Cefuroxime

A COMPARISON BETWEEN GENTAMICIN AND CEFUROXIME

Antibiotics are often administrated prophylactically in spinal procedures to reduce

the risk of infection of the disc space. It is still not known which antibiotics are able to penetrate the intervertebral disc effectively. In a prospective, randomised, double-blind clinical study, we examined the penetration of the intervertebral discs of two commonly used antibiotics, cefuroxime and gentamicin. The patients, randomised into two groups, received either 1.5 g of cefuroxime or 5 mg/kg of gentamicin prophylactically two hours before their intervertebral discs were removed. A specimen of blood, from which serum antibiotic levels were determined, was obtained at the time of discectomy.

Therapeutic levels of antibiotic were detectable in the intervertebral discs of the ten patients who received gentamicin. Only two of the ten patients (20%) who received cefuroxime had a quantifiable level of antibiotic in their discs although therapeutic serum levels of cefuroxime were found in all ten patients. Our results show that cefuroxime does not diffuse into human intervertebral discs as readily as gentamicin. It is possible that the charge due to ionisable groups on the antibiotics can influence the penetration of the antibiotics. We therefore recommend the use of gentamicin in a single prophylactic dose for all spinal procedures in order to reduce the risk of discitis.

J Bone Joint Surg [Br] 2002;84-B: 1036-9. Received 2 October 2001: Accepted 13 March 2002

Infection of the disc space, or discitis, can occur after haematogenous seeding from a distant source or by iatrogenic introduction of bacteria during procedures which violate the disc. It can also spread from a contiguous source of infection. The reported incidence of infection of the disc space after spinal surgery varies from 0.75% to 4%.[1-6] Since the introduction of sensitive MRI which can detect disruption of the disc, there has been an increase in the number of operative procedures for the diagnosis and treatment of such disorders. Studies have suggested that the true incidence of postoperative discitis is higher than has been previously appreciated.6'7 Discitis is a debilitating disorder with a high morbidity. Prophylaxis against infection during spinal surgery has thus been advocated.3,5,7-12 There is still controversy, however, as to which antibiotics are capable of penetrating the disc in effective therapeutic concentrations. 7,10,12-16

The efficacy of antibiotics depends upon both the anatomy and the permeability of the intervertebral disc. In the adult, this is the largest avascular structure in the body.17 Intradiscal nutrition and levels of permeation of antibiotics depend on passive diffusion through the adjacent bony and cartilagenous endplates and the surrounding annulus fibrosus. 17,18 In turn, the permeability of the disc depends on the pore size of the matrix, as well as the molecular weight and charge of the solutes.19

Studies of the penetration of different antibiotics into the lumbar disc of man and animals have shown mixed results.7,9,10,12-16,20-22 There is considerable evidence to suggest that the charge on antibiotics, because of their ionisable groups, is important in determining their ability to diffuse into the disc. 12,20,22 A recent in vitro study using a mouse model has suggested that gentamicin may be more effective than cefuroxime since it is positively charged. It may therefore diffuse more rapidly into the negatively-- charged disc than negatively-charged cefuroxime. Despite their widespread use in all branches of surgery, there has been no study of the penetration of cefuroxime and gentamicin into the human intervertebral disc.

We have therefore compared in a randomised, doubleblind prospective study the penetration of the human intervertebral disc by gentamicin and cefuroxime used prophylactically in spinal surgery. We also determined whether the uptake was within the therapeutic range after intravenous administration of a bolus dose of antibiotic.

Patients and Methods

Between November 1999 and December 2000 we assessed preoperatively 20 patients who were to undergo spinal disc surgery for their suitability to take part in the study. There were eight men and 12 women with a mean age of 52 years (28 to 64). The selection criteria included patients with normal renal function, no previous history of otological damage, no previous adverse reaction to any antibiotic, and no administration of either gentamicin or cefuroxime during the previous six months. Patients then consented and were randomly assigned to receive either cefuroxime or gentamicin. Samples of human disc were obtained during the discectomy.

Each patient received either 1.5 g of cefuroxime or 5 mg/ kg of gentamicin intravenously two hours before surgery. During the operation, any disc tissue removed was

collected and the concentration of antibiotic determined. At the time of removal of the disc, 5 ml of blood were taken for comparative serum analysis of concentrations of antibiotic.

Processing of disc material. Each sample of disc tissue was received in a sterile container. Specimens were washed clean of any excess blood, weighed accurately to 0.1 mg and homogenised manually in 1.0 ml of sterile water using a glass homogeniser. The samples were agitated on a flask shaker for four hours and then centrifuged at 6500 rpm for five minutes. A bacterial growth-inhibition assay, which has been described previously, 13 was used to measure the concentration of cefuroxime in the supernatants of disc homogenate and serum samples. Zones of inhibition from the samples were used to calculate the concentration of antibiotic by reference to a standard curve. Samples containing gentamicin were measured using a fluorescence polarisation immunoassay.23 This technique is based on competition for binding sites on a specific antibody, between the antibiotic in the sample and a labelled antibiotic of known concentration. After the reaction, any excess labelled antibiotic produces an endpoint value inversely proportional to the amount of antibiotic in the sample.

Results

In all ten discs from the patients who received gentamicin, levels of antibiotic were detectable and quantifiable. By contrast, in the disc of patients given cefuroxime, only two of ten had concentrations which were measurable (Table I).

In all patients, the serum antibiotic concentrations were also determined. The mean concentration of serum gentamicin was 12.1 (mu)g/ml (8 to 15) and the mean concentration of gentamicin in the disc 5.9 (mu)g/g (1.1 to 12). The penetration of gentamicin from blood to the disc thus averaged 50%.

The serum concentration of cefuroxime was at least 40 (mu)g/ m1 (the lowest value was 12.5 (mu)g/m1), but its penetration of the disc was only measurable in two of the ten samples. No zone of inhibition occurred around any of the remaining eight samples. The concentration of cefuroxime in these samples must therefore have been less than 0.6 (mu)g/m1, the lower limit of the assay.

No patient developed side-effects from the antibiotics or a postoperative discitis during a follow-up period of six months.

Discussion

Discitis is usually iatrogenic and results either from invasive radiological procedures or spinal surgery.4,5,7,10 A substantial proportion (67% to 87%) of patients is unable to resume their former work despite adequate therapy for postoperative discitis.1,6 Fortunately, intravenous administration of perioperative antibiotics reduces the incidence of postoperative infection.9,0 For this to be effective, it is necessary to know whether the antibiotics penetrate the intervertebral disc and whether the degree of penetration achieves a therapeutic level. Since the human adult disc is an avascular structure, antibiotics enter the disc by passive diffusion. Variation in the rate of diffusion for different antibiotics would thus be expected since this may be affected by many factors, including molecular size and charge, serum protein binding, and antibiotic solubility in different tissues.

In this study, gentamicin and cefuroxime were selected because of their broad-spectrum antibacterial effect and established prophylactic efficacy in orthopaedic surgery. The most common causative agent in spinal infection is Staphylococcus aureus, but the incidence of Pseudomonas aeruginosa, as well as other Gram-negative bacteria, is rising.24 Gentamicin has been used widely in clinical practice against both Gram-positive and Gram-negative organisms. Its important side-effects are ototoxicity, nephrotoxicity, and antibiotic-associated colitis. Most are doserelated. No patient in our study developed any side-effect. Cefuroxime is a second-generation cephalosporin and is less susceptible to inactivation by beta-lactamases than the earlier cephalosporins. It is also more active than the thirdgeneration cephalosporins against Gram-positive bacteria, notably Staphylococcus aureus.

Previous studies have been carried out in vivo using both animal and human models in order to demonstrate the penetration of the first (cefazolin and cefradine) and third generations (ceftriaxone) of cephalosporin, but these have produced conflicting results (Table II). Fraser et al7 showed detectable levels of cefazolin within the discs of sheep when given 30 minutes earlier, but not in those which were killed at 60 and 120 minutes after injection. Boscardin et al 16 demonstrated that the therapeutic level of cefazolin was limited to a so-called `golden period' which appeared approximately 15 to 80 minutes after a high dose of 2 g of cefazolin had been administered. Rhoten et al10 found that levels of cefazolin.and oxacillin were only quantifiable in 40% of the human cervical discs which they studied when 2 g of cefazolin had been given within 60 minutes. This was supported by Lang et al 21 who suggested that a high dose of 2 g of ceftriaxone was necessary to achieve an effective therapeutic level. By contrast, Gibson et al14 were unable to retrieve any cefradine or flucloxacillin from the intervertebral discs of 25 patients undergoing anterior surgery for scoliosis. Using rabbit models, Eismont et al 15 also reported no detectable levels of antibiotics in the intervertebral discs after intravenous administration of either cephalothin or oxacillin.

Gentamicin has been shown to penetrate rabbit discs more readily than penicillin by Riley et al20 who concluded that the charge effect influenced the penetration and distribution of antibiotics. This view was supported by Currier et al 22 who showed that the concentration of gentamicin in the rabbit disc peaked at two hours after an intravenous bolus of the antibiotic. Similarly, other studies12 have demonstrated that positively-charged glycopeptide antibiotics, such as vancomycin and teicoplanin, can penetrate the disc and reach adequate antimicrobial levels.

In our previous experimental study using mouse models,13 we showed that antibiotics which were able to diffuse into the disc were positively charged and those which were unable to penetrate the disc were negatively charged. This observation agrees with that of Urban et al17 who found that the electrical charge of molecules was an important factor in the ability of solutes to diffuse into the nucleus pulposus. Although the size of the molecule, protein binding, and other molecular characteristics also play an important role in the transport and exchange of antibiotics, our study indicates that molecular polarity is dominant in this interaction.

In our patients, the mean concentration of gentamicin of 5.9 (mu)g/g was achieved in the discs two hours after intravenous administration. This is clinically therapeutic, since the minimum inhibition concentration (MIC) against Staphylococcus aureus for gentamicin is 0.12 to 1.0 (mu)g/ml. This provides a large therapeutic margin for error since the level in the disc is 5 to 50 times greater than the MIC. The ease of diffusion into the disc is also shown by this experiment, since the level of gentamicin in the disc was 50% of the serum level two hours after injection.

By contrast, the penetration of the discs by cefuroxime was disappointing. One of the explanations could be that the assay method used was insufficiently sensitive to allow detection of only small amounts of cefuroxime, but the lower limit for detection of cefuroxime in our study was 0.6 (mu)g/m1 which is close to its MIC against Staphylococcus species. Thus, although the antibiotic may be present in the discs, it is likely to be below the therapeutic level. In the two specimens in which cefuroxime was detectable, the serum levels were both greater than 50 (mu)g/ml. This probably relates to a high dose of cefuroxime relative to the weight of the patient and suggests that in order to penetrate the disc effectively, a higher dose of cefuroxime (

In this study, the presentation of the data as a percentage of serum antibiotic levels two hours after administration must be qualified since the serum and disc will each have a curve of antibiotic level against time. The angle of the slope and the magnitude of the peaks for these two curves will be different. Since the half-life in serum is 1.4 to 1.8 hours for cefuroxime and up to four hours (2 to 4) for gentamicin, and the serum concentrations of the antibiotics were high during removal of the disc, the interval of two hours chosen for this study seems to be appropriate.

We have investigated only the penetration of pathological discs by antibiotics and not normal discs such as may be the case in the correction of spinal deformities. Gibson et al14 have shown that neither cefradine nor flucloxacillin, both negatively-charged antibiotics, were detected in either the nucleus pulposus or the annulus fibrosus of a normal human intervertebral disc, despite high blood levels of antibiotics. It is therefore likely that the penetration of the antibiotics is similar in normal and pathological discs. Further conclusions can only be drawn from future studies.

Since invasive techniques and procedures are increasingly used in the diagnosis and treatment of human disc diseases, the possibility of infection of the disc may also increase. It is therefore imperative that a broad-spectrum antibiotic which is known to penetrate the intervertebral disc readily should be administered prophylactically. Based on our results, we recommend the use of gentamicin in a single dose, given at an appropriate time, whenever the intervertebral disc is entered. Rigid adherence to strict aseptic technique is also essential.

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

References

1. Pilgaard S. Discitis (closed space infection) following removal of lumbar intervertebral disc. J Bone Joint Surg [Am] 1969;51-A:7136.

2. EI-Gindi S, Aref S, Salama M, Andrew J. Infection of intervertebral discs after operation. J Bone Joint Surg [Br] 1976;58-13: 114-6.

3. Lindholm TS, Pylkkanen P. Discitis following removal of intervertebral disc. Spine 1982;7:618-22.

4. Fernand R, Lee CK. Postlaminectomy disc space infection: a review of the literature and a report of three cases. Clin Orthop 1986;209:215-8.

5. Osti OL, Fraser RD, Vernon-Roberts B. Discitis after discography: the role of prophylactic antibiotics. J Bone Joint Surg [Br] 1990;72-B:271-4.

6. Rohde V, Meyer B, Schaller C, Hassler WE. Spondylodiscitis after lumbar discectomy: incidence and a proposal for prophylaxis. Spine 1998;23:615-20.

7. Fraser RD, Osti OL, Vernon-Roberts B. Iatrogenic discitis: the role of intravenous antibiotics in prevention and treatment: an experimental study. Spine 1989;14:1025-32.

8. Riley LH. Prophylactic antibiotics for spine surgery: description of a regimen and its rationale. J South Orthop Assoc 1998;7:212-7.

9. Guiboux JP, Cantor JB, Small SD, Zervos M, Herkowitz HN. The effect of prophylactic antibiotics on iatrogenic intervertebral disc infections: a rabbit model. Spine 1995;20:685-8.

10. Rhoten RLP, Murphy MA, Kalfas Hi, Hahn JF, Washington JA.

Antibiotic penetration into cervical discs. Neurosurgery 1995;37:418-21.

11. Lang R, Folman Y, Ravid M, Bental T, Gepstein R. Sequential levels of ceftriaxone in intervertebral disc removed as part of scoliosis surgery. Clin Orthop 1995;315:209-11.

12. Scuderi GJ, Greenberg SS, Banovac K, Martinez OV, Eismont FJ. Penetration of glycopeptide antibiotics in nucleus pulposus. Spine 1993; 14:2039-42.

13. Thomas RWM, Batten JJ, Want S, et al. A new in-vitro model to investigate antibiotic penetration of the intervertebral disc. J Bone Joint Surg [BrI 1995;77-B:967-70.

14. Gibson MJ, Karpinski MRK, Slack RCB, Cowlishaw WA, Webb JK. The penetration of antibiotics into the normal intervertebral disc. J Bone Joint Surg [Br] 1987:69-B:784-6.

15. Eismont FJ, Wiesel SW, Brighton CT, Rothman RH. Antibiotic penetration into rabbit nucleus pulposus. Spine 1987;12:254-6.

16. Boscardin JB, Ringus JC, Feingold DJ, Ruda SC. Human intradiscal levels with cefazolin. Spine 1992;17 Suppl:145-8.

17. Urban JPG, Holm S, Maroudas A, Nachemson A. Nutrition of the intervertebral disk: an in vivo study of solute transport. Clin Orthop 1977;129:101-14.

18. Brown MD. Tsaltas TT. Studies on the permeability of the inter

vertebral disc during skeletal maturation. Spine 1976;1:240-4.

19. Urban JPG, Maroudas A. The measurement of fixed charge density in the intervertebral disc. Biochem Biophys Acta 1979;586:166-78. 20. Riley LH, Banovac K, Martinez OV, Eismont FJ. Tissue distribu

tion of antibiotics in the intervertebral disc. Spine 1994;19:2619-25. 21. Lang R, Folman Y, Ravid M, Bental T, Gepstein R. Penetration of ceftriaxone into the intervertebral disc. J Bone Joint Surg [Am] 1994;76-A:689-91.

22. Currier BL, Banovac K, Eismont FJ. Gentamicin penetration into normal rabbit nucleus pulposus. Spine 1994;19:2614-8.

23. Jolley M, Stroupe SD, Wang CH, et al. Fluorescence polarization immunoassay I: monitoring aminoglycoside antibiotics in serum and plasma. Clin Chem 1981;27:1190-7.

24. Hoelscher GL, Gruber HE, Coldham G, Grisby JH, Hanley EN. Effects of very high concentrations on human intervertebral disc cell proliferation, viability and metabolism in vitro. Spine 2000;25:1871-7.

C. C. Tai, S. Want, N. A. Quraishi, J. Batten, M. Kalra, S. P. F. Hughes

From the Charing Cross and Hammersmith Hospitals, London, England

C. C. Tai, MRCS, Specialist Registrar

N. A. Quraishi, MRCS, Specialist Registrar J. Batten, PhD, Research Assistant

M. Kalra, MB BS, Clinical Assistant S. P. F Hughes, FRCS, Professor

Department of Musculoskeletal Surgery, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK.

S. Want, PhD, Clinical Scientist

Department of Microbiology, Hammersmith Hospital, Hammersmith Hospital Campus, Du Cane Road, London W12 OHS. UK.

Correspondence should be sent to Mr C. C. Tai at the Department of Trauma and Orthopaedic Surgery, Barnet Hospital, Thames House, Wellhouse Lane, Barnet, Hertfordshire EN5 3DJ, UK.

Copyright British Editorial Society of Bone & Joint Surgery Sep 2002
Provided by ProQuest Information and Learning Company. All rights Reserved