1 Intensive Care Unit and Trauma Center and 3 Department of Neurosurgery, Nord Hospital, Marseilles School of Medicine, Marseilles; 2 Department of Pharmacokinetics, Timone Hospital, France
Received 18 February 2002; returned 8 May 2002; revised 18 June 2002; accepted 15 July 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Several studies have described the pharmacokinetics of ciprofloxacin in cerebrospinal fluid (CSF).57 The penetration was excellent when it was compared with the corresponding serum concentrations, but the absolute CSF concentrations were sometimes considered to be subtherapeutic.57 One study has assessed the brain tissue distribution of ciprofloxacin.5 Knowledge of ciprofloxacin brain tissue distribution is an important determinant for prevention of post-operative brain abscesses.
This study was designed to determine whether a 200 mg intravenous (iv) dose of ciprofloxacin could achieve adequate concentrations in brain tissues.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
After institutional approval and informed consent were obtained, 14 patients of either sex, 3876 years of age, undergoing scheduled neurosurgery for brain tumour resection were prospectively enrolled in the study. The inclusion criteria were as follows: age 18 years; no pregnant women; no obesity; elective surgery; absence of prior history of hepatic or renal disease; and no clinical or laboratory signs of infection. Patients with a prior history of a hypersensitive reaction to quinolone antibiotics were excluded. After surgery, patients were carefully followed up for signs of infection, until hospital discharge or on day 30.
Drug administration and sample collection
A 200 mg single iv dose of ciprofloxacin (Ciflox; Bayer, Puteaux, France) was administered over a 20 min period 30 min before skin incision. Blood samples were drawn from a venous line before infusion and 10 min after the end of infusion, and concomitant with each tissue sample. All patients also received normal prophylaxis with a second-generation cephalosporin.
Samples of subcutaneous fat and skull bone were collected on opening and closure. Samples of dura mater and brain tissues were collected during the surgical procedure, 60 min after ciprofloxacin administration. Serum and tissue samples were stored at 80°C until assayed.
Ciprofloxacin assay
Serum samples were analysed according to a validated HPLC-fluorescence method.8 Tissue samples were pulverized following freezing with liquid nitrogen and homogenized in water. Ciprofloxacin was concentrated on a Sep Pack C18 column, eluted with methanol and injected on a C18 nucleosyl column.
Day and between-day levels of interassay precision were 4% and 6.5% (1 mg/L), 11% and 6% (5 mg/L), and 6% and 8% (10 mg/L) for serum samples.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
When compared with the serum concentrations at the same period during the same surgical procedures, tissue concentrations [mean ± S.D. (ratio tissue/serum concentration)] were greater in parietal fat during opening [2.67 ± 1.29 (1.40 ± 1.05) mg/kg] and closure [0.95 ± 0.65 (1.34 ± 1.17) mg/kg], and in dura mater [2.91 ± 2.08 (2.26 ± 1.36) mg/kg] than in skull bone during opening [0.68 ± 0.53 (0.44 ± 0.29) mg/kg] and closure [0.75 ± 0.86 (0.97 ±1.57) mg/kg] or in brain tissue [0.87 ± 0.80 (0.88 ± 0.99) mg/kg]. However, large interindividual variability was observed in both the serum and tissue concentrations, as reported by Davey et al.5
A limitation of our study was that only one brain tissue concentration was determined per individual, and the reported tissue concentrations were unlikely to be the maximum concentrations. A microdialysis study would be an alternative approach to assess tissue penetration of antimicrobial drugs. Where they have been used, microdialysis studies have confirmed that ciprofloxacin concentrations in human soft tissues, which were measured at the sites of effect, may be subinhibitory, despite the fact that effective concentrations were attained in serum.4 Although microdialysis studies provide excellent data, there are many issues that need to be addressed before they become the accepted methodology in tissue penetration studies.9 The cost of a disposable kit is high, and the probe insertion into the human brain is ethically questionable.9 In addition, the data they have generated are in agreement with those from conventional tissue penetration studies.4,9
The MIC90 of ciprofloxacin for Staphylococcus aureus and Staphylococcus epidermidis may be as high as 1 mg/L, and the concentrations achieved in the brain tissue of most of the patients in this study would be considered subtherapeutic.10 Although the choice of an iv dose of 200 mg was determined according to the manufacturers registration specifications,1,2 a dose of 400 mg is more commonly used in severe infections, but, as yet, no recommendations are available for cerebrospinal infections.1 However, the objective of the present study was to determine the penetration of ciprofloxacin into cerebral tissues; the administration of ciprofloxacin to our patients was not performed either for prophylaxis or to cure an infection.
In conclusion, despite good penetration of ciprofloxacin into brain tissues, absolute concentrations after a 200 mg iv dose were not high enough to ensure optimal concentrations in brain tissue. From the linear pharmacokinetics of ciprofloxacin, we postulate that adequate brain tissue concentrations should be achieved with a dose of 400 mg.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Davis, R., Markham, A. & Balfour, J. A. (1996). Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs 51, 101974.[ISI][Medline]
3 . Arcieri, G. M., Becker, N., Esposito, B., Griffith, E., Heyd, A., Neumann, C. et al. (1989). Safety of intravenous ciprofloxacin. A review. American Journal of Medicine 87, 92S7S.[Medline]
4
.
Brunner, M., Hollenstein, U., Delacher, S., Jäger, D., Schmid, R., Lackner, E. et al. (1999). Distribution and antimicrobial activity of ciprofloxacin in human soft tissues. Antimicrobial Agents and Chemotherapy 43, 13079.
5 . Davey, P. G., Charter, M., Kelly, S., Varma, T. R. K., Jacobson, I., Freeman, A. et al. (1994). Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve. Antimicrobial Agents and Chemotherapy 38, 135662.[Abstract]
6 . Gogos, C. A., Maraziotis, T. G., Papadakis, N., Beermann, D., Siamplis, D. K. & Bassaris, H. P. (1991). Penetration of ciprofloxacin into human cerebrospinal fluid in patients with inflamed and non-inflamed meninges. European Journal of Clinical Microbiology and Infectious Diseases 10, 5114.[ISI][Medline]
7 . Nau, R., Prange, H. W., Martell, J., Sharifi, S., Kolenda, H. & Bircher, J. (1990). Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges. Journal of Antimicrobial Chemotherapy 25, 96573.[Abstract]
8 . Horie, M., Saito, K., Nose, N. & Nakazawa, H. (1994). Simultaneous determination of benofloxacin, danofloxacin, enrofloxacin and ofloxacin in chicken tissues by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Sciences and Applications 653, 6976.
9
.
Müller, M. (2002). Microdialysis. British Medical Journal 324, 58891.
10 . Grüneberg, R. N., Felmingham, D., OHare, M. D., Robbins, M. J., Perry, K., Wall, R. A. et al. (1988). The comparative in-vitro activity of ofloxacin. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 919.[ISI][Medline]