Pharmacokinetics of Vancomycin for Inhalation in Cystic Fibrosis

The purpose of this study is to determine the pharmacokinetics and safety of inhaled vancomycin in patients with cystic fibrosis.

Study Overview

• Status: Withdrawn
• Conditions: Cystic Fibrosis; Methicillin-resistant Staphylococcus Aureus
• Intervention / Treatment: Drug: Vancomycin

Detailed Description

The prevalence of methicillin resistant Staphylococcus aureus (MRSA) respiratory infection in patients with cystic fibrosis has increased dramatically over the last decade. Epidemiologic evidence suggests that persistent infection with MRSA may result in an increased rate of decline in FEV1 and shortened survival. Treatment of MRSA is a top priority. Inhaled antibiotics offer the advantage of high concentrations of antibiotic at the site of infection (the airway) while minimizing systemic side effects. Vancomycin is a glycopeptide antibiotic that has activity against MRSA. Anecdotal and retrospective peer-reviewed studies have demonstrated that inhaled vancomycin is safe and potentially effective in patients with cystic fibrosis and MRSA airway infection. Data evaluating the pharmacokinetics of vancomycin in sputum are needed before pursuing treatment trials.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital, Univeristy Hospitals Case Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female ≥ 18 years of age.

• Confirmed diagnosis of CF based on the following criteria:

  • positive sweat chloride > 60 mEq/liter (by pilocarpine iontophoresis) and/or
  • a genotype with two identifiable mutations consistent with CF or abnormal NPD, and
  • one or more clinical features consistent with the CF phenotype.
• Chronic sputum producer able to spontaneously produce sputum
• FEV1 > 40% of predicted normal for age, gender, and height
• Previous use of any inhaled antibiotics within the last year
• Ability to provide written informed consent
• Ability to adhere to the protocol

Exclusion Criteria:

• Use of inhaled or intravenous vancomycin within two weeks of the study visit
• Known history of intolerance to inhaled vancomycin or inhaled albuterol.
• Known history of hypersensitivity to vancomycin or other glycopeptide antibiotics
• History of sputum culture with Burkholderia cepacia complex in the last two years.
• Pregnancy
• Woman who are lactating and not willing to stop nursing on the day of the study visit and the subsequent 48 hours.
• Current use of oral corticosteroids in doses exceeding the equivalent of 10mg of prednisone a day or 20mg of prednisone every other day.
• Patients not willing to hold other inhaled antibiotics (for example TOBI, Cayston, or Colistin) for at least 2 days prior to the study visit.
• Patients not willing to hold loop diuretics (i.e. furosemide, torsemide, ethacrynic acid) on the morning of the study visit.
• History of ABPA or reactive airways disease that has required treatment within the last year.
• Creatinine greater than 2.0 mg/dL within the last year.
• Oxygen saturation ≤ 92% on room air.
• History of patient reported hearing loss
• Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment, or adherence to the protocol.
• History of or listed for solid organ or hematological transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vancomycin for Inhalation; 250 mg vancomycin in 5cc sterile water will be inhaled once. Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system.	Drug: Vancomycin; 250 mg vancomycin in 5cc sterile water will be inhaled once. Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system.; Other Names: Nebulized vancomycin; Inhaled Vancomycin; Vancomycin for inhalation; Aerosolized Vancomycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Curve (AUC)	Pharmacokinetic analysis will be performed with non-compartmental methods. The area under the curve for sputum vancomycin will be determined.	Predose, 5 minutes, one hour, 2 hours, and 6 hours after completion of 250mg of inhaled vancomycin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1% Predicted	Change in FEV1% predicted from baseline to 30 minutes after completion of inhaled vancomycin	30 minutes
Change in Patient Symptoms	Patient's respiratory symptoms and potential side effects from inhaling vancomycin will be queried using a questionnaire prior to inhaling vancomycin, at 15 ±10 minutes, and 4 ± 1 hour after completing inhaled vancomycin.	6 hours
Change in Sputum Cell Counts	Change in sputum cell counts (i.e. eosinophils) between baseline and six hours after completion of inhaled vancomycin.	6 hours
Serum Vancomycin Peak Concentration	Serum vancomycin peak concentration 60 minutes after completion of inhaled vancomycin.	60 minutes
Oxygen Saturation	Continuous oxygen saturation monitoring to be continued throughout vancomycin inhalation and for 5 minutes after inhalation	5 minutes
Adverse Events	Information regarding occurrence of adverse events will be captured throughout the study. Duration (start and stop times), severity/grade, outcome, treatment and relation to study medication will be recorded	6 hours
Maximum Concentration	Pharmacokinetic analysis will be performed with non-compartmental methods. The maximum concentration of sputum vancomycin will be determined.	Predose, 5 minutes, one hour, 2 hours, and 6 hours after completion of 250mg of inhaled vancomycin
Time to Peak Concentration	Pharmacokinetic analysis will be performed with non-compartmental methods. The time to peak concentration for sputum vancomycin will be determined.	Predose, 5 minutes, one hour, 2 hours, and 6 hours after completion of 250mg of inhaled vancomycin

Collaborators and Investigators

• Sponsor: Case Western Reserve University
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Elliott C Dasenbrook, MD MHS, Case Western Reserve University School of Medicine

Publications and helpful links

General Publications

• Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010 Jun 16;303(23):2386-92. doi: 10.1001/jama.2010.791.
• Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med. 2008 Oct 15;178(8):814-21. doi: 10.1164/rccm.200802-327OC. Epub 2008 Jul 31.
• Dasenbrook EC. Update on methicillin-resistant Staphylococcus aureus in cystic fibrosis. Curr Opin Pulm Med. 2011 Nov;17(6):437-41. doi: 10.1097/MCP.0b013e32834b95ed.
• Doe SJ, McSorley A, Isalska B, Kearns AM, Bright-Thomas R, Brennan AL, Webb AK, Jones AM. Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis centres. J Cyst Fibros. 2010 Mar;9(2):104-9. doi: 10.1016/j.jcf.2009.11.009. Epub 2010 Jan 3.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2012
• Primary Completion (Actual): December 23, 2021
• Study Completion (Actual): December 23, 2021

Study Registration Dates

• First Submitted: January 9, 2012
• First Submitted That Met QC Criteria: January 10, 2012
• First Posted (Estimate): January 13, 2012

Study Record Updates

• Last Update Posted (Actual): January 12, 2022
• Last Update Submitted That Met QC Criteria: December 23, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Vancomycin; Pharmacokinetics; Inhalation; Nebulization
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Respiratory Aspiration; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: iVCM 1.0

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No