Impact of Imipenem With Amikacin Pharmacokinetic and Pharmacodynamic

Impact of Imipenem With Amikacin Pharmacokinetic and Pharmacodynamic

The study is a prospective open trial conducted in 4 centers, and designed to determine if pharmacokinetic (PK) and pharmacodynamic (PD) parameters of imipenem, associated with amikacin as empirical therapy, impact microbiological and clinical outcome of patients with Gram negative bacilli (GNB) ventilator-associated pneumonia (VAP).

Inappropriate initial antibiotherapy increases mortality of many serious infections. This is the case for ventilator-associated pneumonia, frequently occurring during intensive care unit (ICU) hospitalization, and whose 48 first hours of treatment are decisive.

It is well established that pharmacokinetic and pharmacodynamic parameters of antibiotics are correlated with their clinical and microbiological effectiveness. However in ICU patients, pharmacokinetic parameters of antibiotics suffer great variations, and bacteria responsible for these infections are usually less sensitive to antibiotics, especially Gram negative bacilli (GNB). An important pharmacodynamic variability may occur at the initial phase of the antibiotic treatment, decisive for the infection's outcome.

We propose to evaluate the correlation between pharmacokinetic and pharmacodynamic profile of the empirical antibiotic therapy and the microbiological and clinical outcome of VAP.

Inclusion Criteria:

1. Age ≥ 18 years
2. Mechanical ventilation for more than 48 hours
3. Clinical suspicion of VAP defined by a new persistent radiological infiltrate and one of the following signs: purulent tracheal aspirations, or temperature of 38°3 or higher, or leucocyte count > 10000/ml
4. Risk of multi resistant bacteria defined as follows: at least 6 days of mechanical ventilation or antibiotic treatment in the 15 previous days
5. Distal pulmonary secretion sample obtained beforehand for microbiological diagnosis by bronchoalveolar lavage via bronchoscopy or blinded protected telescoping catheter via bronchoscopy or blindly
6. Presence of GNB on direct examination of the distal pulmonary secretion sample
7. Realization of a preliminary medical examination. 8- Written inform consent from the patient or relatives. The consent may be obtained after the enrollment if the patient is not able to give consent and if there is no relatives

Exclusion Criteria:

1. Time between distal pulmonary secretion sample taking and the 1st administration of imipenem exceeding 24 hours
2. Pregnancy
3. Severely impaired renal function (creatinine clearance lower than 10 mL/mn or renal replacement therapy)
4. Allergy to imipenem or amikacin
5. Treatment in progress with imipenem or amikacin
6. Death expected within 48 hours following diagnosis of VAP
7. Myasthenia
8. Simultaneous administration of others aminoglycosides
9. Association with intravenous polymyxin or botulinum toxin