Clinical Trials to Reduce the Risk of Antimicrobial Resistance

Bacterial Pneumonia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01570192
• Other study ID #: 10-0060
• Status: Terminated
• Phase: Phase 2
• First received: March 22, 2012
• Last updated: September 1, 2017
• Start date: September 2010
• Est. completion date: April 2015

Study information

• Verified date: September 2017
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 43
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bacterial Pneumonia
• Pneumonia
• Pneumonia, Bacterial

Intervention

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

Locations

Country	Name	City	State
France	Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere	Paris
Germany	Hannover Clinical Trial Center GmbH	Hannover
Spain	Hospital Vall d'Hebron	Barcelona
United States	Emory University	Atlanta	Georgia
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Lerner College of Medicine	Cleveland	Ohio
United States	UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine	Gainesville	Florida
United States	Weill Cornell Medical Center of Cornell University	New York	New York
United States	JMI Laboratories	North Liberty	Iowa
United States	Washington University in St. Louis School of Medicine	Saint Louis	Missouri
United States	InClin, Inc.	San Mateo	California

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain, 

References & Publications (48)

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* Note: There are 48 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	up to 28 days after enrollment
Secondary	Clinical Response	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	End of treatment - up to 28 days after enrollment
Secondary	Clinical Response in Subjects Who Received Prior Antibiotics	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	End of treatment - up to 28 days after enrollment
Secondary	Overall Microbiologic Response	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	End of treatment - up to 28 days after enrollment
Secondary	Pretreatment Pathogen Response	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	End of treatment - up to 28 days after enrollment
Secondary	Suppression of the Emergence of Resistance in Other Gram-negative Pathogens	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	Day 5/Early Extubation
Secondary	Occurrence of Repeat Negative Cultures	Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)	Day 5/Early Extubation
Secondary	Mortality	Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)	14 days
Secondary	Mortality	Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)	28 days