Impact of Imipenem With Amikacin Pharmacokinetic and Pharmacodynamic (IMPACT)

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).

Study Overview

• Status: Completed
• Conditions: Ventilator Associated Pneumonia
• Intervention / Treatment: Drug: Imipenem/Amikacin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Argenteuil, France, 95100
    • Victor Dupouy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 1:Imipenem/Amikacin; patients will receive as empirical therapy for VAP imipenem associated with amikacin.After primary outcome measure, antibiotic therapy will be left at the discretion of the physician in charge of the patient. Imipenem: recommended usual dosage for VAP treatment, IV (in the vein), every 8 hours Amikacin: recommended usual dosage for VAP treatment (20mg/kg), IV (in the vein), single dose (at H0) for the 48 first hours of treatment

Drug: Imipenem/Amikacin; patients will received as empirical therapy for VAP imipenem associated with amikacin.; Other Names: Therapy for VAP imipenem associated with amikacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Variation of numeration (cfu per ml) of GNB, for whom culture of pulmonary samples are positive (higher than defined thresholds), between the quantitative endotracheal aspiration (QAE) obtained at H0 (initiation of treatment) and QAE obtained at H48	Hour 48

Secondary Outcome Measures

Outcome Measure	Time Frame
To describe imipenem and amikacin PK parameters as empirical therapy in ICU patients treated for VAP	Hour 24
To describe imipenem and amikacin PD parameters as empirical therapy in ICU patients treated for VAP	Hour 24
To determine the proportion of patients for whom the pharmacodynamic targets suggested in the literature for aminoglycosides and beta lactams are achieved	Hour 24
To identify sources of variability of imipenem and amikacin PK/PD parameters in ICU patients with VAP	Hour 24
To assess the impact of imipenem and amikacin PK/PD parameters on GNB eradication at day 3	Day 3
To assess the impact of imipenem and amikacin PK/PD parameters variability on the CPIS, clinical score of VAP, measured 48 hours after initiation of the treatment	Hour 48
To assess the impact of imipenem and amikacin PK/PD parameters on the time necessary to observe a CPIS lower or equal to 6	Day 8
To assess the impact of imipenem and amikacin PK/PD parameters on clinical evolution of the VAP after 7 days of antibiotic treatment	Day 8
To assess the impact of imipenem and amikacin PK/PD parameters on serum procalcitonin levels evolution between the initiation of the treatment and 48 hours after the initiation of the treatment of the VAP	Hour 48
To assess the impact of imipenem and amikacin PK/PD parameters on mortality at day 28 (Day 28) 11- to assess the impact of imipenem and amikacin PK/PD parameters on VAP relapse	Day 28
To study emergence of less sensitive bacteria to imipenem and/or amikacin, 48 hours after the initiation of the antibiotic treatment, among GNB isolated in endotracheal aspiration before initiation of this treatment	Hour 48
To study emergence in the tracheal and digestive flora of micro-organisms resistant to imipenem after the first 48 hours of treatment by imipenem	Hour 48

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Olivier PAJOT, MD, Hopital Argenteuil

Publications and helpful links

General Publications

• Burdet C, Pajot O, Couffignal C, Armand-Lefevre L, Foucrier A, Laouenan C, Wolff M, Massias L, Mentre F. Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia. Eur J Clin Pharmacol. 2015 Jan;71(1):75-83. doi: 10.1007/s00228-014-1766-y. Epub 2014 Oct 21.
• Couffignal C, Pajot O, Laouenan C, Burdet C, Foucrier A, Wolff M, Armand-Lefevre L, Mentre F, Massias L. Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens. Br J Clin Pharmacol. 2014 Nov;78(5):1022-34. doi: 10.1111/bcp.12435.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (ACTUAL): September 1, 2011
• Study Completion (ACTUAL): January 1, 2012

Study Registration Dates

• First Submitted: July 28, 2009
• First Submitted That Met QC Criteria: July 30, 2009
• First Posted (ESTIMATE): July 31, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): July 26, 2012
• Last Update Submitted That Met QC Criteria: July 25, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Intensive care unit; Amikacin; Ventilator associated pneumonia; Empirical antibiotic therapy; Imipenem; Gram negative bacilli; Gram negative bacilli infection; Pharmacokinetic / pharmacodynamic
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Anti-Bacterial Agents; Imipenem; Amikacin
• Other Study ID Numbers: P061014; CRC06049 (OTHER: CRC)