Chemoprophylaxis with Cefoxitin and Cephalothin in Orthopedic Surgery: a Comparison

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1981, p Vol. 19, No /81/ $02.00/0 Chemoprophylaxis with Cefoxitin and Cephalothin in Orthopedic Surgery: a Comparison MITCHELL B. ROSENFELD, JAIME CAMPOS, KENNETH R. RATZAN,* AND ISABEL UREDO University ofmiami School of Medicine, Division of Infectious Disease, Mount Sinai Medical Center, Miami, Florida Received 28 October 1980/Accepted 25 February 1981 Forty-eight patients who underwent elective hip or knee surgery were randomly divided into two groups. A total of 22 patients received a single 1-g preoperative bolus of cefoxitin, and 26 patients received a single 1-g preoperative dose of cephalothin. At various time intervals, serum and bone samples were taken during the operative procedure. Our data indicated that whereas serum levels of cefoxitin and cephalothin were maintained for at least 2 h at levels capable of inhibiting most gram-positive cocci and many gram-negative rods, bone levels of cefoxitin only were sustained at therapeutic levels, and those of cephalothin showed a rather rapid decay over a 2-h period. Moreover, in only 58% of the entire cephalothin-treated group were bone levels detectable and then only at a concentration that would inhibit gram-positive cocci. No significant morbidity was observed in either treatment group. Deep wound infections after placement of an endoprosthetic implant in orthopedic surgery often cause catastrophic situations. Because of this, orthopedic surgeons have employed prophylactic antibiotics in an attempt to minimize such complications. Several investigators have shown that there is a marked reduction in the incidence of postoperative wound infections when prophylactic antibiotics are used (1, 3-5, 11). In more than 30% of such infections, staphylococci have been implicated (9). At present, first-generation cephalosporins, such as cephalothin or cefazolin, have been the preferred chemoprophylactic agents because of their excellent anti-staphylococcal activity and lack of appreciable toxicity. In one study, however, 25% of all early wound infections were caused by gram-negative organisms, especially Escherichia coli and Proteus species (9). Many of these bacteria are highly resistant to the older cephalosporins because of their ability to form B8-lactamase enzymes which inactivate these drugs. Further, with increasing physician awareness and improved culturing techniques, anaerobic organisms may be found to play a role in orthopedic infections (12). Although no single antibiotic is presently available to cover all potential pathogens, a recently available antibiotic, cefoxitin, has some unique advantages. Cefoxitin is a semisynthetic cephamycin whose structure closely resembles that of cephalothin. Of critical importance, however, is its resistance to inactivation by bacterial fb-lactamases. This feature not only allows for 826 gram-positive coverage but also a high degree of activity against a variety of gram-negative bacteria, such as indole-positive Proteus and Providencia species, which characteristically are resistant to the older cephalosporins. In addition, cefoxitin is active against more than 80% of Bacteroides fragilis isolates (17). The purpose of this study was to compare the prophylactic efficacy of cephalothin and cefoxitin in patients undergoing endoprosthetic orthopedic surgery. In addition, bone levels of each of these agents were measured from specimens taken at surgery. MATERIALS AND METHODS After informed consent was obtained, the patients were randomly placed into one of two treatment groups in a double-blind fashion. All patients were undergoing elective hip or knee surgery. The indications for surgery included severe osteoarthritis, rheumatoid arthritis, or traumatic fracture. A total of 45 patients underwent an Austin-Moore procedure or total hip replacement, 7 had a total knee replacement, and 1 had an open reduction and wiring of the patella. There were no differences between the two treatment groups with respect to mean age, sex, or type of surgery. No patient received antibiotics for at least 48 h before surgery. Liver and renal function studies were normal in all patients. A single 1-g dose of antibiotic was given as an intravenous bolus for 5 min in the operating room just before the first skin incision and for up to 125 min before removal of the bone sample. Venous blood was obtained immediately before and ca. 5 min after administration of the antibiotic. Another venous blood sample was obtained as the bone sample was removed

2 VOL. 19, 1981 from the patient. The antibiotic was continued in a dose of 1 g intravenously every 4 h for an additional 12 doses. Initially, patients were seen on a daily basis post-operatively. During such visits, wounds were evaluated for signs of infection. In addition, surveillance of infection at other sites, such as the lungs, urinary tract, and site of intravenous line, was performed. If an infection was thought to be present, appropriate specimens for culture were taken. Before surgery and between days 4 and 7 after termination of antibiotic therapy, a urinalysis, urine culture, complete blood count, and biochemical profile were obtained. Assay technique. (i) Serum assay. The assays employed were similar to those described by Cunha et al. (3). After venous blood specimens were allowed to clot, the serum was separated by centrifugation, aspirated, and immediately frozen at -70 C. Assays were performed in duplicate within 1 week of collection. Cephalothin was assayed microbiologically by an agar disk diffusion method with Bacillus subtilis (ATCC 6633) as the indicator organism, as previously described (13). Cefoxitin was also assayed microbiologically by an agar disk diffusion method using a bilayer procedure involving a 10-ml base layer and a 5-ml seed layer with E. coli (MB 3804) as the test organism. A 50-ml amount of brain heart infusion broth was inoculated with the E. coli indicator strain and incubated at 370C for 24 h. The bacteria were harvested and resuspended in 10 ml of brain heart infusion broth. A 4-ml amount of this suspension was then added to 100 ml of nutrient agar at 450C. A total of 5 ml of the seeded medium was poured into petri dishes (100 by 15 mm) containing 10 ml of nutrient agar base layer, distributed evenly, and allowed to cool. The use of the different indicator organisms (B. subtilis for assay of cephalothin and E. coli for assay of cefoxitin) was predicated on the fact that each organism provided the most sensitive assay for its respective antibiotic. Sample dilutions for both antibiotics were done in pooled human serum, and the standard curves were determined. For increasing the sensitivity of the method, 40 Al was pipetted onto a 3/8-in. (ca cm) paper disk and left overnight at room temperature before incubation at 370C. (ii) Bone assay. Bone chips frozen in liquid nitrogen were crushed in a Carver cylinder at a pressure of 10,000 lb/in2 for 1 min. The crushed bone was weighed and diluted to a concentration of 1 g of bone per 1.5 ml of diluent. Preliminary experiments were done to determine the best diluent and the amount of time required to extract each antibiotic. Cephalothin was extracted with 0.1 M phosphate buffer, and cefoxitin was extracted with distilled water. The crushed bone suspended in diluent was shaken in a Gyrotory water bath at 40C for 2 h. The samples were then centrifuged at 5,000 rpm for 20 min at 4 C, and the supernatant was frozen at -70 C. Within 1 week of collection, the frozen supernatant was thawed, and, by means of the same microbiological assay as that used for the serum, the antibiotic concentration within the bone was determined. Because the bone specimens were invariably contaminated with blood containing antibiotic, a correction for this blood content was necessary. Hemoglobin CEFOXITIN AND CEPHALOTHIN CHEMOPROPHYLAXIS 827 determinations were made on all bone samples to ascertain the amount of antibiotic derived from blood contamination of the specimen. This concentration was then subtracted from the total level measured in the bone to determine as closely as possible the actual antibiotic concentration within the bone sample. Bone levels recorded as undetectable either yielded no activity upon assay or had an element of blood contamination that was equal to the total amount of antibiotic within the sample itself. Also, although the lower limit of sensitivity of our microbiological assay was 0.30,ug/ g, bone levels between this limit and 0 were demonstrated. This is explained by the fact that the assay measured total antibiotic within the bone, both true penetration plus blood contamination. Hence, when the blood contamination correction was employed, in some instances a value <0.30 Ag/g was obtained. RESULTS A total of 22 patients received cefoxitin. The mean peak serum level 5 min after administration was 126.6,ug/ml (range, 60 to 240,ug/ml). A total of 26 patients received cephalothin. The mean peak serum level was 113.5,ug/ml (range, 45 to 192 Ag/ml). Each of the two treated groups was divided into two subpopulations depending upon the time interval between administration of the drug and removal of the bone sample. This interval was largely determined by the surgeon's skill and the technical co;nplexity of the operative procedure. Thirteen cefoxitin-treated patients from whom the bone sample was removed 20 to 60 min after administration of the antibiotic had simultaneous mean serum and bone levels of 23.6,g/ml (range, 8.5 to 50,ug/ml) and 4.8,ug/g (range, 0.6 to 11,ug/g), respectively. Nine cefoxitin-treated patients had samples removed 61 to 120 min after receiving the drug. The mean serum level was 15.4,ug/ml (range, 9 to 24,ug/ ml), and the concurrent mean bone level was 4.4,ug/g (range, 1.2 to 12.0,ug/g), not appreciably different from the bone value measured in the 20- to 60-min group. Thirteen cephalothin-treated patients had bone removed in the 20- to 60-min interval. The mean serum level for the entire group at the time of specimen removal was 22.8,ug/ml (range, 4.2 to 46,tg/ml). The simultaneous mean bone level was 0.63,ug/g (range, undetectable to 1.0,tg/g). In seven samples cephalothin was undetectable and, for statistical purposes, these samples were arbitrarily assigned a value of 0. Bone was sampled 61 to 120 min after cephalothin administration in 13 patients. A mean bone level of 0.23,ug/g (range, undetectable to 0.9,ug/g) was attained. Again, samples with undetectable levels were assigned a level of 0. The mean serum level was 8.8,ug/ml (range, 4.4 to 23 jig/ ml) in this group.

3 828 ROSENFELD ET AL. One patient in the cefoxitin group developed purulent drainage from suture holes 12 days post-operatively. Proteus mirabilis susceptible to cefoxitin and Pseudomonas aeruginosa resistant to cefoxitin were cultured. The patient was treated by his private physician with cephapirin (1 g intravenously every 6 h for 4 days) followed by cephalexin (500 mg orally every 8 h for 2 days), and the wound improved. Two patients in the cephalothin-treated group also developed "wound infections." One such patient had a superficial infection that was treated with local care. No cultures were obtained, and no antibiotics were given. The other patient sustained a traumatic dislocation of her newly placed hip prothesis. At reoperation 12 days after the initial implant surgery, a culture of the deep operative site was obtained, although no gross evidence of infection was noted. Staphylococcus aureus susceptible to cephalothin was grown only in broth culture. The patient was treated with cephalothin for 9 days, followed by an 8-day course of cephalexin therapy. A followup examination by her orthopedic surgeon 2 months later revealed no evidence of active deep wound infection. It is doubtful that the S. aureus isolated from this patient was an invasive pathogen. Most likely, it represented a contaminant because it grew only in broth culture and because the patient has continued to do well. It should be noted that in seven specimens (54%) from the cephalothin population sampled early and in four (30%) from the cephalothin group sampled late, no bone levels were attained. The mean serum levels of those patients who had detectable and undetectable bone levels in each of the two time interval groups were 24.6 and 24.57,g/ml (early) and 9.92 and 6.25 pg/ml (late), respectively, suggesting that bone penetration was independent of the serum concentration. Serum samples drawn 4 to 7 days after the final antibiotic dose revealed only a mild elevation in alkaline phosphatase in five cephalothinand four cefoxitin-treated patients. After the second dose, one member of the cephalothin group developed a rash on the arm in which the drug was infused. The antibiotic was discontinued, and the rash spontaneously abated. Another patient in this group had a cardiac arrest before the termination of the surgical procedure and could not be resuscitated. This event was judged to be unrelated to the antibiotic administration. ANTIMICROB. AGENTS CHEMOTHER. DISCUSSION The early work of Burke (2) has provided a theoretical basis for the administration of prophylactic antibiotics. This study with experimentally induced staphylococcal skin lesions in guinea pigs revealed that the antibiotic must be present in the tissue before bacterial lodgement if maximum suppression of infection is to occur (2). In addition, adequate tissue concentrations must be attained for bacterial inhibition. The results of our study revealed that peak serum levels of cefoxitin are achieved early and are not sustained. On the other hand, bone levels at 20 to 60 min and 61 to 120 min are essentially equal, suggesting that high levels are established early and are sustained for at least 2 h. Similarly, peak serum levels of cephalothin also fall off rapidly. However, unlike cefoxitin, there is an apparent rapid decline in measurable levels within bone with the passage of time. Hence, in prolonged surgical procedures, such as total hip replacement, cefoxitin might have an advantage over cephalothin because of its sustained tissue concentration. In all 22 cefoxitin-treated patients, measurable bone levels were attained, whereas, in 11 of the 26 cephalothin-treated patients, bone levels could not be determined. Of these 11 patients, 7, who were in the early group, had a mean serum cephalothin level of [Lg/ml. The other four patients having undetectable levels were in the late group. The mean simultaneous serum cephalothin level in these patients was 6.25,Lg/ml. When these serum values were compared with those of the early and late groups in which a bone level could be determined, little or no difference could be found. Thus, at least for cephalothin, there seemed to be little correlation between the serum level and measurable activity in the bone. Patel et al. were able to document detectable bone cephalothin levels in all but 1 of 20 patients after administration of an initial loading bolus followed by a constant antibiotic infusion (10). By doubling the dose of cephaloridine and cephalexin, Kanyuck and associates showed an approximate twofold increase in both serum and bone concentrations (6). In studies using oxacillin, Kolczun and associates (7) demonstrated a significant increase in bone levels by doubling a single dose. In addition, after constant infusion, measurable bone levels were attained. Further doubling of the constant infusion dose yielded a marked increase in levels (7). These data suggest that a sustained antibiotic level was necessary for bone penetration. Of significance, however, is that none of these investigators commented upon the correction for blood contamination of the bone sample during the assay. In our study, as noted above, comparison of the mean serum cephalothin levels among patients with or without detectable bone levels revealed no significant differences. Unlike the other studies, our data

4 VOL. 19, 1981 CEFOXITIN AND CEPHALOTHIN CHEMOPROPHYLAXIS 829 suggest that cephalothin bone penetration may not be related to the serum level. Why there is such individual variation in bone levels, despite similar or equal serum levels, is a matter of conjecture. In our elderly population, where degenerative joint disease was common, various degrees of avascularity of the bone sample could affect antibiotic penetration. Perhaps contributing to the lower, unmeasurable cephalothin levels is the lack of sensitivity of our assay for desacetylcephalothin, the metabolite of the parent forn. Approximately 33% of cephalothin is metabolized to this compound (15). Eluate from the bone sample might contain both the parent compound and perhaps some portion as its metabolite. The test organism employed within our assay was B. subtilis, and Wick has demonstrated that desacetylcephalothin is five times less active against this organism than is the parent form (18). Consequently, this insensitivity could result in a much lower value, despite the fact that the desacetyl form has some modest antimicrobial activity (17). It is conceivable that bone contains the esterase that degrades cephalothin to its desacetyl forn. Perhaps cephalothin does easily penetrate the bone but is rapidly metabolized even after extraction of the bone specimen from the patient. This, coupled with the inherent insensitivity of the assay for the metabolite, could ultimately translate into lower or unmeasurable tissue levels. The lack of detectable bone cephalothin levels has been noted by other investigators as well (6, 10). Using Staphylococcus epidermidis as a test organism, Patel and associates have suggested that the standard pulverized bone assay technique permits only partial extraction of the antibiotic, leaving a finite, but unknown, quantity trapped within the bone sample (10). Kanyuck et al. found that saline extraction resulted in loss of antimicrobial activity with an assay system which employed Sarcina lutea (6). Although our study employed a phosphate buffer, it is possible that the extraction process was incomplete. Kanyuck has suggested that radiocarbonlabeled cephalothin would yield more accuracy. A more pertinent question is: What is the significance of the detectable bone levels found in this study? One may also be concerned about the reduced anti-staphylococcal activity of cefoxitin. However, the mean levels in each of the cefoxitin groups were sufficient to inhibit growth of most S. aureus and S. epidermidis species (14). Whether bone cefoxitin levels that would have significant and reliable anti-staphylococcal activity can be achieved with lower doses than employed here is subject to conjecture and would require further study. Although the cephalothin levels were significantly lower than those achieved with cefoxitin, cephalothin has been shown to be 10 times more active against staphylococci than is cefoxitin, on a microgram basis (8). For gram-negative bacteria, however, cefoxitin levels were of a magnitude that would inhibit E. coli, Klebsiella pneumoniae, P. mirabilis, Proteus vulgaris, and Providencia species, but not Proteus rettgeri, Proteus morganii, or Serratia marcescens (16), whereas the mean cephalothin levels in both the early and late samples were not sufficient to inhibit any of the gramnegative organisms. Of interest is that the total cost in our hospital for each drug regimen was roughly the same-$58.80 for cefoxitin versus $46.20 for cephalothin. Although there was no significant infectious morbidity in either of the treatment groups, no definite statement concerning the prophylactic attributes of either drug can be made because of the small size of our study population. However, we can state that cefoxitin, unlike cephalothin, showed sustained bone levels for at least 2 h that would inhibit most staphylococci and many commonly isolated gram-negative organisms that could infect periprosthetic sites. Our inability to measure any cephalothin or its metabolite in many specimens may be in part related to the technical aspects of our drug assay. The low or undetectable levels of cephalothin found in our study are not readily explained but may be in some measure related to the metabolism of the drug, perhaps within the bone itself. Although our data suggest that penetrability might be independent of the level within the serum, others have not found this to be so, and more work will be needed to clarify this issue. ITERATURE CITED 1. Boyd, R. J., J. F. Burke, and J. Colton Double blind clinical trial of prophylactic antibiotics in hip fractures. J. Bone Jt. Surg. 55A: Burke, J. 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