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Cefuroxime versus cefazolin as prophylaxis in vascular surgery
Cefuroxime versus cefazolin as prophylaxis in vascular surgery William H. Edwards, Jr., MD, AlIen B. Kaiser, MD, Douglas S. Kemodle, MD, Thomas C. Appleby, MD, WilIiam H. Edwards, Sr., MD, Raymond S. Martin, Ill, MD, Joseph L. Mulherin, Jr., MD, and Charles A. Wood, Jr., Pharm D, Nashville~ Tenn. Although cefazolin prophylaxis has proven efficacy in vascular surgery, Smphylococcus
."reus wound infections are still an important postoperative complication. In cardiac
surgery, cefazolin's susceptibility to hydrolysis by staphylococcal p-Iactamase has been proposed to account for some prophylaxis failures. To determine whether the incidence of vascular wound infections can be reduced by administering a more p-Iactamase-stable cephalosporin, we undertook a prospective, randomized trial of cefuroxime versus cefazolin. Cefuroxime was administered as a 1.5 gm dose before operation and 750 mg every 3 hours during operation. Cefazolin was given as 1 gm before operation and 500 mg every 4 hours during operation. Both agents were continued every 6 hours after operation for 24 hours. Deep wound infections developed in seven of 272 (2.6%) cefuroxime and three of287 (1.0%) cefazolin recipients (p = 0.2). Smphylococcus Q,ureus wound infections occurred in five cefuroxime versus two cefazolin recipients. In vitro evaluation ofsix ofthe study isolates plus an additional eight S. Q,ureus strains from vascular wound infections showed greater susceptibility ofthe strains to cefazolin than ce£uroxime (median minimal inhibitory concentrations of 0.5 and 2.0 p.g/m1, respectively, p < 0.05). Furthermore, despite its more frequent intraoperative redosing, cefuroxime exhibited lower trough serum concentrations than cefazolin. Among cefuroxime recipients, infection-associated procedures were significantly longer than infection-free procedures (p < 0.05), suggesting that low tissue antibiotic concentrations may have contributed to the pathogenesis of these infections. In contrast, the length ofthe procedure was not a risk factor for infection among cefazolin recipients. These data emphasize that, despite its inferior p-Iactamase stability, cefazolin has a superior pharmacokinetic profile and greater antistaphylococcal pOtency. These properties result in a higher ratio of intraoperative serum antibiotic concentration to bacterial inhibitory concentration despite slightly higher intraoperative doses ofcefuroxime. Although the difference was not statistically significant, the trend in infection rates suggest that, at the doses used in this study, cefazolin provides more effective perioperative prophylaxis than cefuroxime. (J VASe SUllG 1992;15:35-42.)
Despite the widespread use of aseptic techniques and prophylactic antibiotics, wound infections continue to complicate "clean" surgical procedures. This has particular significance for vascular surgical procedures because wound and graft infections have high amputation and mortality rates. 1-3 Recent studies have demonstrated an advantage of certain other Prom the Department of Surgery St. Thomas Hospital, Departments ofSurgery and Medicine Vanderbilt University School of ;·Medicine. ~ntcd at .the Thirty-ninth Scientific Meeting of the Internabonal SOCIety for Cardiovascular Surgery, North American CJl:1pter, Boston, Mass., June 3-4, 1991. ~~ requests: William H. Edwards, Jr., MD, St. Thomas McdiCal Plaza East, 4230 Harding Rd. Suite 705 Nashville 1N 37205. '"
U/6/33841
antibiotic regimens over cefazolin in cardiac surgery.4,5 Studies from our institution suggest that failures of cefazolin prophylaxis are due, in part, to the in vivo degradation ofcefazolin by staphylococcal ~-lactamase. 5,6 Accordingly, the prophylactic administration of antibiotics with greater ~-lactamase stability is a plausible way to reduce the risk of surgical wound infection. Among available first and second generation cephalosporins, cefuroxime has been shown to be the most resistant to J3-lactamase hydrolysis by staphylococcal ~-laetamase.6 Accordingly, we undertook to test the hypothesis that a more J3-lactamase-stable antibiotic would lead to a lower wound infection rate. To obtain data to use for selecting an appropriate dosing regime for cefuroxime in patients undergoing 35
Journal of
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36 Edwards et al.
vascular surgery, we first initiated a phased smdy to measure the intraoperative kinetics of this antibiotic. Thirty patients were smdied in this manner. Based on the kinetics of cefuroxime and cefazolin, the second phase of the smdy was initiated: a prospective randomized trial of cefuroxime versus cefazolin in clean vascular surgical procedures involving the abdominal aorta and lower extremity vasculature.
PATIENTS AND METHODS Patient selection Both phases ofthe smdy design were approved by the St. Thomas Hospital Institutional Review Board. Written informed consent was obtained from patients participating in phase I ofthe smdy. Since each antibiotic is approved by the Food and Drug Administration (FDA) for surgical wound infection prophylaxis and is used routinely for prophylaxis in our hospital, informed consent was not obtained from the participants for phase IT. Adult patients scheduled for abdominal aortic and lower extremity peripheral vascular surgical procedures between July 1988 and November 1989 were considered eligible as long as (1) no preoperative antimicrobials had been administered; (2) no preoperative areas of''wet gangrene," cellulitis, or open ulcer were present; (3) there was no history of severe penicillin allergy (anaphylaxis, wheezing or exfoliative dermatitis) or cephalosporin allergy. Patients undergoing procedures involving the brachiocephalic arteries were excluded. To remain in the smdy, patients had to receive, at a minimum, all preoperative and intraoperative doses and at least one postoperative dose of the prophylactic regimen. All patients showered or bathed .with soap containing chlorhexidine the evening before operation. Shaving of the operative site(s) was performed in the holding area immediately before operation. Antibiotic wound irrigation was not performed in any study patientS. Exclusions All patients were randomized to receive cefaz
SURGERY
ing 28 operations were excluded for inadvertent randomization into the other antibiotic group within ·7 days of first randomization. It was thought that these patients should be excluded as most wound infections are not manifest for 5 to 7 days, and the concurrent use of a second antibiotic might mask an infection. All patients who died within the first 5 days of operation were excluded for the same reason. Fifty-seven patients were excluded after initial randomization. Excluded patients were evenly distributed between each prophylactic regimen, and no wound infections occurred among these patients. Pharmacokinetic phase I study Thirty patients were randomized to receive either cefazolin or cefuroxime. Based on - the published pharmacokinetic data,7,8 the initial dose scheduled for cefazolin was 1 gm, and for cefuroxime 1.5 gm. A trough serum concentration of ~ 4 times the minimal inhibitory concentration (MIC) of Staphylococcus aureus for each antibiotic (2 f,Lg/ml for cefazolin and 8 f,Lg/ml for cefuroxime) was considered desirable. 9 The preoperative dose was given as a.bolus at the induction of anesthesia. Arterial blood was collected through a manifold attached to an arterial line. The first 5 ml of each sample was discarded. A blood sample was obtained before drug administration, and after drug administration samples were obtained beginning at 5 minutes, then they were obtained serially over the next 4 hours. Ten samples were taken from each patient. Sera were frozen at - 70° Cuntil the time of assay. Serum antibiotic concentrations were .determined by use of the standard disk. diffusion bioassay methods,10,11 with S. aureus ATCC 6538P (cefazolin) andMicrococcus luteus ATCC 9341 (cefuroxime) as the indicator organisms. Clinical phase IT study By use of block randomization, patients were assigned to either of two prophylactic regimens. Based on the results of the phase I pharmacokinetic study, regimen A ~onsisted of cefuroxime, 1.5 gm . intravenously at induction of anesthesia, 750 mg every 3 hours during operation, and 750 mg every 6 hours for 24 hours after operation. Regimen B consisted of cefazolin 1 gm intravenously at the induction ofanesthesia, 500 mg every 4 hours during operation, and I gm every 6 hours after operation for 24 hours. No dose adjustments were made for renal failure. Placebo doses were not included. All drugs were dispensed in minibags labeled "Zinace~" and marked with time for infusion.
Volume 15 Number 1 January 1992
Cefuroxime versus cejazolin as prophylaxis in vascular sutyery 37
In vitro assays Minimal inhibitory concentrations were determined by use of standard broth microdilution methods. 12 Assays were performed in MuellerHinton broth containing 2% NaC!. Beta-Iactamase typing was performed by use of previou~ly described methods involving whole cell suspensIons of each s. aureus strain. 13 Time-kill curve kinetic'studies were performed by use of published methods in Mueller-Hinton broth with 2% NaCl. 14 Colony counts were determined at 0, 6, 10, and 24 hours after inoculation of broth containing antibiotic with bacteria. Baseline inoculum was adjusted to 5 x 105 colony-forming units. Viable bacteria at each time interval were counted and reported as a percent increase or decrease relative to the baseline colony count (time 0).
data base were reviewed by retrospective chart review. Intraoperative as well as postoperative complications were identified. In a subsequent analysis of these data, it was found necessary to determine the duration of the operative procedure. These data were available on a data base maintained by the St. Thomas Hospital Department ofSurgery. Through the use of these combined data bases, it was possible to determine the duration ofthe operative procedure for 475 (85%) of the study patients. All statistical tests for association of frequencies were performed by chi-square analysis or by rnrotailed Fisher's exact test when expected frequencies were less than five. Comparison of means was obtained by use of the Student's t test. Medians of minimum ·antibiotic inhibitory concentrations were compared by use of the Minitab (DOS microcomputer version, release 7, Minitab, Inc., State College, Pa.) version of the two-sample Wilcoxon rank sum test.
Evaluation of the patients Each patient was inspected daily for signs of wound infection. The patients were seen by one of RESULTS the authors at least once after hospital discharge, and Phase I, pharmacokinetic study late wound complications were reported. The preoperative dose of1.0 gm cefazolin and 1.5 Wound infections were categorized by depth of gm cefuroxime produced comparable peak· serum involvement according to the following definition. antibiotic concentrations (Table I). Although mean Class I infection was superficial involvement of skin concentrations were above our goal of ~ 8 J.Lg/ml for or superficial subcutaneous tissues. Class IIA was cefuroxime throughout the 4-hour period of obserdefined as involvement of deep subcutaneous tissues vation, after 2 hours of observation serum levels of . requiring antibiotics and prolonged (or repeated) three of the 15 patients (20%) receiving cefuroxime hospital stay, repeated office visits for resolution or (class lIB) surgical debridement for resolution. Class were observed to be marginal. Because previous III infections required the involvement of a graft in experience suggested that the mean operative time is the infecting process. Because class I infections have less than 3 hours for vascular surgical procedures at an uncertain relationship to the intraoperative events our hospital, and because there was concern that including the use of prophylactic antibiotics, they frequent intraoperative redosing ofcefuroxime could were not considered further in this study. Wounds inadvertently alert· the surgical team to which antiwere considered to be infected when there was biotic was being used in prophylaxis, a redosing purulence noted in the absence of prior ischemic interval of 3 hours (750 mg) was chosen for the necrosis. intraoperative cefuroxime regimen. All serum conAll infected wounds and wound drainage were centration values for cefazolin remained above the cultured. Each instance of possible infection was targeted minimum concentration throughout the evaluated by at least three of the authors before 4-hour observation period, and 4-hour intraoperative assignment to the infected or noninfected category. redosing with 500 mg was chosen as the intraoperThe overall results of the study were evaluated at - ative cefazolin regimen. The postoperative dosing ~-month intervals by two of the members of the regimen of cefuroxime (750 mg) or cefazoline mvestigation team (A.B.K. and W.H.E., Jr.). (1 gm), each given every 6 hours for four doses, was chosen based on current practice ofvascular surgeons Analysi~ of results at our institution. . Most procedures were recorded on optical scanPhase 11, clinical studies rung .cards before the patient's discharge from the hospItal and entered into the St. Thomas Vascular Five hundred fifty nine evaluable patients were Surgical Database. All patients not entered into the enrolled in'the study; 287 received cefazolin and 272
Journal-of VASCULAR SURGERY
38 Edwards et tU.
Table I. Pharmacokinetics of cefuroxime and cefazolin CejUroxime (15 patients)
Time 5min 10min IS min 30min 60min 120 min 180min 240min
Mean
122 91 79 58 38 26 18 13
± ± ± ± ± ± ± ±
Cefiu;olin (15 patients)
l.mPest l'alue
24 J.Lg/ml 22 J.Lg/ml 23 J.Lg/ml 17 J.Lg/ml 16 J.Lg/ml 14 g/ml 14 glml 10 g/ml
Lowest value
Mean
87IJ.glml 60 J.Lg/ml 52 J.Lg/ml 36 J.Lg/ml 181J.g/ml 10 J.Lglml* 5 J.Lg/ml* 2 J.Lg/ml*
110 100 82 72 56 47 39 33
± 34 J.Lg/ml ± 33 f.Lglml ± 31 J.Lglml ± 26 J.Lglml ± 30 J.Lglml ± 15 f.Lglml ± 10 J.Lg/ml ± 10 J.Lg/ml
*Two patients had this value.
Table 11. Wound infections among patients receiving cefawlin or cefuroxime prophylaxis No. ofinfections by category Prophylaxis Cefazolin Cefuroxime Overall
*p
No. ofinfections (class II orgreater) 3 7
10
No. ofpatients
Percent infected (class II orgreater)
287 272 559
1.0%* 2.6%* 1.8%
1IA
IIB
m
2 4
1 2
0 1
= 0.21
received cefuroxime. The average age in each study group was 66 years. No statistical differences in the presence of predisposing risk factors for infection, including underlying host illnesses such as diabetes mellitus, were observed between patients in the two groups. Ten deep wound infections occurred among study patients, for an overall infection rate of 1.8% (Table 11). Infection developed in three cefazolin and seven cefuroxime recipients. However, the difference in infection rates between the two regimens was not statistic~y significant (1.0% vs 2.6%, respectively, p = 0.2). The only class ill graft infection occurred in the cefuro~e group. This resulted in an aboveknee amputation and was the most severe complication of wound infection observed during this study. Staphylococcus aureus was isolated from 7 ofthe 10 wounds; when more than one pathogen was present in a wound, S. aureus was always identified as the primary pathogen. One S. aureus, isolated from a class lIB wound infection in a cefuroxime recipient, was identified as methicillin-resistant (MICs of 64, 32, and 32 for methicillin, cefazolin, and cefuroxime, respectively). Of the nine enteric gram-negative rods that were isolated, only three tested as sensitive to the cephalothin class disk when tested by the hospital microbiology laboratory by means ofstandard KirbyBauer techniques.
Wound infections were analyzed by procedure and by prophylactic regimen (Table Ill). No infection was isolated from the abdominal or popliteal incision. One infection occurred in the thigh when the patient had an isolated thigh incision. All other infections occurred in patients with groin incisions. A predominance of infections occurred in the cefuroxime/aortofemoral bypass group with an infection rate of 7%. Although this rate was not significantly different from the cefazolin/aortofemoral bypass group (p = 0.12), the unexpectedly high rate prompted a detailed analysis of these infections. Seven infections occurred among 205 cefuroxime recipients undergoing aortofemoral, femoropopliteal, and femoral artery procedures; the mean durations ofthe infection-free versus infectionassociated procedures were 165 and 238 minutes, respectively (p < 0.05). Among the four cefuroxime recipients undergoing an aortofemoral bypass procedure and developing a surgical wound infection, the mean duration of surgery was 270 minutes (range, 230 to 300 minutes); in contrast, the mean duration ofthe procedure for the 54 infection-free patients was 195 minutes (p < 0.01). Analyzed another way, among cefuroxime recipients undergoing an aorto.. femoral bypass procedure oflonger than 230 minutes duration, 4/14 (29%) developed a wound infection, whereas no infections developed among the 44
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Cefuroxime versus cejazolin as prophylaxis in vascular sU"lfery 39
January 1992
Table Ill. Wound infections by site and regimen Prophylactic rtyimen Sut;!Jical procedure (duration) *
All patients No. infection/procedures (%)
Cejazolin - no. of infection/procedure (%)
Cefuroxime - no. of infectum/procedure (%)
Abdominal aortic resection (201)t Aortofemoral bypass (208)+ Femoral lower leg bypass (162)§ Femoral artery surgery (149)11 popliteal artery surgery (136) Total
0/148 (0%) 4/106 (3.8%) 5/237 (2.1%) . 1/59 (1.8%) 0/9 (0%) 10/559 (1.8%)
0/85 (0%) 0/48 (0%) 3/119 (2.5%) 0/30 (0%) 0/5 (0%) 3/287 (1.0%)
0/63 (0%) 4/58 (7%) 2/118 (1.7%) 1/29 (3.4%) 0/4 (0%) 7/272 (2.6%)
*Mean duration of procedures, calculated from records at 85% of the enrolled patients.
t Includes renal artery reconstruction.
*Includes patients requiring aortofemoral-popliteal bypass. §Includes femoral-femoral, femoral-lower leg bypass. IIIncludes femor( 0) femoral bypass; axillofemoral femoral bypass.
patients undergoing this procedure with a shorter duration (p < 0.01). Infections occurred with equal frequency among cefazolin and cefuroxime recipients undergoing femoral/lower leg bypass procedures (2.5% and 1.7%, respectively). A trend existed toward the duration of the infection-associated procedures being shorter among cefazolin than cefuroxime recipients (165 and 216 minutes, respectively). However, this difference was not statistically significant.
In vitro studies Of the two S. aureus isolates from wound infections after cefawlin prophylaxis, one was found to produce the type A staphylococcal 13-lactamase; the other was untypable. One of the five cefuroximeassociated S. aureus isolates was found to produce type A J3-lactamase; one produced type B; two produced type C; and one was unavailable for analysis. The six available S. aureus isolates obtained from study patients and an additional eight strains isolated from all other wound infections occurring in patients undergoing vascular surgery operated on during the same period were available for tube dilution sensitivity testing. The median MIC of these isolates was 2.0 ILg/ml for cefuroxime and 0.5 I-Lg/ml for cefazolin (p < 0.01). Time-kill kinetic curve studies were performed on each of the isolates, excluding the single strain that was intrinsically resistant to methicillin. At high ser:um concentrations (~4 J.tg/ml), both antibiotics dem~nstrated comparable killing activity. However, as nught be expected based on the MIC data, at low ~ncentrations(0.5 J.tg/ml), a wide divergence occurs ID the curves with cefuroxime offering little measurable antimicrobial activity.
DISCUSSION Our results were unexpected in that although the differences were not significant, the higher wound infection rate occurred among the cefuroxime recipients. Faced with the findings of an infection rate of 1% in the cefazolin group versus 2.6% in the cefuroxime group, the study was terminated. Were the same infection rate to persist, a study of approximately 1200 patients would be required to show a significant advantage (p < 0.05) of cefazolin versus cefuroxime. Previous experience from our institution and from other studies in clean surgery suggest that when antibiotics are used in prophylaxis, adequate levels must be maintained throughout the surgical procedure. 15~16 That prophylaxis failures with cefuroxime were associated with prolonged surgical procedures while failures related to cefazolin were not, suggests that despite intraoperative redosing cefuroxime serum; and tissue levels may have fallen too low to be effective for some patients undergoing prolonged procedures. The pharmacokinetics of cefuroxime in patients undergoing vascular surgery in this study are comparable to published data by Sorensen et al./ 7 who reported mean cefuroxime serum levels of 26 and 6.4 J.tg/ml at 2 and 4 hours, respectively, after an intravenous infusion of 1.5 gm. Appreciable intrapatient variability was observed in both studies, with the lowest 4-hour postinfusion serum levels approximating the MIC of S. aureus (i.e., 2.0 f.Lg/ml). Also, the intrapatient variability in our study was considerably greater for cefuroxime than cefazolin - the standard deviation of serum levels obtained 2 to 4 hours after infusion ranged 54% to 83% for cefuroxime compared with < 33% for cefazolin. Connors et al. 18 had previously observed that, despite the constant infusion of cefuroxime, serum and tissue
Journal of
VASCULAR SURGERY
40 Edwards et al.
levels varied widely; and unlike cefazolin, cefuroxime levels correlated poorly with free serum levels. Although investigators have reported that the pharmacokinetics of cefuroxime and cefazolin are comparable when considered in the context of perioperative prophylaxis,19 the reSults of this clinical trial raise concerns that if this agent is administered in accordance with the recommendations of its manufacturers (i.e., every 8 to 12 hours), some patients will have negligible tissue levels by the time of closure. A recent report ofa high S. (,Jureus infection rate among recipients of every 12-hour cefuroxime regimen in cardiac surgery supports this concern. 20 Thus the differences in the pharmacokinetics of the two cephalosporins may be clinically important. In retrospect, more aggressive redosing ofcefuroxime in our study may have overcome this liability. The pharmacokinetic differences may also be compounded by subtle differences in antimicrobial activity of these cephalosporins against S. aureus. As identified by tube dilution sensitivity studies and time-kill kinetic curves, cefazolin is about four times more potent in its antistaphylococcal activity than cefuroxime. As noted in Table I, the lowest serum antibiotic concentration just before the redosing time was 5 J.Lg/ml for cefuroxime and 17 J.Lg/ml for cefazolin. Considered together with the in vitro susceptibility data, it is evident that the ratio of the trough serum level to S.. aureus MIC was much lower among patients receiving cefuroxime than cefazolin (2.5 vs 34, respectively). Whether the magnitude of this difference in the inhibitory capability maintained during operation by the two antibiotics is the sole reason for the clinical observations is uncertain. Regardless, such data emphasize the need to administer large, frequent doses when cefuroxime is administered to patients undergoing surgery. This study does not resolve the issue of whether staphylococcal ~-laetamase contributes to some failures of cef3!Dlin prophylaxis in vascular surgery. Kemodle et al. 6 recently have suggested that staphylococcal survival after perioperative prophylaxis is mediated, in part, by in vivo cefazolin degradation by type A staphylococcal J3-laetamase. Indeed, one impents to performing the current study was the observation that among 19 S. aureus isolates susceptible to methicillin recovered from deep vascular wound infection at St. Thomas Hospital in the 3 years preceding this trial, 14 (74%) produced type A p-laetamase (unpublished data, authors). Type A ~-laetamase is very efficient in hydrolyzing cefazolin, whereas cefuroxime is much more resistant to degradation. 6 Routine susceptibility tests do not
reliably detect ~-lac~ase activity as compared with J nor the presence ofother subtle differences among "sensitive" staphylococci. Since variables other than ~-lactamase stability may also influence in vivo prophylactic efficacy, we sought to compare cefazolin and cefuroxime prospectively in a large clinical trial. Whereas the higher infection rate in the cefuroxime arm of the study prompted an end to the trial before the collection of many associated with cefazolin, the S. aureus infection among patients receivingcefazolin (2/287, or 0.7%) is comparable to what we have observed historically. Additional trials will need to be performed to detennine ifthis rate can be reduced by administering agents with (3-lactamase stability superior to cefazolin, but lacking the less favorable pharmacokinetic profile and inferior antistaphylococcal potency of cefuroxime. In summary, although this study did not show any differences in the rate of infection for the two regimens, differences in the in vitro activity and pharmacokinetic profiles ofcefazolin and cefuroxitne were noted that may have contributed to the clinical findings. Use ofan antibiotic in prophylactic settings magnifies the antibiotic's inadequacies. The study of antibiotics in prophylaxis is an emerging science. In depth analysis of the failure or success of various prophylactic regimens should be vigorously used in ongoing clinical trials.
s. aureus
REFERENCES 1. Szilagyi DE, Smith RF, Elliott JP, Vrandecic MP. Infection in arterial reconstruction with synthetic grafts. Ann Surg:Sep· tember 1972;176:321-33. 2. Goldstone .J, Moore WS~ Infection in vascular proStheses: clinical manifestations and s:urgical management. Surgery 1974;128:225-33. 3. Edwards Jr WH, Martin RS, Jenkins JM, Edwards Sr WH, Mulherin Ir JL. Primary graft infections. I VASC SURG 1987;6:235-9. 4. Slama TG, Sldar SJ, Misinski J, Fess SW. Randomized comparison of cefamandole, cefazolin, and cefuroxime prophylaxis in open-heart surgery. Antimicrob Agents Chemother 1986;29:744-7. 5. Kaiser AB, Petracek MR, Lea IV lW, et al. Efficacy of cefazolin, cefamandole, and gentamicin as prophylactic agents in cardiac surgery. Ann Surg 1987;206:791-7. 6. Kemodle DS, Classen DC, Burke JP, Kaiser AB. Failure of cephalosporins to prevent Staphylococcus aureus surgical wound infections. JAMA 1990;263:961·6. 7. Bnmdtzen RW, Toothaker Rn, Nielson DS, Madsen PO, Welling PG, Craig WA. Pharmacokinetics of cefuroxime in nonnal and impaired renal function: comparison of highpressure liquid chromatography and microbiological assays. Antimicrob Agents Chemother 1981;3:443-9. 8. Bergan T, Digranes A, Schreiner A. Absorption, distribution and elimination of cefazotin in patients wi$ normal renal function. Chemotherapy 1978;24:277-82. 9. Vosti K. Serum bactericidal test: past, present, and future use
Volume IS Number I January 1992
10.
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CejUroxime versus cefazolin as prophylaxis in vascular sU1l1ery 41
in the management ofpatients with infections. CUIT Clin Top Infect Dis 1989;10:43-55. Kavanagh F, Dennin LS. Penicillins. In: Kavanagh F, ed. Textbook of analytical microbiology. New York: Academic Press, 1963:327-39. Kirshbaum A, Arret B. Outline of details for official microbiological assays of antibiotics. J Pharm Sci 1967;56:511-5. National committee for clinical laboratory standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 2nd ed; tentative standard. National Committee for Clinical Laboratory Standards. Villanova, Pa, 1988. Kernodle DS, McGraw PA, Stratton CW, Kaiser AB. Use of extracts versUS whole cell bacterial suspensions in the identification of Sta.phylococcus a.ureus ~-lactamase variants. Antimicrob Agents Chemother 1990;34:~20-5. Stratton CW, Liu C, Weeks LS. Activity of LY146032 compared with that of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxin, and vancomycin against staphylococci as determined by kill-kinetic studies. Antimicrob Agents Chemother 1987;31:1210-5. Kaiser AB, Herringron JL Jr, Jacobs JK, Mulherin JL Jr, Roach AC, Sawyers ]L. Cefoxitin versus erythromycin, neomycin, and cefazolin in colarectal operations: importance
DISCUSSION Dr. Victor Bernhard (Tucson, Ariz.). This study is ail extension of previous investigations demonstrating the authors' long-term interest in prophylactic antibiosis in vascular and other forms of cardiovascular surgery, and they are acknowledged experts with an ability to condua these studies in a very sophisticated manner. It was the authors' stated intention to determine whether cefuroxime, a cephalosporin with greater p-laaamase stability in vitro, would be more reliable than the more commonly used cefawlin in preventing wound or graft infection. Their methodology was sound, and they compared two large patient cohorts with similar clinical and operative characteristics. Their results demonstrated no significant difference between the two regimens under study and, in fact, there appeared to be a trend in favor of .cefazolin. Whether this trend would have become a significant difference would, of course, require a study more than twice the size the one they reported today as acknowledged in their manuscript. This leads us to the conclusion that p-lactamase stability is not the critical issue and.that cefazolin may, in fact, continue to be the drug of ch~lce for prophylaxis in patients undergoing vascular reconstruction. . ' The study speaks for itself; however, there are a few ISSues ~orthy ofdiscussion. In view of their finding that at .least SIX of seven staphylococcal isolates produced P·la~ase, and their findings on their time-kill studies, is ~ ·failure of cefuroxime caused by loss of 13-1actamase in 'Ylvo rather than their ~ vitro findings? Or, is this merely
16.
17.
18.
19.
20.
of the duration of the surgical procedure. Ann Surg 1983; 198:525-30. Goldmann DA, Hopkins CC, Karchmer AW, et al. Cephalothin prophylaxis in cardiac valve surgery: a prospective double-blind comparison of two-day and six-day regimens. J Thorac Cardiovasc Surg 1977;73:470-9. Sorensen TS, Aabech J, Utzon NP, Bronn B, Lorentzen JE. Kinetics of cefuroxime in the groin wound after vascular prosthet;ic implantation. J VAse SURG 1988;8:143-6. Connors JE, DiPiro TT, Hayter RG, Hooker KD, Stanfield JA, Young TR. Assessment ofcefazolin and cefuroxime tissue penetration by using a continuous intravenous infusion. Antimicrob Agents Chemother 1990;34:1128-31. Nix DE, DiPiro fT, Bowden TA Ir, Vallner JJ. Cephalosporins for surgical prophylaxis: computer projections of intraoperative availability. South Med J 1985;78:962-6. Doebbeling BN, Pfaller ~ Kuhns KR, Massanari RM, Behrendt DM, Wenzel RP. Cardiovascular surgery prophylaxis: a randomized, controlled comparison of cefazolin and cefuroxime. J Thorac Cardiovasc Surg 1990; 99:981-9.
Submitted June 10, 1991; accepted Sept. 16, 1991.
related to inadequate dosage? Mter all, their studies regarding dosage and their kinetics were related to serum levels and not tissue levels. I suggest that tissue levels may be the critical issue under these circumstances. We really do not know what tissue levels are required in prophylaxis. This study addresses the occurrence ofwound infection in the early postoperative period, which is the apparent time during which they followed their patients and the time when infection is usually due to things like S. aureus and Escherichia coli, and the like. Graft infections in recent years, however, appear to be occurring later, usually months or years after the insertion of a graft, and are frequently or more frequently caused by S. epidmnidis. These are commonly not accompanied by septic clinical pictures, but rather by a chronic sinus, the failure ofgraft incorporation, or the development of an anastomotic aneurysm. Careful culture techniques indicate that these are frequently due to s. epidermidis if sonication techniques are used. We have also, in our studies, noted that these infections may derive from bacteria resident within the arterial wall at the time of surgery and especially in patients undergoing secondary operations in the same area. How long did you monitor your patients to observe for these more delayed phenomena? Although it would be an enormous task to monitor these large numbers ofpatients in both groups for 2 to 3 years or more, information derived from prolonged follow-up may be of major significance not only with regard to the effectiveness ofthe regimen but also to test the hypothesis that S. epidermidis is a major factor in the
42 Edwards et al.
anastomotic aneurysm formation. Do you intend to observe these patients over a long time? If ~-lactamase stability is not a primary issue, what are the factors that support vascular wound infections in spite of supposedly adequate antibiotic serum levels? Did you retrospectively evaluate all patients with infection for factors in the perioperative period that may have reduced immune competence? And, did infection increase in those patients who were undergoing secondary operative procedures? Finally, what is your current recommendation for the most efficient or most effective antibiotic prophylactic regimen? Dr. William Edwards. Dr. Bernhard asked if the failure caused by ~-lactamase was due to ~-lactamase hydrolysis or serum levels and are tissue levels critical. I think that, yes, tissue levels are critical, but as he stated no one really knows what levels in the tissue should be. Cefuroxime is the most stable cephalosporin by our testing to ~-laetamase hydrolysis, and therefore we picked it as the primary antibiotic to be used in this study to compare with cefazolin. We were concerned about its ~ack of activity against coagulase-negative staphylococcus, which as Dr. Bernhard pointed out. This is a significant pathogen in graft infection, and therefore we were unwilling to change wholeheartedly to cefazolin as the antibiotic of choice before a randomized trial had been performed. We do monitor all our patients, however, I cannot speak specifically as to whether there have been any late graft infections. I do not specifically recall one. We do intend to follow them up over a long period of time to check for failure and for infection in the graft. I think that no patients had secondary procedures. There was no infection increase. We looked at a host of different things that we felt were related to increased infection rates and -could not find any greater number of those in the infected group. We had only 10 patients infected, and so the numbers became very small and were not statistically different from the overall group. As far as the issues ofinfection, the issues in prophylaxis I think are important. Prophylaxis brings out the bad things in antibiotics. They are used over a very short period of time, and I think it is a different science from the
Journal of VASCULAR SURGERY
therapeutic use of antibiotics" It would appear from some of our studies that the MIC to your resident flora may be a more important factor in the prophylaxis. At present we are trying to get at this issue doing another study using cefamandole versus cefawlin. Cefamandole has a closer MIC to cefazolin, and our hospital has a '-greater 13-lactamase stability than cefazolin but not quite as great as cefuroxime. Dr. Douglas Wooster (Toronto, Ontario, Canada). We have looked at a number of cultures and graft infection parameters at the University of Toronto. It is clear that we have to consider three things. One is the bacterial challenge and that is where prophylaxis comes in. Also important are the local conditions in the wound and the host response of the patient. Perhaps these last two items explain some ofthe differences in the patient undergoing cardiac operation vers~ the patient undergoing vascular operation and the type of wound infections that developed. The question ofbacterial challenge and the appropriate prophylactic antibiotic raises the question of what the expected organisms are. We have looked at the skin flora and found that this is often related to the contamination of . the deeper tissues and the graft. I wonder ifyou have looked at the flora ofthe patients that you are studying to see how the skin flora and the deeper tissue flora at the time of the procedure relate to the antibiotic kinetics rather than looking afterward at the established infections. The other point that we found was that there is a difference in skin flora between patients who are have claudication versus those who have rest pain even though they may not have open ulceration. Do you have any clinical parameters that might help us identify the group of patients in which cefawlin may be less effective? I. agree_ with the other discussants that cefawlin should probably still be the first antibiotic of choice, particularly in view of cost and its effectiveness. Dr. Edwards. As far as the question of skin flora, we did not look at that specifically. Most of our patients' infections were staphylococcus, and in general I think that staphylococcus is the major cause of postoperative wound infections.
."reus wound infections are still an important postoperative complication. In cardiac
surgery, cefazolin's susceptibility to hydrolysis by staphylococcal p-Iactamase has been proposed to account for some prophylaxis failures. To determine whether the incidence of vascular wound infections can be reduced by administering a more p-Iactamase-stable cephalosporin, we undertook a prospective, randomized trial of cefuroxime versus cefazolin. Cefuroxime was administered as a 1.5 gm dose before operation and 750 mg every 3 hours during operation. Cefazolin was given as 1 gm before operation and 500 mg every 4 hours during operation. Both agents were continued every 6 hours after operation for 24 hours. Deep wound infections developed in seven of 272 (2.6%) cefuroxime and three of287 (1.0%) cefazolin recipients (p = 0.2). Smphylococcus Q,ureus wound infections occurred in five cefuroxime versus two cefazolin recipients. In vitro evaluation ofsix ofthe study isolates plus an additional eight S. Q,ureus strains from vascular wound infections showed greater susceptibility ofthe strains to cefazolin than ce£uroxime (median minimal inhibitory concentrations of 0.5 and 2.0 p.g/m1, respectively, p < 0.05). Furthermore, despite its more frequent intraoperative redosing, cefuroxime exhibited lower trough serum concentrations than cefazolin. Among cefuroxime recipients, infection-associated procedures were significantly longer than infection-free procedures (p < 0.05), suggesting that low tissue antibiotic concentrations may have contributed to the pathogenesis of these infections. In contrast, the length ofthe procedure was not a risk factor for infection among cefazolin recipients. These data emphasize that, despite its inferior p-Iactamase stability, cefazolin has a superior pharmacokinetic profile and greater antistaphylococcal pOtency. These properties result in a higher ratio of intraoperative serum antibiotic concentration to bacterial inhibitory concentration despite slightly higher intraoperative doses ofcefuroxime. Although the difference was not statistically significant, the trend in infection rates suggest that, at the doses used in this study, cefazolin provides more effective perioperative prophylaxis than cefuroxime. (J VASe SUllG 1992;15:35-42.)
Despite the widespread use of aseptic techniques and prophylactic antibiotics, wound infections continue to complicate "clean" surgical procedures. This has particular significance for vascular surgical procedures because wound and graft infections have high amputation and mortality rates. 1-3 Recent studies have demonstrated an advantage of certain other Prom the Department of Surgery St. Thomas Hospital, Departments ofSurgery and Medicine Vanderbilt University School of ;·Medicine. ~ntcd at .the Thirty-ninth Scientific Meeting of the Internabonal SOCIety for Cardiovascular Surgery, North American CJl:1pter, Boston, Mass., June 3-4, 1991. ~~ requests: William H. Edwards, Jr., MD, St. Thomas McdiCal Plaza East, 4230 Harding Rd. Suite 705 Nashville 1N 37205. '"
U/6/33841
antibiotic regimens over cefazolin in cardiac surgery.4,5 Studies from our institution suggest that failures of cefazolin prophylaxis are due, in part, to the in vivo degradation ofcefazolin by staphylococcal ~-lactamase. 5,6 Accordingly, the prophylactic administration of antibiotics with greater ~-lactamase stability is a plausible way to reduce the risk of surgical wound infection. Among available first and second generation cephalosporins, cefuroxime has been shown to be the most resistant to J3-lactamase hydrolysis by staphylococcal ~-laetamase.6 Accordingly, we undertook to test the hypothesis that a more J3-lactamase-stable antibiotic would lead to a lower wound infection rate. To obtain data to use for selecting an appropriate dosing regime for cefuroxime in patients undergoing 35
Journal of
VASCULAR
36 Edwards et al.
vascular surgery, we first initiated a phased smdy to measure the intraoperative kinetics of this antibiotic. Thirty patients were smdied in this manner. Based on the kinetics of cefuroxime and cefazolin, the second phase of the smdy was initiated: a prospective randomized trial of cefuroxime versus cefazolin in clean vascular surgical procedures involving the abdominal aorta and lower extremity vasculature.
PATIENTS AND METHODS Patient selection Both phases ofthe smdy design were approved by the St. Thomas Hospital Institutional Review Board. Written informed consent was obtained from patients participating in phase I ofthe smdy. Since each antibiotic is approved by the Food and Drug Administration (FDA) for surgical wound infection prophylaxis and is used routinely for prophylaxis in our hospital, informed consent was not obtained from the participants for phase IT. Adult patients scheduled for abdominal aortic and lower extremity peripheral vascular surgical procedures between July 1988 and November 1989 were considered eligible as long as (1) no preoperative antimicrobials had been administered; (2) no preoperative areas of''wet gangrene," cellulitis, or open ulcer were present; (3) there was no history of severe penicillin allergy (anaphylaxis, wheezing or exfoliative dermatitis) or cephalosporin allergy. Patients undergoing procedures involving the brachiocephalic arteries were excluded. To remain in the smdy, patients had to receive, at a minimum, all preoperative and intraoperative doses and at least one postoperative dose of the prophylactic regimen. All patients showered or bathed .with soap containing chlorhexidine the evening before operation. Shaving of the operative site(s) was performed in the holding area immediately before operation. Antibiotic wound irrigation was not performed in any study patientS. Exclusions All patients were randomized to receive cefaz
SURGERY
ing 28 operations were excluded for inadvertent randomization into the other antibiotic group within ·7 days of first randomization. It was thought that these patients should be excluded as most wound infections are not manifest for 5 to 7 days, and the concurrent use of a second antibiotic might mask an infection. All patients who died within the first 5 days of operation were excluded for the same reason. Fifty-seven patients were excluded after initial randomization. Excluded patients were evenly distributed between each prophylactic regimen, and no wound infections occurred among these patients. Pharmacokinetic phase I study Thirty patients were randomized to receive either cefazolin or cefuroxime. Based on - the published pharmacokinetic data,7,8 the initial dose scheduled for cefazolin was 1 gm, and for cefuroxime 1.5 gm. A trough serum concentration of ~ 4 times the minimal inhibitory concentration (MIC) of Staphylococcus aureus for each antibiotic (2 f,Lg/ml for cefazolin and 8 f,Lg/ml for cefuroxime) was considered desirable. 9 The preoperative dose was given as a.bolus at the induction of anesthesia. Arterial blood was collected through a manifold attached to an arterial line. The first 5 ml of each sample was discarded. A blood sample was obtained before drug administration, and after drug administration samples were obtained beginning at 5 minutes, then they were obtained serially over the next 4 hours. Ten samples were taken from each patient. Sera were frozen at - 70° Cuntil the time of assay. Serum antibiotic concentrations were .determined by use of the standard disk. diffusion bioassay methods,10,11 with S. aureus ATCC 6538P (cefazolin) andMicrococcus luteus ATCC 9341 (cefuroxime) as the indicator organisms. Clinical phase IT study By use of block randomization, patients were assigned to either of two prophylactic regimens. Based on the results of the phase I pharmacokinetic study, regimen A ~onsisted of cefuroxime, 1.5 gm . intravenously at induction of anesthesia, 750 mg every 3 hours during operation, and 750 mg every 6 hours for 24 hours after operation. Regimen B consisted of cefazolin 1 gm intravenously at the induction ofanesthesia, 500 mg every 4 hours during operation, and I gm every 6 hours after operation for 24 hours. No dose adjustments were made for renal failure. Placebo doses were not included. All drugs were dispensed in minibags labeled "Zinace~" and marked with time for infusion.
Volume 15 Number 1 January 1992
Cefuroxime versus cejazolin as prophylaxis in vascular sutyery 37
In vitro assays Minimal inhibitory concentrations were determined by use of standard broth microdilution methods. 12 Assays were performed in MuellerHinton broth containing 2% NaC!. Beta-Iactamase typing was performed by use of previou~ly described methods involving whole cell suspensIons of each s. aureus strain. 13 Time-kill curve kinetic'studies were performed by use of published methods in Mueller-Hinton broth with 2% NaCl. 14 Colony counts were determined at 0, 6, 10, and 24 hours after inoculation of broth containing antibiotic with bacteria. Baseline inoculum was adjusted to 5 x 105 colony-forming units. Viable bacteria at each time interval were counted and reported as a percent increase or decrease relative to the baseline colony count (time 0).
data base were reviewed by retrospective chart review. Intraoperative as well as postoperative complications were identified. In a subsequent analysis of these data, it was found necessary to determine the duration of the operative procedure. These data were available on a data base maintained by the St. Thomas Hospital Department ofSurgery. Through the use of these combined data bases, it was possible to determine the duration ofthe operative procedure for 475 (85%) of the study patients. All statistical tests for association of frequencies were performed by chi-square analysis or by rnrotailed Fisher's exact test when expected frequencies were less than five. Comparison of means was obtained by use of the Student's t test. Medians of minimum ·antibiotic inhibitory concentrations were compared by use of the Minitab (DOS microcomputer version, release 7, Minitab, Inc., State College, Pa.) version of the two-sample Wilcoxon rank sum test.
Evaluation of the patients Each patient was inspected daily for signs of wound infection. The patients were seen by one of RESULTS the authors at least once after hospital discharge, and Phase I, pharmacokinetic study late wound complications were reported. The preoperative dose of1.0 gm cefazolin and 1.5 Wound infections were categorized by depth of gm cefuroxime produced comparable peak· serum involvement according to the following definition. antibiotic concentrations (Table I). Although mean Class I infection was superficial involvement of skin concentrations were above our goal of ~ 8 J.Lg/ml for or superficial subcutaneous tissues. Class IIA was cefuroxime throughout the 4-hour period of obserdefined as involvement of deep subcutaneous tissues vation, after 2 hours of observation serum levels of . requiring antibiotics and prolonged (or repeated) three of the 15 patients (20%) receiving cefuroxime hospital stay, repeated office visits for resolution or (class lIB) surgical debridement for resolution. Class were observed to be marginal. Because previous III infections required the involvement of a graft in experience suggested that the mean operative time is the infecting process. Because class I infections have less than 3 hours for vascular surgical procedures at an uncertain relationship to the intraoperative events our hospital, and because there was concern that including the use of prophylactic antibiotics, they frequent intraoperative redosing ofcefuroxime could were not considered further in this study. Wounds inadvertently alert· the surgical team to which antiwere considered to be infected when there was biotic was being used in prophylaxis, a redosing purulence noted in the absence of prior ischemic interval of 3 hours (750 mg) was chosen for the necrosis. intraoperative cefuroxime regimen. All serum conAll infected wounds and wound drainage were centration values for cefazolin remained above the cultured. Each instance of possible infection was targeted minimum concentration throughout the evaluated by at least three of the authors before 4-hour observation period, and 4-hour intraoperative assignment to the infected or noninfected category. redosing with 500 mg was chosen as the intraoperThe overall results of the study were evaluated at - ative cefazolin regimen. The postoperative dosing ~-month intervals by two of the members of the regimen of cefuroxime (750 mg) or cefazoline mvestigation team (A.B.K. and W.H.E., Jr.). (1 gm), each given every 6 hours for four doses, was chosen based on current practice ofvascular surgeons Analysi~ of results at our institution. . Most procedures were recorded on optical scanPhase 11, clinical studies rung .cards before the patient's discharge from the hospItal and entered into the St. Thomas Vascular Five hundred fifty nine evaluable patients were Surgical Database. All patients not entered into the enrolled in'the study; 287 received cefazolin and 272
Journal-of VASCULAR SURGERY
38 Edwards et tU.
Table I. Pharmacokinetics of cefuroxime and cefazolin CejUroxime (15 patients)
Time 5min 10min IS min 30min 60min 120 min 180min 240min
Mean
122 91 79 58 38 26 18 13
± ± ± ± ± ± ± ±
Cefiu;olin (15 patients)
l.mPest l'alue
24 J.Lg/ml 22 J.Lg/ml 23 J.Lg/ml 17 J.Lg/ml 16 J.Lg/ml 14 g/ml 14 glml 10 g/ml
Lowest value
Mean
87IJ.glml 60 J.Lg/ml 52 J.Lg/ml 36 J.Lg/ml 181J.g/ml 10 J.Lglml* 5 J.Lg/ml* 2 J.Lg/ml*
110 100 82 72 56 47 39 33
± 34 J.Lg/ml ± 33 f.Lglml ± 31 J.Lglml ± 26 J.Lglml ± 30 J.Lglml ± 15 f.Lglml ± 10 J.Lg/ml ± 10 J.Lg/ml
*Two patients had this value.
Table 11. Wound infections among patients receiving cefawlin or cefuroxime prophylaxis No. ofinfections by category Prophylaxis Cefazolin Cefuroxime Overall
*p
No. ofinfections (class II orgreater) 3 7
10
No. ofpatients
Percent infected (class II orgreater)
287 272 559
1.0%* 2.6%* 1.8%
1IA
IIB
m
2 4
1 2
0 1
= 0.21
received cefuroxime. The average age in each study group was 66 years. No statistical differences in the presence of predisposing risk factors for infection, including underlying host illnesses such as diabetes mellitus, were observed between patients in the two groups. Ten deep wound infections occurred among study patients, for an overall infection rate of 1.8% (Table 11). Infection developed in three cefazolin and seven cefuroxime recipients. However, the difference in infection rates between the two regimens was not statistic~y significant (1.0% vs 2.6%, respectively, p = 0.2). The only class ill graft infection occurred in the cefuro~e group. This resulted in an aboveknee amputation and was the most severe complication of wound infection observed during this study. Staphylococcus aureus was isolated from 7 ofthe 10 wounds; when more than one pathogen was present in a wound, S. aureus was always identified as the primary pathogen. One S. aureus, isolated from a class lIB wound infection in a cefuroxime recipient, was identified as methicillin-resistant (MICs of 64, 32, and 32 for methicillin, cefazolin, and cefuroxime, respectively). Of the nine enteric gram-negative rods that were isolated, only three tested as sensitive to the cephalothin class disk when tested by the hospital microbiology laboratory by means ofstandard KirbyBauer techniques.
Wound infections were analyzed by procedure and by prophylactic regimen (Table Ill). No infection was isolated from the abdominal or popliteal incision. One infection occurred in the thigh when the patient had an isolated thigh incision. All other infections occurred in patients with groin incisions. A predominance of infections occurred in the cefuroxime/aortofemoral bypass group with an infection rate of 7%. Although this rate was not significantly different from the cefazolin/aortofemoral bypass group (p = 0.12), the unexpectedly high rate prompted a detailed analysis of these infections. Seven infections occurred among 205 cefuroxime recipients undergoing aortofemoral, femoropopliteal, and femoral artery procedures; the mean durations ofthe infection-free versus infectionassociated procedures were 165 and 238 minutes, respectively (p < 0.05). Among the four cefuroxime recipients undergoing an aortofemoral bypass procedure and developing a surgical wound infection, the mean duration of surgery was 270 minutes (range, 230 to 300 minutes); in contrast, the mean duration ofthe procedure for the 54 infection-free patients was 195 minutes (p < 0.01). Analyzed another way, among cefuroxime recipients undergoing an aorto.. femoral bypass procedure oflonger than 230 minutes duration, 4/14 (29%) developed a wound infection, whereas no infections developed among the 44
Volume 15 Number 1
Cefuroxime versus cejazolin as prophylaxis in vascular sU"lfery 39
January 1992
Table Ill. Wound infections by site and regimen Prophylactic rtyimen Sut;!Jical procedure (duration) *
All patients No. infection/procedures (%)
Cejazolin - no. of infection/procedure (%)
Cefuroxime - no. of infectum/procedure (%)
Abdominal aortic resection (201)t Aortofemoral bypass (208)+ Femoral lower leg bypass (162)§ Femoral artery surgery (149)11 popliteal artery surgery (136) Total
0/148 (0%) 4/106 (3.8%) 5/237 (2.1%) . 1/59 (1.8%) 0/9 (0%) 10/559 (1.8%)
0/85 (0%) 0/48 (0%) 3/119 (2.5%) 0/30 (0%) 0/5 (0%) 3/287 (1.0%)
0/63 (0%) 4/58 (7%) 2/118 (1.7%) 1/29 (3.4%) 0/4 (0%) 7/272 (2.6%)
*Mean duration of procedures, calculated from records at 85% of the enrolled patients.
t Includes renal artery reconstruction.
*Includes patients requiring aortofemoral-popliteal bypass. §Includes femoral-femoral, femoral-lower leg bypass. IIIncludes femor( 0) femoral bypass; axillofemoral femoral bypass.
patients undergoing this procedure with a shorter duration (p < 0.01). Infections occurred with equal frequency among cefazolin and cefuroxime recipients undergoing femoral/lower leg bypass procedures (2.5% and 1.7%, respectively). A trend existed toward the duration of the infection-associated procedures being shorter among cefazolin than cefuroxime recipients (165 and 216 minutes, respectively). However, this difference was not statistically significant.
In vitro studies Of the two S. aureus isolates from wound infections after cefawlin prophylaxis, one was found to produce the type A staphylococcal 13-lactamase; the other was untypable. One of the five cefuroximeassociated S. aureus isolates was found to produce type A J3-lactamase; one produced type B; two produced type C; and one was unavailable for analysis. The six available S. aureus isolates obtained from study patients and an additional eight strains isolated from all other wound infections occurring in patients undergoing vascular surgery operated on during the same period were available for tube dilution sensitivity testing. The median MIC of these isolates was 2.0 ILg/ml for cefuroxime and 0.5 I-Lg/ml for cefazolin (p < 0.01). Time-kill kinetic curve studies were performed on each of the isolates, excluding the single strain that was intrinsically resistant to methicillin. At high ser:um concentrations (~4 J.tg/ml), both antibiotics dem~nstrated comparable killing activity. However, as nught be expected based on the MIC data, at low ~ncentrations(0.5 J.tg/ml), a wide divergence occurs ID the curves with cefuroxime offering little measurable antimicrobial activity.
DISCUSSION Our results were unexpected in that although the differences were not significant, the higher wound infection rate occurred among the cefuroxime recipients. Faced with the findings of an infection rate of 1% in the cefazolin group versus 2.6% in the cefuroxime group, the study was terminated. Were the same infection rate to persist, a study of approximately 1200 patients would be required to show a significant advantage (p < 0.05) of cefazolin versus cefuroxime. Previous experience from our institution and from other studies in clean surgery suggest that when antibiotics are used in prophylaxis, adequate levels must be maintained throughout the surgical procedure. 15~16 That prophylaxis failures with cefuroxime were associated with prolonged surgical procedures while failures related to cefazolin were not, suggests that despite intraoperative redosing cefuroxime serum; and tissue levels may have fallen too low to be effective for some patients undergoing prolonged procedures. The pharmacokinetics of cefuroxime in patients undergoing vascular surgery in this study are comparable to published data by Sorensen et al./ 7 who reported mean cefuroxime serum levels of 26 and 6.4 J.tg/ml at 2 and 4 hours, respectively, after an intravenous infusion of 1.5 gm. Appreciable intrapatient variability was observed in both studies, with the lowest 4-hour postinfusion serum levels approximating the MIC of S. aureus (i.e., 2.0 f.Lg/ml). Also, the intrapatient variability in our study was considerably greater for cefuroxime than cefazolin - the standard deviation of serum levels obtained 2 to 4 hours after infusion ranged 54% to 83% for cefuroxime compared with < 33% for cefazolin. Connors et al. 18 had previously observed that, despite the constant infusion of cefuroxime, serum and tissue
Journal of
VASCULAR SURGERY
40 Edwards et al.
levels varied widely; and unlike cefazolin, cefuroxime levels correlated poorly with free serum levels. Although investigators have reported that the pharmacokinetics of cefuroxime and cefazolin are comparable when considered in the context of perioperative prophylaxis,19 the reSults of this clinical trial raise concerns that if this agent is administered in accordance with the recommendations of its manufacturers (i.e., every 8 to 12 hours), some patients will have negligible tissue levels by the time of closure. A recent report ofa high S. (,Jureus infection rate among recipients of every 12-hour cefuroxime regimen in cardiac surgery supports this concern. 20 Thus the differences in the pharmacokinetics of the two cephalosporins may be clinically important. In retrospect, more aggressive redosing ofcefuroxime in our study may have overcome this liability. The pharmacokinetic differences may also be compounded by subtle differences in antimicrobial activity of these cephalosporins against S. aureus. As identified by tube dilution sensitivity studies and time-kill kinetic curves, cefazolin is about four times more potent in its antistaphylococcal activity than cefuroxime. As noted in Table I, the lowest serum antibiotic concentration just before the redosing time was 5 J.Lg/ml for cefuroxime and 17 J.Lg/ml for cefazolin. Considered together with the in vitro susceptibility data, it is evident that the ratio of the trough serum level to S.. aureus MIC was much lower among patients receiving cefuroxime than cefazolin (2.5 vs 34, respectively). Whether the magnitude of this difference in the inhibitory capability maintained during operation by the two antibiotics is the sole reason for the clinical observations is uncertain. Regardless, such data emphasize the need to administer large, frequent doses when cefuroxime is administered to patients undergoing surgery. This study does not resolve the issue of whether staphylococcal ~-laetamase contributes to some failures of cef3!Dlin prophylaxis in vascular surgery. Kemodle et al. 6 recently have suggested that staphylococcal survival after perioperative prophylaxis is mediated, in part, by in vivo cefazolin degradation by type A staphylococcal J3-laetamase. Indeed, one impents to performing the current study was the observation that among 19 S. aureus isolates susceptible to methicillin recovered from deep vascular wound infection at St. Thomas Hospital in the 3 years preceding this trial, 14 (74%) produced type A p-laetamase (unpublished data, authors). Type A ~-laetamase is very efficient in hydrolyzing cefazolin, whereas cefuroxime is much more resistant to degradation. 6 Routine susceptibility tests do not
reliably detect ~-lac~ase activity as compared with J nor the presence ofother subtle differences among "sensitive" staphylococci. Since variables other than ~-lactamase stability may also influence in vivo prophylactic efficacy, we sought to compare cefazolin and cefuroxime prospectively in a large clinical trial. Whereas the higher infection rate in the cefuroxime arm of the study prompted an end to the trial before the collection of many associated with cefazolin, the S. aureus infection among patients receivingcefazolin (2/287, or 0.7%) is comparable to what we have observed historically. Additional trials will need to be performed to detennine ifthis rate can be reduced by administering agents with (3-lactamase stability superior to cefazolin, but lacking the less favorable pharmacokinetic profile and inferior antistaphylococcal potency of cefuroxime. In summary, although this study did not show any differences in the rate of infection for the two regimens, differences in the in vitro activity and pharmacokinetic profiles ofcefazolin and cefuroxitne were noted that may have contributed to the clinical findings. Use ofan antibiotic in prophylactic settings magnifies the antibiotic's inadequacies. The study of antibiotics in prophylaxis is an emerging science. In depth analysis of the failure or success of various prophylactic regimens should be vigorously used in ongoing clinical trials.
s. aureus
REFERENCES 1. Szilagyi DE, Smith RF, Elliott JP, Vrandecic MP. Infection in arterial reconstruction with synthetic grafts. Ann Surg:Sep· tember 1972;176:321-33. 2. Goldstone .J, Moore WS~ Infection in vascular proStheses: clinical manifestations and s:urgical management. Surgery 1974;128:225-33. 3. Edwards Jr WH, Martin RS, Jenkins JM, Edwards Sr WH, Mulherin Ir JL. Primary graft infections. I VASC SURG 1987;6:235-9. 4. Slama TG, Sldar SJ, Misinski J, Fess SW. Randomized comparison of cefamandole, cefazolin, and cefuroxime prophylaxis in open-heart surgery. Antimicrob Agents Chemother 1986;29:744-7. 5. Kaiser AB, Petracek MR, Lea IV lW, et al. Efficacy of cefazolin, cefamandole, and gentamicin as prophylactic agents in cardiac surgery. Ann Surg 1987;206:791-7. 6. Kemodle DS, Classen DC, Burke JP, Kaiser AB. Failure of cephalosporins to prevent Staphylococcus aureus surgical wound infections. JAMA 1990;263:961·6. 7. Bnmdtzen RW, Toothaker Rn, Nielson DS, Madsen PO, Welling PG, Craig WA. Pharmacokinetics of cefuroxime in nonnal and impaired renal function: comparison of highpressure liquid chromatography and microbiological assays. Antimicrob Agents Chemother 1981;3:443-9. 8. Bergan T, Digranes A, Schreiner A. Absorption, distribution and elimination of cefazotin in patients wi$ normal renal function. Chemotherapy 1978;24:277-82. 9. Vosti K. Serum bactericidal test: past, present, and future use
Volume IS Number I January 1992
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CejUroxime versus cefazolin as prophylaxis in vascular sU1l1ery 41
in the management ofpatients with infections. CUIT Clin Top Infect Dis 1989;10:43-55. Kavanagh F, Dennin LS. Penicillins. In: Kavanagh F, ed. Textbook of analytical microbiology. New York: Academic Press, 1963:327-39. Kirshbaum A, Arret B. Outline of details for official microbiological assays of antibiotics. J Pharm Sci 1967;56:511-5. National committee for clinical laboratory standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 2nd ed; tentative standard. National Committee for Clinical Laboratory Standards. Villanova, Pa, 1988. Kernodle DS, McGraw PA, Stratton CW, Kaiser AB. Use of extracts versUS whole cell bacterial suspensions in the identification of Sta.phylococcus a.ureus ~-lactamase variants. Antimicrob Agents Chemother 1990;34:~20-5. Stratton CW, Liu C, Weeks LS. Activity of LY146032 compared with that of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxin, and vancomycin against staphylococci as determined by kill-kinetic studies. Antimicrob Agents Chemother 1987;31:1210-5. Kaiser AB, Herringron JL Jr, Jacobs JK, Mulherin JL Jr, Roach AC, Sawyers ]L. Cefoxitin versus erythromycin, neomycin, and cefazolin in colarectal operations: importance
DISCUSSION Dr. Victor Bernhard (Tucson, Ariz.). This study is ail extension of previous investigations demonstrating the authors' long-term interest in prophylactic antibiosis in vascular and other forms of cardiovascular surgery, and they are acknowledged experts with an ability to condua these studies in a very sophisticated manner. It was the authors' stated intention to determine whether cefuroxime, a cephalosporin with greater p-laaamase stability in vitro, would be more reliable than the more commonly used cefawlin in preventing wound or graft infection. Their methodology was sound, and they compared two large patient cohorts with similar clinical and operative characteristics. Their results demonstrated no significant difference between the two regimens under study and, in fact, there appeared to be a trend in favor of .cefazolin. Whether this trend would have become a significant difference would, of course, require a study more than twice the size the one they reported today as acknowledged in their manuscript. This leads us to the conclusion that p-lactamase stability is not the critical issue and.that cefazolin may, in fact, continue to be the drug of ch~lce for prophylaxis in patients undergoing vascular reconstruction. . ' The study speaks for itself; however, there are a few ISSues ~orthy ofdiscussion. In view of their finding that at .least SIX of seven staphylococcal isolates produced P·la~ase, and their findings on their time-kill studies, is ~ ·failure of cefuroxime caused by loss of 13-1actamase in 'Ylvo rather than their ~ vitro findings? Or, is this merely
16.
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of the duration of the surgical procedure. Ann Surg 1983; 198:525-30. Goldmann DA, Hopkins CC, Karchmer AW, et al. Cephalothin prophylaxis in cardiac valve surgery: a prospective double-blind comparison of two-day and six-day regimens. J Thorac Cardiovasc Surg 1977;73:470-9. Sorensen TS, Aabech J, Utzon NP, Bronn B, Lorentzen JE. Kinetics of cefuroxime in the groin wound after vascular prosthet;ic implantation. J VAse SURG 1988;8:143-6. Connors JE, DiPiro TT, Hayter RG, Hooker KD, Stanfield JA, Young TR. Assessment ofcefazolin and cefuroxime tissue penetration by using a continuous intravenous infusion. Antimicrob Agents Chemother 1990;34:1128-31. Nix DE, DiPiro fT, Bowden TA Ir, Vallner JJ. Cephalosporins for surgical prophylaxis: computer projections of intraoperative availability. South Med J 1985;78:962-6. Doebbeling BN, Pfaller ~ Kuhns KR, Massanari RM, Behrendt DM, Wenzel RP. Cardiovascular surgery prophylaxis: a randomized, controlled comparison of cefazolin and cefuroxime. J Thorac Cardiovasc Surg 1990; 99:981-9.
Submitted June 10, 1991; accepted Sept. 16, 1991.
related to inadequate dosage? Mter all, their studies regarding dosage and their kinetics were related to serum levels and not tissue levels. I suggest that tissue levels may be the critical issue under these circumstances. We really do not know what tissue levels are required in prophylaxis. This study addresses the occurrence ofwound infection in the early postoperative period, which is the apparent time during which they followed their patients and the time when infection is usually due to things like S. aureus and Escherichia coli, and the like. Graft infections in recent years, however, appear to be occurring later, usually months or years after the insertion of a graft, and are frequently or more frequently caused by S. epidmnidis. These are commonly not accompanied by septic clinical pictures, but rather by a chronic sinus, the failure ofgraft incorporation, or the development of an anastomotic aneurysm. Careful culture techniques indicate that these are frequently due to s. epidermidis if sonication techniques are used. We have also, in our studies, noted that these infections may derive from bacteria resident within the arterial wall at the time of surgery and especially in patients undergoing secondary operations in the same area. How long did you monitor your patients to observe for these more delayed phenomena? Although it would be an enormous task to monitor these large numbers ofpatients in both groups for 2 to 3 years or more, information derived from prolonged follow-up may be of major significance not only with regard to the effectiveness ofthe regimen but also to test the hypothesis that S. epidermidis is a major factor in the
42 Edwards et al.
anastomotic aneurysm formation. Do you intend to observe these patients over a long time? If ~-lactamase stability is not a primary issue, what are the factors that support vascular wound infections in spite of supposedly adequate antibiotic serum levels? Did you retrospectively evaluate all patients with infection for factors in the perioperative period that may have reduced immune competence? And, did infection increase in those patients who were undergoing secondary operative procedures? Finally, what is your current recommendation for the most efficient or most effective antibiotic prophylactic regimen? Dr. William Edwards. Dr. Bernhard asked if the failure caused by ~-lactamase was due to ~-lactamase hydrolysis or serum levels and are tissue levels critical. I think that, yes, tissue levels are critical, but as he stated no one really knows what levels in the tissue should be. Cefuroxime is the most stable cephalosporin by our testing to ~-laetamase hydrolysis, and therefore we picked it as the primary antibiotic to be used in this study to compare with cefazolin. We were concerned about its ~ack of activity against coagulase-negative staphylococcus, which as Dr. Bernhard pointed out. This is a significant pathogen in graft infection, and therefore we were unwilling to change wholeheartedly to cefazolin as the antibiotic of choice before a randomized trial had been performed. We do monitor all our patients, however, I cannot speak specifically as to whether there have been any late graft infections. I do not specifically recall one. We do intend to follow them up over a long period of time to check for failure and for infection in the graft. I think that no patients had secondary procedures. There was no infection increase. We looked at a host of different things that we felt were related to increased infection rates and -could not find any greater number of those in the infected group. We had only 10 patients infected, and so the numbers became very small and were not statistically different from the overall group. As far as the issues ofinfection, the issues in prophylaxis I think are important. Prophylaxis brings out the bad things in antibiotics. They are used over a very short period of time, and I think it is a different science from the
Journal of VASCULAR SURGERY
therapeutic use of antibiotics" It would appear from some of our studies that the MIC to your resident flora may be a more important factor in the prophylaxis. At present we are trying to get at this issue doing another study using cefamandole versus cefawlin. Cefamandole has a closer MIC to cefazolin, and our hospital has a '-greater 13-lactamase stability than cefazolin but not quite as great as cefuroxime. Dr. Douglas Wooster (Toronto, Ontario, Canada). We have looked at a number of cultures and graft infection parameters at the University of Toronto. It is clear that we have to consider three things. One is the bacterial challenge and that is where prophylaxis comes in. Also important are the local conditions in the wound and the host response of the patient. Perhaps these last two items explain some ofthe differences in the patient undergoing cardiac operation vers~ the patient undergoing vascular operation and the type of wound infections that developed. The question ofbacterial challenge and the appropriate prophylactic antibiotic raises the question of what the expected organisms are. We have looked at the skin flora and found that this is often related to the contamination of . the deeper tissues and the graft. I wonder ifyou have looked at the flora ofthe patients that you are studying to see how the skin flora and the deeper tissue flora at the time of the procedure relate to the antibiotic kinetics rather than looking afterward at the established infections. The other point that we found was that there is a difference in skin flora between patients who are have claudication versus those who have rest pain even though they may not have open ulceration. Do you have any clinical parameters that might help us identify the group of patients in which cefawlin may be less effective? I. agree_ with the other discussants that cefawlin should probably still be the first antibiotic of choice, particularly in view of cost and its effectiveness. Dr. Edwards. As far as the question of skin flora, we did not look at that specifically. Most of our patients' infections were staphylococcus, and in general I think that staphylococcus is the major cause of postoperative wound infections.