RepRint
Journal of Chemotherapy
ReVieW
linezolid penetration Into Cerebrospinal Fluid and brain Tissue
A. TSONA 1 - S. METALLIDIS 1 - N. FOROGLOU 2 - P. SELVIARIDIS 2 - T. CHRYSANTHIDIS 1
G. LAZARAKI 1 - M. PAPAIOANNOU 2 - J. NIKOLAIDIS 2 - P. NIKOLAIDIS 1
1
1st Internal Medicine Department, Infectious Diseases Division, AHEPA University Hospital, Thessaloniki, Greece.
2
Neurosurgical Department, AHEPA University Hospital, Thessaloniki, Greece.
Correspondence: Metallidis Simeon MD, PhD, AHEPA University Hospital, 1, Stilponos Kyriakidi Str, 54006, Thessaloniki, Greece.
Tel: +30 2310.994656; Fax: +30 2310.994656; E-mail: metallidissimeon@yahoo.gr
Summary
The aim of the study was to evaluate the penetration of
linezolid into cerebrospinal fluid (CSF) and brain tissue
after a single i.v. dose of 600 mg. The penetration of line-
zolid into cerebrospinal fluid and brain tissue was studied
in 18 patients undergoing a neurosurgical procedure. line-
zolid 600 mg i.v. was given with the induction of anesthe-
sia. mean concentrations of linezolid 2h after the final
dose, in serum, cerbrospinal fluid and brain tissue were
assayed by HplC. CSF/serum and brain/serum ratios were
INTRODUCTION
Linezolid is the first of the oxazolidinone group of synthetic
antibiotics 1. It acts by selectively inhibiting the initiation of bac-
terial protein synthesis with a unique mechanism that precludes
cross-resistance to currently available agents 2. It has activity
against clinical isolates of streptococci, staphylococci and ente-
rococci, including strains resistant to beta-lactams and gly-
copeptides, suggesting a potential role in the management of
central nervous system (CNS) infections 3.
Gram-positive cocci are the most frequent pathogens in-
volved in CNS infections 4. Severe CNS infections caused by
Gram-positive pathogens may also be related to head trauma
with skull fracture in neurosurgical patients, especially in the
presence of an external drainage or ventriculoperitoneal shunt.
The frequency of CNS infections subsequent to neurosurgical
procedures is estimated to be ≈ 4% 5. The presence of the blood-
brain barrier restricts the distribution of an antibiotic into the
brain and cerebrospinal fluid (CSF) 6.
To date, linezolid has been shown to be effective in a vari-
ety of infections caused by Gram-positive cocci, including those
where the use of glycopeptide antibiotics was not tolerated 7.
Experience with linezolid for the treatment of CNS infections is
limited to single case reports 8-12 and some other CNS postneu-
rosurgical infections caused by Gram-positive pathogens 5.
Herein we describe the CSF/serum and brain/serum ratios of
linezolid in patients undergoing a neurosurgical procedure.
PATIENTS AND METHODS
Subjects
Approval for the study was granted by the Hospital Ethics
and Research Committee. Eighteen (18) patients (10 males, 8
females) with a mean age of 55 years (range 19–71 years) un-
dergoing a neurosurgical procedure, were recruited. All gave in-
formed written consent. Their mean weight was 75.4 kg (range
55–90 kg). The exclusion criteria were age <18 years, preg-
nancy, CNS infection, linezolid hypersensitivity, uncontrolled
hypertension, severe hepatic or renal impairment, psychiatric
© E.S.I.F.T. srl - Firenze
Vol. 22 - n. 1 (17-19) - 2010
69.57% and 44.66% respectively. Concentrations of line-
zolid were above the mIC90s for staphylococci and strepto-
cocci. The concentrations obtained indicate good
penetration of linezolid into CSF and brain tissue and sup-
port its use in the management of multidrug-resistant
Gram-positive CNS infections.
Key words: linezolid, oxazolidinone, CNS infections,
cerebrospinal fluid, brain, pharmacokinetics
disorder, hematological malignancy or myelosuppression, con-
comitant use of monoamine oxidase (MAO) inhibitors, adren-
ergic bronchodilators, pethidine and buspirone therapy. The
patients enrolled in the study were divided into two groups. The
penetration of linezolid was measured in CSF (Group 1 = 9 pa-
tients undergoing hydrocephalus drainage) and in brain (brain-
adjacent tumor tissue) (Group 2 = 9 patients undergoing brain
tumor excision).
Drug administration
All patients received 600 mg of linezolid (Zyvoxid, Pfizer) as
a 30-min intravenous (i.v.) infusion with the induction of anes-
thesia, as prophylactic chemotherapy.
Sampling
Samples of serum, cerebrospinal fluid, and brain tissue were
collected 2 hours after the end of linezolid infusion. Serum and
CSF were separated by centrifugation at 4000xg for 10 min at
room temperature and then transferred into propylene tubes,
marked and stored at −80°C until analysis. Brain tissue samples
were washed with physiological saline to avoid blood contami-
nation and were left to dry prior to being stored at −80°C until
analysis.
High performance liquid chromatography (HpLC) assay
procedures
Total linezolid concentrations in serum, CSF and brain sam-
ples were measured by an isocratic HPLC method with a Jasco
880-PU intelligent HPLC pump (Jasco, Tokyo, Japan) with a
Fasma 525 programmable detector (Linear Instruments, San
Jose, California, USA). The determination was performed at
room temperature in a Perfectsil 100 Phenyl – 3.5 mm, 250
mm x 4 column (MZ AnalysenTehnik), connected before the in-
jection valve of a Marathon series RS232 auto-sampler (Spark
Holland, Emmen, The Netherlands). The mobile phase con-
sisted of 200 mL of acetonitrile, 200 mL of methanol, 600 mL
of H2O.The flow rate was set at a constant value of 1 mL/min
ISSN 1120-009X
18 A. TSONA - S. METALLIDIS - N. FOROGLOU - P. SELVIARIDIS - T. CHRYSANTHIDIS - G. LAZARAKI - M. PAPAIOANNOU - J. NIKOLAIDIS - P. NIKOLAIDIS
and the measures were performed at 251 nm. The retention
time of linezolid was 7.8 min. Serum, CSF and brain calibra-
tion curves of linezolid were linear over the whole operative con-
centration range (0–50 mg/mL). The lower limit of detection
was determined as 0.15 mg/mL.
The intra-day reproducibility was <6.43% for quality-control
samples containing 1, 5 or 25 mg/L linezolid. The inter-day re-
producibility was <11.58%.
Serum and CSF aliquots (0.5 mL) were mixed with 3 mL of
dichloromethane used as a deproteinizing solution and vortexed
for 2 min. The resulting suspension was centrifuged for 15 min
at 4000xg. The clear subnatant was removed and evaporated
under a stream of nitrogen. The pellet was reconstituted with
0.5 mL of mobile phase and vortexed for 1 min and an aliquot
of 120 mL was injected for drug determination.
Brain samples were homogenized with a Misonix XL2020
Ultrasonic Processor (Sonicator®; Misonix Inc., New York, NY)
with the addition of 1 mL of 0.1M phosphate-buffered saline
(pH 7.1). The resulting homogenized solution was centrifuged
for 10 min at 4000xg. The supernatants were removed and
were injected for HPLC drug determination following the same
procedure described above for the serum and CSF samples.
RESULTS
Eighteen patients (10 men and 8 women) with a mean ± SD
age of 55 ± 15.5 years and a mean weight of 75.4 ± 11.4 kg
were included in the study. Two hours after the end of infusion
of 600 mg of linezolid the mean serum concentration was 6.83
± 3.32 mg/mL in Group 1 and 5.94 ± 1.55 in Group 2, while
the concentrations from the CSF and brain were 5.06 ± 3.53
mg/mL and 2.63 ± 0.78 mg /g, respectively.
There was no statistical difference between the concentra-
tions in samples obtained from the CSF and brain (p = 0.06).
CSF/serum and brain/serum concentrations of linezolid
were 69.57% ± 22.13% and 44.66% ± 9.48%, respectively.
The minimum inhibitory concentration (MIC90) of linezolid is <2
mg/L for staphylococci and enterococci and <1 mg/L for pneu-
mococci. The concentrations of linezolid in serum, CSF and
brain and the MIC90s for the most relevant pathogens are shown
in Figure 1.
DISCUSSION
Treatment of infections in the CNS is complicated due to
different permeability of various antibiotics across the blood-
brain barrier (BBB). The therapy for patients with brain abscess
can be further complicated due to limited penetration of antibi-
otics into the abscess cavity. Antibiotics enter the CSF pre-
dominantly via passive diffusion down a concentration gradient;
the major determinant of CSF penetration is solubility. Inflam-
mation also increases the permeability of the BBB to various
antibiotics.
Linezolid is a synthetic antimicrobial agent with excellent oral
bioavailability and activity against many multidrug-resistant
Gram-positive organisms, including methicillin-resistant Staphy-
lococcus aureus (MRSA), methicillin-resistant Staphylococcus
epidermidis (MRSE), penicillin-resistant pneumococci and van-
comycin-resistant enterococci (VRE). Recent reports have de-
scribed the successful use of linezolid in patients with complex
multidrug-resistant Gram-positive infections, including CNS in-
fections 5,8-17.
The mean serum concentration of linezolid 2 hours follow-
ing an i.v. dose of 600 mg was 6.38 ± 2.48. These concentra-
tions were above the MIC90 for the most relevant pathogens (2
mg/L for staphylococci and enterococci and 1 mg/L for pneu-
mococci), as reported recently by the LEADER 2004 surveil-
lance program 18. At the same time, the concentration in the
brain was 2.63 ± 0.78 mg/Kg and in the CSF 5.06 ± 3.53
mg/Kg. These concentrations were also above the MIC90 for
the most relevant pathogens. These findings parallel those of
Shaikh et al 11 who observed plasma and CNS concentrations
of 7.68 mg/L and 2.05 mg/L respectively 2 hours after the
end of infusion in a patient with vancomycin-resistant entero-
coccus faecium meningitis. In another study by Villani et al 4
the trough concentrations of linezolid in plasma and CNS were
between 0.54 -5.3 mg/L and 1.46-7 mg/L respectively. No
study has ever evaluated the brain tissue concentrations.
We have to take into consideration the limitation of the one
point design of the study. Clinical/bacteriological cure depends
on the entire concentration-time curve.
There are some strains of S. aureus with an MIC of 2-4
mg/L and this could affect therapeutic failures when treating
brain infections where the concentrations are only 2.63 ± 0.78
mg/Kg.
Our results demonstrate a good degree of penetration of
linezolid in the brain and excellent penetration of linezolid in
CSF. CSF/serum and brain/serum ratios were 69.57% and
44.66% respectively.
In conclusion, these data suggest that linezolid will be suc-
cessful in the treatment of Gram-positive infections of the cen-
tral nervous system, as demonstrated by the good brain and CSF
concentrations observed in our study.
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FIGURE 1 - Concentrations of
linezolid related to the MIC90s of
staphylococci, enterococci and
pneumococci.
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