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Candidate, Facility for Anti-infective Drug Development and Innovation, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia
Senior Research Fellow, Facility for Anti-infective Drug Development and Innovation, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University
Associate Professor, Head of Microbiology and Deputy Director of Infectious Diseases, Alfred Hospital, Prahran, Victoria
Infectious Disease Physician, Department of Infectious Diseases, Alfred Hospital
Professor, Director, Facility for Anti-infective Drug Development and Innovation, and Head, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University
at time of writing, Co-Director, Facility for Anti-infective Drug Development and Innovation and Senior Lecturer of Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University; now, Clinical Pharmacologist, Roche Products Ltd., Shire Park, Welwyn Garden City, England
Reprints: Dr. Nation, Facility for Anti-infective Drug Development and Innovation, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia, fax 61 3 99039629, Roger.Nation{at}vcp.monash.edu.au
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CASE SUMMARY: A 69-year-old man had an extraventricular drain inserted following a right cerebellar infarct. On day 6, the CSF culture was positive for coagulase-negative staphylococci; intravenous vancomycin 1 g daily was initiated to treat ventriculitis. A ventriculoperitoneal shunt, inserted on day 35 to manage communicating hydrocephalus, was subsequently removed as symptoms suggesting infection presented. Coagulase-negative Staphylococcus was isolated from shunt reservoir aspirate, and intrathecal vancomycin 10 mg daily was added to the treatment regimen. On day 61, vancomycin was stopped and oral linezolid 600 mg twice daily was started. Linezolid was discontinued 22 days later, with no evidence of ongoing infection. Four blood samples were collected around the seventh dose of linezolid and 5 CSF samples were collected on separate days during treatment. Linezolid concentrations were measured in plasma and CSF by HPLC. Using an ADAPT II maximum a priori Bayesian estimator module, a 2 compartment pharmacokinetic model was fitted to the plasma linezolid concentration data and CSF:predicted plasma concentration ratios (ranging from 0.27 to 1.02) were derived. All CSF concentrations exceeded the reported 90% minimum inhibitory concentration of 2 mg/L for linezolid against coagulase-negative staphylococci.
DISCUSSION: Evidence of the effectiveness of linezolid against central nervous system infections is growing; however, limited data exist describing its CSF penetration. Oral linezolid exhibited good CSF penetration in this patient, which corresponded to positive clinical response.
CONCLUSIONS: Oral linezolid may play a valuable role in the treatment of multiresistant gram-positive central nervous system infections.
Key Words: central nervous system infections, cerebrospinal fluid penetration, coagulase-negative Staphylococcus, linezolid
Published Online, June 13, 2006. www.theannals.com, DOI 10.1345/aph.1H029
The oxazolidinone agent linezolid appears to offer a fresh treatment option with demonstrated high activity against gram-positive organisms in vitro and in vivo.3 Evidence for the effectiveness of linezolid against central nervous system infections is growing. Reports have emerged of successful linezolid treatment of vancomycin-resistant Enterococcus,4-8 methicillin-resistant Staphylococcus aureus,9 hetero-resistant vancomycin-intermediate S. aureus,10 and Staphylococcus epidermidis9,11,12 central nervous system infections. This success is thought to relate to the good CSF penetration observed following intravenous linezolid administration.5,6,13,14
We describe a case of coagulase-negative Staphylococcus ventriculitis successfully treated with oral linezolid and report the extent of CSF penetration.
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On day 2 of admission, an extraventricular drain (EVD) was inserted. However, the patient had further deterioration in his mental status, requiring admission to the intensive care unit for inotropic support, dexamethasone, and assisted ventilation. On day 6, a CSF sample demonstrated neutrophils (14 x 103/mm3); a coagulase-negative staphylococcal organism was isolated and considered to be the cause of EVD-associated ventriculitis. Serratia marcescens was also identified from sputum and bronchoalveolar lavage fluid, which was initially treated with ticarcillin/clavulanic acid 3.1 g every 6 hours, but the organism was not considered to be a cause of ongoing infection. The infected EVD was removed, and intravenous vancomycin 1 g daily was started.
An EVD was reinserted on day 8 due to ventricle enlargement. A repeat CSF sample taken on day 10 and an EVD catheter tip removed on day 22 both isolated coagulase-negative Staphylococcus. Intrathecal vancomycin 7.5 mg twice daily was included in the treatment regimen from day 11 to 22.
The patient subsequently developed communicating hydrocephalus for which a right-sided ventriculoperitoneal (VP) shunt was inserted on day 35. The EVD removed on that same day isolated coagulase-negative Staphylococcus. On day 42, the VP shunt was removed as symptoms and changes suggesting infection presented, including headache and confusion, high infective parameters (C-reactive protein), and elevated neutrophil levels in the aspirate of the shunt reservoir (430 x 103/mm3). Cultures isolated coagulase-negative Staphylococcus with a minimum inhibitory concentration (MIC) for vancomycin of 4 mg/L. An EVD was reinserted on this day because the patient continued to have hydrocephalus and for potential intrathecal vancomycin therapy; intravenous vancomycin was continued. The CSF neutrophil count remained elevated (84 x 103/mm3 on day 52), and intrathecal vancomycin 10 mg daily was started.
On day 61, the CSF neutrophil count was 480 x 103/mm3; both intravenous and intrathecal vancomycin were discontinued due to lack of response and oral linezolid 600 mg twice daily was initiated. The EVD was removed and the patient had regular (every day or second day) lumbar punctures or drainages for CSF microscopy and culture. In the absence of a shunt or EVD, the patient's mental state deteriorated. A computed tomography scan of his brain documented hydrocephalus, requiring reinsertion of a VP shunt on day 72. A CSF sample taken the same day (day 12 of linezolid therapy) showed zero neutrophils and zero growth; there also was no growth from any further CSF samples. Linezolid was stopped 10 days later. During linezolid therapy, hematologic parameters (platelets, hemoglobin concentrations) were monitored at least weekly as part of the prescribed standard of care practices.
The patient remained significantly neurologically impaired, with poor sitting balance, and was able to respond to questions with only yes/no answers. There was no evidence of ongoing infection based on clinical assessment, including presence of fever and appearance of the surgical scars. He was transferred to a rehabilitation hospital 4 days after cessation of linezolid treatment. Outpatient neurosurgical follow-up 6 weeks later showed significant improvement in his mobility and the return of fluent speech. Again, there was no evidence of infection. The clinicians planned to repeat the angiography in 6 months as a check of the aneurysm.
For pharmacokinetic analysis, blood had been collected from the patient immediately before and approximately 2, 4, and 8 hours after administration of the eighth dose of linezolid; plasma was separated from each sample. A CSF sample (from the lumbar drain) was obtained at the same time as the initial blood sample, and other CSF samples were collected for neurologic assessment (protein and glucose concentrations) on days 8 (from lumbar drain), 12, 15, and 22 (via lumbar puncture) of linezolid treatment. Immediately after collection, plasma and CSF samples were stored at -20 °C.
Concentrations of linezolid in both plasma and CSF were measured using HPLC.15 Briefly, sample pretreatment involved the addition of 20 µL of eperezolid (internal standard, 0.10 g/L) and 200 µL of a mixture of 5% trichloroacetic acid and methanol to a 200 µL aliquot of each sample. After mixing, centrifugation at 10 000 g for 10 minutes was performed, followed by a pH adjustment using 3 µL of 0.1% sodium hydroxide solution. Subsequently, aliquots of 20 µL were injected onto a reverse-phase C18 column (5 µm, 150 x 4.6 mm; Phenomenex, Pennant Hills, NSW, Australia). The mobile phase consisted of a mixture of acetonitrile and 2.67 mM acetic acid (25:75, v/v). HPLC analyses were performed using a Shimadzu HPLC system (Shimadzu, Kyoto, Japan); ultraviolet absorbance of the eluent was monitored using a photodiode-array ultraviolet spectrophotometric detector over the range 190-300 nm and was processed at 253 nm. A calibration curve for linezolid ranged from 0.20 to 40 mg/L, with a limit of quantification of 0.20 mg/L. The intra- and interday accuracy (expressed as mean percentage deviation, %) and precision (expressed as coefficient of variation, %) were less than or equal to 4.20% and less than or equal to 3.88%, respectively.
As insufficient quantities of blank CSF were available to allow validation of the method in CSF, the concentrations in this matrix were determined using a plasma standard curve, an approach that has been adopted by others.6 Comparison of triplicate calibration curves constructed in both plasma and water also provided confirmation of the approach, with no significant differences in the mean ± SD of the slope (0.24 ± 0.01 vs 0.26 ± 0.01; p = 0.30, unpaired Student's t-test) and intercept observed (-0.03 ± 0.002 vs -0.03 ± 0.001; p = 0.50).
A previously described 2 compartment structural model was fitted to the plasma linezolid concentration data.16 The patient's pharmacokinetic parameters were characterized using data from the patient and a posteriori Bayesian parameter value estimator in the ADAPT II computer software.16,17 The 24 hour AUC was calculated and averaged over days 1-7 of treatment using numerical integration of the fitted model. The initial Bayesian priors or estimates were derived from results from a pharmacokinetic analysis of a population of severely debilitated and critically ill patients involved in a compassionate-use program.16 The derived function was used to predict the plasma concentrations at the collection times of the additional CSF samples.
Plasma linezolid concentrations collected around dose 8 ranged from a trough (immediately predose) of 3.80 mg/L to a peak (2 h postdose) of 15.4 mg/L. The measured plasma concentrations and the resultant fitted plasma concentration-time profile were well correlated (r2 = 0.99). When considered in relation to time after last linezolid dose, CSF concentrations ranged from 3.90 to 13.7 mg/L (Table 1). The CSF:plasma concentration ratio of the CSF and plasma samples simultaneously collected immediately before dose 7 was close to 1 (Table 1). The derived plasma concentration-time profile was used to obtain predicted plasma concentrations at the collection times of the remaining CSF samples, resulting in CSF:predicted plasma concentration ratios increasing from 0.27 to 1.02 (Table 1). Table 1 represents the predicted plasma and measured CSF linezolid concentrations over the course of a hypothetical dosage interval against time after the previous linezolid dose. The ratio of the AUC of the CSF profile to the AUC of the predicted plasma profile (AUCCSF:AUCplasma) was 0.57.
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In our patient, consecutive CSF samples collected within a single dosage interval were not available. Instead, random CSF samples collected for neurologic assessments were analyzed retrospectively and the measured linezolid concentrations were related to the time after the preceding linezolid dose. A predicted plasma concentration-time profile allowed comparison of these CSF concentrations with corresponding plasma concentrations (Table 1). It should be noted that the pharmacokinetic model used in our study to fit the plasma linezolid concentration data is limited by sparse sampling in the absorption phase.
Table 1 illustrates the predicted plasma concentration-time profile and the profile derived for measured CSF concentrations against time after the previous linezolid dose. The CSF peak linezolid concentration (observed after 12 days of treatment) is both lower and more delayed than that observed in plasma. This is likely to reflect a slow rate of distributional equilibrium in CSF due to the permeability limitations presented by the blood:CSF barrier. As a result of these differing concentration-time profiles, the ratio between corresponding linezolid concentrations in CSF and plasma did not remain constant (Table 1); instead, it approached unity over the hypothetical dosage interval. The calculated AUCCSF:AUCplasma ratio of 0.57 demonstrates high drug exposure within the CSF over this interval. While the pharmacokinetic parameters obtained for our patient varied substantially from the mean values obtained for patients in the compassionate use program, they were within the broad range of values exhibited by linezolid.16
The peak concentrations in both plasma and CSF in our patient were substantially greater than those previously reported in patients treated with intravenous linezolid 600 mg twice daily. The peak plasma and CSF concentrations in one patient after 3 days of linezolid treatment were 11.4 and 3.19 mg/L, respectively.6 In 2 patients for whom peak and trough concentrations were available, plasma and CSF peak concentrations were, for one patient, 12.4 mg/L and 6.90 mg/L, respectively (after 6 days of linezolid treatment), and for the other patient, 11.5 and 5.50 mg/L, respectively (after 8 days of linezolid treatment).14 These differences may be related to the high interpatient pharmacokinetic variability associated with linezolid use,16 and the possibility that steady-state may have not yet been reached in CSF in the previously reported cases.6,14
Regional variation in CSF drug concentrations may also explain the difference in CSF concentrations observed. Nau et al.18 found that, following intravenous administration of ceftriaxone 2 g 3 times daily to 7 patients for extracerebral infections following EVD insertion for hydrocephalus, the peak CSF concentrations were much lower than those previously reported for ceftriaxone in lumbar CSF with uninflamed meninges.19 Similarly, the CSF concentrations of linezolid collected from a lumbar drain or lumbar punctures in our patient predominantly exceeded those previously reported collected from ventriculostomy drains.6,14 The apparent disparity between the ventricular and lumbar sites may relate to only a small fraction of total CSF flow descending through the spinal subarachnoid space into the lumbar regions.20 Further, the potential for drug exchange between the spinal CSF and cord tissue adjacent to this spinal subarachnoid space may impact the lumbar concentrations.
It is evident that the time course of plasma and CSF linezolid concentrations differ, influencing the resultant CSF:plasma concentration ratio. With this in mind, single simultaneous CSF and serum/plasma concentrations may not provide sufficient information to allow accurate assessments of penetration.21 Ideally, a full pharmacokinetic profile for linezolid in both CSF and plasma should be obtained at steady-state concentrations to allow comparison of drug exposure over a whole dosage interval.6 In practice, this can prove difficult, as excess CSF sampling can expose a patient to increased risks of infection. Here, we report the use of a modified method to characterize a complete pharmacokinetic profile of linezolid in CSF over a hypothetical dosage interval. Retrospective analysis of CSF samples obtained for other diagnostic purposes was performed, in conjunction with the characterization of a pharmacokinetic model to predict plasma concentrations at the same times that the CSF samples were evaluated. Collection of CSF samples from the VP shunt of our patient may have allowed for a more direct comparison with the study reported by Shaikh et al.6 However, we were limited to samples collected from either a lumbar drain or puncture during the linezolid treatment course, as part of the patient's usual standard of care.
All measured CSF concentrations, including the trough concentrations, were
well above the reported 90% MIC of 2 mg/L for linezolid against
coagulase-negative
staphylococci.22
This outcome is encouraging as, with staphylococci in particular, the
pharmacodynamic parameter describing the percentage of time that drug
concentrations exceed the MIC has been correlated with successful outcomes
with linezolid therapy, in addition to the ratio of AUC to
MIC.23,24
Further, it is consistent with the clinical findings that, during linezolid
treatment, the CSF neutrophil count fell from 480 x
103/mm3 to 0 and no further CSF samples
exhibited growth. These observations are made without consideration of the
minor protein binding known to be associated with linezolid
(
31%).25
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This article has been cited by other articles:
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  F. Ntziora and M. E Falagas Linezolid for the Treatment of Patients with Central Nervous System Infection Ann. Pharmacother., February 1, 2007; 41(2): 296 - 308. [Abstract] [Full Text] [PDF]
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