Clinical trial NCT05618457: Adjustment of Aminoglycoside Dosing Based on Peak Serum Concentration and Bacterial Minimal Inhibitory Concentration
Official title: Adjustment of Aminoglycoside Dosing Based on Peak Serum Concentration and Bacterial Minimal Inhibitory Concentration
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Aminoglycoside Dosing Based on PK/PD Characteristics
Keywords: Aminoglycosides
Minimal Inhibitory Concentration (MIC)
Gram negative
PK/PD
Peak concentration (Cmax)
Lead sponsor: Hadassah Medical Organization
Sponsor class: OTHER
First posted: 2022-11-16
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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)

Eligibility criteria: 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

Primary outcomes:
measure: Efficacy outcome
timeFrame: up to 1 week after end of therapy
measure: Renal outcome
timeFrame: up to 1 week after end of therapy
measure: Renal outcome
timeFrame: up to 1 week after end of therapy
measure: Aminoglycoside dosing outcomes:
timeFrame: up to 1 week after end of therapy
measure: Aminoglycoside dosing outcomes:
timeFrame: up to 1 week after end of therapy
Secondary outcomes:
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Hadassah Hebrew University Medical Center
Study officials:
affiliation: Director, Antimicrobial Stewardship Program
name: Maya Korem, MD
role: PRINCIPAL_INVESTIGATOR
References: