Official Title: “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 Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• 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, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Antibiotic regimen assignment based on biofilm susceptibility test results
• Active Comparator: 2
  • Antibiotic regimen assignment based on conventional susceptibility test results

Primary Measures

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

Secondary 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)
    

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 14 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Hospital and Regional Medical Center, Seattle

Overall Clinical Trial Officials and Contacts

Samuel M Moskowitz, MD Principal Investigator Children's Hospital and Regional Medical Center, Seattle  

Information obtained from ClinicalTrials.gov on November 19, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00153634

Study ID Number: BURNS03A0

ClinicalTrials.gov Identifier: NCT00153634

Health Authority: United States: Institutional Review Board