- Email: [email protected]
Duration of antimicrobial prophylaxis in vascular surgery
Duration Michael
of Antimicrobial Prophylaxis Vascular Surgery
John C. Hall, FRACS, Keryn J. Christiansen, FRCPA, Marcel Goodman, FRACS, Lawrence-Brown, FRACS, Francis J. Prendergast, FRACS, Peta Rosenberg, BAppSc, Briony Mills, RN, Jane L. Hall, RN, Perth, Australia
BACKGROUND: This randomized clinical trial compares the incidence of wound infection after vascular surgery in patients who received prophylaxis using the same antibiotic as either a singledose or a multiple-dose regimen (until the lines/ drain tubes were removed, but not for more than 5 days). METHODS: Each of the 302 patients who entered the study received ticarcillin 3.0 g/clavulanate 0.1 g (Timentin) intravenously immediately after the induction of anesthesia. Patients randomized to the multiple-dose group received an average of 14.3 doses (range 9 to 20). RESULTS: The incidence of wound infections was 18% (28 of 153) for patients in the single-dose group and 10% (15 of 149) for patients in the multiple-dose group (P = 0.04; relative risk estimate = 2.00, 95% confidence interval = - 1.02 to 3.92). CONCLUSIONS: A multiple-dose antibiotic regimen, rather than single-dose therapy, provides optimal prophylaxis against wound infection for patients undergoing vascular surgery. Am J Surg. 1998; 175:87-90. 0 1998 by Excerpta Medica, Inc.
A
survey by the Vascular Society from the United Kingdom’ revealed wide variations in the use of prophylactic antibiotics. Many surgeons prefer extended regimens and some continue prophylaxis until all of the tubes and lines have been removed from the patient. Evidently, there are concerns that short periods of prophylaxis are inappropriate for patients who are often debilitated, have poor local tissue perfusion, undergo long and sometimes bloody procedures, and require the insertion of implants.* On the other hand, a single-dose of a shortacting agent is known to constitute appropriate prophylaxis for many other types of surgery.“4 Short-term therapy is attractive because of a reduced risk of side effects, a dimin-
From the Departments of General Surgery (JCH, PR, BM, JLH), Clinical Microbiology (KJC), and Vascular Surgery (MG, MLB, FJP), Royal Perth Hospital, Perth, Australia. This study was sponsored by SmithKline Beecham Pharmaceuticals Request for reprints should be addressed to Professor John C. Hall, University Department of Surgery, Royal Perth Hospital, Perth WA 6000, Australia. Manuscript submitted February 5, 1997 and accepted in revised form July 10, 1997.
0 1998 by Excerpta All rights reserved.
in
Medica,
Inc.
ished risk of generating bacterial resistance, as well as reduced acquisition and administration costs.’ In this clinical trial, we have compared the incidence of wound infection after vascular surgery following the administration of the same agent as either short-term prophylaxis or a multiple-dose regimen.
METHODS All adults undergoing vascular surgery within the Royal Perth Hospital between January 1993 and October 1995 were considered for study. For the purposes of this study, vascular surgery was defined as all open arterial procedures. Hence, endovascular procedures were excluded from study. All patients provided informed consent and the study was approved by the Ethics Committee at Royal Perth Hospital. Patients were allocated to one of the two treatment groups based upon computer-generated pseudo-random numbers: a blocked randomization technique was used with 10 patients in each cell. Relevant information was placed within sealed, opaque, serially numbered envelopes so that the entry of patients could be monitored to ensure compliance with the randomization procedure. Patients were not entered into the study until a decision had been made to perform surgery. A research nurse reviewed each theater list to ensure that eligible patients have been considered for entry into the trial. A number of putative risk factors were documented at baseline. Shock was defined according to the criteria listed by Dellinger et al,” ie, clinical signs of reduced peripheral perfusion plus any two of the following: systolic blood pressure (BP) ~80 mm Hg for 1 hour, pulse rate greater than 120 beats per (sinus minute rhythmia) for more than 1 hour, urine output less than 80 mL for any 4-hour period, or use of pressers to maintain the blood pressure for at least 1 hour. Obesity was determined by measurement of the body mass index (BMI)weight (kg) divided by the square of height (M). Insulindependent diabetes mellitus was defined as an episode of ketoacidosis or dependence on insulin, while non-insulindependent diabetes mellitus was indicated by a requirement for oral hypoglycemic medication. All patients received ticarcillin 3.0 g/clavulanate 0.1 g by slow intravenous (IV) infusion (over 30 minutes) immediately after the induction of anesthesia. Patients received an additional dose if the operation was prolonged beyond 3 hours. 7s Patients were randomized to receive the multipledose regimen (ie, until the lines are removed, but <:5 days) received ticarcillin 3.0 g/clavulanate 0.1 g IV at 6 hourly intervals after the initial dose, ie, for a maximum total of 20 doses. This study did not involve the use of placebo agents. 0002-961 O/98/$1 PII SOOO2-9610(97)00270-5
9.00
87
Nosocomial infections were managed in accordance with the institutional antibiotic guidelines. Attempts were made to standardize aspects of perioperative care. Patients received a preoperative chlorhexidine skin wash. There was uniformity in the closure of wounds and drain tubes did not exit through wounds. There was no local irrigation of tissues with solutions containing antimicrobial agents. Patients with postoperative diarrhea had their stools evaluated for the presence of enteropathogens. Wound Infection was defined as the discharge of pus or a serous discharge that contains pathogenic organisms. We also recorded other factors related to wound morbidity and the requirement for wound dressings. Graft infection was defined as an overt clinical event characterized by the need for aggressive interventions and confirmed by microbiology. Hospital stay was the total number of days (in part or whole) that the patient remained in hospital after surgery. The follow-up schedule was maintained until 42 days after the date of surgery. Data were entered into Access 2 (Microsoft, Redmond) and exported for analysis to SPSS for Windows Release 6.0 (SPSS Inc., Chicago, Illinois). A total sample size of 296 patients was based upon the assumption of an absolute difference of 15% in the rate of wound infection being of clinical interest, with the probability of a type I error set at 5% and the power at i’O%.’ Statistical analysis was according to an “intention to treat,” but patients who failed to undergo surgery were excluded from analysis. The proportions of patients with a wound infection in each group were compared using a two-tailed chi-square test with significance being defined as a probability of a type I error of less than 5%, and by declaration of the relative risk including the 95% confidence intervals. All other comparisons were considered to be hypothesis generating exercises.
RESULTS A total of 597 patients had either emergency or elective vascular surgery during the period of study. The reasons for exclusion from study were lack of consent (n = 115), administration of antimicrobial agents within 48 hours of surgery (n = 112), a history of hypersensitivity to penicillin (n = 45), and profound comorbidity (n = 23). In addition there were 10 patients who were randomized but failed to undergo surgery: these patients were excluded from analysis. Patients randomized to the multiple-dose regimen received 2,134 doses of ticarcillin 3.0 g/clavulanate 0.1 g. The median number of doses per patient was 13 (average 14.3, range 9 to 20). The groups were comparable with respect to putative risk factors for a wound infection both at baseline (Table I) and during the perioperative period (Table II). As might be expected, the patients tended to be elderly and dehilitated. Over 40% of the patients had undergone previous cardiovascular surgery and one quarter had a documented prior myocardial infarct. It is of interest that almost one third of the patients were current smokers and that 44% of the patients had more than one wound (the average number of wounds was 1.6). The overall incidence of wound infection was 14.2% (43/302). Patients receiving single-dose prophylaxis had a significantly greater incidence of wound infection than the patients who received the multiple-dose regimen-they 88
THE
AMERICAN
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VOLUME
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TABLE
I Patient
Characteristics
at Baseline Single Dose
Number of patients Female:male ratio Age, years Body mass index Current smoker Diabetes mellitus Insulin dependent Non-insulin dependent New York Heart Classification 1 2 3 4 Previous myocardial infarct Previous stroke Previous transient ischaemic attack Extent of lower limb disease No claudication Claudication Rest pain Tissue necrosis Previous cardiovascular surgery The values
are either
numbers
of pat/en& range
median values with the interquart,le
TABLE
153 37:116 70 (64-75) 25 (22-27) 53 (35)
149 46:103 69 (64-76) 24 (22-27) 39 (26)
3 (2) 31 (20)
3 (2) 16 (11)
19 75 48 11 38 20 15
32 59 43 5 37 16 9
(12) (49) (32) (7) (25) (13) (10)
(21) (40) (29) (3) (25) (11)
(6)
50 (33) 64 (42) 34 (22)
62 (42) 51 (34) 29 (19)
5 (3) 62 (41)
7 15) 65 (44)
Wtti percentages UT parenthesis.
in parentheses
or
II Operative
Events Single Dose (n = 153)
Operation Abdominal aortic aneurysm Groin-distal bypass Aorto-groin bypass Carotid endarterectomy Miscellaneous lower limb Groin procedures Other Operation time, minutes lntraoperative shock Use of cell saver Perioperative blood transfusion Number of wounds per patient 1 2 3 4 Total number of wounds Wound closure Subcuticular Other Total length of wounds, cm Duration of drainage, days The vahes
Multiple Dose
are the numbers
ofpatrents
45 37 25 24
(29) (24) (16) (16)
12(‘3 7 3 180 3 47 32
(5) (2) (150-240) (2) (31) (21)
6 (56) 34 (22) 31 (20)
2 (‘1
Multiple Dose (n = 149) 41 (28) 36 (24) 24 (16) 13 16 15 4 180 3 51 40 83 41 22 3
(56) (28) (15) (2) 243
209 34 28 3
(86) (14) (16-38) (2-4)
255 217 28 28 3
(85) (15) (17-38) (2-4)
with percentages
(9) (11) (10) (3) (145-230) (2) (34) (27)
m parenthesis.
were twice as likely to develop a wound infection according to the estimate of relative risk (Table III). Patients who received single-dose prophylaxis were also observed to have FEBRUARY
1998
ANTIMICROBIAL
TABLE Details
III of Outcome
Events
for the Groups
Wound infection” Graft infection Local abscess or serous discharge (not meeting the criteria for a wound infection) Administration of antibiotics Requirement for wound dressing Total wound dressing days Average wound dressing days Reoperation Reasons for reoperation Amputation/debridement of tissue Revision of graft Haemostasis Coronary artery bypass graft Intestinal adhesions Postoperative stay, days Death
Under
Study
Single Dose (n = 153)
Multiple Dose (n = 149)
28 (18) 1 (
15 (10)
35 (23) 37 (24) 23 (15) 323 2.11 16 (10)
23 (15) 27 (18) 22 (15) 253 1.70 17 (11)
1 (
8 (5) 5 (3) 2 (1) 0 (0) 1 (1) 9 (6-l 3) 8 (5)
7 (5) 3 (2) 4 (3) 2 (1) 1 (1) 9 (7-l 3) 5 (3)
The values are either numbers of patients with percentages n parenthesis medfan valuesw!th the interquafli/e range in parenthesis. + Chi square = 4.79, df = 7, P = 0.047 freiabve risk estimate = 2.00, confidence interval = - 1.02 to 3.92).
or 95%
a higher incidence of wound morbidity such as swelling and erythema, superficial dehiscence, local abscess, and serous discharge. Although the need for additional wound dressings was similar for each group, patients who received single-dose prophylaxis required a greater number of wound dressings. As might be expected, patients undergoing lower limb surgery had the greatest risk of a wound infection, ie, 25% (24 of 95). In this study, the presence of prosthetic graft material was not identified as an independent risk factor for wound infection. The median time of presentation of the wound infections was 13 days (range 2 to 43) (Table IV) contains details of rhe culture isolates. We did not detect any appreciable differences in the resistance patterns of the isolates between the groups. Both groups of patients had similar patterns of adverse events after surgery. No patient died as a result of a wound or graft infection, and 86% (261 of 302) of the patients admitted to the intensive care unit were discharged within 48 hours. We did not observe any major side effects associated with the parenteral administration of ticarcillin 3.0 g/clavulanate 0.1 g. Clostridium dificile was detected in the stools of 3 patients with diarrhea (single-dose = 2, multiple-dose regimen = 1).
COMMENTS Patients undergoing vascular surgery require some form of antibiotic prophylaxis. Branchereau et al’@ observed a significant difference in the incidence of wound infection when they randomized 179 patients to receive either cefazolin (14%) or a placebo (30%). It is now considered inappropriate, and hence unethical, to conduct trials evaluating antibiotic prophylaxis in patients undergoing vascular surgery that contain a “no treatment” control group. THE AMERICAN
PROPHYLAXIS
TABLE
IV
Isolates
from
FOR
VASCULAR
the 25 Patients
with
SURGERY/HALL
Positive
Wound
Single Dose (n = 15) Staphylococcus aureus Enterococcus spp. Mixed coliforms Staphylococcus epidermidis Methicillin-resistant Staphylococcus aureus Escherichia co/i Enterobacter spp. Pseudomonas spp. Klebsiela spp. Proteus spp. Citrobacter diversus Streptococcus oralis Serratia marcescens Peptostreptococcus asaccharolyticus Total number of isolates
ET AL )
Cultures Multiple Dose (n = 10)
5 3 4 1
4 2 1 3
1 1 2 1 1 1 0 1 1 1 23
2 2 0 1 1 1 1 0 0 0 18
The high incidence of wound infection after vascular surgery may surprise some surgeons. For example, besides the wound infections that were declared according to the defined criteria (the discharge of pus or a serous discharge that contains pathogenic organisms), we also found that the incidence of minor wound infections was 19% (58 of 302). Hence, about one third of patients developed wound morbidity after vascular surgery, and this is similar to the situation that occurs after cardiac surgery.” The results of clinical trials may differ from clinical impressions because the results are collected by an unbiased observer during a relatively long period of follow-up. In our study the median presentation time of wound infection was 13 days. Hence, 50% of the wound infections presented at or later than 2 weeks after surgery. The main published studies of antibiotic prophylaxis in vascular surgery have concentrated on the efficacy of specific agents rather than evaluate variations in the duration of therapy. Edwards et al.” compared the use of 24-hour regimens of cefuroxime and cefazolin, while Antrum et all3 compared 24-hour regimens of teicoplanin and cephradine plus metronidazole. This is an important issue because variations in the duration of prophylaxis, rather than the exhibition of differem candidate antibiotics, may have the greatest effect on outcome. In a study of 100 patients undergoing surgery for lower limb ischaemia, Earnshaw et all4 failed to detect a significant difference in the incidence of wound infection after either a 24-hour or a 5-day course of amoxycillin/clavulanate. As in our study, there was a propensity for patients with poor vascularity of the lower limbs to develop wound infections. The extent of blood loss may be another important risk factor. Livingston and Wang” found that an identical dose of cefazolin given as a continuous infusion, rather than as intermittent doses, reduced infection after hemorrhagic shock when using an animal model. The presence of such confounding factors, which may be responsible for imbalances in the equivalence of the groups at baseline, emphasizes the need for caution when interJOURNAL
OF SURGERYa
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1998
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,NTIMIC&
preting the results of clinical trials. Even studies that cony tain relatively large numbers of patients fail to achieve perfect equivalence between the groups under study. For example, in our clinical trial there is a slight predominance in the single-dose group of patients who are smokers, have non-insulin-dependent diabetes mellitus, and have severe cardiac disease. Although these variations do not account for the marked differences in the incidence of wound infection that we observed, they do illustrate the potential danger of uncritically accepting the results of clinical trials that fail to provide a comprehensive account of baseline equivalence, especially if those studies have evaluated small numbers of patients. The pathogens that must be anticipated when administermg prophylaxis for patients undergoing vascular surgery include anaerobes plus mixed gram-positive and gramnegative aerobic organisms. ‘“,12,14 It seems that anaerobes are most likely to contribute to infection when there is tissue ischaemia. The pathogenicity of Staphylococcus epidermidis also requires comment. Wilson et ali6 found that this organism produced wound infections of the same severity as Smphylococcus aureus after cardiac surgery. The antimicrobial agent used in our trial contains the semisynthetic antibiotic ticarcillin sodium and the p-lactimase inhibitor potassium clavulanate. Ticarcillin is derived from the basic penicillin nucleus, 6-amino-penicillanit acid, while clavulanic acid is produced by the fermentation of Streptomyces chuligerus. The result is an agent that has activity against anaerobes and gram-positive and gram-negative aerobic organisms. It is of interest that Calligaro et al” recommend that the initial treatment of extra-cavity arterial graft infections includes vancomycin/ceftazidime or ticarcillin/clavulanic acid regardless of the Gram stain findings until final culture and sensitivity results dictate the use of more selective antibiotics. In addition, Hart and Bailey’* have recently reviewed the pharmacology, in vitro activity, and clinical usefulness of the beta-lactam/beta-lactamase inhibitor combinations. They concluded that these agents were useful alternatives to conventional multi-drug regimens in the management of mixed infections such as foot infections in patients with diabetes and peripheral vascular disease. Early graft infection presents within 3 months of surgery, is usually associated with staphylococcal infection, and often involves a groin wound.‘“,” We only observed two graft infections, one in each group, despite evaluating a relatively large number of patients. This indicates the logistic implausibility of evaluating an adequate number of patients, and for a sufficient period of time, in order to draw reliable conclusions about the prevention of graft infection. In conclusion, our study indicates that it is inappropriate to use single-dose antibiotic prophylaxis for patients undergoing vascular surgery. The reasons why more prolonged
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regimens are necessary remains speculative, but it may relate to the degree of tissue ischaemia and the extent of blood loss during surgery.
REFERENCES 1. Sunderland GT, McKav Al. Survev of antibiotic use bv the Vascular Society. & ] Surg: 1987;74:33’1-332. 2. Hall JC,Christianstn K,Carter MJ, et al. Antibiotic prophylaxis in cardiac operations. Ann Thorucic kg. 1993;56:916-922. 3. Pollock AV. Surgical prophylaxis-the emerging ptcture. Lancer. 1988;1:225-229. 4. Hall JC, Watts JblcK, Press L, et al. Smgle dose antibiotic prophylaxis in contaminated abdommal surgery. Arch Surg. 1989;
124:244-247. 5. Hall JC, Mander
J, Christiansen K, et al. Cost-efficiency of a long-acting cephalosporin agent. Aust NZJ Szrrg. 198858733-735. 6. Dellinger EP, Wertz MJ, Meakins L, et al. Surgical infectton stratification system for intra-abdommal Infection. Arch Surg. 1985; 120:21-29. 7. Harris RL, Yuk JH, Cribari C, et al. Cefamandole levels durmg thoracoabdominal aortic aneurysm surgery. J Vass Surg. 1991;14:
668-672. 8. Bansal MB, Chuah SK, Thadepahi H. In eritro activity and in viuo evaluation of ticarcillin plus clavulanic acid against aerobic and anaerobic bacteria. Am .I Med. 1985;79(suppl 5B):33-38. 9. Fleiss JL. Srutisticnl Methods for Rates rind Proportions. New York: John Wiley 6, Sons; 1973. 10. Branchereau A, Ondo N’Dong F, La Selve L. Antibioprevention in reconstructive arterial surgery: a double-blind study. Presse Med. 1987;16:1633-1635. 11. Hall JC, Christiansen K, Carter MJ, et al. Antibiotic prophylaxis in cardiac operations. Ann Thorac Surg. 1993;56:916-922. 12. Edwards WH Jr, Kaiser AB, Kernodle DS, et al. Cefuroxime versus cefazolin as prophylaxis in vascular surgery. J Vast Surg. 1992;15:35-42. 13. Antrum RM, Galvin K, Gorst K, et al. Teicoplanin vs cephradine and metronidazole in the prophylaxis of sepsis following vascular surgery: an interim analysis of an ongoing trial. Eur J Surg. 1992;567:43-46. 14. Eamshaw JJ, Hopkinson BR, Slack RGB, Makin GS. Risk factors in vascular surgical sepsis. Ann Roy Coil Surg Engl. 1988;70: 139-143. 15. Livingston DH, Wang MT. Continuous infusion of cefazolin is superior to intermittent dosing in decreasing infection after hemorrhagic shock. Am .I Slog. 1993;165:203-207. 16. Wilson PA, Gruneberg RN, Treasure T, et al. Staphyk>coccus epidermidis as a cause of postoperative wound infection after cardiac surgery: assessment of pathogenicity. Br J Surg. 1988;75:168170. 17. Call&o KD, Veith FJ, Schwartz ML, et al. Recommendations for initial antibiotic treatment of extracavitary arterial graft mfections. Aml Surg. 1995;170:123-125. 18. Hart SM, Bailey EM. A practical look at the clinical usefulness of the beta-lactam/beta-lactamase inhibitor combinations. Ann Pharmncotherapy. 1996;30:1130-1140. 19. Fletcher JP, Dryden M, Sorrel1 TC. Infection of vascular prosthesis. Aust NZ .I Surg. 1991;61:432-435. 20. Strachan CJL. The prevention of orthopaedic and vascular graft infections. J Hasp Infect. 1995;3O(suppl):54-63.
FEBRUARY
1998
1
of Antimicrobial Prophylaxis Vascular Surgery
John C. Hall, FRACS, Keryn J. Christiansen, FRCPA, Marcel Goodman, FRACS, Lawrence-Brown, FRACS, Francis J. Prendergast, FRACS, Peta Rosenberg, BAppSc, Briony Mills, RN, Jane L. Hall, RN, Perth, Australia
BACKGROUND: This randomized clinical trial compares the incidence of wound infection after vascular surgery in patients who received prophylaxis using the same antibiotic as either a singledose or a multiple-dose regimen (until the lines/ drain tubes were removed, but not for more than 5 days). METHODS: Each of the 302 patients who entered the study received ticarcillin 3.0 g/clavulanate 0.1 g (Timentin) intravenously immediately after the induction of anesthesia. Patients randomized to the multiple-dose group received an average of 14.3 doses (range 9 to 20). RESULTS: The incidence of wound infections was 18% (28 of 153) for patients in the single-dose group and 10% (15 of 149) for patients in the multiple-dose group (P = 0.04; relative risk estimate = 2.00, 95% confidence interval = - 1.02 to 3.92). CONCLUSIONS: A multiple-dose antibiotic regimen, rather than single-dose therapy, provides optimal prophylaxis against wound infection for patients undergoing vascular surgery. Am J Surg. 1998; 175:87-90. 0 1998 by Excerpta Medica, Inc.
A
survey by the Vascular Society from the United Kingdom’ revealed wide variations in the use of prophylactic antibiotics. Many surgeons prefer extended regimens and some continue prophylaxis until all of the tubes and lines have been removed from the patient. Evidently, there are concerns that short periods of prophylaxis are inappropriate for patients who are often debilitated, have poor local tissue perfusion, undergo long and sometimes bloody procedures, and require the insertion of implants.* On the other hand, a single-dose of a shortacting agent is known to constitute appropriate prophylaxis for many other types of surgery.“4 Short-term therapy is attractive because of a reduced risk of side effects, a dimin-
From the Departments of General Surgery (JCH, PR, BM, JLH), Clinical Microbiology (KJC), and Vascular Surgery (MG, MLB, FJP), Royal Perth Hospital, Perth, Australia. This study was sponsored by SmithKline Beecham Pharmaceuticals Request for reprints should be addressed to Professor John C. Hall, University Department of Surgery, Royal Perth Hospital, Perth WA 6000, Australia. Manuscript submitted February 5, 1997 and accepted in revised form July 10, 1997.
0 1998 by Excerpta All rights reserved.
in
Medica,
Inc.
ished risk of generating bacterial resistance, as well as reduced acquisition and administration costs.’ In this clinical trial, we have compared the incidence of wound infection after vascular surgery following the administration of the same agent as either short-term prophylaxis or a multiple-dose regimen.
METHODS All adults undergoing vascular surgery within the Royal Perth Hospital between January 1993 and October 1995 were considered for study. For the purposes of this study, vascular surgery was defined as all open arterial procedures. Hence, endovascular procedures were excluded from study. All patients provided informed consent and the study was approved by the Ethics Committee at Royal Perth Hospital. Patients were allocated to one of the two treatment groups based upon computer-generated pseudo-random numbers: a blocked randomization technique was used with 10 patients in each cell. Relevant information was placed within sealed, opaque, serially numbered envelopes so that the entry of patients could be monitored to ensure compliance with the randomization procedure. Patients were not entered into the study until a decision had been made to perform surgery. A research nurse reviewed each theater list to ensure that eligible patients have been considered for entry into the trial. A number of putative risk factors were documented at baseline. Shock was defined according to the criteria listed by Dellinger et al,” ie, clinical signs of reduced peripheral perfusion plus any two of the following: systolic blood pressure (BP) ~80 mm Hg for 1 hour, pulse rate greater than 120 beats per (sinus minute rhythmia) for more than 1 hour, urine output less than 80 mL for any 4-hour period, or use of pressers to maintain the blood pressure for at least 1 hour. Obesity was determined by measurement of the body mass index (BMI)weight (kg) divided by the square of height (M). Insulindependent diabetes mellitus was defined as an episode of ketoacidosis or dependence on insulin, while non-insulindependent diabetes mellitus was indicated by a requirement for oral hypoglycemic medication. All patients received ticarcillin 3.0 g/clavulanate 0.1 g by slow intravenous (IV) infusion (over 30 minutes) immediately after the induction of anesthesia. Patients received an additional dose if the operation was prolonged beyond 3 hours. 7s Patients were randomized to receive the multipledose regimen (ie, until the lines are removed, but <:5 days) received ticarcillin 3.0 g/clavulanate 0.1 g IV at 6 hourly intervals after the initial dose, ie, for a maximum total of 20 doses. This study did not involve the use of placebo agents. 0002-961 O/98/$1 PII SOOO2-9610(97)00270-5
9.00
87
Nosocomial infections were managed in accordance with the institutional antibiotic guidelines. Attempts were made to standardize aspects of perioperative care. Patients received a preoperative chlorhexidine skin wash. There was uniformity in the closure of wounds and drain tubes did not exit through wounds. There was no local irrigation of tissues with solutions containing antimicrobial agents. Patients with postoperative diarrhea had their stools evaluated for the presence of enteropathogens. Wound Infection was defined as the discharge of pus or a serous discharge that contains pathogenic organisms. We also recorded other factors related to wound morbidity and the requirement for wound dressings. Graft infection was defined as an overt clinical event characterized by the need for aggressive interventions and confirmed by microbiology. Hospital stay was the total number of days (in part or whole) that the patient remained in hospital after surgery. The follow-up schedule was maintained until 42 days after the date of surgery. Data were entered into Access 2 (Microsoft, Redmond) and exported for analysis to SPSS for Windows Release 6.0 (SPSS Inc., Chicago, Illinois). A total sample size of 296 patients was based upon the assumption of an absolute difference of 15% in the rate of wound infection being of clinical interest, with the probability of a type I error set at 5% and the power at i’O%.’ Statistical analysis was according to an “intention to treat,” but patients who failed to undergo surgery were excluded from analysis. The proportions of patients with a wound infection in each group were compared using a two-tailed chi-square test with significance being defined as a probability of a type I error of less than 5%, and by declaration of the relative risk including the 95% confidence intervals. All other comparisons were considered to be hypothesis generating exercises.
RESULTS A total of 597 patients had either emergency or elective vascular surgery during the period of study. The reasons for exclusion from study were lack of consent (n = 115), administration of antimicrobial agents within 48 hours of surgery (n = 112), a history of hypersensitivity to penicillin (n = 45), and profound comorbidity (n = 23). In addition there were 10 patients who were randomized but failed to undergo surgery: these patients were excluded from analysis. Patients randomized to the multiple-dose regimen received 2,134 doses of ticarcillin 3.0 g/clavulanate 0.1 g. The median number of doses per patient was 13 (average 14.3, range 9 to 20). The groups were comparable with respect to putative risk factors for a wound infection both at baseline (Table I) and during the perioperative period (Table II). As might be expected, the patients tended to be elderly and dehilitated. Over 40% of the patients had undergone previous cardiovascular surgery and one quarter had a documented prior myocardial infarct. It is of interest that almost one third of the patients were current smokers and that 44% of the patients had more than one wound (the average number of wounds was 1.6). The overall incidence of wound infection was 14.2% (43/302). Patients receiving single-dose prophylaxis had a significantly greater incidence of wound infection than the patients who received the multiple-dose regimen-they 88
THE
AMERICAN
JOURNAL
OF
SURGERY@
VOLUME
175
TABLE
I Patient
Characteristics
at Baseline Single Dose
Number of patients Female:male ratio Age, years Body mass index Current smoker Diabetes mellitus Insulin dependent Non-insulin dependent New York Heart Classification 1 2 3 4 Previous myocardial infarct Previous stroke Previous transient ischaemic attack Extent of lower limb disease No claudication Claudication Rest pain Tissue necrosis Previous cardiovascular surgery The values
are either
numbers
of pat/en& range
median values with the interquart,le
TABLE
153 37:116 70 (64-75) 25 (22-27) 53 (35)
149 46:103 69 (64-76) 24 (22-27) 39 (26)
3 (2) 31 (20)
3 (2) 16 (11)
19 75 48 11 38 20 15
32 59 43 5 37 16 9
(12) (49) (32) (7) (25) (13) (10)
(21) (40) (29) (3) (25) (11)
(6)
50 (33) 64 (42) 34 (22)
62 (42) 51 (34) 29 (19)
5 (3) 62 (41)
7 15) 65 (44)
Wtti percentages UT parenthesis.
in parentheses
or
II Operative
Events Single Dose (n = 153)
Operation Abdominal aortic aneurysm Groin-distal bypass Aorto-groin bypass Carotid endarterectomy Miscellaneous lower limb Groin procedures Other Operation time, minutes lntraoperative shock Use of cell saver Perioperative blood transfusion Number of wounds per patient 1 2 3 4 Total number of wounds Wound closure Subcuticular Other Total length of wounds, cm Duration of drainage, days The vahes
Multiple Dose
are the numbers
ofpatrents
45 37 25 24
(29) (24) (16) (16)
12(‘3 7 3 180 3 47 32
(5) (2) (150-240) (2) (31) (21)
6 (56) 34 (22) 31 (20)
2 (‘1
Multiple Dose (n = 149) 41 (28) 36 (24) 24 (16) 13 16 15 4 180 3 51 40 83 41 22 3
(56) (28) (15) (2) 243
209 34 28 3
(86) (14) (16-38) (2-4)
255 217 28 28 3
(85) (15) (17-38) (2-4)
with percentages
(9) (11) (10) (3) (145-230) (2) (34) (27)
m parenthesis.
were twice as likely to develop a wound infection according to the estimate of relative risk (Table III). Patients who received single-dose prophylaxis were also observed to have FEBRUARY
1998
ANTIMICROBIAL
TABLE Details
III of Outcome
Events
for the Groups
Wound infection” Graft infection Local abscess or serous discharge (not meeting the criteria for a wound infection) Administration of antibiotics Requirement for wound dressing Total wound dressing days Average wound dressing days Reoperation Reasons for reoperation Amputation/debridement of tissue Revision of graft Haemostasis Coronary artery bypass graft Intestinal adhesions Postoperative stay, days Death
Under
Study
Single Dose (n = 153)
Multiple Dose (n = 149)
28 (18) 1 (
15 (10)
35 (23) 37 (24) 23 (15) 323 2.11 16 (10)
23 (15) 27 (18) 22 (15) 253 1.70 17 (11)
1 (
8 (5) 5 (3) 2 (1) 0 (0) 1 (1) 9 (6-l 3) 8 (5)
7 (5) 3 (2) 4 (3) 2 (1) 1 (1) 9 (7-l 3) 5 (3)
The values are either numbers of patients with percentages n parenthesis medfan valuesw!th the interquafli/e range in parenthesis. + Chi square = 4.79, df = 7, P = 0.047 freiabve risk estimate = 2.00, confidence interval = - 1.02 to 3.92).
or 95%
a higher incidence of wound morbidity such as swelling and erythema, superficial dehiscence, local abscess, and serous discharge. Although the need for additional wound dressings was similar for each group, patients who received single-dose prophylaxis required a greater number of wound dressings. As might be expected, patients undergoing lower limb surgery had the greatest risk of a wound infection, ie, 25% (24 of 95). In this study, the presence of prosthetic graft material was not identified as an independent risk factor for wound infection. The median time of presentation of the wound infections was 13 days (range 2 to 43) (Table IV) contains details of rhe culture isolates. We did not detect any appreciable differences in the resistance patterns of the isolates between the groups. Both groups of patients had similar patterns of adverse events after surgery. No patient died as a result of a wound or graft infection, and 86% (261 of 302) of the patients admitted to the intensive care unit were discharged within 48 hours. We did not observe any major side effects associated with the parenteral administration of ticarcillin 3.0 g/clavulanate 0.1 g. Clostridium dificile was detected in the stools of 3 patients with diarrhea (single-dose = 2, multiple-dose regimen = 1).
COMMENTS Patients undergoing vascular surgery require some form of antibiotic prophylaxis. Branchereau et al’@ observed a significant difference in the incidence of wound infection when they randomized 179 patients to receive either cefazolin (14%) or a placebo (30%). It is now considered inappropriate, and hence unethical, to conduct trials evaluating antibiotic prophylaxis in patients undergoing vascular surgery that contain a “no treatment” control group. THE AMERICAN
PROPHYLAXIS
TABLE
IV
Isolates
from
FOR
VASCULAR
the 25 Patients
with
SURGERY/HALL
Positive
Wound
Single Dose (n = 15) Staphylococcus aureus Enterococcus spp. Mixed coliforms Staphylococcus epidermidis Methicillin-resistant Staphylococcus aureus Escherichia co/i Enterobacter spp. Pseudomonas spp. Klebsiela spp. Proteus spp. Citrobacter diversus Streptococcus oralis Serratia marcescens Peptostreptococcus asaccharolyticus Total number of isolates
ET AL )
Cultures Multiple Dose (n = 10)
5 3 4 1
4 2 1 3
1 1 2 1 1 1 0 1 1 1 23
2 2 0 1 1 1 1 0 0 0 18
The high incidence of wound infection after vascular surgery may surprise some surgeons. For example, besides the wound infections that were declared according to the defined criteria (the discharge of pus or a serous discharge that contains pathogenic organisms), we also found that the incidence of minor wound infections was 19% (58 of 302). Hence, about one third of patients developed wound morbidity after vascular surgery, and this is similar to the situation that occurs after cardiac surgery.” The results of clinical trials may differ from clinical impressions because the results are collected by an unbiased observer during a relatively long period of follow-up. In our study the median presentation time of wound infection was 13 days. Hence, 50% of the wound infections presented at or later than 2 weeks after surgery. The main published studies of antibiotic prophylaxis in vascular surgery have concentrated on the efficacy of specific agents rather than evaluate variations in the duration of therapy. Edwards et al.” compared the use of 24-hour regimens of cefuroxime and cefazolin, while Antrum et all3 compared 24-hour regimens of teicoplanin and cephradine plus metronidazole. This is an important issue because variations in the duration of prophylaxis, rather than the exhibition of differem candidate antibiotics, may have the greatest effect on outcome. In a study of 100 patients undergoing surgery for lower limb ischaemia, Earnshaw et all4 failed to detect a significant difference in the incidence of wound infection after either a 24-hour or a 5-day course of amoxycillin/clavulanate. As in our study, there was a propensity for patients with poor vascularity of the lower limbs to develop wound infections. The extent of blood loss may be another important risk factor. Livingston and Wang” found that an identical dose of cefazolin given as a continuous infusion, rather than as intermittent doses, reduced infection after hemorrhagic shock when using an animal model. The presence of such confounding factors, which may be responsible for imbalances in the equivalence of the groups at baseline, emphasizes the need for caution when interJOURNAL
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,NTIMIC&
preting the results of clinical trials. Even studies that cony tain relatively large numbers of patients fail to achieve perfect equivalence between the groups under study. For example, in our clinical trial there is a slight predominance in the single-dose group of patients who are smokers, have non-insulin-dependent diabetes mellitus, and have severe cardiac disease. Although these variations do not account for the marked differences in the incidence of wound infection that we observed, they do illustrate the potential danger of uncritically accepting the results of clinical trials that fail to provide a comprehensive account of baseline equivalence, especially if those studies have evaluated small numbers of patients. The pathogens that must be anticipated when administermg prophylaxis for patients undergoing vascular surgery include anaerobes plus mixed gram-positive and gramnegative aerobic organisms. ‘“,12,14 It seems that anaerobes are most likely to contribute to infection when there is tissue ischaemia. The pathogenicity of Staphylococcus epidermidis also requires comment. Wilson et ali6 found that this organism produced wound infections of the same severity as Smphylococcus aureus after cardiac surgery. The antimicrobial agent used in our trial contains the semisynthetic antibiotic ticarcillin sodium and the p-lactimase inhibitor potassium clavulanate. Ticarcillin is derived from the basic penicillin nucleus, 6-amino-penicillanit acid, while clavulanic acid is produced by the fermentation of Streptomyces chuligerus. The result is an agent that has activity against anaerobes and gram-positive and gram-negative aerobic organisms. It is of interest that Calligaro et al” recommend that the initial treatment of extra-cavity arterial graft infections includes vancomycin/ceftazidime or ticarcillin/clavulanic acid regardless of the Gram stain findings until final culture and sensitivity results dictate the use of more selective antibiotics. In addition, Hart and Bailey’* have recently reviewed the pharmacology, in vitro activity, and clinical usefulness of the beta-lactam/beta-lactamase inhibitor combinations. They concluded that these agents were useful alternatives to conventional multi-drug regimens in the management of mixed infections such as foot infections in patients with diabetes and peripheral vascular disease. Early graft infection presents within 3 months of surgery, is usually associated with staphylococcal infection, and often involves a groin wound.‘“,” We only observed two graft infections, one in each group, despite evaluating a relatively large number of patients. This indicates the logistic implausibility of evaluating an adequate number of patients, and for a sufficient period of time, in order to draw reliable conclusions about the prevention of graft infection. In conclusion, our study indicates that it is inappropriate to use single-dose antibiotic prophylaxis for patients undergoing vascular surgery. The reasons why more prolonged
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regimens are necessary remains speculative, but it may relate to the degree of tissue ischaemia and the extent of blood loss during surgery.
REFERENCES 1. Sunderland GT, McKav Al. Survev of antibiotic use bv the Vascular Society. & ] Surg: 1987;74:33’1-332. 2. Hall JC,Christianstn K,Carter MJ, et al. Antibiotic prophylaxis in cardiac operations. Ann Thorucic kg. 1993;56:916-922. 3. Pollock AV. Surgical prophylaxis-the emerging ptcture. Lancer. 1988;1:225-229. 4. Hall JC, Watts JblcK, Press L, et al. Smgle dose antibiotic prophylaxis in contaminated abdommal surgery. Arch Surg. 1989;
124:244-247. 5. Hall JC, Mander
J, Christiansen K, et al. Cost-efficiency of a long-acting cephalosporin agent. Aust NZJ Szrrg. 198858733-735. 6. Dellinger EP, Wertz MJ, Meakins L, et al. Surgical infectton stratification system for intra-abdommal Infection. Arch Surg. 1985; 120:21-29. 7. Harris RL, Yuk JH, Cribari C, et al. Cefamandole levels durmg thoracoabdominal aortic aneurysm surgery. J Vass Surg. 1991;14:
668-672. 8. Bansal MB, Chuah SK, Thadepahi H. In eritro activity and in viuo evaluation of ticarcillin plus clavulanic acid against aerobic and anaerobic bacteria. Am .I Med. 1985;79(suppl 5B):33-38. 9. Fleiss JL. Srutisticnl Methods for Rates rind Proportions. New York: John Wiley 6, Sons; 1973. 10. Branchereau A, Ondo N’Dong F, La Selve L. Antibioprevention in reconstructive arterial surgery: a double-blind study. Presse Med. 1987;16:1633-1635. 11. Hall JC, Christiansen K, Carter MJ, et al. Antibiotic prophylaxis in cardiac operations. Ann Thorac Surg. 1993;56:916-922. 12. Edwards WH Jr, Kaiser AB, Kernodle DS, et al. Cefuroxime versus cefazolin as prophylaxis in vascular surgery. J Vast Surg. 1992;15:35-42. 13. Antrum RM, Galvin K, Gorst K, et al. Teicoplanin vs cephradine and metronidazole in the prophylaxis of sepsis following vascular surgery: an interim analysis of an ongoing trial. Eur J Surg. 1992;567:43-46. 14. Eamshaw JJ, Hopkinson BR, Slack RGB, Makin GS. Risk factors in vascular surgical sepsis. Ann Roy Coil Surg Engl. 1988;70: 139-143. 15. Livingston DH, Wang MT. Continuous infusion of cefazolin is superior to intermittent dosing in decreasing infection after hemorrhagic shock. Am .I Slog. 1993;165:203-207. 16. Wilson PA, Gruneberg RN, Treasure T, et al. Staphyk>coccus epidermidis as a cause of postoperative wound infection after cardiac surgery: assessment of pathogenicity. Br J Surg. 1988;75:168170. 17. Call&o KD, Veith FJ, Schwartz ML, et al. Recommendations for initial antibiotic treatment of extracavitary arterial graft mfections. Aml Surg. 1995;170:123-125. 18. Hart SM, Bailey EM. A practical look at the clinical usefulness of the beta-lactam/beta-lactamase inhibitor combinations. Ann Pharmncotherapy. 1996;30:1130-1140. 19. Fletcher JP, Dryden M, Sorrel1 TC. Infection of vascular prosthesis. Aust NZ .I Surg. 1991;61:432-435. 20. Strachan CJL. The prevention of orthopaedic and vascular graft infections. J Hasp Infect. 1995;3O(suppl):54-63.
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