Journal of Hospital Infection (1990) 1.5, 283-286
SHORT
REPORT
A comparison between imipenem and metronidazole prophylaxis against sepsis following appendicectomy D. S. Burkitt, Departments
of
I. A. Donovan,
SuivgeFy and Birmingham, Accepted
R. Wise
Microbiology, B18 7&H,
for publication
and
P. Lowe
Dudley Uk’
16 December
Road
Hospital
1989
Summary: A single preoperative dose of imipenem/cilastatin was compared with metronidazole for the prevention of infectious sequelae following emergency appendicectomy. Patients with established sepsis rcccivcd in or ampicillin, gentamicin and addition 72 h of either intravenous imipenem metronidazole postoperatively. Two hundred and sixty-eight patients were studied. Wound infection rate in low-risk patients was 9% for metronidazole and 8% for imipenem. When sepsis was already established intrapcritoneally the wound infection rate was 24% for the triple therapy regimen and 8% for imipenem. There was no statistically significant difference between the infection rates in the two groups of treatment whatever the state of the appendix, but there was a trend in favour of imipenem in those patients with a perforated appendix.
Keywords: Appendicitis;
imipenem/cilastatin;
metronidazole.
Introduction Imipenem is a carbapenem antibiotic combined with cilastatin, a reversible Cilastatin blocks the metabolism of inhibitor of a renal dipeptidase. imipenem thus maintaining the concentration of intact antibiotic in the of imipenem (Norrby et al. urine (Kahan et al., 1983). Th e b road spectrum 1983) suggests that it may be useful for prophylaxis of infection after appendicectomy where contamination with both aerobic and anaerobic pathogens may occur and might be more efficacious than the anti-anaerobic agent metronidazole which, as a recent review has shown, is currently often used on its own for this purpose (Krukowski et al., 1988).
Correspondence 7QH.
to: Mr I. A. Donovan,
Consultant
0195%6701/90/030283+04$03.00/0
Surgeon, Dudley Road Hospital, 0
283
1990
The
Birmingham
Hospital
InfccLiun
B18 Socirty
284
D. S. Burkitt Patients
et al.
and methods
The aim of this prospective randomized study was to compare a single preoperative intravenous dose of imipenem with metronidazole in preventing the infectious sequelae of emergency appendicectomy. All patients were given intravenously either 500 mg of metronidazole (M) or 500 mg of imipenem/cilastatin (I) on induction of anaesthesia. Those patients with a normal or inflamed appendix did not receive any further antimicrobial therapy. In cases where the appendix was gangrenous or perforated, 72 h of postoperative therapy was given. If the initial randomization was metronidazole then intravenous ampicillin 500 mg 6-hourly, metronidazole 500 mg 8-hourly and gentamicin 4-5 mg kg-’ day-’ in divided doses (AGM72) were prescribed. Those patients who were initially randomized to imipenem received a further treatment with 500 mg imipenem 6-hourly intravenously (172) for 72 hours. The use of topical antibiotics or antiseptics was prohibited. The use of peritoneal or wound drains was discouraged but if used they were to be brought out through a separate stab incision. All wounds were closed primarily. Randomization of treatment was based on a random number table and was established prior to the study. The randomized drug was placed in a sealed numbered box and the boxes were used sequentially. All patients over 12 y of age with a clinical diagnosis of acute appendicitis were considered for the study. Patients were excluded from the study if they were already taking antibiotics, were allergic to p-lactam antibiotics or metronidazole or were pregnant. After removal the appendix was cut in half; the distal half being sent for histology and the proximal half for bacteriological culture by routine procedures to note the sensitivity of isolates to imipenem. A sample of intraperitoneal pus, if present, was also sent for culture. The condition of the wound was assessed daily during the patients’ admission by an infection control nurse who was unaware of the treatment that had been given. Wound infection was defined as the discharge of pus from the wound either spontaneously or following surgical drainage (Ljungquist, 1964). Each patient was reviewed in outpatients by one of the authors (D.B.), between four and six weeks postoperatively. Failure to attend resulted in a further appointment, a telephone call or a questionnaire sent to the patient’s home. Approval for this study was obtained from the Ethics Committee of the West Birmingham Health Authority. Statistical analysis was performed using the x2 test with Yates correction when appropriate and Fisher’s Exact test. Results
Of three withdrawn
hundred patients initially due to protocol violations.
entered into the study, 32 were Of the 29 patients given prophylaxis
Imipenem
prophylaxis
in appendicitis
285
and subsequently withdrawn, nine had metronidazole, 13 had imipenem, four had AGM72 and three were given 172. There were eight wound three received metronidazole, one received infections in this group; imipenem, three had AGM72 and one was given 172. There were no deaths in the series nor any intra-abdominal abscesses. The mean age of the whole group was 25 yrs, 24.8 yrs in those without a wound infection and 26.5 yrs in those who developed sepsis. The age range was 12 to 81 yrs. The mean weight and surface area were higher in those patients who developed a wound infection than in those who did not: 64.8 kg ZIS. 61.8 kg and 1.72 m2 US. 1.66 m2 respectively. Of the 268 patients who completed the protocol, 217 had normal or acutely inflamed appendices for which 110 received metronidazole and 107 had imipenem. Of 5 1 patients with gangrenous or perforated appendices, 25 received AGM72 and 26 had 172. Table I shows the incidence of wound infection in the different groups. Only five of the 27 wound infections (19”/,) were diagnosed before the patient was discharged from hospital. There was no significant difference between the infection rate in the two groups whatever the state of the appendix. The 90% confidence limits for the overall 4% difference in infection rates are * 7%. In the perforated group where the difference in infection rates was greatest (39%) the 90% confidence limits are f 34%. Three patients had an adverse reaction to imipenem. Two developed phlebitis proximal to the cannula, and one patient developed a generalized rash after seven doses. Swabs for microbiology were taken from only 12/27 infected wounds as many of the infections only became apparent after the patients had left hospital. From two of the three patients who received metronidazole swabs grew coliforms, the other swab was sterile; of the five patients who received imipenem three were sterile and the others grew Staphylococcus aweus and Escherichia coli. From the four who received AGM72, Klebsiella sp., E. coli and mixed bowel flora were isolated. All isolates in all the patients in the study were reported by the laboratory to be sensitive to imipenem. Table
I. Comparison
Appendix
Normal Inflamed Gangrenous* Perforated* Total
of infection
rates in the two treatment appendix at operation
Metronidazole Number of Infection patients 51 59 13 12 135
%
groups according
to status of the
Imipenem/cilastation Number of Infection patients
%
30 77 8 18
0 9 0 2
0 12
:
16 3 0 50
16
12
133
11
8
antibiotics
(see Methods section for details).
8 2
*Patients in these categories also received postoperative
17
286
D. S. Burkitt
et al.
Discussion
In this study patients who received imipenem developed fewer wound infections than those in the other group, but the difference was not statistically significant. Only five of the 27 infections developed in hospital, the remainder occurring after discharge. The late presentation of infection in a large number of patients has been reported previously in other studies (Bates et al., 1980; Morris et al., 1980; Lau et al., 1983); presumably it is due to the antibiotics reducing the severity of the infectious process and delaying its presentation. There were no wound infections in those patients with gangrenous appendicitis. In view of the small sample size this may have occurred by chance but the view has been expressed (Krukowski et al., 1988) that these patients are not a particularly high risk group and may be managed in the same way as those with normal appendices or acute inflammation. This study lends support to that view. The strongest trend in favour of imipenem prophylaxis against wound infection was in those patients with perforated appendices (see Table I). Imipenem has the advantage over the combination therapy of the convenience of a single agent and apparent lack of major side effects. These results suggest that a large study of imipenem compared with standard practices should be undertaken in patients with perforated appendicitis to see if the trend described here becomes statistically significant. The authors are grateful to the following consultants who allowed us to study their patients: Professor P. G. Bevan, Mr A. Clain, Mr M. A. Feldman, Mr M. L. Obeid, Mr J. P. Neoptolemos and Mr M. J. R. Lee and to all their junior staff and the nurses of the Infection Control Unit. We are also grateful to Merck, Sharp and Dohme Ltd who provided the antibiotics for the study.
References Bates, T., Touquet, V. L. R., Tutton, M. K., Mahmoud, S. E. & Reuther, J. W. A. (1980). Prophylactic metronidazole in appendicectomy: a controlled trial. British Journal of Surgery 67, 547-550. Kahan, F. M., Kropp, H., Sundelof, J. G. & Birnbaum, J. (1983). Thienamycin: development of imipenem-cilastatin. ‘Journal of Antimicrobial Chemotherapy 12 (Suppl. D), l-35. Krukowski, Z. H., Irwin, S. T., Denholm, S. & Matheson, N. A. (1988). Preventing wound infection after appendicectomy: a review. British Journal of Surgery 75, 1023-1033. Lau, W. Y., Fan, S. T., Yiu, T. F., Poon, G. P. & Wong, S. H. (1983). Prophylaxis of post-appendicectomy sepsis by metronidazole and cefotaxime; a randomised, prospective and double blind trial. British Journal of Surgery 70, 670-672. Ljungquist, U. (1964). Wound sepsis after clean operations. Lancet 1, 1095-1097. Morris, W. T., Innes, D. B., Richardson, R. A. et al. (1980). The prevention of post-appendicectomy sepsis by Metronidazole and Cefazobi: a controlled double blind trial. Australian and New Zealand Journal of Surgery 50, 429433. Norrby, Sr., Bjarnegard, B., Ferber, F. & Jones, K. H. (1983). Pharmacokinetics of imipenem in healthy volunteers. Journal of Antimicrobial Chemotherapy 12 (Suppl. D), 109-124.
SHORT
REPORT
A comparison between imipenem and metronidazole prophylaxis against sepsis following appendicectomy D. S. Burkitt, Departments
of
I. A. Donovan,
SuivgeFy and Birmingham, Accepted
R. Wise
Microbiology, B18 7&H,
for publication
and
P. Lowe
Dudley Uk’
16 December
Road
Hospital
1989
Summary: A single preoperative dose of imipenem/cilastatin was compared with metronidazole for the prevention of infectious sequelae following emergency appendicectomy. Patients with established sepsis rcccivcd in or ampicillin, gentamicin and addition 72 h of either intravenous imipenem metronidazole postoperatively. Two hundred and sixty-eight patients were studied. Wound infection rate in low-risk patients was 9% for metronidazole and 8% for imipenem. When sepsis was already established intrapcritoneally the wound infection rate was 24% for the triple therapy regimen and 8% for imipenem. There was no statistically significant difference between the infection rates in the two groups of treatment whatever the state of the appendix, but there was a trend in favour of imipenem in those patients with a perforated appendix.
Keywords: Appendicitis;
imipenem/cilastatin;
metronidazole.
Introduction Imipenem is a carbapenem antibiotic combined with cilastatin, a reversible Cilastatin blocks the metabolism of inhibitor of a renal dipeptidase. imipenem thus maintaining the concentration of intact antibiotic in the of imipenem (Norrby et al. urine (Kahan et al., 1983). Th e b road spectrum 1983) suggests that it may be useful for prophylaxis of infection after appendicectomy where contamination with both aerobic and anaerobic pathogens may occur and might be more efficacious than the anti-anaerobic agent metronidazole which, as a recent review has shown, is currently often used on its own for this purpose (Krukowski et al., 1988).
Correspondence 7QH.
to: Mr I. A. Donovan,
Consultant
0195%6701/90/030283+04$03.00/0
Surgeon, Dudley Road Hospital, 0
283
1990
The
Birmingham
Hospital
InfccLiun
B18 Socirty
284
D. S. Burkitt Patients
et al.
and methods
The aim of this prospective randomized study was to compare a single preoperative intravenous dose of imipenem with metronidazole in preventing the infectious sequelae of emergency appendicectomy. All patients were given intravenously either 500 mg of metronidazole (M) or 500 mg of imipenem/cilastatin (I) on induction of anaesthesia. Those patients with a normal or inflamed appendix did not receive any further antimicrobial therapy. In cases where the appendix was gangrenous or perforated, 72 h of postoperative therapy was given. If the initial randomization was metronidazole then intravenous ampicillin 500 mg 6-hourly, metronidazole 500 mg 8-hourly and gentamicin 4-5 mg kg-’ day-’ in divided doses (AGM72) were prescribed. Those patients who were initially randomized to imipenem received a further treatment with 500 mg imipenem 6-hourly intravenously (172) for 72 hours. The use of topical antibiotics or antiseptics was prohibited. The use of peritoneal or wound drains was discouraged but if used they were to be brought out through a separate stab incision. All wounds were closed primarily. Randomization of treatment was based on a random number table and was established prior to the study. The randomized drug was placed in a sealed numbered box and the boxes were used sequentially. All patients over 12 y of age with a clinical diagnosis of acute appendicitis were considered for the study. Patients were excluded from the study if they were already taking antibiotics, were allergic to p-lactam antibiotics or metronidazole or were pregnant. After removal the appendix was cut in half; the distal half being sent for histology and the proximal half for bacteriological culture by routine procedures to note the sensitivity of isolates to imipenem. A sample of intraperitoneal pus, if present, was also sent for culture. The condition of the wound was assessed daily during the patients’ admission by an infection control nurse who was unaware of the treatment that had been given. Wound infection was defined as the discharge of pus from the wound either spontaneously or following surgical drainage (Ljungquist, 1964). Each patient was reviewed in outpatients by one of the authors (D.B.), between four and six weeks postoperatively. Failure to attend resulted in a further appointment, a telephone call or a questionnaire sent to the patient’s home. Approval for this study was obtained from the Ethics Committee of the West Birmingham Health Authority. Statistical analysis was performed using the x2 test with Yates correction when appropriate and Fisher’s Exact test. Results
Of three withdrawn
hundred patients initially due to protocol violations.
entered into the study, 32 were Of the 29 patients given prophylaxis
Imipenem
prophylaxis
in appendicitis
285
and subsequently withdrawn, nine had metronidazole, 13 had imipenem, four had AGM72 and three were given 172. There were eight wound three received metronidazole, one received infections in this group; imipenem, three had AGM72 and one was given 172. There were no deaths in the series nor any intra-abdominal abscesses. The mean age of the whole group was 25 yrs, 24.8 yrs in those without a wound infection and 26.5 yrs in those who developed sepsis. The age range was 12 to 81 yrs. The mean weight and surface area were higher in those patients who developed a wound infection than in those who did not: 64.8 kg ZIS. 61.8 kg and 1.72 m2 US. 1.66 m2 respectively. Of the 268 patients who completed the protocol, 217 had normal or acutely inflamed appendices for which 110 received metronidazole and 107 had imipenem. Of 5 1 patients with gangrenous or perforated appendices, 25 received AGM72 and 26 had 172. Table I shows the incidence of wound infection in the different groups. Only five of the 27 wound infections (19”/,) were diagnosed before the patient was discharged from hospital. There was no significant difference between the infection rate in the two groups whatever the state of the appendix. The 90% confidence limits for the overall 4% difference in infection rates are * 7%. In the perforated group where the difference in infection rates was greatest (39%) the 90% confidence limits are f 34%. Three patients had an adverse reaction to imipenem. Two developed phlebitis proximal to the cannula, and one patient developed a generalized rash after seven doses. Swabs for microbiology were taken from only 12/27 infected wounds as many of the infections only became apparent after the patients had left hospital. From two of the three patients who received metronidazole swabs grew coliforms, the other swab was sterile; of the five patients who received imipenem three were sterile and the others grew Staphylococcus aweus and Escherichia coli. From the four who received AGM72, Klebsiella sp., E. coli and mixed bowel flora were isolated. All isolates in all the patients in the study were reported by the laboratory to be sensitive to imipenem. Table
I. Comparison
Appendix
Normal Inflamed Gangrenous* Perforated* Total
of infection
rates in the two treatment appendix at operation
Metronidazole Number of Infection patients 51 59 13 12 135
%
groups according
to status of the
Imipenem/cilastation Number of Infection patients
%
30 77 8 18
0 9 0 2
0 12
:
16 3 0 50
16
12
133
11
8
antibiotics
(see Methods section for details).
8 2
*Patients in these categories also received postoperative
17
286
D. S. Burkitt
et al.
Discussion
In this study patients who received imipenem developed fewer wound infections than those in the other group, but the difference was not statistically significant. Only five of the 27 infections developed in hospital, the remainder occurring after discharge. The late presentation of infection in a large number of patients has been reported previously in other studies (Bates et al., 1980; Morris et al., 1980; Lau et al., 1983); presumably it is due to the antibiotics reducing the severity of the infectious process and delaying its presentation. There were no wound infections in those patients with gangrenous appendicitis. In view of the small sample size this may have occurred by chance but the view has been expressed (Krukowski et al., 1988) that these patients are not a particularly high risk group and may be managed in the same way as those with normal appendices or acute inflammation. This study lends support to that view. The strongest trend in favour of imipenem prophylaxis against wound infection was in those patients with perforated appendices (see Table I). Imipenem has the advantage over the combination therapy of the convenience of a single agent and apparent lack of major side effects. These results suggest that a large study of imipenem compared with standard practices should be undertaken in patients with perforated appendicitis to see if the trend described here becomes statistically significant. The authors are grateful to the following consultants who allowed us to study their patients: Professor P. G. Bevan, Mr A. Clain, Mr M. A. Feldman, Mr M. L. Obeid, Mr J. P. Neoptolemos and Mr M. J. R. Lee and to all their junior staff and the nurses of the Infection Control Unit. We are also grateful to Merck, Sharp and Dohme Ltd who provided the antibiotics for the study.
References Bates, T., Touquet, V. L. R., Tutton, M. K., Mahmoud, S. E. & Reuther, J. W. A. (1980). Prophylactic metronidazole in appendicectomy: a controlled trial. British Journal of Surgery 67, 547-550. Kahan, F. M., Kropp, H., Sundelof, J. G. & Birnbaum, J. (1983). Thienamycin: development of imipenem-cilastatin. ‘Journal of Antimicrobial Chemotherapy 12 (Suppl. D), l-35. Krukowski, Z. H., Irwin, S. T., Denholm, S. & Matheson, N. A. (1988). Preventing wound infection after appendicectomy: a review. British Journal of Surgery 75, 1023-1033. Lau, W. Y., Fan, S. T., Yiu, T. F., Poon, G. P. & Wong, S. H. (1983). Prophylaxis of post-appendicectomy sepsis by metronidazole and cefotaxime; a randomised, prospective and double blind trial. British Journal of Surgery 70, 670-672. Ljungquist, U. (1964). Wound sepsis after clean operations. Lancet 1, 1095-1097. Morris, W. T., Innes, D. B., Richardson, R. A. et al. (1980). The prevention of post-appendicectomy sepsis by Metronidazole and Cefazobi: a controlled double blind trial. Australian and New Zealand Journal of Surgery 50, 429433. Norrby, Sr., Bjarnegard, B., Ferber, F. & Jones, K. H. (1983). Pharmacokinetics of imipenem in healthy volunteers. Journal of Antimicrobial Chemotherapy 12 (Suppl. D), 109-124.
