Clinical trial NCT04178629: Ceftobiprole's Cerebrospinal Fluid Penetration in Patients With External Ventricular Derivation (CEFTO-EVD)
Official title: Characterization of Ceftobiprole's Cerebrospinal Fluid Penetration in Patients With External Ventricular Derivation
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Pharmacokinetics
Cerebral Ventriculitis
Cephalosporins
Cerebrospinal Fluid
Keywords: Ceftobiprole
External Ventricular Derivation
Cerebrospinal fluid penetration
ATP Binding Cassette Transporter, Subfamily B, Member 1
Tissue Distribution
Lead sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Sponsor class: OTHER
Collaborators: name: University of Turin, Italy
name: University of Pisa
name: Università degli Studi di Brescia
First posted: 2019-11-26
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patient admitted in Intensive Care Unit or Neurosurgical Unit of Hospital "Spedali Civili di Brescia" (BS, Italy), according to Inclusion and Exclusion Criteria, with an EVD and concomitant Ceftobiprole therapy. When ceftobiprole will be administered i.v. for the first time, patients will be enrolled in the study.

Brief summary: The Cerebrospinal fluid penetration of ceftobiprole has been studied in an animal model of meningitidis. Ceftobiprole is bactericidal, well tolerated and it has anti-biofilm activity. Altogether, these pharmacodynamics and pharmacokinetic properties of ceftobiprole are suitable for its use in case of External Ventricular Derivation(EVD)-related ventriculitis. Nowadays there are no human studies on the penetration and efficacy of ceftobiprole in the CSF. The study aims to evaluate characteristics of the CSF penetration of Ceftobiprole after intravenous administration in patients with EVD, that need for a concomitant infection this therapy (prescribed by an Infectious Diseases doctor).

Detailed description: According with Inclusion and Exclusion criteria, patients with an EVD and concomitant ceftobiprole therapy will be enrolled in the study.

In particular, ceftobiprole will be prescribed by an expert infectivologist, in accordance with the MHRA guidelines.

Once the patients will be enrolled, Ceftobiprole will be administered by 2 hr i.v. infusion at the following dosage:

* normal renal function: 500mg every 8 hr
* mild renal impairment (50-80mL/min): 500mg every 8 hours
* moderate (30-49mL/min): 500mg every 12 hours
* severe (\<30mL/min): 250mg every 12 hours.

The following blood and CSF sample will be drowned only during the third dose of antibiotic therapy. Blood Samples (1 mL each) will be obtained at the following time points: before and at the end of infusion of ceftobiprole, then 0.5, 1, 2, 2.5, 3 and 4 hr after drug administration (total of 8 samples), using a single venous or arterial line cannulation. CSF samples: 0.5ml will be drawned from implanted EVD with a sterile field at the same blood sample time-point, and at 6, 8 and 10 hr after the end of drug administration (11 samples total).

CSF and blood will be spin-down at 3000 rpm for 10 minutes and then stored at -80°C.

Samples will be sent all in once by courier to Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin (Italy) in order to determine the serum and CSF concentration.

Ceftobiprole concentrations (both in plasma/serum and CFS) will be analyzed with EMA validated LC-MS/MS methods.

MDR1 gene polymorphisms will be analyzed with RT-PCR instrument, using commercial genetic probes on the blood samples.

Eligibility criteria: Inclusion Criteria:

* Age\>18
* Patients with External Ventricular Derivation (EVD)
* Patients who receive ceftobiprole for any infection where Ceftobiprole could be used, as judged by an expert infectivologist
* Patients or their relatives/parents who consent to study participation

Exclusion Criteria:

* Patients with end-stage renal insufficiency
* Patients with a BMI\>30
* Pregnancy
* Moribund patients
* Allergy to cephalosporine or ceftobiprole
* Refusal to participate in the study

Primary outcomes:
measure: Ceftobiprole's CSF penetration
timeFrame: Blood samples: before infusion, end of infusion, then 30 minutes, 1 hour, 2 hours, 2,5 hours, 3 hours, 4 hours after end of administration; CSF samples: at the same time of blood samples, then at 6 hours, 8 hours and 10 hours after end of administration
Secondary outcomes:
measure: Ceftobiprole's MDR1 role
timeFrame: The MDR1 gene will be analyzed on whole blood samples, by real-time PCR, through study completion, an average of 18 months.
measure: Ceftobiprole's efficacy in CSF
timeFrame: The measurement is assessed through study completion, an average of 18 months.
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
Study officials:
affiliation: Università degli Studi di Brescia
name: Simone Piva
role: PRINCIPAL_INVESTIGATOR
References: