Nosocomial pneumonia or severe tracheobronchitis caused by Gram-negative pathogens in subjects that requiring mechanical ventilation.
Conditions
Interventions
Trade Name: Meropenem Accordpharma 1 g POLVO PARA SOLUCION INYECTABLE Y PARA PERFUSION EFG
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: MER
Sponsors
Fundación Investigación Biomédica Hospital Ramón y Cajal
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: The inclusion criteria are the following (all should be fulfilled): 1. Males and non-pregnant, non-lactating females, 18 years of age or older 2. Currently intubated and mechanically-ventilated subjects in the ICU 3. Suspicion of lower respiratory tract infection defined as at least two of the following: ? fever, defined as a tympanic/ rectal/core temperature > 38,3°C , or hypothermia, defined as a rectal/core body temperature of 10 000/mm3 or 15% regardless of the peripheral leukocyte count; ? new onset of purulent sputum or respiratory secretions, or a change in the character of sputum; ? a new or progressive pulmonary infiltrate on chest X-rays. 4. Presence of Gram-negative organism(s) by Gram stain OR by culture of pre-therapy respiratory specimen (eg, endotracheal aspirate [ETA], bronchoalveolar lavage [BAL], or mini-BAL) OR previous colonization 48h before screening. 5. Initial empiric antimicrobial regimen combining meropenem with an aminoglycoside or a fluoroquinolone active on Pseudomonas, plus MRSA coverage when indicated, in accordance with the ATS/IDSA guidelines for HAP/VAP/HCAP. 6. At least two risk factors for multidrug-resistant organisms: ? Antimicrobial therapy in the preceding two weeks; ? Current hospitalization = 5 days; ? High frequency (> 10%) of antibiotic resistance in the community or in the specific hospital unit; ? Immunosuppressive disease and/or therapy; ? Residence in a nursing home or extended care facility. 7. Clinical pulmonary infection score (CPIS) = 6 8. Expected to remain intubated and mechanically ventilated for = 72 hours based on investigator estimate. 9. Expected to participate in the study through 28 days post first dose of meropenem. 10. Provision of written informed consent by the subject or a family member or a close relative within 36 hours after the beginning of the initial antibiotic therapy. [A waiver of consent will be asked to each Ethical Committee allowing for randomizing patients when they are unable to give consent and no, family member or a close relative can be contacted, in accordance with law specifications of emergency consent. In that case, patients will be asked to give their consent for continuation of the trial when their condition permits]. 11. In order to be eligible for the primary microbiologically evaluable population (Micro-ITT Analysis Set), subjects must demonstrate presence of Gram-negative organism(s) by semi-quantitative or quantitative cultures of pre-therapy respiratory secretions in concentrations above prespecified values (ETA cultures =105 CFU/mL; BAL cultures =104 CFU/mL) 12. Affiliation to a social security system (recipient or assign) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 35 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: Any of the following would exclude the subject from participation in the study: 1. Subjects who have received antibiotic therapy for Gram-negative LRT infection for =36 hours at the time of randomization 2. Subjects with known or suspected type 1 hypersensitivity (e.g., anaphylaxis) to betalactam and/or cephalosporin 3. Infection caused by a pathogen resistant to meropenem 4. Subjects taking valproic acid for a seizure disorder will not be included. Other anticonvulsants are allowed. 5. Subjects who have had a left hemisphere stroke (right hemisphere is allowed) within five days and there is an increased risk of fatal brain oedema as indicated by a major early computerized tomography hypodensity exceeding 50% of the middle cerebral artery territory, and/or involvement of additional vascular territories 6. Subjects who have cystic fibrosis, human immunodeficiency virus (HIV) infection with CD4 count 28 days 18. Subjects who were previously enrolled in this study 19. Patients under curatorship or tutorship
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To document the superiority of the MON4STRAT approach for reaching and maintaining a meropenem pre-determined PK-PD target (optimized for efficacy, mitigation of drug resistance and control of adverse effects) during the whole duration of treatment of hospitalized subjects with nosocomial pneumonia or severe tracheobronchitis requiring mechanical ventilation caused by Gram-negative pathogens when compared to conventional therapies.;Secondary Objective: To determine whether the MON4STRAT approach is associated with a relevant clinical benefit in terms of clinical cure rate, mortality, duration of mechanical ventilation, pathogen eradication, emergence of drug resistance, safety, and healthcare utilization.;Primary end point(s): The main PK/PD efficacy assessment will be determined every day during antibiotic treatment course in the modified intent-to-treat (ITT) study population. Primary endpoint is the proportion of time from day 1 after randomization to end of therapy (EOT) in which the free meropenem trough concentration in serum was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC > 2 and = 8 µg/mL, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC).;Timepoint(s) of evaluation of this end point: 17 Months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ? Proportion of time from day 1 after randomization to end of therapy (EOT) in which the free meropenem trough concentration in serum was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC >2 and =8 µg/mL, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC) in the modified Micro-ITT (patients with microbiologically confirmed pneumonia or ventilator-associated tracheobronchitis) sets of patients. ? Clinical response rates observed at test of cure (TOC) visit (7 to 10 days after last study drug infusion) in the modified ITT and Micro-ITT (patients with microbiologically confirmed pneumonia or ventilator-associated tracheobronchitis) sets of patients. ? Rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp.: defined as a change of antibiotic MIC by two tube dilutions (four fold) from baseline in the modified ITT and Micro-ITT sets of patients. ? Microbiological response rates at EOT and TOC (7 to 10 days after last meropenem infusion): will be judged as satisfactory (documented eradication, presumed eradication,) or unsatisfactory (documented persistence, presumed persistence, or recurrence), based on the results of the respiratory specimen cultures obtained at EOT and TOC. ? Time to LRT bacterial eradication, as assessed by follow-up cultures of ETA obtained on days 3, 5, 7 and EOT in the modified ITT and Micro-ITT sets of patients. ? Day-14 and day-28 all-cause mortality in the modified ITT and Micro-ITT sets of patients. ? ICU and hospital length of stay in the modified ITT and Micro-ITT sets of patients. ? Number of mechanical ventilation-free days between days 1 and 28 after randomization, defined as the number of days of unassisted breathing in the modified ITT and Micro-ITT sets of patients. ? Number of antibiotic-free days between days 1 and | — |
Countries
France, Spain
Contacts
Public ContactMarta del Álamo
Fundación Investigación Biomédica Hospital Ramón y Cajal
Outcome results
None listed