Penetration of doripenem in human brain: an observational microdialysis study in patients with acute brain injury

Poeppl, Wolfgang; Zeitlinger, Markus; Donath, Oliver; Wurm, Gabriele; Müller, Markus; Botha, Florin; Illievich, U. M.; Burgmann, Heinz

doi:10.1016/j.ijantimicag.2011.11.019

Cited by 16 publications

(8 citation statements)

References 15 publications

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“…Probe recoveries in this study were higher than those estimated in our previous investigation on meropenem brain distribution in two critical care patients (19% Ϯ 7% and 29% Ϯ 7%), even though larger cutoff probes (CMA 71, 100 kDa), were used with the same flow rate (12). Brain distribution of antibiotics using microdialysis has been reported only in rare occasions with various molecules, including vancomycin, rifampin, fosfomycin, doripenem, and meropenem (12,(19)(20)(21)(22). In vivo recovery was estimated in only two occasions, either by no net flux (12) or by retrodialysis by drug (20).…”

Section: Discussionmentioning

confidence: 59%

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Dahyot‐Fizelier

Frasca

Grégoire

et al. 2013

Antimicrob Agents Chemother

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Central nervous system (CNS) antibiotic distribution was described mainly from cerebrospinal fluid data, and only few data exist on brain extracellular fluid concentrations. The aim of this study was to describe brain distribution of cefotaxime (2 g/8 h) by microdialysis in patients with acute brain injury who were treated for a lung infection. Microdialysis probes were inserted into healthy brain tissue of five critical care patients. Plasma and unbound brain concentrations were determined at steady state by high-performance liquid chromatography. In vivo recoveries were determined individually using retrodialysis by drug. Noncompartmental and compartmental pharmacokinetic analyses were performed. Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations, with a mean cefotaxime unbound brain-to-plasma area under the curve ratio equal to 26.1 ؎ 12.1%. This result was in accordance with the brain input-to-brain output clearances ratio (CL in,brain /CL out,brain ). Unbound brain concentrations were then simulated at two dosing regimens (4 g every 6 h or 8 h), and the time over the MICs (T>MIC) was estimated for breakpoints of susceptible and resistant Streptococcus pneumoniae strains. T>MIC was higher than 90% of the dosing interval for both dosing regimens for susceptible strains and only for 4 g every 6 h for resistant ones. In conclusion, brain distribution of cefotaxime was well described by microdialysis in patients and was limited.

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Section: Discussionmentioning

confidence: 59%

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Dahyot‐Fizelier

Frasca

Grégoire

et al. 2013

Antimicrob Agents Chemother

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“…Microdialysis in human brain can also be combined with neurosurgical procedures, for example before removal of epileptogenic brain tissue. In such settings microdialysis can also be used to measure brain penetration of drugs [41–46], and provides the possibility to determine brain pharmacokinetics in conjunction with resulting biochemical efficacy of therapeutic approaches [40, 47, 48]. …”

Section: What Methods Are Available To Obtain Information On Unbound mentioning

confidence: 99%

Utility of CSF in translational neuroscience

Lange

2013

J Pharmacokinet Pharmacodyn

102

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Human cerebrospinal fluid (CSF) sampling is of high value as the only general applicable methodology to obtain information on free drug concentrations in individual human brain. As the ultimate interest is in the free drug concentration at the CNS target site, the question is what CSF concentrations may tell us in that respect. Studies have been performed in rats and other animals for which concentrations in brain extracellular fluid (brain ECF) as a target site for many drugs, have been compared to (cisterna magna) CSF concentrations, at presumed steady state conditions,. The data indicated that CSF drug concentrations provided a rather good indication of, but not a reliable measure for predicting brain ECF concentrations. Furthermore, comparing rat with human CSF concentrations, human CSF concentrations tend to be higher and display much more variability. However, this comparison of CSF concentrations cannot be a direct one, as humans probably had a disease for which CSF was collected in the first place, while the rats were healthy. In order to be able to more accurately predict human brain ECF concentrations, understanding of the complexity of the CNS in terms of intrabrain pharmacokinetic relationships and the influence of CNS disorders on brain pharmacokinetics needs to be increased. This can be achieved by expanding a currently existing preclinically derived physiologically based pharmacokinetic model for brain distribution. This model has been shown to successfully predict data obtained for human lumbar CSF concentrations of acetaminophen which renders trust in the model prediction of human brain ECF concentrations. This model should further evolute by inclusion of influences of drug properties, fluid flows, transporter functionalities and different disease conditions. Finally the model should include measures of target site engagement and CNS effects, to ultimately learn about concentrations that best predict particular target site concentrations, via human CSF concentrations.

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“…In order to establish that a drug has reached the site of pharmacological action in the CNS, there are strong theoretical reasons to favour the brain ECF compartment where the MD technique is currently the only option in human patients. This is further highlighted in studies analysing antibiotic concentrations (meropenem and doripenem) in the brain ECF compartment following TBI (73,74). In patients with TBI, bacterial meningitis and other cerebral infectious complications occur in up to 17.2% of TBI patients (75,76), and the risk increases the longer the period of external ventricular drain monitoring is (77).…”

Section: Microdialysis To Monitor Drug Pharmacokinetics In the Cnsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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Abstract.Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

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Penetration of doripenem in human brain: an observational microdialysis study in patients with acute brain injury

Cited by 16 publications

References 15 publications

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Utility of CSF in translational neuroscience

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

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