Simultaneous determination of vancomycin and ceftazidime in cerebrospinal fluid in craniotomy patients by high-performance liquid chromatography.

A simple, accurate and rapid method for simultaneous analysis of vancomycin and ceftazidime in cerebrospinal fluid (CSF), utilizing high-performance liquid chromatography (HPLC), has been developed and thoroughly validated to satisfy strict FDA guidelines for bioanalytical methods. Protein precipitation was used as the sample pretreatment method. In order to increase the accuracy, tinidazole was chosen as the internal standard. Separation was achieved on a Diamonsil C18 column (200 mm x 4.6mm I.D., 5 microm) using a mobile phase composed of acetonitrile and acetate buffer (pH 3.5) (8:92, v/v) at room temperature (25 degrees C), and the detection wavelength was 240 nm. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was applied to determine vancomycin and ceftazidime concentrations in CSF in five craniotomy patients.

Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation.

BACKGROUND: Ceftazidime and meropenem are frequently used in the empirical treatment of hospital-acquired cerebrospinal fluid (CSF) infections. Although their dispositions in CSF have been described, the ability of these agents to achieve critical pharmacodynamic targets against the array of nosocomial CSF Gram-negative bacteria encountered in practice has not been reported. METHODS: Serum and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and who received ceftazidime or meropenem. Concentration-time profiles in serum and CSF were modelled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified using population pharmacokinetic analysis [Big Non-Parametric Adaptive Grid (BigNPAG)]. A Monte Carlo simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T(>MIC) for ceftazidime 2 g intravenously every 8 h and meropenem 2 g intravenously every 8 h. The Gram-negative infection isolates of the seven most prevalent Gram-negative bacilli from the Meropenem Yearly Susceptibility Test Information Collection Program were used as a measure of contemporary MIC distribution. RESULTS: Post-Bayesian measures of bias and precision, observed-predicted plots and R(2) values were highly acceptable for both drugs. Although the PTA in CSF was approximately one dilution higher for ceftazidime compared with meropenem at a given MIC value, the cumulative fraction of response (CFR) in CSF against all Gram-negatives was markedly higher for meropenem when compared with ceftazidime secondary to the higher occurrence of lower MIC values for meropenem. Both agents had a low CFR against Pseudomonas aeruginosa. CONCLUSIONS: The pharmacodynamics of meropenem was superior to that of ceftazidime against Gram-negative pathogens in the CSF.

Determination of ceftazidime in plasma and cerebrospinal fluid by micellar electrokinetic chromatography with direct sample injection.

A simple micellar electrokinetic chromatography (MEKC) with UV detection at 254 nm for analysis of ceftazidime in plasma and in cerebrospinal fluid (CSF) by direct injection without any sample pretreatment is described. The separation of ceftazidime from biological matrix was performed at 25 degrees C using a background electrolyte consisting of Tris buffer with sodium dodecyl sulfate (SDS) as the electrolyte solution. Under optimal MEKC condition, good separation with high efficiency and short analyses time is achieved. Several parameters affecting the separation of the drug from biological matrix were studied, including pH and concentration of the Tris buffer and SDS. Using cefazolin as an internal standard (IS), the linear ranges of the method for the determination of ceftazidime in plasma and in CSF were all over the range of 3-90 microg/mL; the detection limit of the drug in plasma and in CSF (signal-to-noise ratio = 3; injection 0.5 psi, 5 s) was 2.0 microg/mL. The applicability of the proposed method for determination of ceftazidime in plasma and CSF collected after intravenous administration of 2 g ceftazidime in patients with meningitis was demonstrated.

Cerebrospinal fluid ceftazidime kinetics in patients with external ventriculostomies.

Ceftazidime has proven to be effective for the treatment of bacterial meningitis caused by multiresistant gram-negative bacteria. Since nosocomial central nervous system infections are often accompanied by only a minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 8). Serum and CSF were drawn repeatedly after the administration of the first dose of ceftazidime (3 g over 30 min intravenously), and concentrations were determined by high-performance liquid chromatography by using UV detection. The concentrations of ceftazidime in CSF were maximal at 1 to 13 h (median, 5.5 h) after the end of the infusion and ranged from 0.73 to 2.80 mg/liter (median, 1.56 mg/liter). The elimination half-lives were 3.13 to 18.1 h (median, 10.7 h) in CSF compared with 2.02 to 5.24 h (median, 3.74 h) in serum. The ratios of the areas under the concentration-time curves in CSF and serum (AUCCSF/AUCS) ranged from 0.027 to 0.123 (median, 0.054). After the administration of a single dose of 3 g, the maximum concentrations of ceftazidime in CSF were approximately four times higher than those after the administration of 2-g intravenous doses of cefotaxime (median, 0.44 mg/liter) and ceftriaxone (median, 0.43 mg/liter) (R. Nau, H. W. Prange, P. Muth, G. Mahr, S. Menck, H. Kolenda, and F. Sörgel, Antimicrob. Agents Chemother. 37:1518-1524, 1993). The median AUCCSF/AUCS ratio of ceftazidime was slightly below that of cefotaxime (0.12), but it was 1 order of magnitude above the median AUCCSF/AUCS of ceftriaxone (0.007) (Nau et al., Antimicrob. Agents Chemother. 37:1518-1524, 1993). The concentrations of ceftazidime observed in CSF were above the MICs for most Pseudomonas aeruginosa strains. However, they are probably not high enough to be rapidly bactericidal. For this reason, the daily dose should be increased to 12 g in cases of P. aeruginosa infections of the central nervous system when the blood-CSF barrier is minimally impaired.

Analysis of ceftriaxone and ceftazidime distribution in cerebrospinal fluid of and cerebral extracellular space in awake rats by in vivo microdialysis.

In vivo microdialysis was used to estimate the extracellular concentrations of ceftazidime and ceftriaxone, two expanded-spectrum cephalosporins commonly used in the treatment of bacterial meningitis, in two brain regions (the right corpus striatum and the left lateral ventricle_ of awake, freely moving rats. Antibiotics were administered by constant intravenous infusion at 18 mg/h until steady-state levels were reached. Ceftriaxone levels measured at the steady state in the extracellular space of the corpus striatum (0.80 +/- 0.17 micrograms/ml) were statistically equivalent to those obtained in the cerebrospinal fluid of the lateral ventricle (0.71 +/- 0.15 micrograms/ml). The ratios of these levels in the brain to the steady-state levels in plasma were 0.5 +/- 0.1% for both regions. The postinfusion concentrations of ceftriaxone in the brain declined monoexponentially, with an elimination half-life similar to that obtained in plasma. However, the mean antibiotic concentration of ceftazidime in the striatum (2.2 +/- 0.4 micrograms/ml) was lower (P < 0.001) than that in the lateral ventricle (3.8 +/- 0.5% and 4.0 +/- 1.8%, respectively) were higher than those obtained with ceftriaxone. Moreover, the half-life of ceftazidime elimination from plasma was lower than that obtained in the two brain regions. It was concluded that the in vivo microdialysis technique yields useful data on antibiotic distribution in the extracellular space of the brain, that the distribution may not be homogeneous, and that the decay of postinfusion concentrations in the brain may be different from the decay of postinfusion concentrations in plasma.

Pharmacokinetic profiles of ceftazidime in cochlear perilymph, cerebrospinal fluid and plasma: a high-performance liquid chromatographic study.

A pharmacokinetic profile of the antibiotic ceftazidime was established for perilymph, cerbrospinal fluid (CSF) and plasma in 12 guinea pigs using the technique of high-performance liquid chromatography. The mean peak levels of 13.35 mg/l in perilymph and 140.54 mg/l in plasma were reached within the first hour after a single intravenous dose of 100 mg/kg. The CSF mean peak level of 5.36 mg/l, however, was not attained until 3 h after injection. The half-life was about 4 h in perilymph, more than 6 h in CSF and less than 2 h in plasma. Six hours following administration, the perilymph drug concentration remained higher than the plasma level. The study indicates that ceftazidime has excellent penetration into perilymph. It is concluded that ceftazidime should be a very useful agent in the treatment of bacterial labyrinthitis caused by susceptible organisms.

[Serum and cerebrospinal fluid kinetics of ceftazidime]. / Serum- und Liquorkinetik von Ceftazidim.

Ceftazidime serum concentrations and cerebrospinal fluid (CSF) penetration across non-inflamed meninges were evaluated in 10 patients after intravenous application of 2 g ceftazidime over a period of 30 min. After a continuous increase during infusion the highest level of ceftazidime in serum with 172.27 micrograms/ml (+/- 60.43 micrograms/ml) was ascertained at the end of the infusion. The further development demonstrated a continuous decrease of serum concentrations. Concentrations in serum followed a two-compartment open kinetic model. Mean distribution volume was 17.6 l, the total clearance was 142.97 ml/min, half-life was 1.8 h and the determined area under the curve was 139.89 micrograms x min/ml. Penetration of ceftazidime into CSF could only be pointed out in 5 patients. The highest level with 5.11 micrograms/ml (+/- 1.2 micrograms/ml) was observed 32 min after starting the infusion. A steady state with CSF-concentrations over 2 micrograms/ml could be ascertained during the following 4 hours in these patients. Obviously high statistic significance (p less than or equal to 0.01) was present when penetration into CSF was correlated to body surface area (BSA) using the exact Fisher test with Yates correction. Penetration of ceftazidime into CSF across non-inflamed meninges with therapeutic concentrations over a period of 4 hours could only be achieved when BSA was less than 1.95 m2. Further investigations in more patients are necessary to evaluate if BSA is the only parameter which affects distribution of ceftazidime into CSF.

Delayed cerebrospinal fluid sterilization in infants with Hemophilus influenzae type b meningitis.

Cerebrospinal fluid (CSF) sterilization after greater than 24 h of intravenous antibiotic therapy (delayed CSF sterilization) was noted in two infants treated with ceftizoxime and ceftazidime for bacterial meningitis. A case-control study was conducted of children between 6 w and 6 y of age treated between 1975 and 1985 at one institution for bacterial meningitis to determine risk factors for delayed CSF sterilization. Hemophilus influenzae type b was isolated from all children (n = 5) with delayed CSF sterilization, compared with only 78% of all children in the study (n = 83). In children with H. influenzae type b disease, children less than 6 mo of age were at higher risk than older children for delayed CSF sterilization (odds ratio = 7.5, 95% confidence limits = 1.4, 40.0). Factors not associated with delayed CSF sterilization included time of follow-up lumbar puncture, CSF total or differential white blood cell count, and CSF protein and glucose concentrations. Despite the in vitro antimicrobial susceptibility of H. influenzae type b to ceftizoxime and ceftazidime, delayed CSF sterilization may occur in infants receiving these antibiotics for bacterial meningitis.

Concentrations of ceftazidime, tobramycin and ampicillin in the cerebrospinal fluid of newborn infants.

Thirty-five neonates with suspected septicaemia were randomized to treatment with tobramycin or ceftazidime, both in combination with ampicillin. Concentrations of antibiotics in the CSF were measured 1 h after the third, fourth or fifth injection. In 13 of 17 neonates tobramycin CSF concentrations were below 0.5 mg/l. Ceftazidime CSF concentrations ranged from 2.5 to 17 mg/l, which should be sufficient for treatment of infections with group B streptococci and most aerobic gram-negative bacilli but not all strains of Staphylococcus aureus. Ampicillin CSF concentrations ranged from 1 to 80 mg/l, which should be sufficient for treatment of meningitis caused by enterococci and Listeria monocytogenes, the most important neonatal pathogens not covered by ceftazidime.

CSF pharmacokinetics of ceftazidime in neurosurgical patients with an external ventriculostomy.

In 11 neurosurgical patients (seven women, four men, aged 22-73 years) undergoing external ventriculostomy, serum and cerebrospinal fluid (CSF) pharmacokinetics of ceftazidime (CAZ) administered as a chemoprophylactic agent were evaluated. Concentrations of CAZ in CSF correlated significantly (p less than 0.05) with serum concentrations and with leucocyte counts in CSF. Peak concentrations in CSF (range 0-25.5 mg/l) exceeded the MIC90 of Staphylococcus species in two and of Pseudomonas and Enterobacter species in five of 11 patients. The MIC90 values of the other relevant bacteria causing CNS infections in these patients were surpassed in nine of 11 patients.

[Pharmacokinetics of ceftazidime in the cerebrospinal fluid]. / Pharmacocinétique de la ceftazidime dans le liquide céphalorachidien.

A compound potentially effective in the treatment of meningitis should reach high concentrations in CSF. In animal experimental models, ceftazidime levels of 5-25 micrograms/ml were demonstrated during administration of doses generating serum levels similar to those achieved in humans. Human studies later confirmed CSF levels of 5-10 micrograms/ml in patients with meningitis. Ceftazidime CSF kinetic properties are adequate for use of this compound in patients with meningitis due to susceptible organisms.

Drug transfer into cerebrospinal fluid after simultaneous administration of ampicillin with ceftriaxone or ceftazidime in rabbits with Staphylococcus aureus meningitis.

Meningitis was induced in white rabbits with a non beta-lactamase producing strain of Staphylococcus aureus. There was no significant difference in the CSF level of ceftazidime after simultaneous administration of ceftazidime with ampicillin or after ceftazidime alone. In contrast the percentage CSF penetration of ampicillin decreased from 8.81% after administration of ampicillin alone to 2.77% after the simultaneous administration of ampicillin with ceftazidime. The ratio of AUC in CSF and serum was 19.4% after ampicillin alone and 7.71% after simultaneous administration with ceftazidime. When ceftriaxone was combined with ampicillin there was no effect on the CSF penetration of either drug. Cephalosporins have unpredictable effects on the CSF concentration of ampicillin, probably due to variable effects on the penetration of ampicillin from blood to CSF.

Treatment of bacterial meningitis with ceftazidime.

Ceftazidime was prospectively evaluated in the treatment of bacterial meningitis in 19 pediatric patients. Haemophilus influenzae type b (HIB) was the etiologic agent in 17 patients, and Streptococcus pneumonia and Neisseria meningitidis were the etiologic agents in one patient each. Ceftazidime was administered intravenously in a dosage of 150 mg/kg/day divided into eight hourly doses for a mean of 15 days (range, 14 to 22 days) for H. influenzae type b meningitis. The clinical and microbiologic response was appropriate in all cases. The mean ceftazidime CSF concentration was 6.7 micrograms/ml at approximately 2 hours following iv infusions. This concentration was 16- to greater than 100-fold the minimal bactericidal concentration determined for the isolated pathogens. These preliminary observations support ceftazidime as a candidate cephalosporin for the treatment of bacterial meningitis caused by H. influenzae. Additional study is required to further define its role in meningitis caused by S. pneumoniae and N. meningitidis.

Review of Pseudomonas aeruginosa meningitis with special emphasis on treatment with ceftazidime.

Pseudomonas aeruginosa meningitis is a rare disease and the optimal antibiotic therapy for this condition is not well established. Results of therapy using various regimens reported since 1960 are reviewed. Ceftazidime, an investigational cephalosporin with potent antipseudomonal activity, has been used to treat P. aeruginosa meningitis in Europe and North America. The results in 24 patients are analyzed here. Most patients had failed to respond to other regimens before commencing therapy with ceftazidime. Nineteen (79.2%) of these patients were cured, and only three (12.5%) were considered therapeutic failures. Hence, ceftazidime is a useful agent in the treatment of gram-negative bacillary meningitis and may be superior to other cephalosporins on the market for the treatment of pseudomonas meningitis. Since development of resistance is a concern, however, it may be prudent to use a concomitant parenteral aminoglycoside with ceftazidime for the first week in the treatment of P. aeruginosa meningitis.

Ceftazidime in neonatal infections.

Ninety one neonates received 108 courses of intravenous ceftazidime (25 mg/kg, 12 hourly) over a study period of 15 months. Fourteen had clinically and bacteriologically proved infections. Only one of these had resistant organisms. Four (two with group B beta haemolytic streptococcal infections, one with Escherichia coli meningitis, and one with Staphylococcal aureus septicaemia) failed to respond despite adequate treatment. Bacteriological eradication or clinical improvement, or both, were obtained in the remaining nine. Routine biochemical and haematological values were monitored and there were no side effects. High serum ceftazidime concentrations, well exceeding the minimum inhibitory concentration for most common neonatal pathogens were obtained and maintained throughout treatment. Penetration into the cerebrospinal fluid was excellent in eight of the nine cases studied. Ceftazidime has a theoretical role as a broad spectrum antibiotic suitable for neonatal use with no evident side effects. In this study, however, it was only appropriate for Gram negative infections, and was ineffective against Gram positive organisms. Ceftazidime cannot therefore be recommended as monotherapy before the results of bacteriological culture are known.

Pharmacokinetics and cerebrospinal fluid penetration of ceftazidime in children with meningitis.

The single dose pharmacokinetics and cerebrospinal fluid (CSF) penetration of ceftazidime were determined in 10 children with bacterial meningitis. Serum ceftazidime pharmacokinetics showed a distinct age dependence in which the clearance in children less than 1 month of age was markedly reduced. Ceftazidime concentrations in CSF, which ranged from 1.4-8.5 micrograms/ml, exceeded the minimum bactericidal concentrations for infecting pathogens throughout the 8-hour sampling period. These concentrations were found to be independent of CSF cell count, protein concentration or the day of therapy on which the study was performed. The ratio of CSF to serum ceftazidime concentration increased with time, suggesting that ceftazidime was cleared more slowly from CSF than from peripheral blood. Our data support the initiation of a study comparing the efficacy of ceftazidime to conventional therapy in children with bacterial meningitis.

Sequential ventricular fluid concentrations of ceftazidime--report of three cases.

Three adult subjects, each with a ventriculostomy, received ceftazidime 2g iv q8h for three doses. Serial samples of serum and CSF ventricular fluid were obtained following the third dose; ceftazidime concentrations were measured by high pressure liquid chromatography. In one patient without inflammatory cells in the CSF, ceftazidime CSF concentrations were only approximately 0.3 micrograms/ml. In two other patients who had inflammatory cells and blood in the CSF, concentrations of ceftazidime in ventricular fluid demonstrated a slow rise and decline over an eight-hour period. Although contamination of the CSF by blood in these two patients confounds the interpretation of the concentrations achieved, it is concluded that obtaining serial samples of CSF from a ventriculostomy offers a more realistic appraisal of the dynamics of antibiotic penetration compared with the single-point method.