Optimized Antibiotic Therapy in Patients With Subarachnoid Haemorrhage (ES) and Cerebral Haemorrhage (EC) (TANDEM)

Prospective Study Evaluating Plasma Exposure of Optimized Antibiotic Therapy According to TDM in Patients With Subarachnoid Haemorrhage (ES) and Cerebral Haemorrhage (EC)

A recent prospective observational clinical study conducted in an intensive care unit of a third level US university hospital showed that 94% of patients with ES and 50% of those with EC had an ARC for a duration of at least one day during the hospital stay.

Although there is currently a great deal of evidence describing ARC in various subgroups of critically ill patients, on the other hand there is little documentation regarding the effect that ARC can have on exposure to renally eliminated drugs.

Therefore, the aim of this study is to prospectively evaluate the proportion of plasma under-exposure to hydrophilic antimicrobials in patients with ES or EC and with ARC, in order to verify whether the recommended dosage regimens for these drugs are adequate for reaching the pharmacodynamic targets of therapeutic efficacy.

Study Overview

• Status: Recruiting
• Conditions: Subarachnoid Hemorrhage; Therapeutic Drug Monitoring; Intracerebral Hemorrhage
• Intervention / Treatment: Drug: Piperacillin/tazobactam; Drug: Meropenem; Drug: Daptomycin; Drug: Ceftobiprole; Drug: Linezolid; Drug: Vancomycin; Drug: Fluconazol; Drug: Acyclovir; Drug: Gentamicins; Drug: Amikacin; Drug: Ganciclovir

Detailed Description

Haemorrhagic stroke is a devastating disease with a high rate of disability and mortality. In addition to the direct effects of the haemorrhagic event and to the secondary neurological complications, patients with haemorrhagic strokes are predisposed to medical complications that can have a direct impact on both clinical outcome and treatment costs. It has been estimated that between 79% and 100% of patients with subarachnoid haemorrhage (ES) and cerebral haemorrhage (EC) have at least one of these complications. Among them, the most common are infections, seizures, hyponatremia, hypomagnesemia, hypokalemia and venous thromboembolism.

A possible reason that can be responsible for such a high frequency of complications, especially infectious, can be identified in a pathophysiological alteration of the circulatory and renal haemodynamics of this population. Specifically, these patients frequently have a hyperdynamic state which results in a high renal clearance (CrCl) (augmented renal clearance - ARC, defined as a measured CrCl ≥ 130 ml/min/1.73m2). In this regard, a recent prospective observational clinical study conducted in an intensive care unit of a third level US university hospital showed that 94% of patients with ES and 50% of those with EC had an ARC for a duration of at least one day during the hospital stay.

In consideration of the fact that the ARC has been historically underestimated and that an accurate assessment of renal function through the measured CrCl is not regularly carried out on all patients even if they are critical, the main risk from the point of view of therapeutic appropriateness is that of not adjust the dosing regimen of drugs eliminated through the kidney in relation to the presence and extent of the ARC. Moreover, the clinician often ignores the time course of the ARC as well as the modalities with which to carry out the dosage adjustment. This could lead to sub-therapeutic concentrations for renally excreted drugs, as typically are water-soluble antibiotics such as beta-lactams, aminoglycosides, daptomycin, linezolid, antifungal fluconazole and antivirals ganciclovir and aciclovir, resulting in an increase in the risk of therapeutic failure.

Although there is currently a great deal of evidence describing ARC in various subgroups of critically ill patients, on the other hand there is little documentation regarding the effect that ARC can have on exposure to renally eliminated drugs.

Therefore, the aim of this study is to prospectively evaluate the proportion of plasma under-exposure to hydrophilic antimicrobials in patients with ES or EC and with ARC, in order to verify whether the recommended dosage regimens for these drugs are adequate for reaching the pharmacodynamic targets of therapeutic efficacy.

• Study Type: Observational
• Enrollment (Anticipated): 104

Contacts and Locations

• Study Contact: Name: TIZIANA BOVE, MD, AP; Phone Number: +390432555501; Email: TIZIANA.BOVE@UNIUD.IT
• Study Contact Backup: Name: LUIGI VETRUGNO, MD, AP; Phone Number: +390432555501; Email: LUIGI.VETRUGNO@UNIUD.IT

Study Locations

• Italy
  • Udine, Italy, 33100
    • Recruiting
    • Anesthesiology and Intensive Care Clinic - Department of Medicine - ASUIUD
    • Contact: Luigi Vetrugno, Doctor; Phone Number: +393382873386; Email: luigi.vetrugno@asuiud.sanita.fvg.it
    • Contact: Tiziana Bove, Professor; Phone Number: +393474785763; Email: tiziana.bove@asuiud.sanita.fvg.it
  • Udine, Italy, 33100
    • Not yet recruiting
    • Terapia Intensiva 1
    • Contact: Cristian Deana, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients admitted to the ICU due to intracranial haemorrage or subaracnoid haemorrage

Description

Inclusion Criteria:

• Patients of both sexes > 18 years admitted for ES or EC
• Patients to which one or more water-soluble antibiotics, antifungals or antivirals subject of the present study are prescribed
• Patients who present ARC

Exclusion Criteria:

• Patients in whom the plasma samples are contaminated
• Patients in whom the plasma samples are performed in a way that does not comply with the prepared company protocol.
• Patients with BMI < 18 kg / m2.
• Patients with a serum creatinine > 1.4 mg / dL at entry
• Pregnant patients.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Underexposure to antimicrobial therapy	Prospective evaluation of the proportion of plasma underexposure to hydrophilic antimicrobials due to ARC in patients with subarachnoid haemorrhage (ES) and / or cerebral haemorrhage (EC).	2 years from the date of approval

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T > MIC	Evaluation of the achievement of the pharmacokinetic / pharmacodynamic target of therapeutic efficacy through the calculation of the parameter T > MIC	2 years from the date of approval
AUC / MIC	Evaluation of the achievement of the pharmacokinetic / pharmacodynamic target of therapeutic efficacy through the calculation of the parameter AUC / MIC	2 years from the date of approval
Performance of ClCr estimation formulas	Evaluation of the performance of the common CrCl estimation formulas compared to the CrCl measured in the estimation of the systemic clearance of the drugs being studied	2 years from the date of approval

Collaborators and Investigators

• Sponsor: Azienda Sanitaria-Universitaria Integrata di Udine

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Anticipated): October 1, 2021
• Study Completion (Anticipated): October 1, 2021

Study Registration Dates

• First Submitted: October 14, 2019
• First Submitted That Met QC Criteria: October 17, 2019
• First Posted (Actual): October 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 21, 2021
• Last Update Submitted That Met QC Criteria: July 19, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Subarachnoid Hemorrhage; Therapeutic Drug Monitoring; Intracerebral Hemorrhage
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Cerebral Hemorrhage; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; beta-Lactamase Inhibitors; Vancomycin; Linezolid; Gentamicins; Meropenem; Daptomycin; Amikacin; Piperacillin; Ganciclovir; Acyclovir; Tazobactam; Piperacillin, Tazobactam Drug Combination; Ceftobiprole; Ceftobiprole medocaril
• Other Study ID Numbers: CEUR-2019-Os-162

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Database will be available upon reasonable request
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

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