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

Not Applicable

Recruiting

• Conditions: Aminoglycoside Dosing Based on PK/PD Characteristics
• Interventions: Drug: Aminoglycoside dose adjustment

• Registration Number: NCT05618457
• Lead Sponsor: Hadassah Medical Organization

Brief Summary

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.

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 Timeline

• Study Start: 2021-12-01
• Study First Submitted: 2022-10-30
• Study First Submitted QC: 2022-11-08
• Study First Posted: 2022-11-16
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-28
• Last Update Posted: 2024-03-01
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 151

Inclusion Criteria

Not provided

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Aminoglycoside dose adjustment	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

Primary Outcome Measures

Name	Time	Method
Efficacy outcome	up to 1 week after end of therapy	proportion of patients where treatment failure was suspected and attributed to AG dose reduction
Renal outcome	up to 1 week after end of therapy	Mean serum creatinine change at end of therapy vs. baseline
Aminoglycoside dosing outcomes:	up to 1 week after end of therapy	Mean change in AG dose following adjustment

Trial Locations

Locations (1)

Hadassah Hebrew University Medical Center; 🇮🇱 Jerusalem, Israel