Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

Nau, Roland; Prange, Hilmar

doi:10.1007/bf00203787

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…The relatively long elimination half-life of meropenem in CSF suggests accumulation after repeated dosing. Assuming linear kinetics, mean CSF drug concentrations in steady state can be estimated from the AUC CSF after the first dose by dividing AUC CSF by the dosing interval (17). The mean AUC CSF of meropenem was 8.55 mg ⅐ h/liter.…”

Section: Discussionmentioning

confidence: 99%

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

Nau

Lassek

Kinzig‐Schippers

et al. 1998

Antimicrob Agents Chemother

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The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum (C maxCSF) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [t 1/2β] of 7.36 ± 2.89 h in CSF versus t 1/2βof 1.69 ± 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

Nau

Lassek

Kinzig‐Schippers

et al. 1998

Antimicrob Agents Chemother

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“…The long elimination half-life of piperacillin and tazobactam in CSF suggests likely accumulation after repeated dosing. Assuming linear kinetics, mean steadystate concentrations in CSF can be estimated from single-dose kinetic data by dividing the AUC CSF by the dosing interval (17). Using the median AUC CSF of tazobactam of 4.7 mg ⅐ h/ liter and administering the commercial product of 6 g of piperacillin and 0.75 g of tazobactam every 6 h would lead to an estimated mean steady-state tazobactam concentration of 1.18 mg/liter of CSF.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients

Nau

Kinzig‐Schippers

Sörgel

et al. 1997

Antimicrob Agents Chemother

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Its broad antibacterial spectrum qualifies the combination of piperacillin and tazobactam for therapy of nosocomial bacterial central nervous system (CNS) infections. Since these infections sometimes are accompanied by only minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 9; age range, 48 to 75 years). After administration of the first dose of piperacillin (6 g)-tazobactam (0.5 g) over 30 min intravenously, serum and CSF were drawn repeatedly and analyzed by high-performance liquid chromatography. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations of piperacillin in CSF ranged from 8.67 to <0.37 mg/liter (median, 3.42 mg/liter), and those of tazobactam ranged from 1.37 to 0.11 mg/liter (median, 0.45 mg/liter). CSF maxima were observed, in median, 1.5 and 2 h after the end of the infusion. Elimination in CSF was considerably slower than in serum (median half-life at beta phase for piperacillin, 5.9 h in CSF versus 1.47 h in serum; for tazobactam, 6.1 h versus 1.34 h). For tazobactam, the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in serum was approximately three times as high as that for piperacillin (medians, 0.106 versus 0.034). In view of the tazobactam concentrations in CSF observed in this study, the practice of using a constant concentration of 4 mg of tazobactam per liter for MIC determination is inadequate for intracranial infections. Larger amounts of tazobactam than the standard dose of 0.5 g three times daily may be necessary for CNS infections.

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“…These data can be used for a detailed calculation of pharmacokinetic parameters of the drug exchange between CSF and serum ( Fig. 2) and for the estimation of steady-state CSF concentrations (171).…”

Section: Methods To Study Drug Concentrations In the Cns In Humansmentioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

Abstract: Together with the MIC and MBC of the causative pathogen, the estimate is of value in the choice of antibacterial drug and the dosing regimen in central nervous system infections.

Cited by 12 publications

References 13 publications

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

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