journal
of Hospital
The value
Injection
of oral
C. S. McArdle’,
’ University Hospital,
(1991)
19 (Supplement
C),
59-64
antibiotic prophylaxis tract surgery
C. G. Morran2, J. D. Sleigh” and
in biliary
L. Pettit’, C. G. Gemmell”, G. S. Tillotson’
Department of Surgery, Royal Infirmary, Glasgow, 2C’rosshouse Kilmarnock, Ayrshire, 3Department of Bacteriology, Royal In.rmary, Glasgoul and “Bayer (UK) Ltd, Newbuq
Summary:
In this study the relationship between the presence or absence of organisms in bile or on closing wound swabs and the subsequent development of wound sepsis was confirmed. There was no significant difference in the incidence of septic complications among three treatment groups in which cefuroxime (iv) and ciprofloxacin (iv or oral) were administered. Consideration of costs attributable to the choice of antibiotic prophylaxis suggests that oral ciprofloxacin in biliary tract surgery may offer significant advantages. Keywords: infection;
Cefuroxime; biliary surgery.
ciprofloxacin;
prophylaxis;
bile
culture;
wound
Introduction The value of antibiotic prophylaxis in biliary tract surgery is now well-established. A recent overview confirmed that (a) antibiotic prophylaxis in biliary tract surgery is effective and (b) there were no differences in wound infection rates between patients treated with firstsecond- or third-generation cephalosporins, or those treated with single dose compared with multiple dose regimens. It was concluded that the choice of treatment could largely be made on the basis of cost. Ciprofloxacin is a 4-quinolone antibacterial agent which acts by inhibiting DNA gyrase, a bacterial topisomerase which is responsible for negative supercoiling of DNA within the bacterial cell.’ It has an extended antibacterial spectrum and is highly active against both Gram-negative and Gram-positive bacteria.2 Of particular interest, however, is the fact that it achieves high tissue and bile levels following oral administration.3x” Clearly the use of oral ciprofloxacin for prophylaxis would offer significant advantages in terms of cost and ease of administration. The aim of the present study was, therefore, to compare the effect of ciprofloxacin with that of cefuroxime, the antibiotic currently used in our Unit, for prophylaxis of wound infection following biliary tract surgery.
60
C. S. McArdle
et al.
Patients and methods Consecutive patients undergoing biliary tract surgery were randomly allocated to receive one of the following three regimens: (a) cefuroxime 1.5 mg intravenously (iv) on induction of anaesthesia; (b) ciprofloxacin 200 mg iv on induction of anaesthesia; (c) ciprofloxacin 750 mg orally one hour before anaesthesia. The choice of abdominal incision and technique of cholecystectomy were at the discretion of the surgeons; all drains were brought out through separate stab wounds. During surgery, a sample of bile and a closing wound swab were obtained for bacteriological culture. Samples were transported immediately to the laboratory and incubated under aerobic, microaerophilic and anaerobic conditions for 48 h. Culture media for bile and wound specimens included 6% horse blood agar, 6% horse blood agar incorporating gentamicin sulphate (15 mg I-‘), MacConkey agar and Robertson’s cooked meat broth. Any bacteria isolated were identified by API systems (API-bioMerieux, Basingstoke, UK) and their susceptibility to various antimicrobials measured by the Stokes technique. Wounds were assessed daily by a single observer until the patient was discharged; at their first return visit, usually 4 weeks after leaving hospital, patients were also questioned about the presence or absence of any wound discharge after leaving hospital. Wound sepsis was defined as the presence of pus, either discharging spontaneously or requiring drainage. Major wound sepsis was defined as the discharge of pus with constitutional disturbance. Patient assessment data was subjected to categorical data analysis and testing using the x2 and Kendall’s z statistical tests. A 5% level of significance was adopted throughout. The study was approved by the Hospital Ethical Committee and informed consent obtained. Results Two hundred and eight patients were included in the study, of whom 193 were evaluable. The groups were comparable in terms of sex, age, weight, preoperative haematological and biochemical parameters (Table I), the extent of surgery, the type of incision and degree of urgency (Table II). Approximately one-third (56/193) of patients had positive bile cultures; a similar proportion of patients (68/193) had positive closing wound swabs (Table III). The commonest organisms isolated from bile were members of the Enterobacteriaceae, Enterococcus faecalis and coagulase-negative staphylococci (Table IV). The commonest organisms isolated from closing wound swabs were coagulase-negative staphylococci, whilst postoperative wound swabs yielded Gram-positive cocci, in particular Staphylococcus aureus.
Antibiotic Table
I. Demographic
No. of patients Male:female Mean age (years) Mean weight (kg) Haemoglobin (g dl-‘) Bilirubin C’rea Albumin
Table
II.
prophylaxis
C’ompavison
in
comparison
69 I’):50 52 68 134 40 5,s -II
67 17:so 51 63 13.4 37 -4.0 42
72 21:51 53 66 134 16 5.0 II
of surgical
procedures
by treatment
Ciprofloxacin (iv)
69 so
67 50
4
3 1 4 6 7
i 0 5 -F
Ciprotloxacin (oral) 7? 51 H 2 h h 3 2
45 31
44 12
79 21
82 18
8-l 16
of culture-positice
specimens
Cefuroxime (iv)
swab
group
49 38
take?z.from
Percentage
wound
groups Ciprotlosacin (oral)
Specimen
Bile Closing
oj trmtmerzt Ciproflosacin (iv)
No. of patients Cholecystectomy Exploration of common bile duct Bypass Additional procedure Complex Hepatic artery catheter Laparotomy & biops! Incision (‘X) Vertical Subcostal Urgency (%) Elective IJrger,t
II I. Incideme
61
surgery
Cefuroxime (iv)
Cefuroxime (iv)
Table
biliary
32 36
putients
peuopercztiw!\
incidence
Ciprofloxacin (iv) 33 45
Ciprofloxacin (oral) 32 2x
C. S. McArdle
62 Table Organism
IV.
Bacteria Bile
Coagulase-negative staphylococci
isolatedfrom Closing
14 20
Escherichia coli Enterococcus spp. (inc. E. faecalis) Clostridium perfringens Klebsiella spp. Staphylococcus aureus
et al. all specimens
wound swab
Postoperative swab
wound
47 7
15 7 :
Non-haemolytic streptococci Others
2 7
A correlation between positive bile and closing wound swabs and subsequent wound sepsis was demonstrated (Table V). This did not vary according to the prophylactic regimen used.
Table
V. Correlation of wound sepsis rates with culture of bile and closing wound swabs Wound
sepsis (%)
Bile culture Positive Negative Closing wound Positive Negative
22 10 swab 17 3
Wound sepsis occurred in 10% of evaluable patients. There was no difference in the incidence of wound infection and duration of postoperative stay among treatment groups (Table VI). Table
VI.
Incidence
ization
of postoperative wound infections and duration of hospitalamong patients undergoing biliary tract surgery Cefuroxime (iv)
Wound
Ciprofloxacin (iv)
Ciprofloxacin (oral)
infection (10.79%)
Mean postoperative stay (days)
9
(9.7(L)
(9.06%)
10
Adverse reactions were not reported in any of the treatment
9
groups.
Antibiotic
prophylaxis
in biliary
surgery
63
Discussion Postoperative sepsis remains a major cause for concern for all surgeons undertaking gastrointestinal tract surgery. Wound sepsis, though rarely fatal, causes considerable patient discomfort and significantly increases the risk of wound dehiscence or incisional hernia and prolongs the duration and cost of hospitalization. Wound sepsis may also be associated with more serious complications including deep intra-abdominal sepsis and septicaemia which do produce significant morbidity and may sometimes prove fatal. Any intra-abdominal procedure in which the integrity of the gastrointestinal tract is breached is likely to result in postoperative septic complications. Approximately 30% of patients undergoing biliary tract surgery have been shown to have positive bile cultures at the time of surgery,s the commonest organisms being members of the Enterobacteriaceae and streptococci. Without prophylaxis, the incidence of wound sepsis in such patients is c. 20%. Previous studies have shown that there is a close correlation between the presence of bacteria in the bile fluid at the time of surgery and the subsequent development of septic complications.h The principles of antibiotic prophylaxis are now vvell-established. The choice of antibiotic depends on the pathogenic microorganisms likely to be present in the bile at the time of surgery, vvhile the mode of administration should be chosen to achieve high tissue levels at the time of surgery, without provoking toxicity or precipitating the emergence of resistant organisms. In order to achieve high tissue levels, antibiotics were usually administered parenterally. Randomized prospective controlled trials undertaken in the late 1970s clearly demonstrated the value of prophylactic antibiotics. In most studies wound sepsis fell from C. 20% in the control group to less than 5% in the treated group. ’ These findings have been widely accepted and have been absorbed into routine surgical practice. Since then, a wide range of antibiotics have been studied but none has offered an obvious advantage. In the recent Dutch meta-analysis,” the results of 42 randomized, controlled trials with a total of 4129 patients were analysed. Patients treated with antibiotics were compared with patients who did not receive antibiotics. In the control groups the overall wound infection rate was 15%, ranging from 3 to 47%. There was an overall difference of 9% in favour of antibiotic prophylaxis. Comparison of wound infection rates in patients treated with first generation vs second or third generation cephalosporins (1128 patients in 11 trials), as well as single-dose versus multiple-dose regimens (1226 patients in 15 trials) did not show significant difference, either individually or in overall evaluation. ‘I’he authors, therefore, concluded that the choice of antibiotic should be governed by cost. These costs should include all the concomitant ‘on costs’ such as disposables, nursing and medical time, pharmacy labour etc., in addition to the basic price of the antibiotic prescribed.
C. S. McArdle
64
et al.
References 1. Zeiler 2. 3.
4. 5.
6. 7. 8.
HJ, Grohe K. The in-vitro and in-vivo activity of ciprofloxacin. Eur J Clin Microbial 1984; 3: 339-343. Felmingham D, O’Hare MD, Robbens MJ er al. Comparative in-vitro studies with 4-quinolone antimicrobials. Drugs Exp Clin Res 1985; 11: 317-329. Dan M, Werbin M, Gorea A, Nagar H, Berger SA. Concentrations of ciprofloxacin in human liver, gallbladder, and bile following oral administration. Eur J Clin Pharmacol 1987; 32 (Suppl. 1): S125. Grozinger KH, Beermann D, Elsas S. Biliary kinetics of ciprofloxacin in humans. Rev Infect Dis 1988; 11 (Suppl. 5): S1132-1133. Cox JL, Helfrich LR, Pass HI, Osterhaut S, Shingleton WW. The relationship between biliary tract infections and post-operative complications. Surg Gynecol Obstetr 1978; 146: 233-236. Chetlin SH, Elliott DW. Pre-operative antibiotics in biliary surgery. Arch Surg 1973; 107: 319-323. Karran SJ, Allen S, Lewington U, Seal D, Reeves D. Cefuroxime prophylaxis in biliary surgery. R Sot Med Int Congr Symp Series 1980; 38: 27-34. Meijer WS, Schmitz PIM and Jeekel J. Meta-analysis of randomised controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990; 77: 283-290.
of Hospital
The value
Injection
of oral
C. S. McArdle’,
’ University Hospital,
(1991)
19 (Supplement
C),
59-64
antibiotic prophylaxis tract surgery
C. G. Morran2, J. D. Sleigh” and
in biliary
L. Pettit’, C. G. Gemmell”, G. S. Tillotson’
Department of Surgery, Royal Infirmary, Glasgow, 2C’rosshouse Kilmarnock, Ayrshire, 3Department of Bacteriology, Royal In.rmary, Glasgoul and “Bayer (UK) Ltd, Newbuq
Summary:
In this study the relationship between the presence or absence of organisms in bile or on closing wound swabs and the subsequent development of wound sepsis was confirmed. There was no significant difference in the incidence of septic complications among three treatment groups in which cefuroxime (iv) and ciprofloxacin (iv or oral) were administered. Consideration of costs attributable to the choice of antibiotic prophylaxis suggests that oral ciprofloxacin in biliary tract surgery may offer significant advantages. Keywords: infection;
Cefuroxime; biliary surgery.
ciprofloxacin;
prophylaxis;
bile
culture;
wound
Introduction The value of antibiotic prophylaxis in biliary tract surgery is now well-established. A recent overview confirmed that (a) antibiotic prophylaxis in biliary tract surgery is effective and (b) there were no differences in wound infection rates between patients treated with firstsecond- or third-generation cephalosporins, or those treated with single dose compared with multiple dose regimens. It was concluded that the choice of treatment could largely be made on the basis of cost. Ciprofloxacin is a 4-quinolone antibacterial agent which acts by inhibiting DNA gyrase, a bacterial topisomerase which is responsible for negative supercoiling of DNA within the bacterial cell.’ It has an extended antibacterial spectrum and is highly active against both Gram-negative and Gram-positive bacteria.2 Of particular interest, however, is the fact that it achieves high tissue and bile levels following oral administration.3x” Clearly the use of oral ciprofloxacin for prophylaxis would offer significant advantages in terms of cost and ease of administration. The aim of the present study was, therefore, to compare the effect of ciprofloxacin with that of cefuroxime, the antibiotic currently used in our Unit, for prophylaxis of wound infection following biliary tract surgery.
60
C. S. McArdle
et al.
Patients and methods Consecutive patients undergoing biliary tract surgery were randomly allocated to receive one of the following three regimens: (a) cefuroxime 1.5 mg intravenously (iv) on induction of anaesthesia; (b) ciprofloxacin 200 mg iv on induction of anaesthesia; (c) ciprofloxacin 750 mg orally one hour before anaesthesia. The choice of abdominal incision and technique of cholecystectomy were at the discretion of the surgeons; all drains were brought out through separate stab wounds. During surgery, a sample of bile and a closing wound swab were obtained for bacteriological culture. Samples were transported immediately to the laboratory and incubated under aerobic, microaerophilic and anaerobic conditions for 48 h. Culture media for bile and wound specimens included 6% horse blood agar, 6% horse blood agar incorporating gentamicin sulphate (15 mg I-‘), MacConkey agar and Robertson’s cooked meat broth. Any bacteria isolated were identified by API systems (API-bioMerieux, Basingstoke, UK) and their susceptibility to various antimicrobials measured by the Stokes technique. Wounds were assessed daily by a single observer until the patient was discharged; at their first return visit, usually 4 weeks after leaving hospital, patients were also questioned about the presence or absence of any wound discharge after leaving hospital. Wound sepsis was defined as the presence of pus, either discharging spontaneously or requiring drainage. Major wound sepsis was defined as the discharge of pus with constitutional disturbance. Patient assessment data was subjected to categorical data analysis and testing using the x2 and Kendall’s z statistical tests. A 5% level of significance was adopted throughout. The study was approved by the Hospital Ethical Committee and informed consent obtained. Results Two hundred and eight patients were included in the study, of whom 193 were evaluable. The groups were comparable in terms of sex, age, weight, preoperative haematological and biochemical parameters (Table I), the extent of surgery, the type of incision and degree of urgency (Table II). Approximately one-third (56/193) of patients had positive bile cultures; a similar proportion of patients (68/193) had positive closing wound swabs (Table III). The commonest organisms isolated from bile were members of the Enterobacteriaceae, Enterococcus faecalis and coagulase-negative staphylococci (Table IV). The commonest organisms isolated from closing wound swabs were coagulase-negative staphylococci, whilst postoperative wound swabs yielded Gram-positive cocci, in particular Staphylococcus aureus.
Antibiotic Table
I. Demographic
No. of patients Male:female Mean age (years) Mean weight (kg) Haemoglobin (g dl-‘) Bilirubin C’rea Albumin
Table
II.
prophylaxis
C’ompavison
in
comparison
69 I’):50 52 68 134 40 5,s -II
67 17:so 51 63 13.4 37 -4.0 42
72 21:51 53 66 134 16 5.0 II
of surgical
procedures
by treatment
Ciprofloxacin (iv)
69 so
67 50
4
3 1 4 6 7
i 0 5 -F
Ciprotloxacin (oral) 7? 51 H 2 h h 3 2
45 31
44 12
79 21
82 18
8-l 16
of culture-positice
specimens
Cefuroxime (iv)
swab
group
49 38
take?z.from
Percentage
wound
groups Ciprotlosacin (oral)
Specimen
Bile Closing
oj trmtmerzt Ciproflosacin (iv)
No. of patients Cholecystectomy Exploration of common bile duct Bypass Additional procedure Complex Hepatic artery catheter Laparotomy & biops! Incision (‘X) Vertical Subcostal Urgency (%) Elective IJrger,t
II I. Incideme
61
surgery
Cefuroxime (iv)
Cefuroxime (iv)
Table
biliary
32 36
putients
peuopercztiw!\
incidence
Ciprofloxacin (iv) 33 45
Ciprofloxacin (oral) 32 2x
C. S. McArdle
62 Table Organism
IV.
Bacteria Bile
Coagulase-negative staphylococci
isolatedfrom Closing
14 20
Escherichia coli Enterococcus spp. (inc. E. faecalis) Clostridium perfringens Klebsiella spp. Staphylococcus aureus
et al. all specimens
wound swab
Postoperative swab
wound
47 7
15 7 :
Non-haemolytic streptococci Others
2 7
A correlation between positive bile and closing wound swabs and subsequent wound sepsis was demonstrated (Table V). This did not vary according to the prophylactic regimen used.
Table
V. Correlation of wound sepsis rates with culture of bile and closing wound swabs Wound
sepsis (%)
Bile culture Positive Negative Closing wound Positive Negative
22 10 swab 17 3
Wound sepsis occurred in 10% of evaluable patients. There was no difference in the incidence of wound infection and duration of postoperative stay among treatment groups (Table VI). Table
VI.
Incidence
ization
of postoperative wound infections and duration of hospitalamong patients undergoing biliary tract surgery Cefuroxime (iv)
Wound
Ciprofloxacin (iv)
Ciprofloxacin (oral)
infection (10.79%)
Mean postoperative stay (days)
9
(9.7(L)
(9.06%)
10
Adverse reactions were not reported in any of the treatment
9
groups.
Antibiotic
prophylaxis
in biliary
surgery
63
Discussion Postoperative sepsis remains a major cause for concern for all surgeons undertaking gastrointestinal tract surgery. Wound sepsis, though rarely fatal, causes considerable patient discomfort and significantly increases the risk of wound dehiscence or incisional hernia and prolongs the duration and cost of hospitalization. Wound sepsis may also be associated with more serious complications including deep intra-abdominal sepsis and septicaemia which do produce significant morbidity and may sometimes prove fatal. Any intra-abdominal procedure in which the integrity of the gastrointestinal tract is breached is likely to result in postoperative septic complications. Approximately 30% of patients undergoing biliary tract surgery have been shown to have positive bile cultures at the time of surgery,s the commonest organisms being members of the Enterobacteriaceae and streptococci. Without prophylaxis, the incidence of wound sepsis in such patients is c. 20%. Previous studies have shown that there is a close correlation between the presence of bacteria in the bile fluid at the time of surgery and the subsequent development of septic complications.h The principles of antibiotic prophylaxis are now vvell-established. The choice of antibiotic depends on the pathogenic microorganisms likely to be present in the bile at the time of surgery, vvhile the mode of administration should be chosen to achieve high tissue levels at the time of surgery, without provoking toxicity or precipitating the emergence of resistant organisms. In order to achieve high tissue levels, antibiotics were usually administered parenterally. Randomized prospective controlled trials undertaken in the late 1970s clearly demonstrated the value of prophylactic antibiotics. In most studies wound sepsis fell from C. 20% in the control group to less than 5% in the treated group. ’ These findings have been widely accepted and have been absorbed into routine surgical practice. Since then, a wide range of antibiotics have been studied but none has offered an obvious advantage. In the recent Dutch meta-analysis,” the results of 42 randomized, controlled trials with a total of 4129 patients were analysed. Patients treated with antibiotics were compared with patients who did not receive antibiotics. In the control groups the overall wound infection rate was 15%, ranging from 3 to 47%. There was an overall difference of 9% in favour of antibiotic prophylaxis. Comparison of wound infection rates in patients treated with first generation vs second or third generation cephalosporins (1128 patients in 11 trials), as well as single-dose versus multiple-dose regimens (1226 patients in 15 trials) did not show significant difference, either individually or in overall evaluation. ‘I’he authors, therefore, concluded that the choice of antibiotic should be governed by cost. These costs should include all the concomitant ‘on costs’ such as disposables, nursing and medical time, pharmacy labour etc., in addition to the basic price of the antibiotic prescribed.
C. S. McArdle
64
et al.
References 1. Zeiler 2. 3.
4. 5.
6. 7. 8.
HJ, Grohe K. The in-vitro and in-vivo activity of ciprofloxacin. Eur J Clin Microbial 1984; 3: 339-343. Felmingham D, O’Hare MD, Robbens MJ er al. Comparative in-vitro studies with 4-quinolone antimicrobials. Drugs Exp Clin Res 1985; 11: 317-329. Dan M, Werbin M, Gorea A, Nagar H, Berger SA. Concentrations of ciprofloxacin in human liver, gallbladder, and bile following oral administration. Eur J Clin Pharmacol 1987; 32 (Suppl. 1): S125. Grozinger KH, Beermann D, Elsas S. Biliary kinetics of ciprofloxacin in humans. Rev Infect Dis 1988; 11 (Suppl. 5): S1132-1133. Cox JL, Helfrich LR, Pass HI, Osterhaut S, Shingleton WW. The relationship between biliary tract infections and post-operative complications. Surg Gynecol Obstetr 1978; 146: 233-236. Chetlin SH, Elliott DW. Pre-operative antibiotics in biliary surgery. Arch Surg 1973; 107: 319-323. Karran SJ, Allen S, Lewington U, Seal D, Reeves D. Cefuroxime prophylaxis in biliary surgery. R Sot Med Int Congr Symp Series 1980; 38: 27-34. Meijer WS, Schmitz PIM and Jeekel J. Meta-analysis of randomised controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990; 77: 283-290.
