Standard vs. Biofilm Susceptibility Testing in Cystic Fibrosis (CF)

Standard vs. Biofilm Susceptibility Testing in CF

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Chronic Bronchitis
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; 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
Active Comparator: 2; 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical efficacy: Pre- to post-treatment change in FEV1	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	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	during active enrollment (March 2004-November 2007)

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Collaborators: 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

Publications and helpful links

General 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. doi: 10.1128/JCM.42.5.1915-1922.2004.
• 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. doi: 10.1093/jac/dki338. Epub 2005 Sep 27.

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: September 8, 2005
• First Submitted That Met QC Criteria: September 9, 2005
• First Posted (Estimate): September 12, 2005

Study Record Updates

• Last Update Posted (Estimate): March 13, 2008
• Last Update Submitted That Met QC Criteria: March 12, 2008
• Last Verified: November 1, 2007

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Pseudomonas aeruginosa; Chronic bronchitis; Biofilms; Antibiotic susceptibility testing
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Infant, Newborn, Diseases; Bronchial Diseases; Genetic Diseases, Inborn; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pancreatic Diseases; Fibrosis; Disease Susceptibility; Cystic Fibrosis; Bronchitis; Bronchitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Ciprofloxacin; Meropenem; Azithromycin; Tobramycin; Clavulanic Acid; Amikacin; Piperacillin; Ceftazidime; Tazobactam; Piperacillin, Tazobactam Drug Combination; Ticarcillin; Ticarcillin-clavulanic acid
• Other Study ID Numbers: BURNS03A0