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

Study Overview
=================
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. If Cmax/MIC=8-12 - no intervention (aminoglycoside dose unchanged). If Cmax/MIC>12 - decreasing AG dose accordingly, based on clinical calculators, to achieve target Cmax/MIC 10; 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 ID physician will be consulted for need for alternative therapy. If AG dose has been adjusted, ascertaining PK/PD target attainment (repeat timely peak level determination following dose adjustment). 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)

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

Conditions
-----------------
Aminoglycoside Dosing Based on PK/PD Characteristics

Intervention / Treatment
-----------------
* Drug: Aminoglycoside dose adjustment


Participation Criteria
=================
Eligibility Criteria
-----------------
Adult patients (≥18yr) Any infection treated with IV gentamycin or amikacin and approved by the consultant infectious diseases specialist, excluding neurosurgical infections, pneumonia, endocarditis or endovascular infections Normal renal function or mild renal impairment (eGFR≥40ml/min) On extended-interval AG and an expected remaining AG course of at least 4 days At least one microbiological specimen with identification of an AG-susceptible pathogen and MIC determination and Signed informed consent form Exclusion Criteria: Age<18yr Neurosurgical infections, pneumonia, endocarditis or endovascular infections eGFR<40ml/min Empirical aminoglycoside treatment Non Gram-negative pathogen No MIC available for the pathogen Expected remaining treatment duration of less than 4 days

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Aminoglycoside dose adjustment<br>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<br>* Eligible patients may have the aminoglycoside dose adjusted based on pathogen MIC, to attain the PK/PD target of Cam/MIC 10 (8-12)<br>|

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 | 
| Renal outcome | Mean SCr change at end of therapy vs. 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PK/PD, Aminoglycosides, Minimal Inhibitory Concentration (MIC), Gram negative, Peak concentration (Cmax)