Ceftobiprole's Cerebrospinal Fluid Penetration in Patients With External Ventricular Derivation (CEFTO-EVD) (CEFTO-EVD)

Characterization of Ceftobiprole's Cerebrospinal Fluid Penetration in Patients With External Ventricular Derivation

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).

Study Overview

• Status: Unknown
• Conditions: Pharmacokinetics; Cerebrospinal Fluid; Cerebral Ventriculitis; Cephalosporins

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.

• Study Type: Observational
• Enrollment (Anticipated): 15

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy, 25123
    • Recruiting
    • Spedali Civili di Brescia
    • Contact: Simone Piva; Phone Number: +393332564230 +393332564230; Email: simone.piva@unibs.it
    • Contact: Fabio Turla; Phone Number: +393332564230; Email: fabioturla2@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ceftobiprole's CSF penetration	Evaluate the Cerebrospinal Fluid penetration of Ceftobiprole in patients with External Ventricular Derivation. Ceftobiprole concentrations (both in plasma/serum and CFS) will be analyzed with EMA fully validated LC-MS/MS methods.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ceftobiprole's MDR1 role	Evaluate the role of MDR1 polymorphisms in modulating ceftobiprole CSF penetration.	The MDR1 gene will be analyzed on whole blood samples, by real-time PCR, through study completion, an average of 18 months.
Ceftobiprole's efficacy in CSF	In vitro, the efficacy of ceftobiprole against the most common pathogen causing Ventricular Meningitis (MRSA, MRSE, Pseudomonas Aeruginosa and Enterobacteriaceae) will be assessed using the percentage of time during which the free CSF ceftobiprole concentration remains above the minimal inhibitory concentration (MIC)	The measurement is assessed through study completion, an average of 18 months.

Collaborators and Investigators

• Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Collaborators: University of Pisa; University of Turin, Italy; Università degli Studi di Brescia
• Investigators: Principal Investigator: Simone Piva, Università degli Studi di Brescia

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2019
• Primary Completion (Anticipated): November 1, 2020
• Study Completion (Anticipated): November 1, 2020

Study Registration Dates

• First Submitted: October 15, 2019
• First Submitted That Met QC Criteria: November 25, 2019
• First Posted (Actual): November 26, 2019

Study Record Updates

• Last Update Posted (Actual): November 26, 2019
• Last Update Submitted That Met QC Criteria: November 25, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Ceftobiprole; External Ventricular Derivation; Cerebrospinal fluid penetration; ATP Binding Cassette Transporter, Subfamily B, Member 1; Tissue Distribution
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Viral Diseases; Central Nervous System Infections; Encephalitis; Cerebral Ventriculitis
• Other Study ID Numbers: NP3617

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The database is in RedCap. We could share all data
• IPD Sharing Time Frame: already available
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No