a Bristol Centre for Antimicrobial Research and Evaluation (BCARE), Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB; b Department of Orthopaedics, Southmead Hospital, Bristol BS10 5NB, UK
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Recently, Scaglione et al.6 found that for cefodizime and ceftriaxone, bone concentrations were similar to serum free-antibiotic concentrations and concluded that serum protein binding may be an important parameter that determines the penetration of cephalosporins into bone. This would suggest that agents with low serum protein binding [e.g. cefuroxime (35%)] would penetrate bone better than agents with moderate [e.g. cefamandole (70%)] or high [e.g. ceftriaxone (95%)] protein binding.7 Such an observation, however, would be in poor agreement with data on the efficacy of these agents and results from our earlier studies where we were unable to detect differences in the bone penetration of cefuroxime and cefamandole.5,8
In this study, we have used a one-group study design where cefamandole and ceftriaxone were administered simultaneously to 13 patients undergoing routine hip arthroplasty. This approach allows direct comparison between concentrations of the two agents in serum, bone, fat and drainage fluid and an assessment of the impact of the higher protein binding of ceftriaxone on bone penetration.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
This was approved by the local medical research ethics committee and all patients gave written informed consent. Thirteen patients who had not received antibiotics in the preceding 72 h and were undergoing routine total hip replacement were enrolled in the study. For seven patients after the induction of anaesthesia, and immediately before the first incision, cefamandole 1 g and ceftriaxone 1 g were administered through a forearm vein, with further doses of cefamandole 1 g administered 8 and 16 h after the operation. The remaining six patients received cefamandole 1 g and ceftriaxone 1 g 8 h before the operation and further doses of cefamandole 1 g immediately and 8 and 16 h after the operation. Routine total hip replacement was performed on all patients and samples of bone, fat and blood were collected 10, 20 and 30 min after the induction of anaesthesia. Samples of the haematoma fluid draining from the operation site were collected over the periods 68 h and 1416 h after the operation and samples of blood were collected before administration of cefamandole at 8 and 16 h. Blood and haematoma samples were centrifuged, the supernatant removed and the samples stored at 70°C until assayed.
HPLC assay procedures
Samples were assayed for the presence of cefamandole and ceftriaxone by an HPLC method that permitted the simultaneous assay of both agents.5 The chromatography was performed on a Hypersil 5ODS column (HPLC Technology Ltd, Macclesfield, UK) using a mobile phase of methanol:water:phosphoric acid (25:74:1) with detection by UV absorbance at 254 nm. Bone and fat samples were processed as described previously and the two antibiotics were extracted in phosphate-buffered saline at 4°C for 5 h.5 All samples and standards were mixed with an equal volume of acetonitrile and 10 µL of the supernatant resulting after centrifugation was injected into the chromatograph.
![]() |
Results and discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Although higher concentrations of ceftriaxone than cefamandole were seen in both bone and fat samples, we were unable to detect any differences in the degree of penetration of the two agents into these tissues after correction for the systemic blood concentrations (Student's paired t-test; P > 0.05). For both agents, bone concentrations were approximately 1520% of the systemic blood concentrations and for fat the figure was 1015%. As seen in earlier studies,46 there was wide inter-patient variability in the bone and fat concentrations, and in the ratio of these to the systemic blood concentrations, underlining the difficulties of comparing tissue penetration where a conventional two-group design has been used.
Relatively few published studies have used a single-group design to look at the penetration of ß-lactams into bone, but none has reported any significant differences in the penetration of the agents studied that are dependent upon protein binding. For instance, no differences were found in the bone penetration of moxalactam and cefazolin,9 cephradine and cefuroxime,10 or cefamandole and cefuroxime,5 despite marked differences in the reported protein binding of these agents (cefuroxime, 3035%; cefamandole, 70%; cephradine, <10%; cefazolin, 80%; moxalactam, 4050%; and ceftriaxone, 95%).7 This contrasts with the results from a conventional two-group study where Scaglione et al.6 found that the concentrations of cefodizime and ceftriaxone in bone samples appeared to be related to free antibiotic rather than total antibiotic concentrations. As a consequence, they concluded that, when assessing cephalosporins for use in orthopaedic surgery, the extent of protein binding is a major determinant of the penetration into bone. This would suggest that an agent such as cefuroxime, with a low protein binding of 35%, would penetrate bone better than agents with higher protein binding, such as cefamandole or ceftriaxone. As we can find no evidence to support this opinion, either in the results from this study, or in the literature, we would suggest that there is not a clear relationship between serum protein binding and penetration of cephalosporins into bone. This is consistent with the findings of other tissue penetration studies where, although ß-lactams with very high protein binding (>90%) exhibited slightly lower penetration into some tissues, no clear relationship between the degree of protein binding and tissue penetration could be established.11 In these studies, factors such as lipid solubility were postulated as being more important determinants for the penetration of ß-lactams into tissues such as bone.
In conclusion, although we observed differences in the absolute concentrations of ceftriaxone and cefamandole in both bone and fat tissues, we did not detect any significant differences between the agents in the degree to which they penetrate bone or fat. For both agents the absolute concentrations seen in bone and fat at the time of operation, and for haematoma 24 h after the operation, exceeded the MIC for susceptible staphylococci and would be expected to give adequate prophylaxis. We could find no evidence that the penetration of these agents into bone is influenced by the extent of serum protein binding and would advise against the use of serum protein binding as a parameter to assess the suitability of cephalosporins for use in orthopaedic surgery.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Bannister, G. C., Auchincloss, J. M., Johnson, D. P. & Newman, J. H. (1988). The timing of tourniquet application in relation to prophylactic antibiotic administration. Journal of Bone and Joint SurgeryBritish Volume 70, 3224.
3 . Williams, D. N., Gustilo, R. B., Beverly, R. & Kind, A. C. (1983). Bone and serum concentrations of five cephalosporin drugs. Relevance to prophylaxis and treatment in orthopaedic surgery. Clinical Orthopaedics and Related Research 179, 25365.[Medline]
4 . Leigh, D. A., Marriner, J., Nisbet, D., Powell, H. D., Church, J. C. & Wise, K. (1982). Bone concentrations of cefuroxime and cefamandole in the femoral head in 96 patients undergoing total hip replacement surgery. Journal of Antimicrobial Chemotherapy 9, 30311.[ISI][Medline]
5 . Lovering, A. M., Perez, J., Bowker, K. E., Reeves, D. S., MacGowan, A. P. & Bannister, G. (1997). Comparison of the penetration of cefuroxime and cephamandole into bone, fat and haematoma fluid in patients undergoing total hip replacement. Journal of Antimicrobial Chemotherapy 40, 99104.[Abstract]
6 . Scaglione, F., De Martini, G., Peretto, L., Ghezzi, R., Baratelli, M., Arcidiacono, M. M. et al. (1997). Pharmacokinetic study of cefodizime and ceftriaxone in sera and bones of patients undergoing hip arthroplasty. Antimicrobial Agents and Chemotherapy 41, 22924.[Abstract]
7 . White, L. O. & Andrews, J. M. (1998). The ß-lactams. In Clinical Antimicrobial Assays, (Reeves, D. S., Wise, R., Andrews, J. M. & White, L. O., Eds), pp. 93121. Oxford University Press, Oxford.
8 . Periti, P. & Jacchia, E. (1989). Ceftriaxone as short-term antimicrobial chemoprophylaxis in orthopedic surgery: a 1-year multicenter follow-up. Preliminary results of a controlled multicenter study. European Surgical Research 21, Suppl. 1, 2532.[ISI]
9 . Polk, R., Hume, A., Kline, B. J. & Cardea. J. (1983). Penetration of moxalactam and cefazolin into bone following simultaneous bolus or infusion. Clinical Orthopaedics and Related Research 177, 21621.[Medline]
10 . Leigh, D. A. (1989). Determination of serum and bone concentrations of cephradine and cefuroxime by HPLC in patients undergoing hip and knee joint replacement surgery. Journal of Antimicrobial Chemotherapy 23, 87783.[Abstract]
11 . Wise, R. (1996). Tissue penetration of the fourth generation parenteral cephalosporins. Journal of Chemotherapy 8, Suppl. 2, 6370.
Received 1 August 2000; returned 2 October 2000; revised 2 November 2000; accepted 20 November 2000