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Cerebrospinal fluid ceftazidime kinetics in patients with external ventriculostomies
1Department of Neurology, University of Göttingen, Germany.
Abstract:
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.
Insights
Ceftazidime effectively treats bacterial meningitis, achieving significant cerebrospinal fluid (CSF) concentrations. Higher daily doses may be needed for Pseudomonas aeruginosa central nervous system infections with a compromised blood-CSF barrier.
Area of Science:
- Pharmacokinetics and infectious disease research.
- Antibiotic efficacy in central nervous system infections.
Background:
- Nosocomial central nervous system infections often involve minor blood-cerebrospinal fluid (CSF) barrier dysfunction.
- Multiresistant gram-negative bacteria are a concern in meningitis treatment.
Purpose of the Study:
- To evaluate ceftazidime concentrations in CSF in patients with noninflammatory occlusive hydrocephalus and external ventriculostomy.
- To compare ceftazidime CSF penetration with cefotaxime and ceftriaxone.
Main Methods:
- Eight patients with external ventriculostomy received a single 3g intravenous dose of ceftazidime.
- Serum and CSF samples were collected for ceftazidime concentration determination via high-performance liquid chromatography (HPLC) with UV detection.
- Pharmacokinetic parameters including peak concentration, half-life, and area under the concentration-time curve (AUC) ratio (CSF/serum) were calculated.
Main Results:
- Ceftazidime CSF concentrations peaked between 1-13 hours (median 5.5h) post-infusion, ranging from 0.73-2.80 mg/L (median 1.56 mg/L).
- CSF elimination half-lives (median 10.7h) were longer than serum half-lives (median 3.74h).
- The median CSF/serum AUC ratio was 0.054, indicating moderate penetration. Ceftazidime CSF concentrations were higher than cefotaxime and ceftriaxone.
Conclusions:
- Ceftazidime demonstrates good penetration into the CSF in patients with minimally impaired blood-CSF barriers.
- Observed CSF concentrations exceed MICs for many Pseudomonas aeruginosa strains but may not be rapidly bactericidal.
- A daily dose of 12g ceftazidime is recommended for CNS P. aeruginosa infections with impaired blood-CSF barriers.