Adjustment of Aminoglycoside Dosing Based on Peak Serum Concentration and Bacterial Minimal Inhibitory Concentration

Aminoglycoside (AG) antibiotics have been in clinical use since the 1960s for treating various infections. The main safety concern related to AG use is nephrotoxicity. Based on validated pharmacokinetic-pharmacodynamic (PK-PD) principles shown to predict efficacy, AG dosing has shifted over the past 2 decades from multiple daily dosing to extended-interval dosing, with concomitant reduction in nephrotoxicity. Currently, AG daily dose is calculated according to the patients' adjusted body weight, assuming a common minimal inhibitory concentration (MIC) value.

We hypothesize that once pathogen identity and actual MIC become available, AG daily doses may be further adjusted, using the same PK-PD indices.

In order to investigate this hypothesis, we are conducting a prospective clinical study in which AG doses will be adjusted based on patient- and pathogen-specific factors, while assessing efficacy and safety.

Study Overview

• Status: Recruiting
• Conditions: Aminoglycoside Dosing Based on PK/PD Characteristics
• Intervention / Treatment: Drug: Aminoglycoside dose adjustment

Detailed Description

Intervention for all eligible patients:

calculation of Cmax/MIC based on MIC determination and timely peak level determination performed 30 minutes after the first or second AG dose following pathogen identity and MIC availability (as Individual timely monitoring is essential for individual dose adjustment, this will require one additional blood sample to routine clinical practice). If a peak-level monitoring is not available, Cmax will be assessed using commonly used pharmacokinetic prediction tools (equations/calculators.

1. If Cmax/MIC=8-12 - no intervention (aminoglycoside dose unchanged).
2. If Cmax/MIC>12 - decreasing AG dose accordingly, based on clinical calculators, to achieve target Cmax/MIC~10;
3. If Cmax/MIC<8 - increasing AG dose accordingly, based on clinical calculators, to achieve target Cmax/MIC~10; If the calculated dose is larger than acceptable AG dosing, an infectious diseases physician will be consulted for need for alternative therapy.
4. If AG dose has been adjusted, ascertaining PK/PD target attainment (repeat timely peak level determination following dose adjustment).
5. Monitoring clinical and microbiological course and outcomes:

5.1 Clinical efficacy microbiological and clinical cure, in-hospital mortality 5.2 Safety - renal function during therapy, at end of therapy and at discharge or at day 7 after end of therapy, whichever is earlier. Any deterioration in renal function compared with baseline will be categorized according to the RIFLE criteria.

5.3 Aminoglycoside dosing data (proportion end extent of dose adjustments performed)

• Study Type: Interventional
• Enrollment (Estimated): 151
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: EHud Horwitz, PhD; Phone Number: +972502799755; Email: ehud.horwitz@mail.huji.ac.il
• Study Contact Backup: Name: Maya Korem, MD; Phone Number: +972508573173; Email: MayaK@hadassah.org.il

Study Locations

• Israel
  • Jerusalem, Israel, 12000
    • Recruiting
    • Hadassah Hebrew University Medical Center
    • Contact: EHud Horwitz, PhD; Phone Number: +972502799755; Email: ehud.horwitz@mail.huji.ac.il
    • Contact: Maya Korem, MD; Phone Number: +972508573173; Email: MayaK@hadassah.org.il
    • Sub-Investigator: Jacob Strahilevitz, MD
    • Sub-Investigator: Jonathan Oster, MD
    • Sub-Investigator: Sara Israel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. Adult patients (≥18yr)
2. Any infection treated with IV gentamycin or amikacin and approved by the consultant infectious diseases specialist, excluding neurosurgical infections, pneumonia, endocarditis or endovascular infections
3. Normal renal function or mild renal impairment (eGFR≥40ml/min)
4. On extended-interval AG and an expected remaining AG course of at least 4 days
5. At least one microbiological specimen with identification of an AG-susceptible pathogen and MIC determination and
6. Signed informed consent form

Exclusion Criteria:

1. Age<18yr
2. Neurosurgical infections, pneumonia, endocarditis or endovascular infections
3. eGFR<40ml/min
4. Empirical aminoglycoside treatment
5. Non Gram-negative pathogen
6. No MIC available for the pathogen
7. Expected remaining treatment duration of less than 4 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Aminoglycoside dose adjustment; Eligible patients will be assessed for attainment of PK/PD target under standard dosing, dose adjustment to attain target will be proposed where appropriate	Drug: Aminoglycoside dose adjustment; Eligible patients may have the aminoglycoside dose adjusted based on pathogen MIC, to attain the PK/PD target of Cam/MIC~10 (8-12)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy outcome	proportion of patients where treatment failure was suspected and attributed to AG dose reduction	up to 1 week after end of therapy
Renal outcome	Proportion of patients fulfilling RIFLE criteria (any category) baseline	up to 1 week after end of therapy
Aminoglycoside dosing outcomes:	Proportion of patients where AG dose was adjusted based on PK-PD parameters	up to 1 week after end of therapy
Aminoglycoside dosing outcomes:	Mean change in AG dose following adjustment	up to 1 week after end of therapy
Renal outcome	Mean serum creatinine change at end of therapy vs. baseline	up to 1 week after end of therapy

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization
• Investigators: Principal Investigator: Maya Korem, MD, Director, Antimicrobial Stewardship Program

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: October 30, 2022
• First Submitted That Met QC Criteria: November 8, 2022
• First Posted (Actual): November 16, 2022

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Aminoglycosides; PK/PD; Minimal Inhibitory Concentration (MIC); Gram negative; Peak concentration (Cmax)
• Other Study ID Numbers: 0557-21-HMO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: YES

Drug and device information, study documents

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