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Clinical Trials to Reduce the Risk of Antimicrobial Resistance

Sponsor
University of Florida (Other)
Overall Status
Terminated
CT.gov ID
NCT01570192
Collaborator
(none)
43
Enrollment
11
Locations
2
Arms
55
Duration (Months)
3.9
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm).

Condition or Disease Intervention/Treatment Phase
  • Drug: IV meropenem
  • Drug: I.V. Meropenem
  • Drug: Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h
  • Drug: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
  • Device: tobramycin nebulization
 Phase 2

Detailed Description

The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.

Study Design

Study Type:
Interventional
Actual Enrollment :
43 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
This is an open-label study with 1:1 randomization between two active treatment groups.
Primary Purpose:
Treatment
Official Title:
Impact of Aggressive Empiric Antibiotic Therapy and Duration of Therapy on the Emergence of Antimicrobial Resistance During the Treatment of Hospitalized Subjects With Pneumonia Requiring Mechanical Ventilation
Study Start Date :
Sep 1, 2010
Actual Primary Completion Date :
Apr 1, 2015
Actual Study Completion Date :
Apr 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: IV meropenem; parenteral aminoglycoside

Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.

Drug: IV meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Other Names:
  • Merrem I.V.

    • Drug: Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h
    a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)

    Drug: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
    Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.

    Device: tobramycin nebulization
    tobramycin nebulization 600mg/day
    Active Comparator: I.V. Meropenem

    Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.

    Drug: I.V. Meropenem
    Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage
    Other Names:
  • Merrem I.V.

    • Drug: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
    Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Suppression and Emergence of Resistance [up to 28 days after enrollment]

      The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.

    Secondary Outcome Measures

    1. Clinical Response [End of treatment - up to 28 days after enrollment]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    2. Clinical Response in Subjects Who Received Prior Antibiotics [End of treatment - up to 28 days after enrollment]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    3. Overall Microbiologic Response [End of treatment - up to 28 days after enrollment]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    4. Pretreatment Pathogen Response [End of treatment - up to 28 days after enrollment]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    5. Suppression of the Emergence of Resistance in Other Gram-negative Pathogens [Day 5/Early Extubation]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    6. Occurrence of Repeat Negative Cultures [Day 5/Early Extubation]

      Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)

    7. Mortality [14 days]

      Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)

    8. Mortality [28 days]

      Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:

    Written informed consent by the subject/subject's LAR.

    Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.

    Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility

    Women of childbearing potential if their pregnancy test is negative

    Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically.). While less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy was not efficacious and enrollment will be allowed.)

    Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP:

    Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia

    Within 36 hours before the start of empiric study therapy, a quantitative culture of Bronchoscopic BAL fluid must be obtained.

    Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5.

    Exclusion Criteria:

    Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure.

    Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity.

    Women who are pregnant or lactating.

    Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled into the study at the discretion of the site investigator.

    Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.

    Subjects with primary lung cancer or another malignancy metastatic to the lungs.

    Subjects who were previously enrolled in this study.

    Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.

    Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug.

    Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.

    Subjects with little chance of survival for the duration of study therapy.

    Subjects with an APACHE II score >35.

    Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.

    Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.

    Subjects who have undergone bone marrow transplantation.

    Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 InClin, Inc. San Mateo California United States 94403
    2 UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine Gainesville Florida United States 32610
    3 Emory University Atlanta Georgia United States 30322-4250
    4 Northwestern University Chicago Illinois United States 60611
    5 JMI Laboratories North Liberty Iowa United States 52317
    6 Washington University in St. Louis School of Medicine Saint Louis Missouri United States 63130
    7 Weill Cornell Medical Center of Cornell University New York New York United States 10065
    8 Cleveland Clinic Lerner College of Medicine Cleveland Ohio United States 44195
    9 Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere Paris France Cedex 13
    10 Hannover Clinical Trial Center GmbH Hannover Germany 30625
    11 Hospital Vall d'Hebron Barcelona Spain 08035

    Sponsors and Collaborators

    • University of Florida

    Investigators

    • Principal Investigator: George L Drusano, MD, University of Florida

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    University of Florida
    ClinicalTrials.gov Identifier:
    NCT01570192
    Other Study ID Numbers:
    • 10-0060
    First Posted:
    Apr 4, 2012
    Last Update Posted:
    Sep 29, 2017
    Last Verified:
    Sep 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by University of Florida
    gram negative pathogens
    Pseudomonas aeruginosa
    Acinetobacter
    HCAP
    VABP
    HABP
    Additional relevant MeSH terms:
    Pneumonia
    Pneumonia, Bacterial
    Vancomycin
    Gentamicins
    Meropenem
    Linezolid
    Tobramycin
    Amikacin

    Study Results

    Participant Flow

    Recruitment Details We had 8 clinical sites: recruitment into the study began September 2010 and ended April 10, 2015.
    Pre-assignment Detail Enrolled participants were excluded from the trial before assignment to groups because participants had no qualifying organisms; this includes participants with no growth on screening BAL, those with < 104 CFU/mL on BAL, and those with only Gram-positive bacteria cultured from the BAL.
    Arm/Group Title IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Arm/Group Description Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens. IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. tobramycin nebulization: tobramycin nebulization 600mg/day Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion. I.V. Meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.
    Period Title: Overall Study
    STARTED 13 30
    COMPLETED 6 17
    NOT COMPLETED 7 13

    Baseline Characteristics

    Arm/Group Title IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem Total
    Arm/Group Description Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens. IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. tobramycin nebulization: tobramycin nebulization 600mg/day Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion. I.V. Meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. Total of all reporting groups
    Overall Participants 13 30 43
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    6
    46.2%
    20
    66.7%
    26
    60.5%
    >=65 years
    7
    53.8%
    10
    33.3%
    17
    39.5%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.2
    (18.3)
    58.4
    (12.6)
    59.2
    (14.4)
    Sex: Female, Male (Count of Participants)
    Female
    7
    53.8%
    13
    43.3%
    20
    46.5%
    Male
    6
    46.2%
    17
    56.7%
    23
    53.5%
    Region of Enrollment (participants) [Number]
    United States
    11
    84.6%
    18
    60%
    29
    67.4%
    France
    2
    15.4%
    11
    36.7%
    13
    30.2%
    Spain
    0
    0%
    1
    3.3%
    1
    2.3%
    Baseline acute physiology and chronic health evaluation II (APACHE II) score (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    22.6
    (4.6)
    21.0
    (6.2)
    21.5
    (5.8)

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Suppression and Emergence of Resistance
    Description The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.
    Time Frame up to 28 days after enrollment

    Outcome Measure Data

    Analysis Population Description
    All patients in the ME population with BAL at baseline and at Day 5/EE and pathogens collected at baseline BAL and at Day 5/EE BAL.
    Arm/Group Title IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Arm/Group Description Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens. IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. tobramycin nebulization: tobramycin nebulization 600mg/day Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion. I.V. Meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.
    Measure Participants 0 6
    suppression of emergence of resistance
    5
    38.5%
    emergence of resistance
    1
    7.7%
    2. Secondary Outcome
    Title Clinical Response
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame End of treatment - up to 28 days after enrollment

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside MEGroup - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 6 18
    Count of Participants [Participants]
    2
    15.4%
    8
    26.7%
    2
    4.7%
    8
    NaN
    3. Secondary Outcome
    Title Clinical Response in Subjects Who Received Prior Antibiotics
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame End of treatment - up to 28 days after enrollment

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 3 5 4 6
    Count of Participants [Participants]
    1
    7.7%
    2
    6.7%
    1
    2.3%
    2
    NaN
    4. Secondary Outcome
    Title Overall Microbiologic Response
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame End of treatment - up to 28 days after enrollment

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 6 18
    Count of Participants [Participants]
    2
    15.4%
    6
    20%
    2
    4.7%
    7
    NaN
    5. Secondary Outcome
    Title Pretreatment Pathogen Response
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame End of treatment - up to 28 days after enrollment

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 6 18
    Count of Participants [Participants]
    3
    23.1%
    9
    30%
    3
    7%
    11
    NaN
    6. Secondary Outcome
    Title Suppression of the Emergence of Resistance in Other Gram-negative Pathogens
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame Day 5/Early Extubation

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 1 1 1 2
    Count of Participants [Participants]
    1
    7.7%
    1
    3.3%
    1
    2.3%
    2
    NaN
    7. Secondary Outcome
    Title Occurrence of Repeat Negative Cultures
    Description Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
    Time Frame Day 5/Early Extubation

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 4 17
    Count of Participants [Participants]
    3
    23.1%
    6
    20%
    3
    7%
    7
    NaN
    8. Secondary Outcome
    Title Mortality
    Description Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
    Time Frame 14 days

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 6 18
    Count of Participants [Participants]
    1
    7.7%
    0
    0%
    2
    4.7%
    2
    NaN
    9. Secondary Outcome
    Title Mortality
    Description Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    The ME population, 19 subjects were analyzed and the m-MITT population, 24 were analyzed. Not all subjects were evaluable for each endpoint.
    Arm/Group Title ME Group - Meropenem Plus Aminoglycoside ME Group - Meropenem Only m-MITT Group - Meropenem Plus Aminoglycoside m-MITT Group - Meropenem Only
    Arm/Group Description Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population Percentage of patients with successful responses by efficacy endpoint, Microbiologic Evaluable (ME) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population. Percentage of patients with successful responses by efficacy endpoint, Microbiologically modified ITT (m-MITT) group and population.
    Measure Participants 4 15 6 18
    Count of Participants [Participants]
    2
    15.4%
    1
    3.3%
    3
    7%
    3
    NaN

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Arm/Group Description Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens. IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. tobramycin nebulization: tobramycin nebulization 600mg/day Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion. I.V. Meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.
    All Cause Mortality
    IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/13 (46.2%) 11/30 (36.7%)
    Cardiac disorders
    cardiogenic shock 0/13 (0%) 0 1/30 (3.3%) 1
    cardiac arrest 1/13 (7.7%) 1 1/30 (3.3%) 1
    AICD fired/NSTEMI 0/13 (0%) 0 1/30 (3.3%) 1
    PEA arrest 1/13 (7.7%) 1 0/30 (0%) 0
    Gastrointestinal disorders
    reinforced duodenal ulcer 1/13 (7.7%) 1 0/30 (0%) 0
    General disorders
    multi-organ failure 0/13 (0%) 0 2/30 (6.7%) 2
    multi-organ failure due to distributive and cardiogenic shock 1/13 (7.7%) 1 0/30 (0%) 0
    stroke 0/13 (0%) 0 1/30 (3.3%) 1
    pulmonary embolism 0/13 (0%) 0 1/30 (3.3%) 1
    refractory shock 0/13 (0%) 0 1/30 (3.3%) 1
    septic shock 0/13 (0%) 0 1/30 (3.3%) 1
    cardiorespiratory arrest 0/13 (0%) 0 1/30 (3.3%) 1
    Respiratory, thoracic and mediastinal disorders
    pneomonia 1/13 (7.7%) 1 1/30 (3.3%) 1
    COPD with acute exacerbation 0/13 (0%) 0 1/30 (3.3%) 1
    pneumothorax 1/13 (7.7%) 1 0/30 (0%) 0
    Skin and subcutaneous tissue disorders
    cutaneous eruption 0/13 (0%) 0 1/30 (3.3%) 1
    Other (Not Including Serious) Adverse Events
    IV Meropenem; Parenteral Aminoglycoside I.V. Meropenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/13 (0%) 0/30 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Dr. George L. Drusano
    Organization University of Florida, Department of Medicine
    Phone 407-313-7060
    Email gdrusano@ufl.edu
    Responsible Party:
    University of Florida
    ClinicalTrials.gov Identifier:
    NCT01570192
    Other Study ID Numbers:
    • 10-0060
    First Posted:
    Apr 4, 2012
    Last Update Posted:
    Sep 29, 2017
    Last Verified:
    Sep 1, 2017