The penetration of ceftriaxone and cefamandole into bone, fat and haematoma and relevance of serum protein binding to their penetration into bone

A. M. Loveringa,*, T. R. Walsha, G. C. Bannisterb and A. P. MacGowana

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
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Thirteen patients undergoing total hip replacement were given ceftriaxone 1 g and cefamandole 1 g simultaneously, either immediately or 8 h before surgery. For both agents the concentrations seen in the bone and fat during the operation, and for haematoma fluid <=24 h after the operation, exceeded the MIC for susceptible staphylococci and would be expected to provide adequate prophylaxis. Although ceftriaxone concentrations in bone and fat were significantly higher than those of cefamandole, after correction for the simultaneous blood concentrations, we were unable to detect any differences in the bone or fat penetration of the two agents. We conclude that there is no evidence that cephalosporins with a lower serum protein binding penetrate bone better than ones with higher serum protein binding.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Antibiotic prophylaxis is now an integral part of orthopaedic surgery and has helped to reduce the incidence of post-operative sepsis to the low levels seen currently.1 Although there is a degree of variability between individual surgeons in the antibiotics used, for operations such as hip or knee arthroplasty most use a second generation cephalosporin, such as cefuroxime or cefamandole.1 Over the years, marginal differences in pharmacokinetic profile between the individual agents used for prophylaxis have been reported. These have usually not been statistically significant and have included reports of higher levels, better penetration and more rapid penetration for certain agents.24 Previously, in a series of studies evaluating cefuroxime and cefamandole, we were unable to find any clinically relevant differences in pharmacokinetic profile between the two agents to suggest that one agent would be better than the other when used for prophylaxis.5

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
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Study protocol

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 6–8 h and 14–16 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
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
After administration of ceftriaxone 1 g and cefamandole 1 g to patients undergoing total hip replacement, at the time of operation, concentrations of ceftriaxone in the blood, bone and fat were significantly higher (Student's paired t-test; P < 0.05) than those of cefamandole, irrespective of whether the agents were given immediately, or 8 h, before surgery (Tables I and IIGoGo). This is consistent with the longer half-life and prolonged serum profile seen with ceftriaxone (t1/2: ceftriaxone, 8 h; cefamandole, 0.8 h)7 and is in broad agreement with other studies where bone concentrations of ceftriaxone and cefamandole of 10–20 and 5–25 mg/L, respectively, have been reported during routine hip arthroplasty.26,8 These concentrations are well in excess of the MICs of 0.25–2 mg/L for susceptible staphylococci and should equate to adequate prophylaxis during surgery.


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Table I. The concentration and degree of penetration of cefuroxime and cefamandole into bone, fat and haematoma in seven patients undergoing total hip arthroplasty when antibiotics were given immediately before surgery
 

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Table II. The concentration and degree of penetration of cefuroxime and cefamandole into bone, fat and haematoma in six patients undergoing total hip arthroplasty when antibiotics were given 8 h before surgery
 
Although adequate prophylactic concentrations of both agents were found at the time of operation, it is important to maintain prophylaxis during the 24 h after surgery as single-dose regimens for agents with short half-lives, such as cefamandole, have poorer outcome than multiple dosing regimens.1 When given 8 h before surgery, mean ceftriaxone concentrations of 30–50 mg/L were observed in bone and fat at the time of operation, confirming that prophylactic concentrations were maintained in bone and surrounding tissues for >8 h after the single dose administration. In contrast, as seen in earlier studies,5 cefamandole concentrations in bone 8 h after dosing were barely therapeutic, underlining the requirement for further dosing to extend the period of prophylaxis beyond 8 h after surgery. In haematoma samples collected 6–8 and 14–16 h after surgery, ceftriaxone and cefamandole concentrations were above the MIC for most potential pathogens, irrespective of whether the agents were given at the time of operation or 8 h earlier. The concentrations of both agents in blood samples taken at the same time as the haematoma samples were collected were lower than those in the haematoma fluid (Tables I and IIGoGo), confirming that the concentrations seen in the drain fluid were indicative of the tissue concentrations surrounding the operation site and were not simply representative of the concentrations in the systemic circulation.

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 15–20% of the systemic blood concentrations and for fat the figure was 10–15%. 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, 30–35%; cefamandole, 70%; cephradine, <10%; cefazolin, 80%; moxalactam, 40–50%; 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
 
* Corresponding author. Tel: +44-117-9595653; Fax: +44-117-9593217; E-mail: Lovering_a{at}southmead.swest.nhs.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . Dougall, T. W., Duthie, R., Maffulli, N. & Hutchison, J. D. (1996). Antibiotic prophylaxis: theory and reality in orthopaedics. Journal of the Royal College of Surgeons of Edinburgh 41, 321–2.[ISI][Medline]

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 Surgery—British Volume 70, 322–4.

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, 253–65.[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, 303–11.[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, 99–104.[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, 2292–4.[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. 93–121. 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, 25–32.[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, 216–21.[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, 877–83.[Abstract]

11 . Wise, R. (1996). Tissue penetration of the fourth generation parenteral cephalosporins. Journal of Chemotherapy 8, Suppl. 2, 63–70.

Received 1 August 2000; returned 2 October 2000; revised 2 November 2000; accepted 20 November 2000