin, cefoxitin, and cefotaxime in a prepaid medical practice. Am J Surg 1987; 153: 341-6. 8. Guglielmo J, Hohn DC, Koo PJ, Hunt TK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. A critical analysis of the literature. Arch Surg 1983; 118: 943-55. 9. Polk HC Jr., L&z-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969; 66: 97-103. 10. Wise R, Baker S, Livingstone R. Comparison of cefotaxime and moxalactam pharmacokinetics and tissue levels. Antimicrob Aeents Chemother 1980: 18: 369-71. 1 r: Wittmann DH, Scha&& HH, Welter J, Seidel H. Verfiigbarkeit von Cefotaxim. Munch Med Wschr 1980: 122: 63741. 12. Cruse PJE, Foord R. The epidemiology of wound infection. A IO-year prospective study of 62,939 wounds. Surg Clin North Am 1980; 60: 27-40. 13. Carmine AA, Brodgen RN, Heel RC, Speight TM, Avery GS. Cefotaxime. A review of its antibacterial activity, pharmacological properties and therapeutic use., Drugs 1983; 25: 223-89. 14. Terry BA. Cost-effective application of the Centers for Disease Control guidelines for prevention of surgical wound infections. Am J Infect Control 1985; 13: 232-5.
VOLUME 158 NOVEMBER 1989
In a multicenter prospective, randomized study, the efficacy of a single preoperative dose of 1 g of cefotaxime for avoiding wound infections was compared with four 2-g doses of cefoxitin. In the study, 1,451 patients with infection risk factors who underwent gastroduodenal or biliary surgery were included, of whom 722 received cefotaxime and 729 cefoxitin. The characteristics of both groups were comparable. The frequency of wound infectious in the cefotaxime group was 3.3 percent and in the cefoxitin group, 7.6 percent. The difference was statistically significant. The lowest rate of wound infection (0.63 percent) was achieved when cefotaxime was administered during the last hour before surgery. In both groups, the frequency of infections was directly related to the duration of operation. Hospital stay was, on average, 3 days longer in patients with wound infections. After cost-benefit analysis, we have concluded that cefotaxime treatment results in substantial reduction of costs derived from antibiotic prophylaxis.
I
n a recent prospective study, surgical wound infections accounted for 3.2 percent of clean wounds; the incidence increased to 5.1 percent in patients requiring emergency operations and to 7.8 percent in conditions thought to predispose to infection [I]. In gastroduodenal and biliary surgery, the prophylactic administration of a betalactam antibiotic is considered adequate when infection risk factors are present. Cefoxitin is the most widely used cefalosporin for this indication. Nevertheless, since after the National Nosocomial Infection Study [2], gram-negative organisms and anaerobes now constitute 70 percent of the pathogens responsible for this complications, the From the Department of Microbiology, University of Salamanca, Salamanna, Spain, the Department of General Surgery, Hospital de San Pablo, Barcelona, Spain; and the Institut Municipal d’Investigaci6 MMica, Universitat Aut6noma de Barcelona, Barcelona, Spain. Requests for reprints should be addressed to CarlcxsVallv6, MD, Travessera de Gracia, 47-49,08021-Barcelona, Spain. Partially presented at the 17th National Congress of Surgery, Madrid, Spain, November 6-9, 1988. Supported in part by Hoe&t Ib& ica, S.A., Barcelona and Roussel Ib&ica, S.A., Madrid, Spain.
428
THE AMERICAN JOURNAL OF SURGERY
application of cefalosporin derivatives with a wider spectrum of activity may yield more favorable results. The findings of Louie et al [3] and Tasker et al [4] suggest that a preoperative single dose of cefotaxime reduces the incidence of wound infections after gastroduodenal surgery and after cholecystectomy to very low levels. We determined that in order to obtain significant results in a comparative study, a larger number of patients than those included in the aforementioned trials was needed; this goal could best be achieved in a multicenter trial. In addition, since wound infections are directly responsible for an increase in length of hospitalization, the economic benefits associated with the use of newer cephalosporins are worth considering. PATIENTS
AND METHODS
The study was a prospective, nonblinded, randomized comparison of the prophylactic administration of cefotaxime and cefoxitin for the prevention of postoperative infections. Cefotaxime was administered as a 1 g single dose before beginning operation. Cefoxitin was given in four doses of 2 g each, the first one before the operation and subsequent ones 6,12, and 18 hours postoperatively. Both antibiotics were administered intravenously. Patients of both genders aged 18 years or over undergoing gastroduodenal or biliary surgery were eligible for the study if they presented with at least one of the risk factors detailed in Table I. Concomitant administration of other antibiotics was not allowed. Other exclusion criteria were pregnancy or lactation, hypersensitivity to beta-lactams, renal or hepatic insufficiency, and terminal illness. The following variables were recorded for each patient: duration of hospital stay, date and duration of intervention, time of administration of the first dose of the antibiotic, date of onset and remission of wound infection and fever, and measures adopted for treatment of wound infection, According to the proposal of the National Research Council [5], surgical wound infection was defined as cellulitis with purulent secretion, with or without dehisccnce. Whenever wound infection occurred, a bacteriologic study and an antimicrobial susceptibility test were performed. Fever during the first 24 hours after operation was evaluated in all cases. Information on all adverse events was recorded, including onset, intensity, evolution, and possible causality relationship. In order to perform a cost-benefit analysis, the annual number of abdominal surgical interventions, the average hospital stay of these patients, and the daily hospitalization costs in the participating centers were requested. The infection rates in both groups were compared by the Fisher exact test. Differences in mean postoperative
VOLUME 158 NOVEMBER 1989
TABLE I Mstrtbutlon ot Risk Factors In 1,451 Patients
Risk Factors Age over 60 years Obesity or rnalnutrlt~n Diabetes Treatment wlth cortioosteroids Previous bile duct surgery Emergency surgery Bile duct exploration Bile duct stones Acute cholecystltis Obstrwtlve jaundice Prevlous gastrectoiny
Cefotaxima
Procedures
Cefotaxima
C+foxitin
Operation on esophagus Incision and excision of stomach Othw operation on stomach Incision, excision, 8 anastomosis of intestine Operatkm on liver Operation on gallbladder 8. biliary tract Operation on pancreas other operation on abdominal region No information available
2 08 96 2 5 512 2 6 16
2 03 104 0 3 514 2 9 5
Total
729
722
P Value
Cefoxitin
404 274 70 5 21 101 310 126 104 89 2
TABLE II Surgical Procedures in 1,451 Pathmts
417 234 79 4 14 136 291 90 132 73 ..
NS <0.05 NS NS NS <0.02 NS <0.07 <0.05 NS NS
NS = not significant.
defined according to the classification of the United States Department of Health [6’J. In seven of the patients treated with cefotaxime and in six of the patients treated with cefoxitin, there was no information available about infection of the surgical wound. Among the remaining 722 patients treated with cefotaxime, wound infection was verified in 24 (3.3 percent) during a follow-up period of 16 days. Fifty-four of 716 patients treated prophylactically with cefoxitin (7.5 percent) developed wound infection during the ldday follow-up period. The difference between percentages was statistically significant (p <0.002). As shown in Figure 1 (cumulative percentages), 90 percent of the infections appeared between the second and seventh days after surgery. One hundred sixty-nine patients in the cefotaxime group (23.4 percent) and 204 in the cefoxitin group (28.5 percent) developed fever after surgery. The most frequent reasons for fever were wound infections (23 cases in the cefotaxime group, 51 cases in the cefoxitin group), and respiratory tract infections (36 cases in the cefotaxime group, 40 cases in the cefoxitin group). Bacterial growth was achieved in 17 of 19 culture specimens from cefotaxime patients and in 42 of the 48 specimens
hospital stay were assessed with the Student’s t test. For the cost-benefit analysis, 95 percent confidence intervals were estimated
RESULTS The study was performed between March 1987 and March 1988. A total of 1,45 1 patients who underwent abdominal surgery at 41 hospitals participated. Among those patients, 729 were treated prophylactically with cefotaxime and 722 with cefoxitin. The patients were an average of 6 1 years of age in the cefotaxime group and 62 years of age in the cefoxitin group. Sex distribution was the same in both groups: 57 percent were female and 43 percent were male. The distribution of risk factors is detailed in Table I. The cefotaxime group included more patients who were obese or had bile duct stones than the cefoxitin group; the latter group included more patients who had emergency surgery or had acute cholecystitis. Overall, risk factors were evenly distributed among both study groups. Table II displays the surgical procedures,
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THE AMERICAN JOURNAL OF SURGERY
VOLUME 158 NOVEMBER 1989
429
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llrq
lo-
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195
412
3-
LB 397/
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Flgure 3. Duratbm ot surgery and fwqwmy al wound lnbctbns. Vallms onthetopdeachcobmnretefto the total number ot patknts.
121-240 m
Time of administration before beginning surgery (minutes) I-
from the cefoxitin patients. The influence of time of onset of prophylactic treatment on wound infection frequency is shown in Figure 2. In the cefotaxime group, wound infections were less frequent when prophylaxis administration took place during the last hour before operation (0.63 percent when the antibiotic was administered less than 60 minutes before onset of surgery and 4 percent when time elapsed was over 2 hours). This relationship was not observed in the cefoxitin group. The duration of surgery was evenly distributed among both groups of
patients. As expected I, infections were more frequent in patients who underwent longer operations (Figure 3). Treatment of wound infections consisted of debridement and administration of antibiotics. Patients received one to three antibiotics during 2 to 10 days in both study groups. In patients without wound infection, the hospital stay was 10.2 f 0.3 days. When wound infection developed, this figure increased to 13.7 f 1.3 days. The difference was statistically significant (p
430
158
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
NOVEMBER
1989
CEFOTAXIME
TABLE III
TABLE IV
Protoaol (kvuons Cefotaxima Cefoxitln
DOV&tbllS
No infurmatbn abcut time of adrninktration of annblotic A&nhWraUon of antibiotic with Wterap6utlc
7
2
7
4
Conoomittant administratlon of other antibiotics Ri8kfactorsnotpreMnt No Infrxmntbn about risk factors No infamatlar about outoome Of prophylactic nWasWe8
9
5
17 1 7
14 3 6
ToteI’
IN GASTRODLJODENAL AND BILMY
40
34
SURGERY
Cost-Banefll AnriysW
l-bspitalizatlon for woundInfection Incre8w of ho@tal stay in cases of wound infection (d) Hospitallurtlon cosvd Cost of ho8pitalization in cases ofwoundhlfecth Antibiotic treatment of wound infection Average cost of antiblotlcld Number of antibiotics per patient Duration of treatment (d) Cost of antibiotic treatment
3.4 $144.43 $491
$22.16 1.4 6 $186.15
Cverall cost of wound infection
‘Thetotalisqrwtathanthenlmberofpati~wlthdrawnfromthe study (cefotnxlma 39 pmtkMs, cefoxltin 32 patients) because some patients were wmawn for moTe than one mason.
Cefoxitin prophylaxis Cost of cefoxltin Probability of wound Infection Cost of treatment of wound infection (0.077 X $677.15) Cost of proptlylaxis per patient
11 adverse drug reactions were recorded, 3 of which were associated with cefotaxime and 8 with cefoxitin. Cefotaxime events were locahzed to the skin. In the cefoxitin group, three events were skin reactions, three were cases of gastrointestinal intolerance, and one event was related to the central nervous system. The intensity of the reaction was mild to moderate, and causality was rated between “possible” and “probable.” All reactions resolved spontaneously; in one only case was administration of cefoxitin interrupted. Eleven patients (4 in the cefotaxime group, 7 in the cefoxitin group) died during the immediate postoperative period, in no case was a relationship with the antibiotic employed established. Thirty-nine patients in the cefotaxime group (5.4 percent) and 32 in the cefoxitin group (4.5 percent) did not meet all the protocol specifications (Table III). The characteristics (age, sex distribution, risk factors, and surgical procedures) of the patients fulfii the protocol speci& cations were identical to the characteristics of the patient population included in the trial. The frequency of wound infection in these patients was 3.3 percent in the cefotaxime group (690 patients) and 7.7 percent in the cefoxitin group (690 patients). The difference was statistically significant (p
Cefomxime prophylaxis Cefotaxime cost Probability of wouxi InfectIon Cost of treatment of wound infection (0.033 x $677.15) Cost of prophylaxis per patient Reduction of prophylaxis costs per patkNIt by cefotaxime instead of cefoxltin
$677.15
$52.29 0.077 $52.14 $104.43 $6.29 0.033 $22.35 $26.64 $75.71
Costs in U.S. dollars were calculatedtakln9 into accountthe averexchangerate In 1987 (one U.S. dollar = 123.46 pesetaa) l
95 percent confidence intervals for the frequency of wound infection, the lower limit of savings was $59.87/ patient and the upper limit, $91 A/patient. Data provided by 12 hospitals led us to conclude that in the 41 participating hospitals, the total number of gastroduode nal and biliary operations in which antibiotic prophylaxis was indicated amounted to 2,019 cases in 1987; therefore, the total savings could be estimated as being between $121,439 and $184,529. COMMENTS The method followed in this study combined the advantages of a controlled clinical trial with the practical approach of clinical observation. The random allocation of both prophylactic measures and the high number of patients included allowed a high degree of generalization concerning the results obtained. The evaluation of the results achieved after both the “intention-to-treat” analysis and the “explanatory” analysis (patients fulfilling the inclusion and exclusion criteria) shows that the frequency of wound infections with the prophylactic administration of cefotaxime is about two times lower than when using cefoxitin for the same purpose. In a study that was published when our study was beiig conducted, Jones et al [ 7], for the same type of surgery, reported a frequency of wound infection of 0 in 60 patients treated with cefotaxime and 1.7 percent in 60 patients treated with cefoxitin. Taking into account the corresponding confidence intervals (0 to 6 percent for cefotaxime, 0 to 9 percent for cefoxitin), we concluded
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that the present study broadly corroborates the results of that study. The bacteriologic findings coincide qualitatively and quantitatively with the broad analysis conducted by Gugliehno et al [S] in 1983, with Escherichia coli and Staphylococcus aureus being the most frequent isolates; therefore, the results achieved in the present study could be applied to the general circumstances regarding gastroduodenal and biliary surgery. The importance of the timing of initiation of antibiotic prophylaxis has been recognized previously [9]. When cefotaxime was administered up to 1 hour before operation, the frequency of wound infections was up to three times lower than when administration took place earlier. Prophylactic administration of cefotaxime during the last hour before operation ensures optimal results. This observation is in agreement with the kinetic characteristics of this cefalosporin derivative [IO,1I 1. Cruse and Foord [12] have described the direct relationship between length of operation and wound infection rate. Our results agree with this observation and may lead to the practice of administering a second dose of cefotaxime when the duration of surgery exceeds two hours. Although clearly requested on case report forms, under-reporting of adverse drug reactions occurred in our study. Jones et al [7] recorded 3.8 percent adverse reactions for cefotaxime and 7 percent for cefoxitin in a series of 1,036 patients. Our percenta es were less. On the other hand, data from the literature B131 confirm the observation of Jones and co-workers. Our cost-benefit analysis must be considered a lessthan-perfect approach to the real situation. For example, the costs related to the administration of an antibiotic or to the surgical treatment of an infection, as well as the indirect costs, could not be addressed. Nevertheless, the economic importance of surgical wound infections has already been emphasized by Terry [14]. In the study by Jones et al [7], a saving of $90.30/patient was calculated when using cefotaxime instead of cefoxitin. Thii figure surprisingly coincides with our own calculations. From this study it may be concluded that (1) cefotaxime is more effective than cefoxitin in the prophylaxis of wound infections in high-risk patients submitted to gastroduodenal and biliary surgery; (2) optimal results are achieved when cefotaxime is administered immediately before operation; (3) in cases of prolonged operation (more than 2 hours), it may be advisable to administer a second dose of 1 g of cefotaxime intravenously; and (4) the use of cefotaxime as a standard agent for wound infection prophylaxis in patients with risk factors may lead to an important reduction in the costs involved in gastroduodenal and biliary surgery.
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It is difficult to justify publishing the horde of submittedpapers dealing with one more antibioticapplied to mainstreamgeneral surgicalprocedures. On the other hand, this study, by virtueof the large number of seemingly similar patients admitted to the trial, discloses differences that most workers in the field may have doubted exist. Whether this is of real value and can be confirmed in broad practice remains to be seen.
REFERENCES 1. Gil-Egea MJ, Pi-Sunyer MT, Verdaguer A, Sanz F, SitgesSerra A, Torre Eleizegui L. Surgical wound infections: prospective study of 4,468 clean wounds. Infect Control 1987; 8: 277-280. 2. US. Centers for Disease Control. Nosocomial infection surveillance, 1983. MMWR CDC Surveill Summ 1985; 33: 9-21. 3. Lottie TJ, Blanchard R, Yaffe C, Lertzman J, McLeod J. Randomized, double-blind comparison of cefotaxime, cefoxitin, cefazolin or placebo as prophylaxis during gastric, small bowel or complicated biliary surgery. J Antimicrob Chemother 1984; 14 (suppl B): 255-62. 4. Tasker DG, G’Maley V, Lewis P, Karran SJ. Cefotaxime in the prophylaxis of wound infection following cholecystectomy. In: Spitzy KI-I, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. Viemta: International Congress of Chemotherapy, 1983: 22-25. 5. National Academy of Sciences-National Research Council. Postoperative wound infections: the influence of ultraviolet irradiations of the operating room and of various other factors. Ann Surg 1964; 160 (suppl 2): 1-192. 6. International Classification of Diseases. Clinical classification. Vol. 3. U.S. Department of Health and Human Services publication no. (PHS) 80-1260. 2nd ed., 1980. 7. Jones RN, Wojeski W, Bakke J, Porter C, Searles M. Antibiotic prophylaxis of 1036 patients undergoing elective surgical proce dures. A prospective, randomized comparative trial of cefazolin, cefoxitin, and cefotaxime in a prepaid medical practice. Am J Surg 1987; 153: 341-6. 8. Guglielmo J, Hohn DC, Koo PJ, Hunt TK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. A critical analysis of the literature. Arch Surg 1983; 118: 943-55. 9. Polk HC Jr., L&z-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969; 66: 97-103. 10. Wise R, Baker S, Livingstone R. Comparison of cefotaxime and moxalactam pharmacokinetics and tissue levels. Antimicrob Aeents Chemother 1980: 18: 369-71. 1 r: Wittmann DH, Scha&& HH, Welter J, Seidel H. Verfiigbarkeit von Cefotaxim. Munch Med Wschr 1980: 122: 63741. 12. Cruse PJE, Foord R. The epidemiology of wound infection. A IO-year prospective study of 62,939 wounds. Surg Clin North Am 1980; 60: 27-40. 13. Carmine AA, Brodgen RN, Heel RC, Speight TM, Avery GS. Cefotaxime. A review of its antibacterial activity, pharmacological properties and therapeutic use., Drugs 1983; 25: 223-89. 14. Terry BA. Cost-effective application of the Centers for Disease Control guidelines for prevention of surgical wound infections. Am J Infect Control 1985; 13: 232-5.
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