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

NCT ID: NCT00153634

Last Updated: 2008-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-03-31
• Study Completion Date: 2007-11-30

Brief Summary

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.

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.

Conditions

Cystic Fibrosis; Chronic Bronchitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Antibiotic regimen assignment based on biofilm susceptibility test results

Group Type: EXPERIMENTAL

IV amikacin

Intervention Type: DRUG

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

PO azithromycin

Intervention Type: DRUG

250 mg once daily

IV ceftazidime

Intervention Type: DRUG

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

PO ciprofloxacin

Intervention Type: DRUG

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

IV meropenem

Intervention Type: DRUG

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

IV piperacillin-tazobactam

Intervention Type: DRUG

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

IV ticarcillin-clavulanate

Intervention Type: DRUG

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

IV tobramycin

Intervention Type: DRUG

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

Antibiotic regimen assignment based on conventional susceptibility test results

Group Type: ACTIVE_COMPARATOR

IV amikacin

Intervention Type: DRUG

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

PO azithromycin

Intervention Type: DRUG

250 mg once daily

IV ceftazidime

Intervention Type: DRUG

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

PO ciprofloxacin

Intervention Type: DRUG

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

IV meropenem

Intervention Type: DRUG

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

IV piperacillin-tazobactam

Intervention Type: DRUG

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

IV ticarcillin-clavulanate

Intervention Type: DRUG

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

IV tobramycin

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

PO azithromycin

250 mg once daily

Intervention Type: DRUG

IV ceftazidime

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

Intervention Type: DRUG

PO ciprofloxacin

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

Intervention Type: DRUG

IV meropenem

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

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

Seattle Children's Hospital

OTHER

Sponsor Role: lead

Principal Investigators

Samuel M Moskowitz, MD

Role: PRINCIPAL_INVESTIGATOR

Seattle Children's Hospital

Jane L Burns, MD

Role: STUDY_CHAIR

Children's Hospital and Regional Medical Center

Locations

University of Iowa

Iowa City, Iowa, United States

Washington University St. Louis

St Louis, Missouri, United States

University of Cincinnati

Cincinnati, Ohio, United States

Ohio State University

Columbus, Ohio, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Baylor College of Medicine

Houston, Texas, United States

Children's Hospital and Regional Medical Center

Seattle, Washington, United States

University of Washington Medical Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 15131149 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16188918 (View on PubMed)

Other Identifiers

BURNS03A0

Identifier Type: -

Identifier Source: org_study_id