Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis
© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
BACKGROUND: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF.
OBJECTIVES: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF.
METHODS: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF.
RESULTS: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L.
CONCLUSIONS: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:79 |
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| Enthalten in: |
The Journal of antimicrobial chemotherapy - 79(2024), 2 vom: 01. Feb., Seite 429-442 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ngougni Pokem, Perrin [VerfasserIn] |
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| Links: |
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| Themen: |
03QB156W6I |
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| Anmerkungen: |
Date Completed 02.02.2024 Date Revised 02.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/jac/dkad398 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM366438948 |
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| 100 | 1 | |a Ngougni Pokem, Perrin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis |
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| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a BACKGROUND: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF | ||
| 520 | |a OBJECTIVES: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF | ||
| 520 | |a METHODS: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF | ||
| 520 | |a RESULTS: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L | ||
| 520 | |a CONCLUSIONS: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a temocillin |2 NLM | |
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| 650 | 7 | |a Penicillins |2 NLM | |
| 700 | 1 | |a Liu, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Parker, Suzanne L |e verfasserin |4 aut | |
| 700 | 1 | |a Verroken, Alexia |e verfasserin |4 aut | |
| 700 | 1 | |a Collienne, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Finet, Patrice |e verfasserin |4 aut | |
| 700 | 1 | |a Wijnant, Gert-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Laterre, Pierre-François |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Jason A |e verfasserin |4 aut | |
| 700 | 1 | |a Van Bambeke, Françoise |e verfasserin |4 aut | |
| 700 | 1 | |a Wittebole, Xavier |e verfasserin |4 aut | |
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