Pharmacokinetics and protein binding of linezolid in cerebrospinal fluid and serum in a case of post-neurosurgical bacterial meningitis

We describe a case of bacterial meningitis in a patient administered linezolid (LZD). The ratio of free to total LZD concentrations in cerebrospinal fluid (CSF) was 1 for all measurements, and the LZD concentration in CSF measured at the trough level was almost the same as the free serum concentration.     

Measurement of lactic acid in cerebrospinal fluid of patients with infections of the central nervous system

The concentration of lactic acid in cerebrospinal fluid (CSF) was determined by gas-liquid chromatography in 205 samples of CSF from 97 patients with or without infections of the central nervous system. Patients without infection or those with nonbacterial (presumably viral) meningitis consistently had low concentrations of lactic acid in CSF (i.e., less than or equal to 35 mg/100 ml), whereas patients with bacterial or tuberculosis meningitis consistently had concentrations of lactic acid in CSF of greater than 35 mg/100 ml. There was no overlap in concentrations of lactic acid between these two groups. Further, lactic acid concentrations in CSF from patients partially treated for meningitis were generally greater than 35 mg/100 ml through the third day of therapy and, thereafter, progressively declined to less than 20 mg/100 ml by the seventh to 10th day of therapy. Relapse of bacterial infection was consistently documented by a recurrence of an increased concentration of lactic acid in CSF. Preliminary experience with determination of the concentration of lactic acid in CSF suggests that it may be useful in distinguishing bacterial (with or without positive cultures) and tuberculous meningitis from meningitis due to nonbacterial causes.     

Vancomycin‐resistant enterococcal meningitis in an autologous stem cell transplant recipient cured with linezolid

Enterococci are an unusual cause of meningitis, with most cases reported in the literature preceded by neurosurgical procedures. Spread to the meninges from an enterococcal bloodstream infection is even more rare, with few cases reported in the literature. We report the first documented case, to our knowledge, of successful treatment of vancomycin‐resistant enterococcal (VRE) meningitis with linezolid therapy in an immunosuppressed hematopoietic stem cell transplant recipient. Our case highlights the success of monotherapy with linezolid for VRE meningitis. A literature review is provided, which reveals that there is little evidenced‐based data on the optimal therapy for VRE meningitis.     

Serum S100B levels in patients with cerebral and extracerebral infectious disease

S100B has been shown to increase in cerebrospinal fluid (CSF) and serum after various neurological diseases and it has been postulated that S100B could serve as a serum marker for brain damage. However there is limited information concerning serum S100B levels in infectious diseases of the brain. Blood samples were collected from patients at the Department of Infectious Diseases at or soon after admission. The different diagnoses studied were bacterial meningitis, pneumonia, viral meningitis, cerebral abscess, enteritis, erysipelas, viral encephalitis and neuroborreliosis. A serum S100B level > 0.15 microg/l was defined as increased. 57 patients were included in the study. S100B was elevated in 33% of patients (19/57). 73% (8/11) of patients with bacterial meningitis showed increased levels compared to 7% (1/14) of patients with viral meningitis. Viral encephalitis showed the highest mean S100B levels (mean 0.58 microg/l). 25% (6/24) of patients with extracerebral infections showed raised S100B levels. S100B levels were generally higher in patients with cerebral infections than in extracerebral infections. However, both false negative and false positive S100B levels were observed which may limit the use of S100B as a brain specific serum marker.     

Cefamandole and ampicillin therapy in experimental Haemophilus influenzae meningitis.

Cefamandole and ampicillin were compared in the therapy of experimental Haemophilus influenzae meningitis in rabbits. Three dosages of each drug were administered as a continuous intravenous infusion for 8 hr to 24 infected animals. Samples of serum and cerebrospinal fluid (CSF) were obtained at 0, 4, and 8 hr for determination of antibiotic concentrations and bacterial titers in CSF. Serum levels of cefamandole were higher, but CSF concentrations of both antibiotics were similar. With the 60-mg/kg per hr dose, the mean serum level was 106 +/- 61 mug/ml for cefamandole and 58 +/- 32 mug/ml for ampicillin (P less than 0.05). With this dosage the mean level in CSF was 7.3 +/- 8.4 mug/ml for cefamandole and 9.5 +/- 5.4 mug/ml for ampicillin (P = 0.26). The percentage penetration ([concentration in CSF/concentration in serum] X 100%) was higher for ampicillin (mean, 18.8% +/- 8.9%) than for cefamandole (mean, 5.6% +/- 3.8%) with all dosages tested (P less than 0.001). The rate of bacterial killing in vivo during therapy was similar with both drugs. The efficacy of cefamandole and ampicillin given intramuscularly for five days (250 mg every 8 hr) was examined in 42 rabbits. Twelve of 14 untreated control rabbits died within 24-72 hr of inoculation. In contrast, 11 of 14 rabbits treated with cafamandole and 10 of 14 rabbits treated with ampicillin were cured of their infections. Cefamandole compared favorably with ampicillin in the therapy of experimental H. influenzae meningitis.     

Correlation between serum linezolid concentration and the development of thrombocytopenia

We evaluated the possible association between trough linezolid (LZD) concentrations and platelet counts using a dose-response curve with a logit model equation. We demonstrated that trough LZD concentrations correlated with platelet counts. A significant decrease in platelet count was observed in patients with trough LZD concentrations higher than 22.1 μg/ml.     

Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda

Culture adapted T. b. gambiense isolated from Northwest Uganda were exposed to 0.001-0.14 microg/ml melarsoprol or 1.56-100 microg/ml DL-alpha-difluoromethylornithine (DFMO). Minimum inhibitory concentrations (MICs) of each drug were scored for each isolate after a period of 10 days drug exposure. The results indicate that T. b. gambiense isolates from Northwest Uganda had elevated MIC values for melarsoprol ranging from 0.009 to 0.072 microg/ml as compared with T. b. gambiense isolates from Cote d'Ivoire with MIC values ranging from 0.001 to 0.018 microg/ml or with T. b. rhodesiense from Southeast Uganda with MIC values from 0.001 to 0.009 microg/ml. All MIC values obtained fell below expected peak melarsoprol concentrations in serum of treated patients. However, it may not be possible to maintain constant drug concentrations in serum of patients as was the case in our in vitro experiments. Importantly, the MIC of 0.072 microg/ml exhibited by one of the isolates from Northwest Uganda was above levels attainable in CSF indicating that this isolate would probably not be eliminated from CSF of treated patients. PCR amplification of the gene encoding the P2-like adenosine transporter followed by restriction digestion with Sfa NI enzyme revealed presence of fragments previously observed in a trypanosome clone with laboratory-induced arsenic resistance. From our findings it appears that reduced drug susceptibility may be one factor for the frequent relapses of sleeping sickness after melarsoprol treatment occurring in Northwest Uganda.     

Predictive Value of Serum and Cerebrospinal Fluid Procalcitonin Levels for the Diagnosis of Bacterial Meningitis

Background: The value of serum and cerebrospinal fluid (CSF) procalcitonin for differentiating between acute bacterial and viral meningitis was assessed and compared to other parameters which are usually used in clinical practice. Patients: 45 adult patients (20 with bacterial and 25 with tick-borne encephalitis, TBE) were included in this prospective study. Results: The median serum procalcitonin level in patients with bacterial meningitis was 6.45 ng/ml (range 0.25–43.76 ng/ml) and in the group with viral meningitis 0.27 ng/ml (range 0.05–0.44 ng/ml). 11 patients with bacterial meningitis had an elevated procalcitonin concentration not only in serum, but also in CSF. A serum procalcitonin level > 0.5 ng/ml had a positive predictive value for bacterial meningitis of 100% and a negative predictive value of 93%, while corresponding values for CSF procalcitonin were 100% and 74%, respectively. Conclusion: Serum and CSF procalcitonin concentrations > 0.5 ng/ml appear to be a reliable indicator of bacterial central nervous system (CNS) infection, with maximal positive predictive values and high negative predictive values. Received: October 23, 2000 · Revision accepted: June 1, 2001     

Successful treatment with linezolid in two cases of methicillin-resistant Staphylococcus aureus infections in the orthopedic field

We have reported two orthopedic patients with Methicillin-resistant Staphylococcus aureus (MRSA) infections successfully treated with linezolid. The first case was a 64-years-old man with bacteremia, spondylitis and psoas abscesses caused by MRSA. He was treated with arbekacin (ABK) and vancomycin (VCM), and then became afebrile. However he complained of a recurrence of fever and oliguria, we administered linezolid for two weeks intravenously because of fluctuating renal dysfunction. Thereafter his clinical conditions improved. The second case was a 26-years-old man with MRSA infection of the pelvis after a trauma. He was treated with teicoplanin (TEIC) for two weeks. However the minimum inhibiratory concentrations (MICs) of TEIC and VCM against MRSA, isolated from the wounds, were 4 micrograms/ml each, we administered linezolid intravenously and the patient was successfully treated in four weeks. Linezolid has been proven to have high efficacy against MRSA by some trials abroad. But the agent has the indication only for VRE by the Medical Insurance in Japan. These cases also suggest that linezolid is useful for MRSA infections in these cases.     

Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV

INTRODUCTION: Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF). METHODS: LPV was measured by liquid chromatography/mass spectrometry in 31 CSF-plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 microg/l. RESULTS: Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 microg/l (range, < 3.7 to 608; typical trough values approximately 4000 microg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 microg/l [interquartile range (IQR), 4805-9620] and all CSF samples had measurable LPV concentrations: median 17.0 microg/l (IQR, 12.1-22.7). The median CSF-plasma ratio was 0.23% (range, 0.12-0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus. CONCLUSIONS: In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.     

The penetration of cephalosporins across the blood-brain barrier and its clinical significance

The penetration of Cefuroxime (CXM), Ceftazidime (CTZ), Cefotaxime (CTX), Ceftizoxime (CZX), and Ceftriaxone (CTRX) across the blood-brain barrier was studied in 119 patients with or without meningitis after an intravenous injection of 2 grams. Cephalosporins were undetectable or their concentrations very low in the cerebrospinal fluid (CSF), when there was no inflammation in the meninges. On the contrary, the mean CSF concentrations of cephalosporins were 2.21-5.36 micrograms/ml and the CSF/serum ratios 3.73-31.80% in acute stage of purulent meningitis. The CSF levels of all the five cephalosporins were much higher than the mean MICs of the common pathogens of bacterial meningitis as well as that of Enterobacteriaceae. It is thus shown that these five new cephalosporins are useful for treatment of meningitis including those caused by gram-negative bacilli.     

Follistatin (FS) in human cerebrospinal fluid and regulation of FS expression in a mouse model of meningitis

OBJECTIVE: Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice. METHODS: FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry. RESULTS: FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression. CONCLUSIONS: The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.     

Cerebrospinal fluid penetration of high doses of intravenous ciprofloxacin in meningitis.

Nosocomial meningitis due to gram-negative organisms is a difficult clinical problem to manage because of both antibiotic resistance and poor penetration of many antimicrobials across the blood-brain barrier. Ciprofloxacin has potential in treating this condition when used in high doses. We investigated the plasma and cerebrospinal fluid (CSF) levels of ciprofloxacin in a patient with Pseudomonas aeruginosa meningitis who was treated with 400 mg of intravenous ciprofloxacin every 8 hours. Ciprofloxacin levels in plasma peaked at 10.29 mg/L without resulting in accumulation (8-hour trough levels, <1 mg/L), whereas the CSF level increased to 0.9 mg/L. This CSF level was confirmed to be similar 1 week later. After 1 week of therapy, during which there were no side effects attributable to ciprofloxacin, the organism was eradicated, and there was some clinical improvement. We recommend that 400 mg of intravenous ciprofloxacin every 8 hours be considered for treatment of difficult-to-treat gram-negative bacillary meningitis.     

An automated biological assay to determine levels of the trypanocidal drug melarsoprol in biological fluids

For the investigation of the pharmacokinetic properties of a drug, methods for sensitive and precise quantification are a prerequisite. Only few functional methods exist for the determination of the trypanocidal drug melarsoprol in biological fluids: A bioassay which requires microscopical evaluation and two HPLC methods, which require sample extraction and are difficult to automatize due to the drug's properties. We report the development of an automated biological assay, based on the fluorescent dye Alamar blue. To validate the assay for melarsoprol, 108 serum and 37 cerebrospinal fluid (CSF) samples were spiked with melarsoprol at concentrations of 17-92 ng/ml for CSF and 17 ng/ml-2.2 microg/ml for serum. The precision (repeatability) expressed as the interday average coefficient of variation was 9.9% for serum and 18.8% for CSF samples over the respective concentration range. The accuracy (measurement for the systematic error) of the test was 99.4% for serum and 96.4% for CSF. The assay's limit of quantitation with the use of the trypanosome stock STI 704 BABA was 4 ng/ml for both serum and CSF samples.     

Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome

The urokinase-type plasminogen activator system has been suggested to play a pathophysiological role in brain damage. The aim of this study was to evaluate CSF levels of suPAR in 183 patients clinically suspected of having meningitis on admission. Of these, 54 patients were found to have purulent meningitis, 63 had lymphocytic meningitis, 12 had encephalitis, and 54 patients were suspected of, but had no evidence of, meningitis. There was a significant difference in suPAR levels among patient groups (Kruskal Wallis test, p < 0.0001) with significantly higher CSF suPAR levels in patients with CNS infection (purulent meningitis: median suPAR 2.41 microg/l (range 0.12-35), lymphocytic meningitis: 1.10 microg/l (0.15-5.31), and encephalitis (1.77 microg/l (0.17-11.7)) than in patients without meningitis (0.64 microg/l (0-5.34) (Dunn's multiple comparison test, p < 0.05). Also, patients with purulent meningitis had significantly higher CSF suPAR levels than patients with lymphocytic meningitis (p < 0.001). Patients with purulent meningitis who died (n = 8, 4.9 microg/l (1.3-35) had significantly higher CSF levels of suPAR than patients who survived (n = 46, 2.1 microg/l (0.1-24), Mann Whitney, p = 0.046). Employing a cut-off point of 3.1 and above, the OR (95%CI) for fatal outcome was 11.9 (1.4-106), univariate logistic regression analysis, p = 0.026. In conclusion, CSF suPAR levels may be an important predictor for fatal outcome in purulent meningitis.     

Interleukin 12 measurement in the cerebrospinal fluid of infants with purulent meningitis

We measured IL-12 concentrations in the CSF of patients with purulent meningitis. Twenty-three infants who were admitted between 1997 and 2003 and diagnosed as having purulent meningitis were included in this study. All patients in this study were admitted by the 3rd day of illness. After admission, appropriate antibiotics were administered to all infants. Two infants died and two other infants developed cerebral palsy and mental retardation (adverse outcome group). None of the other patients showed any neurologic abnormalities at discharge (good outcome group). As a control group, 16 infants who were diagnosed with diseases other than purulent meningitis were also investigated. The CSF IL-12 p40 concentrations in meningitis infants on admission (median [range], 1,890 [< 15-7,770] pg/ml) were significantly higher compared with those in the control group (p < 0.001). Among infants with meningitis, there were no significant differences on admission between patients with adverse outcome group and those with good outcome group. Consecutive measurements were performed in 17 infants with meningitis including the 2 infants with adverse outcome group. The concentration in the infants with adverse outcome group seemed to decrease more gradually than that in those with good outcome group. IL-12 induces production of interferon-gamma, which enhances the function of polymorphonuclear leukocytes. IL-12 may contribute to local host defenses in the subarachnoid space.     

Antibiotic therapy, endotoxin concentration in cerebrospinal fluid, and brain edema in experimental Escherichia coli meningitis in rabbits

We investigated the effect of cefotaxime and chloramphenicol on endotoxin concentrations in cerebrospinal fluid (CSF) and on the development of brain edema in rabbits with Escherichia coli meningitis. Both antibiotics were similarly effective in reducing bacterial titers. Cefotaxime, but not chloramphenicol, induced a marked increase of endotoxin in CSF, from log10 1.5 +/- 0.8 to log10 2.8 +/- 0.7 ng/ml (P less than .01). This result was associated with an increase in brain water content (405 +/- 12 g of water/100 g of dry weight compared with 389 +/- 8 g in untreated controls; P less than .01), whereas in animals treated with chloramphenicol, brain water content was identical to controls. The cefotaxime-induced increase in endotoxin concentration and brain edema were both neutralized by polymyxin B, which binds to the lipid A moiety of endotoxin, or by a monoclonal antibody to lipid A. These results indicate that treating gram-negative bacillary meningitis with selected antibiotics induces increased endotoxin concentrations in CSF that are associated with brain edema.     

Linezolid resistance in a clinical isolate of Staphylococcus aureus

The new oxazolidinone antimicrobial, linezolid, has been approved for the treatment of infections caused by various gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Although instances of linezolid resistance in VRE have been reported, resistance has not been encountered among clinical isolates of S aureus. We have characterised an MRSA isolate resistant to linezolid that was recovered from a patient treated with this agent for dialysis-associated peritonitis.     

Studies on digitalis. 23. Blood-brain barrier of digitoxin in humans.

Data on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio-immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis. Mean serum digitoxin concentration was 12.4 ng/ml (SD 2.6) and mean CSF concentration 0.84 ng/ml (SD 0.22) giving a CSF/serum ratio of 0.07 (SD 0.03). Serum digitoxin protein binding was 97.4% (SD 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SD 1.43). Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.     

Low sensitivity of serum procalcitonin in bacterial meningitis in adults

Several studies have suggested high predictive values of serum procalcitonin (PCT) for the discrimination of bacterial and viral meningitis in children and adults. Here, we report PCT serum concentrations in 12 adults suffering from bacterial meningitis. PCT on admission was normal ( < or = 500 pg/ml) in 3 and between 500 and 1,000 pg/ml in 2 patients without evidence of concurrent bacterial infections. Conversely, in 5 patients with PCT concentrations between 2,268 and 38,246 pg/ml other infections were present. PCT concentrations were higher with typical meningitis agents (pneumococci and meningococci 12,679 +/- 13,092 pg/ml vs. other bacteria 4048 +/- 9187 pg/ml, p = 0.041) whilst in nosocomial bacterial meningitis after neurosurgery (n = 3) serum PCT remained normal. We believe that PCT is of limited diagnostic value in adults suffering from bacterial meningitis, especially in cases due to unusual agents or of nosocomial origin. Elevated PCT in bacterial meningitis may indicate the presence of bacterial inflammation outside the central nervous system.