Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy

Levofloxacin is a fluoroquinolone antibiotic characterized by a broad antimicrobial spectrum that covers, among other organisms, the pathogens most frequently responsible for acute bacterial meningitis (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Escherichia coli) and also other sporadic agents of central nervous system (CNS) infections, such as Streptococcus agalactiae (13). In in vitro studies based on the time-kill curve method, levofloxacin was recently shown to exhibit synergistic (or at least additive) activity with some beta-lactam antibiotics against both gram-positive and gram-negative microorganisms (11, 27, 33, 35). The degree of this synergy was sometimes of the same extent as that which occurs between beta-lactams and aminoglycosides (4). Previous pharmacokinetic studies documented that levofloxacin could adequately penetrate the cerebrospinal fluid (CSF) in the presence of meningeal inflammation both in animals and in humans (8, 32). However, ratios of the concentration in CSF to the concentration in plasma (CSF to plasma concentration ratios) may vary substantially according both to different sampling times and to the status of the blood-CSF barrier. For example, Ohi et al. (23) found that 3 h after the administration of a single 200-mg dose of levofloxacin to healthy volunteers with uninflamed meninges, the CSF to plasma ratio ranged between 0.08 and 0.24. Although assessment of the level of antibiotic exposure in CSF on the basis of a single sampling time might provide incomplete information (19), an evaluation of exposure based on multiple sampling times covering the whole dosing interval should be more meaningful (19). Moreover, although most fluoroquinolones are lipophilic agents whose penetration into CSF should be only minimally affected by the degree of meningeal inflammation, assessment of the penetration of levofloxacin into the CSF in the presence of an uninflamed blood-CSF barrier would be more informative. Finally, considering that antibiotic concentrations may be severalfold higher at the lumbar CSF level than at the ventricular CSF level (21), it might be more appropriate to assess the level of exposure in the latter compartment. The purpose of this study was to assess levofloxacin ventricular CSF concentrations during the whole dosing interval in patients with minimal alteration of the blood-brain barrier, namely, hydrocephalic patients with external ventriculostomies.