Brain tissue penetration of ciprofloxacin following a single intravenous dose

Marc Leone1,*, Emmanuelle Sampol-Manos2, Dominique Santelli1, Stéphanie Grabowski2, Bernard Alliez3, Alain Durand2, Bruno Lacarelle2 and Claude Martin1

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
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ciprofloxacin distribution was assessed in cerebral tissues in 14 patients undergoing craniotomy. The study objective was to determine the brain tissue/serum concentration ratio of ciprofloxacin. Patients received a single intravenous (iv) 200 mg dose of ciprofloxacin. Mean (± S.D.) tissue/serum concentration ratios were (mg/kg): parietal fat during opening 1.40 ± 1.05, during closure 1.34 ± 1.17, in the dura mater 2.26 ± 1.36, in skull bone during opening 0.44 ± 0.29, during closure 0.97 ± 1.57 and in brain tissue 0.88 ± 0.99. Mean (± S.D.) concentrations of ciprofloxacin in brain tissue were 0.87 ± 0.08 mg/kg, suggesting that a dose >200 mg iv ciprofloxacin is required to ensure therapeutic concentrations in brain tissue.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cephalosporins are frequently used for prophylaxis in neurosurgery, with vancomycin used as an alternative agent in allergic patients or when there is a risk of post-operative infections due to methicillin-resistant staphylococci.1 Owing to a low incidence of side effects and significant activity against organisms encountered during neurosurgical procedures,2,3 quinolones would be good candidates for prophylaxis during neurosurgery.4

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
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects and study design

After institutional approval and informed consent were obtained, 14 patients of either sex, 38–76 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
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
Fourteen patients (age 57 ± 12 years, weight 69 ± 14 kg, height 165 ± 15 cm) undergoing brain tumour excision fulfilled the study criteria and were enrolled in this study. None of the 14 patients experienced any side effects from the study drug, particularly convulsions, and no post-operative infectious complications occurred. Ciprofloxacin serum concentrations and tissue concentrations 10 min after the end of infusion and at the different operative times are shown in Figure 1. Mean S.D.) tissue/serum concentration ratios were (mg/kg): during opening in subcutaneous fat 1.40 ± 1.05, in skull bone 0.44 ± 0.29 and in dura mater 2.26 ± 1.36; during closure in skull bone 0.97 ± 1.57 and in subcutaneous fat 1.34 ± 1.17; and in brain tissue 0.88 ± 0.99.



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Figure 1. Serum (black bars) and tissue (grey bars) ciprofloxacin concentrations at different periods during the surgical procedures (results are means ± S.D.).

 

    Discussion
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
Few studies have investigated the brain penetration of ciprofloxacin. Davey et al.,5 in a study involving five patients, reported that 750 mg of ciprofloxacin achieved concentrations in brain tissue that were at least as great as the concentrations in serum. The discrepancy between this observation and our results, where concentrations in brain tissue were only 87% of the serum concentrations, is possibly due to the different shapes of the concentration–time curves in serum and brain tissue. With a longer interval between dosing and measurement of concentrations, it is likely that a higher brain tissue concentration relative to the corresponding serum concentration would result. Compared with a 750 mg oral dose and considering a bioavailability value close to 80%, our dose represented a three-fold reduction.1,3

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 manufacturer’s 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
 
* Correspondence address. Service de Réanimation Polyvalente, Hôpital Nord, 13915 Marseille cedex 20, France. Tel: +33-4-91968650; Fax: +33-4-91962818; E-mail: marc.leone{at}ap-hm.fr Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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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, 1356–62.[Abstract]

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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, 965–73.[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, 69–76.

9 . Müller, M. (2002). Microdialysis. British Medical Journal 324, 588–91.[Free Full Text]

10 . Grüneberg, R. N., Felmingham, D., O’Hare, 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, 9–19.[ISI][Medline]