Clinical Trials to Reduce the Risk of Antimicrobial Resistance

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01570192

Enrollment

Registered

2012-04-04

Start date

2010-09-30

Completion date

2015-04-30

Last updated

2017-09-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bacterial Pneumonia

Keywords

gram negative pathogens, Pseudomonas aeruginosa, Acinetobacter, HCAP, VABP, HABP

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).

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.

Interventions

DRUGIV meropenem

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).

DRUGI.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

DRUGParenteral 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)

DRUGLinezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.

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

DEVICEtobramycin nebulization

tobramycin nebulization 600mg/day

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

This is an open-label study with 1:1 randomization between two active treatment groups.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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)
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)
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)
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)
Occurrence of Repeat Negative Cultures	Day 5/Early Extubation	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Mortality	14 days	Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
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)

Countries

France, Germany, Spain, United States

Participant flow

Recruitment details

We had 8 clinical sites: recruitment into the study began September 2010 and ended April 10, 2015.

Pre-assignment details

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.

Participants by arm

Arm	Count
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. 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	13
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. 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.	30
Total	43

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	changed to palliative care	1	0
Overall Study	no qualifying organism	6	12
Overall Study	Physician Decision	0	1

Baseline characteristics

Characteristic	IV Meropenem; Parenteral Aminoglycoside	I.V. Meropenem	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	7 Participants	10 Participants	17 Participants
Age, Categorical Between 18 and 65 years	6 Participants	20 Participants	26 Participants
Age, Continuous	61.2 years STANDARD_DEVIATION 18.3	58.4 years STANDARD_DEVIATION 12.6	59.2 years STANDARD_DEVIATION 14.4
Baseline acute physiology and chronic health evaluation II (APACHE II) score	22.6 units on a scale STANDARD_DEVIATION 4.6	21.0 units on a scale STANDARD_DEVIATION 6.2	21.5 units on a scale STANDARD_DEVIATION 5.8
Region of Enrollment France	2 participants	11 participants	13 participants
Region of Enrollment Spain	0 participants	1 participants	1 participants
Region of Enrollment United States	11 participants	18 participants	29 participants
Sex: Female, Male Female	7 Participants	13 Participants	20 Participants
Sex: Female, Male Male	6 Participants	17 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 13	0 / 30
serious Total, serious adverse events	6 / 13	11 / 30

Outcome results

Primary

Number of Participants With Suppression and Emergence of Resistance

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

Population: 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	Measure	Group	Value (NUMBER)
I.V. Meropenem	Number of Participants With Suppression and Emergence of Resistance	suppression of emergence of resistance	5 participants
I.V. Meropenem	Number of Participants With Suppression and Emergence of Resistance	emergence of resistance	1 participants

Secondary

Clinical Response

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