Early-onset Ventilator-associated Pneumonia in Adults: Comparison of 8 Versus 15 Days of Antibiotic Treatment

Comparison of Two Lengths of Treatment in Early-onset Ventilated Associated Pneumonia

The duration of treatment of community acquired pulmonary infection varies between 5 and 14 days according to the authors (22), or even 3 days with new drugs having long half-life (2). For nosocomial pulmonary infection, treatment durations are not standardized (5). It is simply mentioned the concept of "usual" treatment of at least 15 days. However, recent studies used 10 days of treatment without significant decrease in the rate of healing compared to usual treatment. It is essential to clarify the optimal duration of antibiotic treatment. Indeed, any excessive extension of treatment may increase the occurrence of adverse effects (renal toxicities, hepatic...), and induce resistance of bacteria to antibiotics (selection pressure), colonization of the patient by Multiresistant bacteria and an increase in the cost of treatment

Study Overview

• Status: Completed
• Conditions: Pneumonia Ventilator Associated
• Intervention / Treatment: Drug: Augmentin, Ceftriaxone, Cefotaxime, netilmycin, tobramycin; Drug: compare 8 to15 days of antibiotic treatment

Detailed Description

This is a prospective, randomized, open, multi-center study.

3.1 Primary Objective

Show that antibiotic therapy of 8 or 15 days is equivalent in terms of clinical cure rates in the treatment of early onset nosocomial pulmonary infection in patients under mechanical ventilation.

3.2 Secondary Objective

• Study of nosocomial infections: assessing the influence of the duration of antibiotic treatment on the rate of fatal pulmonary and extra-pulmonary infection (definition of nosocomial infections: annex XIII).

  • Study of bacterial Ecology: research of changes in the flora of the gut under treatment and analysis of pathological samples (antibiotic resistance phenotypes +/-genotypes).

• Economic Survey: analyze the costs related to the treatment of nosocomial pneumonia and its complications in two study groups.

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 4

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:

Early onset nosocomial pneumonia in patients under mechanical ventilation since at least 24 h Patients aged 18 years or more The patient must be able to receive either one of the two arms of treatment defined for the study Information on the patient and his family informed consent obtained during the first three days Bacteria sensitive to the specified antibiotic regimen

Exclusion Criteria:

• Patients do not match the criteria for inclusion
• 18 years of age, pregnant Patients
• Another infectious outbreak documented the day of the BAL.
• Patients with acquired immunosuppression (blood diseases, HIV,...), induced (immunosuppressive drugs, cancer, radiation therapy) or congenital.
• Steroids for a period exceeding 15 days.
• Leukopenia (1000 GB/mm (or neutropenia (500 PN/mm)
• Purulent pleural effusion, pulmonary abscess
• Cystic fibrosis

• Antibiotic treatment according to the following terms:

  1. Ongoing curative antibiotic therapy
  2. Antibiotics within 3 days before the diagnosis of VAP, except surgical antibiotic prophylaxis (defined according to the consensus conference "antibiotic prophylaxis in the surgical environment in adult" December 11, 1992) (27)
  3. Use of antibiotics not authorized in the study (see list)
• Allergy to antibiotics used in the study
• Inclusion in another study assessing antibiotic treatment, either the treatment or prevention of nosocomial pulmonary disease
• Refusal to participate
• Lack of informed consent by the patient or his family

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 8 days of antibiotic treatment; Patients will receive a combination antibiotic during 5 days and then 3 days of a single Beta Lactam antibiotic	Drug: Augmentin, Ceftriaxone, Cefotaxime, netilmycin, tobramycin; All patients included in the study will be treated by a combination of antibiotics during the first 5 days, then by monotherapy for either 3 or 10 days according to their allocated group.; Beta-Lactams:Amoxicillin + clavulanic Acid : 2 g TDS for 3 days, then 1 g TDSCeftriaxone : 2 g OD during 3 days, then 1 g ODCefotaxime : 2 g TDS during 3 days, then 1 g TDS; AminoglycosidesTobramycin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure)Netilmicin : loading dose of 10 mg/kg OD, then 8 mg/kg OD (adaptation in case of renal failure)Dibekacin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure); Other Names: Amoxicillin; Clavulanic acid; Drug: compare 8 to15 days of antibiotic treatment; All patients included in the study will be treated by a combination of antibiotics during the first 5 days, then by monotherapy for either 3 or 10 days according to their allocated group. • Beta-Lactams: Amoxicillin + clavulanic Acid : 2 g TDS for 3 days, then 1 g TDS; Ceftriaxone : 2 g OD during 3 days, then 1 g OD; Cefotaxime : 2 g TDS during 3 days, then 1 g TDS Aminoglycosides; Tobramycin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure); Netilmicin : loading dose of 10 mg/kg OD, then 8 mg/kg OD (adaptation in case of renal failure); Dibekacin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure); Other Names: Amoxicillin; Clavulanic acid
ACTIVE_COMPARATOR: 15 days antibiotic treatment; All patients included in the study will be treated by a combination of antibiotics during the first 5 days, then by monotherapy for 10 days according to the group. The beta-lactam antibiotics will be administered in high doses during the first 3 days of treatment. Aminoglycosides will be administered in a single daily dose, with a loading dose the first day of treatment.	Drug: compare 8 to15 days of antibiotic treatment; All patients included in the study will be treated by a combination of antibiotics during the first 5 days, then by monotherapy for either 3 or 10 days according to their allocated group. • Beta-Lactams: Amoxicillin + clavulanic Acid : 2 g TDS for 3 days, then 1 g TDS; Ceftriaxone : 2 g OD during 3 days, then 1 g OD; Cefotaxime : 2 g TDS during 3 days, then 1 g TDS Aminoglycosides; Tobramycin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure); Netilmicin : loading dose of 10 mg/kg OD, then 8 mg/kg OD (adaptation in case of renal failure); Dibekacin : loading dose of 6 mg/kg OD, then 5 mg/kg OD (adaptation in case of renal failure); Other Names: Amoxicillin; Clavulanic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cure of respiratory infection	The primary endpoint of the present study was the clinical cure rate at day 21. Complete clinical recovery was determined by the absence of the following criteria: death, septic shock (except when associated with a documented non-respiratory infection), intercurrent adverse event attributable to the protocol (or for which attributability to the protocol could not be ruled out) requiring modified antibiotic treatment, and patients who relapsed.	21 days after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of secondary infections	The study focused on establishing incidence of secondary nosocomial infections; number of patients on antibiotic treatment; total number of days of antibiotic treatment; duration of MV; number of patients still under ventilation; number of patients still in ICU; length of stay in ICU on day 21; and mortality rate at 3 months.	21 days

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Besançon
• Collaborators: GlaxoSmithKline; French Society for Intensive Care; SmithKline Beecham
• Investigators: Principal Investigator: Gilles R CAPELLIER, MD, PhD, Centre Hospitalier Universitaire de Besancon

Publications and helpful links

General Publications

• Capellier G, Mockly H, Charpentier C, Annane D, Blasco G, Desmettre T, Roch A, Faisy C, Cousson J, Limat S, Mercier M, Papazian L. Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment. PLoS One. 2012;7(8):e41290. doi: 10.1371/journal.pone.0041290. Epub 2012 Aug 31.

Study record dates

Study Major Dates

• Study Start: January 1, 1998
• Primary Completion (ACTUAL): September 1, 2002
• Study Completion (ACTUAL): November 1, 2002

Study Registration Dates

• First Submitted: November 29, 2011
• First Submitted That Met QC Criteria: March 19, 2012
• First Posted (ESTIMATE): March 21, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): March 21, 2012
• Last Update Submitted That Met QC Criteria: March 19, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: treatment; Antibiotic; ventilator associated pneumonia; duration
• 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; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protein Synthesis Inhibitors; beta-Lactamase Inhibitors; Ceftriaxone; Anti-Bacterial Agents; Amoxicillin; Tobramycin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Cefotaxime; Cefoxitin; Netilmicin
• Other Study ID Numbers: CHUB/GC001