Standard vs. Biofilm Susceptibility Testing in Cystic Fibrosis (CF) - Full Text View

Sponsor:	Seattle Children's Hospital
Collaborator:	Cystic Fibrosis Foundation
Information provided by:	Seattle Children's Hospital
ClinicalTrials.gov Identifier:	NCT00153634

Purpose

This was a randomized multi-center clinical trial to compare the microbiological efficacy, clinical efficacy, and safety of using standard versus biofilm susceptibility testing of P. aeruginosa sputum isolates to guide antibiotic selection for treatment of airway infection in clinically stable patients with CF.

Condition	Intervention
Cystic Fibrosis Chronic Bronchitis	Drug: IV amikacin Drug: PO azithromycin Drug: IV ceftazidime Drug: PO ciprofloxacin Drug: IV meropenem Drug: IV piperacillin-tazobactam Drug: IV ticarcillin-clavulanate Drug: IV tobramycin

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Standard vs. Biofilm Susceptibility Testing in CF

Resource links provided by NLM:

Further study details as provided by Seattle Children's Hospital:

Primary Outcome Measures:

Microbiological efficacy: Change in P. aeruginosa density [ Time Frame: from enrollment (up to day -21) to end of treatment (day 12-14) ]

Secondary Outcome Measures:

Clinical efficacy: Pre- to post-treatment change in FEV1 [ Time Frame: from initiation (day 0) to end of treatment (day 12-14) ]
Safety: Adverse events, including new onset of acute pulmonary exacerbation and/or the need to change antibiotic therapy during the treatment period [ Time Frame: from enrollment (up to day -21) to end of treatment (day 12-14) ]
Feasibility: Average costs and time per assay; rate of patient withdrawal because resistance patterns preclude randomization; self-reported technician satisfaction [ Time Frame: during active enrollment (March 2004-November 2007) ]

Enrollment:	75
Study Start Date:	March 2004
Study Completion Date:	November 2007

Arms	Assigned Interventions
1: Experimental Antibiotic regimen assignment based on biofilm susceptibility test results	Drug: IV amikacin 5-7.5 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site Drug: PO azithromycin 250 mg once daily Drug: IV ceftazidime 50 mg/kg every 8 hours, up to 2 grams every 8 hours Drug: PO ciprofloxacin 500 mg every 12 hours if weight <50 kg 750 mg every 12 hours if weight ≥50 kg Drug: IV meropenem 40 mg/kg every 8 hours, up to 2 grams every 8 hours Drug: IV piperacillin-tazobactam 100 mg/kg of piperacillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only Drug: IV ticarcillin-clavulanate 100 mg/kg of ticarcillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only Drug: IV tobramycin 2.5-3.3 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site
2: Active Comparator Antibiotic regimen assignment based on conventional susceptibility test results	Drug: IV amikacin 5-7.5 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site Drug: PO azithromycin 250 mg once daily Drug: IV ceftazidime 50 mg/kg every 8 hours, up to 2 grams every 8 hours Drug: PO ciprofloxacin 500 mg every 12 hours if weight <50 kg 750 mg every 12 hours if weight ≥50 kg Drug: IV meropenem 40 mg/kg every 8 hours, up to 2 grams every 8 hours Drug: IV piperacillin-tazobactam 100 mg/kg of piperacillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only Drug: IV ticarcillin-clavulanate 100 mg/kg of ticarcillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only Drug: IV tobramycin 2.5-3.3 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site

Arms

Assigned Interventions

1: Experimental

Antibiotic regimen assignment based on biofilm susceptibility test results

Drug: IV amikacin

5-7.5 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site

Drug: PO azithromycin

250 mg once daily

Drug: IV ceftazidime

50 mg/kg every 8 hours, up to 2 grams every 8 hours

Drug: PO ciprofloxacin

500 mg every 12 hours if weight <50 kg 750 mg every 12 hours if weight ≥50 kg

Drug: IV meropenem

40 mg/kg every 8 hours, up to 2 grams every 8 hours

Drug: IV piperacillin-tazobactam

100 mg/kg of piperacillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only

Drug: IV ticarcillin-clavulanate

100 mg/kg of ticarcillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only

Drug: IV tobramycin

2.5-3.3 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site

2: Active Comparator

Antibiotic regimen assignment based on conventional susceptibility test results

Drug: IV amikacin

5-7.5 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site

Drug: PO azithromycin

250 mg once daily

Drug: IV ceftazidime

50 mg/kg every 8 hours, up to 2 grams every 8 hours

Drug: PO ciprofloxacin

500 mg every 12 hours if weight <50 kg 750 mg every 12 hours if weight ≥50 kg

Drug: IV meropenem

40 mg/kg every 8 hours, up to 2 grams every 8 hours

Drug: IV piperacillin-tazobactam

100 mg/kg of piperacillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only

Drug: IV ticarcillin-clavulanate

100 mg/kg of ticarcillin component every 6 hours, up to 3 grams every 6 hours; antibiotic combination formulated in a fixed ratio, thus dosing is described for first component only

Drug: IV tobramycin

2.5-3.3 mg/kg every 8 hrs or previous dose; start at previous recent stable dose then monitor serum levels and adjust dose, if needed, per standard clinical practice at the site

Detailed Description:

Patients were screened to determine eligibility and to obtain a sputum culture. Eligible patients were randomized to either the standard or biofilm study arm. Antibiotic selection was performed centrally according to a standard algorithm using the susceptibility test results of the assigned study arm. On Day 0, patients were started on a 14-day course of two antibiotics as selected per protocol. Antibiotics were administered intravenously (IV) and/or orally. A follow-up phone call or visit occurred on Day 7. An end of treatment visit was conducted after completion of antibiotic therapy. A total of 39 patients were randomized. Many screened patients were ineligible for randomization based on microbiology results.

Eligibility

Ages Eligible for Study:	14 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of CF based on the following: sweat chloride > 60 mEq/L (by quantitative pilocarpine iontophoresis), or genotype with 2 identifiable mutations consistent with CF; and one or more clinical features consistent with CF.
Age ≥ 14 years (changed from ≥ 18 years by protocol amendment).
Able to expectorate sputum at screening.
History of persistent positivity for P. aeruginosa on respiratory culture (at least three positive oropharyngeal (OP), sputum and/or bronchoscopy cultures in the 24 months prior to screening).
Able to reproducibly perform pulmonary function testing.
Clinically stable at screening, with no evidence of pulmonary exacerbation.
Written informed consent provided.

Exclusion Criteria:

Sputum culture negative for P. aeruginosa or density less than 10E5 CFU/gm at screening.
Sputum culture positive for B. cepacia at screening.
Presence of P. aeruginosa in sputum with off-scale resistance to all antibiotics by either method of susceptibility testing at screening. (changed from multiply-resistant P. aeruginosa by protocol amendment)
History of B. cepacia positive respiratory culture within 24 months prior to screening.
Hospitalization or treatment for a pulmonary exacerbation within 2 months prior to screening.
Administration of parenteral anti-pseudomonal antibiotics within 2 months prior to screening.
Treatment with oral or inhaled anti-pseudomonal antibiotics, or azithromycin or other macrolides within 14 days prior to screening.
History of allergy (urticarial rash, diffuse erythroderma, serum sickness) to more than two groups of antibiotics (aminoglycosides, penicillins, cephalosporins, monobactams, macrolides, or quinolones) that are a therapeutic option.
History of anaphylaxis or other life threatening complication to any antibiotic in the six groups that are a therapeutic option.
History of abnormal renal function (serum creatinine > 1.5 x upper limit of normal) within one year of enrollment.
History of abnormal liver function tests (> 2.5 x upper limit of normal) within one year of enrollment.
Clinically documented hearing loss that precludes treatment with aminoglycosides.
Post lung transplantation.
Positive pregnancy test or female who is lactating or is not practicing an acceptable method of birth control.
Presence of a condition or abnormality that in the opinion of an investigator would compromise the safety of the patient or the quality of the data.
Administration of any investigational agent within 30 days prior to screening.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00153634

Locations

United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Missouri
Washington University St. Louis
St. Louis, Missouri, United States, 63110
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43205
University of Cincinnati
Cincinnati, Ohio, United States, 45267-0557
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Children's Hospital and Regional Medical Center
Seattle, Washington, United States, 98105-0371
University of Washington Medical Center
Seattle, Washington, United States, 98195

Sponsors and Collaborators

Seattle Children's Hospital

Cystic Fibrosis Foundation

Investigators

Principal Investigator:	Samuel M Moskowitz, MD	Seattle Children's Hospital
Study Chair:	Jane L Burns, MD	Children's Hospital and Regional Medical Center

More Information

Publications:

Moskowitz SM, Foster JM, Emerson J, Burns JL. Clinically feasible biofilm susceptibility assay for isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. J Clin Microbiol. 2004 May;42(5):1915-22.

Moskowitz SM, Foster JM, Emerson JC, Gibson RL, Burns JL. Use of Pseudomonas biofilm susceptibilities to assign simulated antibiotic regimens for cystic fibrosis airway infection. J Antimicrob Chemother. 2005 Nov;56(5):879-86. Epub 2005 Sep 27.

Study ID Numbers:	BURNS03A0
Study First Received:	September 8, 2005
Last Updated:	March 12, 2008
ClinicalTrials.gov Identifier:	NCT00153634 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Seattle Children's Hospital:

Cystic fibrosis
Antibiotic susceptibility testing
Pseudomonas aeruginosa
Chronic bronchitis
Biofilms

Additional relevant MeSH terms:

Anti-Infective Agents
Disease Attributes
Molecular Mechanisms of Pharmacological Action
Bronchial Diseases
Fibrosis
Clavulanic Acids
Piperacillin-tazobactam combination product
Ceftazidime
Anti-Bacterial Agents
Ciprofloxacin
Ticarcillin-clavulanic acid
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Infections
Respiratory Tract Diseases

Therapeutic Uses
Meropenem
Azithromycin
Clavulanic Acid
Infant, Newborn, Diseases
Bronchitis
Genetic Predisposition to Disease
Nucleic Acid Synthesis Inhibitors
Disease Susceptibility
Tobramycin
Enzyme Inhibitors
Tazobactam
Pharmacologic Actions
Bronchitis, Chronic
Digestive System Diseases

ClinicalTrials.gov processed this record on February 08, 2010