S621
Multicenter Trial of Prophylaxis with Clindamycin Plus Aztreonam or Cefotaxime in Gynecologic Surgery Costantino Mangioni, Luigi Bianchi, Pier F. Bolis, Alberto M. Lomeo, Francesco Mazzeo, Luigi Ventriglia, and Salvatore Scalambrino
From the Department of Obstetrics and Gynecology, S. Gerardo Hospital, Monza; the Department of Obstetrics and Gynecology, Cosenza; the Obstetric and Gynecological Clinic, University of Pavia, Pavia; the Department of Obstetrics and Gynecology, Potenza; the Institute of Surgery, University of Naples, Naples; and Medical Direction, Squibb-Italia, Rome, Italy
The incidence of infective complications following gynecologic surgery differs according to the type of procedure. With vaginal hysterectomy, for example, flora at the opening of the vagina, including both gram-positive and gram-negative aerobes and anaerobes, may contaminate the surgical field and cause infection at the operative site. Infection can also result from complementary procedures, such as colposuspension for urinary-stress incontinence, anterior and posterior repair for vaginal prolapse, exeresis of parametria and pelvic lymph nodes for uterine cancer, and multiple endoperitoneal and retroperitoneal biopsies for ovarian cancer; any of these procedures increases both the duration of surgery and the area of the surgical field, thus increasing the risk of infection as well. Morbidity attributable to infection, including both that at the operative site (abdominal, vaginal, or wound infection) and that due to fever, can be largely prevented with appropriate surgical procedures - such as disinfection of the skin and vagina, mechanical preparation of the bowel, and management of drainage of the bladder and of the spaces created by the surgery-and with antibiotic prophylaxis.
Reprints and correspondence: Professor Costantino Mangioni, Department of Obstetrics and Gynecology, S. Gerardo Hospital, Via Solferino 16, 20052 Monza (Milan), Italy. Reviews of Infectious Diseases 1991;13(Suppl7):8621-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0049$02.00
The incidence of infective complications following abdominal and vaginal hysterectomy decreases with adequate antibiotic prophylaxis to as low as 12%-32 % of the rate expected without perioperative antibiotic therapy [1-4]. An antibiotic appropriate for prophylaxis must be active against those pathogens most likely to be involved in postoperative infections and must reach therapeutic concentrations in tissues before the time of possible bacterial contamination. Such concentrations must then be maintained from the time of surgical opening to the sealing of the wound, which occurs 1'\.13 hours after suture. Prolongation of prophylaxis beyond the first postoperative day offers no additional protection. In recognition of the need for appropriate antibiotic prophylaxis, a prospective, randomized, multicenter clinical trial was undertaken to compare aztreonam (which is selectively active against gram-negative bacilli [5]) with cefotaxime (which is active against gram-positive and gram-negative aerobes [6]) in terms of safety and efficacy for prophylaxis of infective complications following abdominal and vaginal hysterectomy. Both agents were given in combination with clindamycin, which is known for its activity against anaerobic pathogens. In this trial the two regimens were administered in three doses, with the first dose given at the induction of anesthesia. In many studies this abbreviated schedule has decreased the incidence of postoperative infective episodes, with a reduction of the adverse reactions and the costs associated with long-term treatment, which is widely used in Italy.
Downloaded from http://cid.oxfordjournals.org/ at University of Wyoming Libraries on March 30, 2015
A prospective, randomized, multicenter study was conducted on the efficacy and safety of two prophylactic antibiotic regimens in both abdominal and vaginal hysterectomy. Patients received three intravenous doses of clindamycin (900 mg) plus either aztreonam (1 g) or cefotaxime (1 g); the doses were given at the induction of anesthesia and 8 and 16 hours later. A total of 170 patients undergoing abdominal hysterectomy and 142 patients undergoing vaginal hysterectomy completed the trial and were evaluated. Following abdominal hysterectomy infections occurred at the operative site in 1.2% of patients given a regimen including aztreonam and in 4.7% of those given a regimen including cefotaxime; the difference between the two groups was not significant. Neither were significant differences observed in the incidence of fever, the incidence of bacteriuria, the need for postoperative antibiotics, or the duration of postoperative hospitalization, although results were slightly better for patients receiving clindamycin plus aztreonam. Followingvaginal hysterectomy,slightly but not significantly better results for the same parameters were obtained in the group given clindamycin plus cefotaxime. Diarrhea was the only adverse reaction attributable to antibiotic treatment and occurred more frequently in patients given cefotaxime. It was concluded that the two regimens were similarly effective and safe in preventing infections following hysterectomy.
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Patients and Methods
Table 1. Characteristics of patients undergoing abdominal hysterectomy and receiving prophylaxis with aztreonam/c1indamycin (AC) or cefotaxime/c1indamycin (CC).
I
Value for indicated group Characteristic* Evaluability: no. of patients Age (y): mean ± SD (range) General condition: no. (%) of patients Good Fair Poor Postmenopause: no. (%) of patients Diagnosis of neoplasia: no. (%) of patients Preoperative hospital stay (d): mean ± SD (range) Surgical procedure: no. (%) of patients Total hysterectomy Radical hysterectomy Hysterectomy plus appendectomy Duration of surgery (min): mean ± SD (range) Duration of postoperative catheterization (d): mean ± SD (range)
* Each category is folJowed by
AC 80 52 ± 11 (25-82)
CC 90 50 ± 8 (27-74)
Ch.a~acteristics of patients undergoing vaginal hysterectomy and receiving prophylaxis with aztreonam/c1indamycin (AC) or cefotaxime/c1indamycin (CC).
Table 2.
Value for indicated group 72 (90.0) 8 (10.0) 0(...)
75 (83.3) 14 (15.6) 1 (1.1)
29 (36.3)
37 (41.1)
23 (28.8)
22 (24.4)
8 ± 6 (1-26)
7 ± 6 (1-30)
74 (92.5) 6 (7.5)
81 (90.0) 9 (10.0)
13 (16.2)
11 (12.2)
100 ± 50 (35-200)
4 ± 3 (1-14)
92 ± 49 (40-240)
4 ± 3 (1-17)
an indication of how the data are expressed.
Characteristic
AC
Evaluability: no. of patients 72 Age (y): mean ± SD (range) 59 ± 11 (40-83) General condition: no. (%) of patients 54 (75.0) Good 18 (25.0) Fair 0(...) Poor Postmenopause: no. (%) of 51 (70.8) patients Diagnosis of neoplasia: 31 (43.1) no. (%) of patients Preoperative hospital stay (d): mean ± SD 7 ± 6 (1-25) (range) Duration of surgery (min): 125 ± 40 (45-240) mean ± SD (range) Duration of postoperative catheterization (d): 4 ± 2 (1-10) mean ± SD (range)
* Each category
CC 70 56 ± 12 (35-78)
53 (75.7) 17 (24.3) 0(...) 46 (65.7) 27 (38.6)
7 ± 6 (1-32) 115 ± 38 (45-180)
4 ± 2 (1-11)
is folJowed by an indication of how the data are expressed.
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'Between October 1987 and April 1988, women ~25 years of age who were scheduled for vaginal or abdominal hysterectomy at any of five Italian centers were randomly assigned to receive three perioperative doses of clindamycin (900 mg) plus either aztreonam (l g) or cefotaxime (l g). All medications were given intravenously at the induction of anesthesia and 8 and 16 hours later. Exclusion criteria included allergy to cephalosporins, hepatic or renal dysfunction, established infection, or antibiotic use within the week preceding surgery. Patients with granulocytopenia and those receiving corticosteroid therapy also were excluded. Of the 189 patients enrolled in the abdominal hysterectomy group, 89 were randomized to treatment with aztreonam/clindamycin and 100 to treatment with cefotaxime/clindamycin. Subsequently, nine aztreonam-treated patients and 10 cefotaxime-treated patients were excluded because of intraoperative changes in the planned procedure or use of antibiotics during postoperative hospital stay without a precise diagnosis of infection; thus the final population studied included 80 patients given aztreonam/clindamycin and 90 given cefotaxime/ clindamycin. The two groups were comparable in terms of age, general condition, menopausal status, diagnosis, and duration of preoperative hospitalization, although there were differences in preoperative management techniques used at the various centers (table 1).
Of 153 patients undergoing vaginal hysterectomy with or without vaginal repair, 75 were assigned to aztreonam/clindamycin therapy and 78 to cefotaxime/clindamycin treatment. Three and eight patients from these groups, respectively, were eventually excluded on the basis of the criteria described for the abdominal hysterectomy group; thus the evaluable population consisted of 72 patients given aztreonam/clindamycin and 70 given cefotaxime/clindamycin. There were no statistically significant differences between the two cohorts in age, general condition, menopausal status, diagnosis, or duration of preoperative hospital stay (table 2). Vaginal hysterectomy was associated with anterior and posterior repair in four cases in each treatment group. Routine perioperative care included daily examination and recording of vital signs and body temperature every 8 hours. Microbiologic controls varied with the procedure. Urine samples for culture were taken from all patients preoperatively, on the third postoperative day, at the removal of the bladder catheter, and at discharge from the hospital. For patients undergoing vaginal hysterectomy, vaginal swab specimens were taken preoperatively, on the fourth or fifth postoperative day, and at discharge from the hospital. For patients undergoing abdominal hysterectomy, wound swab samples were taken at closure of the abdominal wall, on the fourth or fifth postoperative day, and at discharge from the hospital. After discharge (39-46 days after surgery), patients underwent a final clinical evaluation to rule out the development of late infective morbidity. At that time vaginal swab samples and urine samples were collected for culture from all patients. For the purposes of this study, infection of the abdominal
Gynecologic Surgery
RID 1991;13 (Suppl 7)
uria occurred after the third postoperative day and were considered to be attributable primarily to the persistence of bladder drainage, not to failure of prophylaxis. At 36.2 % and 40.0%, respectively, the incidences of postoperative fever in the two groups may seem high, but these figures include cases of mild hyperpyrexia, which is frequent in this kind of patient and often resolves spontaneously without antibiotic therapy. Wide differences were observed among the five centers involved in the study with regard to the need for postoperative antibiotic therapy. Only one center, for example, used locally administered antibiotics in the treatment of serous vaginal discharge with a positive swab culture and without other symptoms of vaginal infection (figure 1). It was determined that the variability among centers in the duration of postoperative hospitalization reflected differences in postoperative management rather than in infective morbidity. Vaginal hysterectomy. Following vaginal hysterectomy, results were slightly but not significantly better in the cefotaxime/clindamycin group with regard to infection at the operative site, fever, the need for postoperative local or systemic antibiotic therapy, and bacteriuria (table 4). The high incidence of vaginal wall infections is probably due to a different
50
Results
43
Abdominal hysterectomy. Surgical wound infections following abdominal hysterectomy occurred in 1. 2 % of patients given aztreonam/clindamycin and in 4.7 % of those given cefotaxllne/clindamycin (difference not significant). Although the results (all parameters of infection) were slightly better for patients treated with aztreonam/clindamycin, no significant differences between the regimens were observed in the incidence of fever, the incidence of bacteriuria, the need for postoperative antibiotics, or the duration of postoperative hospitalization (table 3). Bacteriuria was detected in 12.5 % and 11.1 % of patients in the aztreonam/clindamycin and cefotaxime/clindamycin groups, respectively. The majority (90%) of cases ofbacteriTable 3. Postoperative events in patients undergoing abdominal hysterectomy and receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). Value for indicated group*
Postoperative event Wound infection Vaginal cuff infection Bacteriuria Fever Need for antibiotic therapy Hospital stay
AC (n = 80) 1 (1.2) 0(...)
10 (12.5) 29 (36.2) 15 (18.8) 10 ± ~ (5-46)
l1li
40
* All values except those for hospital stay are expressed as the number (percentage) of patients; values for hospital stay are expressed as the mean number of days ± SD (range).
LOCAL
•
BOTH
10
CENTERS
Figure 1. Antibiotic treatment, by center, in patients undergoing abdominal hysterectomy.
Table 4. Postoperative events in patients undergoing vaginal hysterectomy and receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). Value for indicated group*
(n = 90)
(3.3) (1.1) (11.1) (40.0) (23.3) ± 3 (6-29)
SYSTEMIC
IIGJJJ
20
CC 3 1 10 36 21 10
EVALUABLE PATIENTS
~
Postoperative event Vaginal wall infection Bacteriuria Fever Need for antibiotic therapy Hospital stay
(n
11 24 29 27
CC
AC = 72)
(15.3) (33.3) (40.3) (37.5) 8 ± 3 (2-15)
(n = 70)
6 19 23 19 9
(8.6) (27.1) (32.9) (27.1) ± 3 (4-21)
* All values except that for hospital stay are expressed as the number (percentage) of patients; values for hospital stay are expressed as the mean number of days ± SD (range).
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wound (only for abdominal hysterectomy) or the vaginal wall (only for vaginal hysterectomy) was defined as purulent discharge with a positive or negative culture, serous discharge with a positive culture, or erythema and/or induration requiring systemic antibiotic therapy. Pelvic cellulitis was defined as fever, pelvic pain, edema, induration and pain at pressure of the vaginal cuff, and smelly discharge without localized purulence of the vaginal cuff. Pelvic abscess was documented by laparoscopy, laparotomy, ultrasound, or operative drainage of pus. Vaginal cuff abscess was defined as fever, pelvic pain, and purulent discharge from the vaginal cuff. Fever was defined as a temperature of ~37.5°C on any day except during the first 24 hours after surgery, regardless of association with other signs or symptoms of infection. Finally, bacteriuria was defined as a positive culture with ~1()5 cfu/mL in a midstream urine specimen, ~102 cfu/mL in a catheter urine specimen obtained during irrigation, and ~1()4 cfu/mL in a catheter urine specimen, with or without other signs of infection. Infection that occurred distal to the surgical site (i.e., bronchopneumonia or phlebitis) was recorded but is not considered further in this preliminary report. For statistical analysis of demographic and perioperative data as well as results, significance was established at P < .5.
S623
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Mangioni et al.
60
-
~
SYSTEMIC
D
LOCAL
•
BOTH
40
'" ffi
~
2i
30
20
10
CENTERS
Figure 2. Antibiotic treatment, by center, in patients undergoing vaginal hysterectomy.
interpretation of the protocol definition at a single center. In fact, a slight serous discharge and a positive vault swab are quite commonin these patients on about the fourthpostoperative day, at which time the vaginal flora returns to its preoperative state. Using a strict interpretation of the protocol definition, onecenterconsidered all patients withtheseclinical and microbiologic features to be infected. Thehighpercentage of patients treated with local and/or systemic antibiotics at that center also reflects this interpretation (figure 2). In contrast, other centers more often related the failure of prophylaxisto the presence of localand systemic signsand symptoms of infection.
Discussion Despite the different in vitro antimicrobial profiles of aztreonamand cefotaxime, resultswere not significantly different when each of these two drugs was used with clindamycin for short-term prophylaxis in this comparative trial. Theoretically, aztreonam/c1indamycin should be more protective than cefotaxime/c1indamycin, since aztreonam shows higher
Table 5. Pathogens isolated from sites of infection following abdominal or vaginal hysterectomy in patients receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). No. of isolates from indicated infection in indicated group Wound infection Pathogen Gram-positive aerobes Gram-positive cocci Staphylococcus aureus I3-Hemolytic Streptococcus Streptococcus agalactiae Streptococcus faecalis Gram-negative aerobes Escherichia coli Enterobacter species Enterobacter aerogenes Enterobacter cloacae Klebsiella species Proteus species Proteus mirabilis Pseudomonas species Pseudomonas aeruginosa Not identified
Vaginal wall infection
Bacteriuria
Total
AC
CC
AC
CC
AC
CC
AC
CC
0 0 0 0 0
0 0 0 0 1
1 0 0 0 2
0 0 0 0 2
0 2 1 1 5
0 0 0 0 0
1 2 1 1 7
0 0 0 0 3
1 0 0 0 0 0 0 0 0 0
1 1 0 0 0 0 0 0 0 0
11
2 0 0 0 1 1 0 2 0 0
10
17 0 1 0 1 2 0 8 1 1
22 0 0 1 0 2 1 2 1 13
20 1 1 0 2 3 0
0 0 1 0 0 0 0 0 0
0 0 0 0 2 1 2 1 13
10 1 1
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The discussion in the preceding sectionregardingfever and bacteriuria is applicable to patients undergoing vaginal hysterectomy as well as to those undergoing abdominal hysterectomy. Pathogens. No anaerobes were isolated from infection sites; gram-negative aerobes were isolated more frequently than were gram-positiveorganisms (table 5). Gram-positive bacilliwereisolatedonly from patientsgivenaztreonam, and Streptococcus faecalis represented66 % of all gram-positive isolates. Gram-negative bacilliwereisolated more frequently after prophylaxiswith cefotaxime/clindamycin. Escherichia coli and Pseudomonas species were the most frequently isolated bacteria, representing 76% and 10%, respectively, of the gram-negative isolates from aztreonam-treated patients and 53 % and 29 %, respectively, of those from cefotaximetreated patients. Adverse reactions. Diarrheaunrelatedto pseudomembranous colitis was the only adverse reaction that was related to the prophylactic antibiotics. The rate of its occurrencewas 0.7% and 2.5 % in the aztreonam and cefotaxime groups, respectively.
57 EVALUABLE PATIENTS
50
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Gynecologic Surgery
The two schedules of prophylaxis reviewed were found to be safe. Mild diarrhea unrelated to pseudomembranous colitis was the only adverse reaction and was more frequent with cefotaxime than with aztreonam. In conclusion, aztreonam and cefotaxime-in combination with clindamycin - seem to be equally effective in preventing postoperative infections in patients undergoing abdominal and vaginal hysterectomy, but additional analyses are needed to determine whether these observations hold for subgroups of patients. References 1. Polk BF, Tager IB, Shapiro M, Goren-White B, Goldstein P, Schoenbaum Sc. Randomizedclinical trial of perioperative cefazolinin preventing infection after hysterectomy. Lancet 1980;1:437-41 2. Breeden JT, Mayo JE. Low dose prophylactic antibiotics in vaginal hysterectomy. Obstet Gynecol 1974;43:379-85 3. Micka! A, Curole 0, Lewis C. Cefoxitin sodium: double-blind vaginal hysterectomy prophylaxis in premenopausal patients. Obstet Gynecol 1980;56:222-5 4. Ledger WJ, Gee C, Lewis WP. Guidelines for antibiotic prophylaxis in gynecology. Am J Obstet Gynecol 1975;121:1038-45 5. Paradelis AG, Stathopoulos AG, TselentisJ, Delidou K, Stavraksi A, Crassaris LG. Comparative antibacterial activity of aztreonam and other antimicrobial agents against gram-negative microorganisms. Chemioterapia 1985;4(Suppl 1):14-22 6. Forsgren A. Comparative in vitro activity of first, second and third generation cephalosporins. Acta Pathologica et Microbiologica Scandinavica, Section B: Microbiology 1981;89:221-5
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in vitro activity against gram-negative bacilli and the efficacy of cefotaxime against gram-positive bacteria should add nothing to that of clindamycin. The lack of statistically significant differences in infection rates after prophylaxis with either agent plus clindamycin conflicts with this hypothesis, although this finding could be explained by the wide differences in the incidence of infection at the various participating centers, by the type of analysis done, or by the sample of patients studied. In fact, factors such as age, menopausal status, and use of aggressive surgical procedures seem to influence the effect of prophylaxis. Moreover, some problems arose from different interpretations ofinfection criteria and different therapeutic approaches among the centers participating in the trial. For example, vaginal wall infection was defined in the study protocol as serous discharge with a positive culture-a situation fairly common in patients who have undergone vaginal hysterectomy. Four centers interpreted this definition in a broad sense, considering as infected only those patients with major systemic or local signs and rarely treating patients who had no such signs with antibiotics. On the contrary, one center used a strict interpretation of infection criteria, considered almost all patients infected, and treated these patients with antibiotics (figures 1 and 2). The central coordinating group for the trial decided not to exclude the patients at this center from analysis, since there was no overt violation of the protocol and the bias affected both treatment arms, increasing total rates of infection but not modifying the accuracy of the comparison.
S625
Multicenter Trial of Prophylaxis with Clindamycin Plus Aztreonam or Cefotaxime in Gynecologic Surgery Costantino Mangioni, Luigi Bianchi, Pier F. Bolis, Alberto M. Lomeo, Francesco Mazzeo, Luigi Ventriglia, and Salvatore Scalambrino
From the Department of Obstetrics and Gynecology, S. Gerardo Hospital, Monza; the Department of Obstetrics and Gynecology, Cosenza; the Obstetric and Gynecological Clinic, University of Pavia, Pavia; the Department of Obstetrics and Gynecology, Potenza; the Institute of Surgery, University of Naples, Naples; and Medical Direction, Squibb-Italia, Rome, Italy
The incidence of infective complications following gynecologic surgery differs according to the type of procedure. With vaginal hysterectomy, for example, flora at the opening of the vagina, including both gram-positive and gram-negative aerobes and anaerobes, may contaminate the surgical field and cause infection at the operative site. Infection can also result from complementary procedures, such as colposuspension for urinary-stress incontinence, anterior and posterior repair for vaginal prolapse, exeresis of parametria and pelvic lymph nodes for uterine cancer, and multiple endoperitoneal and retroperitoneal biopsies for ovarian cancer; any of these procedures increases both the duration of surgery and the area of the surgical field, thus increasing the risk of infection as well. Morbidity attributable to infection, including both that at the operative site (abdominal, vaginal, or wound infection) and that due to fever, can be largely prevented with appropriate surgical procedures - such as disinfection of the skin and vagina, mechanical preparation of the bowel, and management of drainage of the bladder and of the spaces created by the surgery-and with antibiotic prophylaxis.
Reprints and correspondence: Professor Costantino Mangioni, Department of Obstetrics and Gynecology, S. Gerardo Hospital, Via Solferino 16, 20052 Monza (Milan), Italy. Reviews of Infectious Diseases 1991;13(Suppl7):8621-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0049$02.00
The incidence of infective complications following abdominal and vaginal hysterectomy decreases with adequate antibiotic prophylaxis to as low as 12%-32 % of the rate expected without perioperative antibiotic therapy [1-4]. An antibiotic appropriate for prophylaxis must be active against those pathogens most likely to be involved in postoperative infections and must reach therapeutic concentrations in tissues before the time of possible bacterial contamination. Such concentrations must then be maintained from the time of surgical opening to the sealing of the wound, which occurs 1'\.13 hours after suture. Prolongation of prophylaxis beyond the first postoperative day offers no additional protection. In recognition of the need for appropriate antibiotic prophylaxis, a prospective, randomized, multicenter clinical trial was undertaken to compare aztreonam (which is selectively active against gram-negative bacilli [5]) with cefotaxime (which is active against gram-positive and gram-negative aerobes [6]) in terms of safety and efficacy for prophylaxis of infective complications following abdominal and vaginal hysterectomy. Both agents were given in combination with clindamycin, which is known for its activity against anaerobic pathogens. In this trial the two regimens were administered in three doses, with the first dose given at the induction of anesthesia. In many studies this abbreviated schedule has decreased the incidence of postoperative infective episodes, with a reduction of the adverse reactions and the costs associated with long-term treatment, which is widely used in Italy.
Downloaded from http://cid.oxfordjournals.org/ at University of Wyoming Libraries on March 30, 2015
A prospective, randomized, multicenter study was conducted on the efficacy and safety of two prophylactic antibiotic regimens in both abdominal and vaginal hysterectomy. Patients received three intravenous doses of clindamycin (900 mg) plus either aztreonam (1 g) or cefotaxime (1 g); the doses were given at the induction of anesthesia and 8 and 16 hours later. A total of 170 patients undergoing abdominal hysterectomy and 142 patients undergoing vaginal hysterectomy completed the trial and were evaluated. Following abdominal hysterectomy infections occurred at the operative site in 1.2% of patients given a regimen including aztreonam and in 4.7% of those given a regimen including cefotaxime; the difference between the two groups was not significant. Neither were significant differences observed in the incidence of fever, the incidence of bacteriuria, the need for postoperative antibiotics, or the duration of postoperative hospitalization, although results were slightly better for patients receiving clindamycin plus aztreonam. Followingvaginal hysterectomy,slightly but not significantly better results for the same parameters were obtained in the group given clindamycin plus cefotaxime. Diarrhea was the only adverse reaction attributable to antibiotic treatment and occurred more frequently in patients given cefotaxime. It was concluded that the two regimens were similarly effective and safe in preventing infections following hysterectomy.
RID 1991;13 (Suppl 7)
Mangioni et al.
S622
Patients and Methods
Table 1. Characteristics of patients undergoing abdominal hysterectomy and receiving prophylaxis with aztreonam/c1indamycin (AC) or cefotaxime/c1indamycin (CC).
I
Value for indicated group Characteristic* Evaluability: no. of patients Age (y): mean ± SD (range) General condition: no. (%) of patients Good Fair Poor Postmenopause: no. (%) of patients Diagnosis of neoplasia: no. (%) of patients Preoperative hospital stay (d): mean ± SD (range) Surgical procedure: no. (%) of patients Total hysterectomy Radical hysterectomy Hysterectomy plus appendectomy Duration of surgery (min): mean ± SD (range) Duration of postoperative catheterization (d): mean ± SD (range)
* Each category is folJowed by
AC 80 52 ± 11 (25-82)
CC 90 50 ± 8 (27-74)
Ch.a~acteristics of patients undergoing vaginal hysterectomy and receiving prophylaxis with aztreonam/c1indamycin (AC) or cefotaxime/c1indamycin (CC).
Table 2.
Value for indicated group 72 (90.0) 8 (10.0) 0(...)
75 (83.3) 14 (15.6) 1 (1.1)
29 (36.3)
37 (41.1)
23 (28.8)
22 (24.4)
8 ± 6 (1-26)
7 ± 6 (1-30)
74 (92.5) 6 (7.5)
81 (90.0) 9 (10.0)
13 (16.2)
11 (12.2)
100 ± 50 (35-200)
4 ± 3 (1-14)
92 ± 49 (40-240)
4 ± 3 (1-17)
an indication of how the data are expressed.
Characteristic
AC
Evaluability: no. of patients 72 Age (y): mean ± SD (range) 59 ± 11 (40-83) General condition: no. (%) of patients 54 (75.0) Good 18 (25.0) Fair 0(...) Poor Postmenopause: no. (%) of 51 (70.8) patients Diagnosis of neoplasia: 31 (43.1) no. (%) of patients Preoperative hospital stay (d): mean ± SD 7 ± 6 (1-25) (range) Duration of surgery (min): 125 ± 40 (45-240) mean ± SD (range) Duration of postoperative catheterization (d): 4 ± 2 (1-10) mean ± SD (range)
* Each category
CC 70 56 ± 12 (35-78)
53 (75.7) 17 (24.3) 0(...) 46 (65.7) 27 (38.6)
7 ± 6 (1-32) 115 ± 38 (45-180)
4 ± 2 (1-11)
is folJowed by an indication of how the data are expressed.
Downloaded from http://cid.oxfordjournals.org/ at University of Wyoming Libraries on March 30, 2015
'Between October 1987 and April 1988, women ~25 years of age who were scheduled for vaginal or abdominal hysterectomy at any of five Italian centers were randomly assigned to receive three perioperative doses of clindamycin (900 mg) plus either aztreonam (l g) or cefotaxime (l g). All medications were given intravenously at the induction of anesthesia and 8 and 16 hours later. Exclusion criteria included allergy to cephalosporins, hepatic or renal dysfunction, established infection, or antibiotic use within the week preceding surgery. Patients with granulocytopenia and those receiving corticosteroid therapy also were excluded. Of the 189 patients enrolled in the abdominal hysterectomy group, 89 were randomized to treatment with aztreonam/clindamycin and 100 to treatment with cefotaxime/clindamycin. Subsequently, nine aztreonam-treated patients and 10 cefotaxime-treated patients were excluded because of intraoperative changes in the planned procedure or use of antibiotics during postoperative hospital stay without a precise diagnosis of infection; thus the final population studied included 80 patients given aztreonam/clindamycin and 90 given cefotaxime/ clindamycin. The two groups were comparable in terms of age, general condition, menopausal status, diagnosis, and duration of preoperative hospitalization, although there were differences in preoperative management techniques used at the various centers (table 1).
Of 153 patients undergoing vaginal hysterectomy with or without vaginal repair, 75 were assigned to aztreonam/clindamycin therapy and 78 to cefotaxime/clindamycin treatment. Three and eight patients from these groups, respectively, were eventually excluded on the basis of the criteria described for the abdominal hysterectomy group; thus the evaluable population consisted of 72 patients given aztreonam/clindamycin and 70 given cefotaxime/clindamycin. There were no statistically significant differences between the two cohorts in age, general condition, menopausal status, diagnosis, or duration of preoperative hospital stay (table 2). Vaginal hysterectomy was associated with anterior and posterior repair in four cases in each treatment group. Routine perioperative care included daily examination and recording of vital signs and body temperature every 8 hours. Microbiologic controls varied with the procedure. Urine samples for culture were taken from all patients preoperatively, on the third postoperative day, at the removal of the bladder catheter, and at discharge from the hospital. For patients undergoing vaginal hysterectomy, vaginal swab specimens were taken preoperatively, on the fourth or fifth postoperative day, and at discharge from the hospital. For patients undergoing abdominal hysterectomy, wound swab samples were taken at closure of the abdominal wall, on the fourth or fifth postoperative day, and at discharge from the hospital. After discharge (39-46 days after surgery), patients underwent a final clinical evaluation to rule out the development of late infective morbidity. At that time vaginal swab samples and urine samples were collected for culture from all patients. For the purposes of this study, infection of the abdominal
Gynecologic Surgery
RID 1991;13 (Suppl 7)
uria occurred after the third postoperative day and were considered to be attributable primarily to the persistence of bladder drainage, not to failure of prophylaxis. At 36.2 % and 40.0%, respectively, the incidences of postoperative fever in the two groups may seem high, but these figures include cases of mild hyperpyrexia, which is frequent in this kind of patient and often resolves spontaneously without antibiotic therapy. Wide differences were observed among the five centers involved in the study with regard to the need for postoperative antibiotic therapy. Only one center, for example, used locally administered antibiotics in the treatment of serous vaginal discharge with a positive swab culture and without other symptoms of vaginal infection (figure 1). It was determined that the variability among centers in the duration of postoperative hospitalization reflected differences in postoperative management rather than in infective morbidity. Vaginal hysterectomy. Following vaginal hysterectomy, results were slightly but not significantly better in the cefotaxime/clindamycin group with regard to infection at the operative site, fever, the need for postoperative local or systemic antibiotic therapy, and bacteriuria (table 4). The high incidence of vaginal wall infections is probably due to a different
50
Results
43
Abdominal hysterectomy. Surgical wound infections following abdominal hysterectomy occurred in 1. 2 % of patients given aztreonam/clindamycin and in 4.7 % of those given cefotaxllne/clindamycin (difference not significant). Although the results (all parameters of infection) were slightly better for patients treated with aztreonam/clindamycin, no significant differences between the regimens were observed in the incidence of fever, the incidence of bacteriuria, the need for postoperative antibiotics, or the duration of postoperative hospitalization (table 3). Bacteriuria was detected in 12.5 % and 11.1 % of patients in the aztreonam/clindamycin and cefotaxime/clindamycin groups, respectively. The majority (90%) of cases ofbacteriTable 3. Postoperative events in patients undergoing abdominal hysterectomy and receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). Value for indicated group*
Postoperative event Wound infection Vaginal cuff infection Bacteriuria Fever Need for antibiotic therapy Hospital stay
AC (n = 80) 1 (1.2) 0(...)
10 (12.5) 29 (36.2) 15 (18.8) 10 ± ~ (5-46)
l1li
40
* All values except those for hospital stay are expressed as the number (percentage) of patients; values for hospital stay are expressed as the mean number of days ± SD (range).
LOCAL
•
BOTH
10
CENTERS
Figure 1. Antibiotic treatment, by center, in patients undergoing abdominal hysterectomy.
Table 4. Postoperative events in patients undergoing vaginal hysterectomy and receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). Value for indicated group*
(n = 90)
(3.3) (1.1) (11.1) (40.0) (23.3) ± 3 (6-29)
SYSTEMIC
IIGJJJ
20
CC 3 1 10 36 21 10
EVALUABLE PATIENTS
~
Postoperative event Vaginal wall infection Bacteriuria Fever Need for antibiotic therapy Hospital stay
(n
11 24 29 27
CC
AC = 72)
(15.3) (33.3) (40.3) (37.5) 8 ± 3 (2-15)
(n = 70)
6 19 23 19 9
(8.6) (27.1) (32.9) (27.1) ± 3 (4-21)
* All values except that for hospital stay are expressed as the number (percentage) of patients; values for hospital stay are expressed as the mean number of days ± SD (range).
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wound (only for abdominal hysterectomy) or the vaginal wall (only for vaginal hysterectomy) was defined as purulent discharge with a positive or negative culture, serous discharge with a positive culture, or erythema and/or induration requiring systemic antibiotic therapy. Pelvic cellulitis was defined as fever, pelvic pain, edema, induration and pain at pressure of the vaginal cuff, and smelly discharge without localized purulence of the vaginal cuff. Pelvic abscess was documented by laparoscopy, laparotomy, ultrasound, or operative drainage of pus. Vaginal cuff abscess was defined as fever, pelvic pain, and purulent discharge from the vaginal cuff. Fever was defined as a temperature of ~37.5°C on any day except during the first 24 hours after surgery, regardless of association with other signs or symptoms of infection. Finally, bacteriuria was defined as a positive culture with ~1()5 cfu/mL in a midstream urine specimen, ~102 cfu/mL in a catheter urine specimen obtained during irrigation, and ~1()4 cfu/mL in a catheter urine specimen, with or without other signs of infection. Infection that occurred distal to the surgical site (i.e., bronchopneumonia or phlebitis) was recorded but is not considered further in this preliminary report. For statistical analysis of demographic and perioperative data as well as results, significance was established at P < .5.
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Mangioni et al.
60
-
~
SYSTEMIC
D
LOCAL
•
BOTH
40
'" ffi
~
2i
30
20
10
CENTERS
Figure 2. Antibiotic treatment, by center, in patients undergoing vaginal hysterectomy.
interpretation of the protocol definition at a single center. In fact, a slight serous discharge and a positive vault swab are quite commonin these patients on about the fourthpostoperative day, at which time the vaginal flora returns to its preoperative state. Using a strict interpretation of the protocol definition, onecenterconsidered all patients withtheseclinical and microbiologic features to be infected. Thehighpercentage of patients treated with local and/or systemic antibiotics at that center also reflects this interpretation (figure 2). In contrast, other centers more often related the failure of prophylaxisto the presence of localand systemic signsand symptoms of infection.
Discussion Despite the different in vitro antimicrobial profiles of aztreonamand cefotaxime, resultswere not significantly different when each of these two drugs was used with clindamycin for short-term prophylaxis in this comparative trial. Theoretically, aztreonam/c1indamycin should be more protective than cefotaxime/c1indamycin, since aztreonam shows higher
Table 5. Pathogens isolated from sites of infection following abdominal or vaginal hysterectomy in patients receiving prophylaxis with either aztreonam plus clindamycin (AC) or cefotaxime plus clindamycin (CC). No. of isolates from indicated infection in indicated group Wound infection Pathogen Gram-positive aerobes Gram-positive cocci Staphylococcus aureus I3-Hemolytic Streptococcus Streptococcus agalactiae Streptococcus faecalis Gram-negative aerobes Escherichia coli Enterobacter species Enterobacter aerogenes Enterobacter cloacae Klebsiella species Proteus species Proteus mirabilis Pseudomonas species Pseudomonas aeruginosa Not identified
Vaginal wall infection
Bacteriuria
Total
AC
CC
AC
CC
AC
CC
AC
CC
0 0 0 0 0
0 0 0 0 1
1 0 0 0 2
0 0 0 0 2
0 2 1 1 5
0 0 0 0 0
1 2 1 1 7
0 0 0 0 3
1 0 0 0 0 0 0 0 0 0
1 1 0 0 0 0 0 0 0 0
11
2 0 0 0 1 1 0 2 0 0
10
17 0 1 0 1 2 0 8 1 1
22 0 0 1 0 2 1 2 1 13
20 1 1 0 2 3 0
0 0 1 0 0 0 0 0 0
0 0 0 0 2 1 2 1 13
10 1 1
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The discussion in the preceding sectionregardingfever and bacteriuria is applicable to patients undergoing vaginal hysterectomy as well as to those undergoing abdominal hysterectomy. Pathogens. No anaerobes were isolated from infection sites; gram-negative aerobes were isolated more frequently than were gram-positiveorganisms (table 5). Gram-positive bacilliwereisolatedonly from patientsgivenaztreonam, and Streptococcus faecalis represented66 % of all gram-positive isolates. Gram-negative bacilliwereisolated more frequently after prophylaxiswith cefotaxime/clindamycin. Escherichia coli and Pseudomonas species were the most frequently isolated bacteria, representing 76% and 10%, respectively, of the gram-negative isolates from aztreonam-treated patients and 53 % and 29 %, respectively, of those from cefotaximetreated patients. Adverse reactions. Diarrheaunrelatedto pseudomembranous colitis was the only adverse reaction that was related to the prophylactic antibiotics. The rate of its occurrencewas 0.7% and 2.5 % in the aztreonam and cefotaxime groups, respectively.
57 EVALUABLE PATIENTS
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Gynecologic Surgery
The two schedules of prophylaxis reviewed were found to be safe. Mild diarrhea unrelated to pseudomembranous colitis was the only adverse reaction and was more frequent with cefotaxime than with aztreonam. In conclusion, aztreonam and cefotaxime-in combination with clindamycin - seem to be equally effective in preventing postoperative infections in patients undergoing abdominal and vaginal hysterectomy, but additional analyses are needed to determine whether these observations hold for subgroups of patients. References 1. Polk BF, Tager IB, Shapiro M, Goren-White B, Goldstein P, Schoenbaum Sc. Randomizedclinical trial of perioperative cefazolinin preventing infection after hysterectomy. Lancet 1980;1:437-41 2. Breeden JT, Mayo JE. Low dose prophylactic antibiotics in vaginal hysterectomy. Obstet Gynecol 1974;43:379-85 3. Micka! A, Curole 0, Lewis C. Cefoxitin sodium: double-blind vaginal hysterectomy prophylaxis in premenopausal patients. Obstet Gynecol 1980;56:222-5 4. Ledger WJ, Gee C, Lewis WP. Guidelines for antibiotic prophylaxis in gynecology. Am J Obstet Gynecol 1975;121:1038-45 5. Paradelis AG, Stathopoulos AG, TselentisJ, Delidou K, Stavraksi A, Crassaris LG. Comparative antibacterial activity of aztreonam and other antimicrobial agents against gram-negative microorganisms. Chemioterapia 1985;4(Suppl 1):14-22 6. Forsgren A. Comparative in vitro activity of first, second and third generation cephalosporins. Acta Pathologica et Microbiologica Scandinavica, Section B: Microbiology 1981;89:221-5
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in vitro activity against gram-negative bacilli and the efficacy of cefotaxime against gram-positive bacteria should add nothing to that of clindamycin. The lack of statistically significant differences in infection rates after prophylaxis with either agent plus clindamycin conflicts with this hypothesis, although this finding could be explained by the wide differences in the incidence of infection at the various participating centers, by the type of analysis done, or by the sample of patients studied. In fact, factors such as age, menopausal status, and use of aggressive surgical procedures seem to influence the effect of prophylaxis. Moreover, some problems arose from different interpretations ofinfection criteria and different therapeutic approaches among the centers participating in the trial. For example, vaginal wall infection was defined in the study protocol as serous discharge with a positive culture-a situation fairly common in patients who have undergone vaginal hysterectomy. Four centers interpreted this definition in a broad sense, considering as infected only those patients with major systemic or local signs and rarely treating patients who had no such signs with antibiotics. On the contrary, one center used a strict interpretation of infection criteria, considered almost all patients infected, and treated these patients with antibiotics (figures 1 and 2). The central coordinating group for the trial decided not to exclude the patients at this center from analysis, since there was no overt violation of the protocol and the bias affected both treatment arms, increasing total rates of infection but not modifying the accuracy of the comparison.
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