Study of Concentration and Antimicrobial Activity of Antibiotics Used for Catheter-Related Infections (CONAN)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Clinica Universidad de Navarra, Universidad de Navarra
Sponsor:
Collaborator:
University of Navarrra Hospital (Clinica Universitaria)
Information provided by (Responsible Party):
José Luis del Pozo, Clinica Universidad de Navarra, Universidad de Navarra
ClinicalTrials.gov Identifier:
NCT01592032
First received: April 24, 2012
Last updated: December 17, 2013
Last verified: December 2013
  Purpose

The antibiotic lock technique (ALT) is used as local treatment for Catheter-Related Bacteremia (CRB). It consists in the administration of a concentrated antibiotic solution with a calculated volume to fill the lumen of the catheter, avoiding the antibiotic to reach the systemic circulation. The lock solution is left inside of the catheter for a defined period of hours or days before been removed. This technique exposes the intraluminal catheter surface to high concentrations of an antibiotic that could penetrate into the biofilm and therefore, achieve bacterial eradication. It has been demonstrated that the concentrations of antibiotic required to destroy sessile bacteria embedded in biofilm have to be 100 to 1000 times the concentration used to destroy planktonic bacteria.

There is controversy regarding the compatibility between the in vitro and in vivo activity of heparin alone or in combination with some antibiotics in lock solutions. At present, the Infectious Diseases Society of America (IDSA) Guidelines for treatment and management of CRB, recommend to change the antibiotic solution every 24 hours from the beginning of the lock technique in a B-II evidence level.

Justification of the Study: The investigators expect to determine the stability of the concentration of vancomycin, teicoplanin, linezolid, daptomycin and tigecycline used in lock solutions, and to probe the maximal time that the concentration of antibiotic used in lock solution keeps its in vivo antimicrobial activity.

The results could optimize the current recommendation for antibiotic lock protocol, maintaining equal therapeutic efficacy than the daily lock technique, identifying the more stable and antimicrobial antibiotic against gram positive cocci, improving the quality of medical assistance by decreasing the manipulation of the port, the risk of complications, the length of hospitalization or attendance to Day Hospital Clinic for treatment of CRB, and to reduce the sanitary economical burden associated.

Study Hypothesis: An antibiotic lock solution maintains in vivo stability, concentration and antimicrobial activity for at least 10 days after its infusion inside a subcutaneous port catheter.


Condition Intervention Phase
Catheter-related Bloodstream Infection.
Bacteremia.
Drug: Administration of vancomycin in antibiotic lock solution
Drug: Administration of teicoplanin in antibiotic lock solution
Drug: Administration of linezolid in antibiotic lock solution
Drug: Administration of daptomycin in antibiotic lock solution
Drug: Administration of tigecycline in antibiotic lock solution
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Concentration and Antibiotic Activity in Antibiotic Lock Solutions

Resource links provided by NLM:


Further study details as provided by Clinica Universidad de Navarra, Universidad de Navarra:

Primary Outcome Measures:
  • Antibiotic concentration in catheter-lock solutions at the end of day 1. [ Time Frame: 1 day ] [ Designated as safety issue: Yes ]
    25 patients will be randomized in groups of 5 patients. The groups are vancomycin, teicoplanin, linezolid, daptomycin and tigecycline. At the end of day 1 the concentration of vancomycin, teicoplanin and daptomycin will be performed by HPLC. The concentration of linezolid and tigecycline will be assessed by liquid chromatography-mass spectrometry (LC-MS). The cutt-off value for antibiotic media concentration in each randomized group is 1mg/ml. A confirmed antibiotic concentration media value >1mg/ml will allow continuing with next 25 patients to be randomized for 3 days of catheter lock. Any of the arms will be interrupted if <1mg/ml.

  • Antibiotic concentration in catheter-lock solutions at the end of day 3. [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]
    The arms that achieved >1mg/ml of antibiotic media concentration will continue with the catheter-lock (CL). Another 25 patients will be randomized for the same antibiotic lock solutions for 3 days. At the end of day 3 of CL, the concentration of vancomycin, teicoplanin and daptomycin will be performed by HPLC. The concentration of linezolid and tigecycline will be assessed by LC-MS. Again, a confirmed antibiotic concentration media value >1mg/ml will allow continuing with another 25 patients to be randomized for the 5 days catheter lock solution. Any of the arms will be interrupted if <1mg/ml.

  • Antibiotic concentration in catheter-lock solutions at the end of day 5. [ Time Frame: 5 days ] [ Designated as safety issue: Yes ]
    The arms that reached >1mg/ml of antibiotic media concentration in the 3 days groups will continue with a new group of 25 patients that will be randomized for the same antibiotic lock solutions for 5 days. At the end of day 5, the concentration of vancomycin, teicoplanin and daptomycin will be performed by HPLC. The concentration of linezolid and tigecycline will be assessed by LC-MS. Again, a confirmed antibiotic concentration media value >1mg/ml will allow continuing with new 25 patients to be randomized for the 7 days catheter lock solution. Any of the arms will be interrupted if <1mg/ml.

  • Antibiotic concentration in catheter-lock solutions at the end of day 7. [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    The arms with >1mg/ml of antibiotic media concentration in the 5 days groups will continue with another 25 patients that will be randomized for the same antibiotic lock solutions for 10 days. At the end of day 7, the concentration of vancomycin, teicoplanin and daptomycin will be performed by HPLC. The concentration of linezolid and tigecycline will be assessed by LC-MS. Again, a confirmed antibiotic concentration media value >1mg/ml will allow continuing with a new group of 25 patients to be randomized for the 10 days of catheter lock solution. Any of the arms will be interrupted if <1mg/ml.

  • Antibiotic concentration in catheter-lock solutions at the end of day 10. [ Time Frame: 10 days ] [ Designated as safety issue: Yes ]
    The arms with > 1mg/ml of antibiotic media concentration in the 7 days groups of catheter lock will continue with the last 25 patients that will be randomized for the same antibiotic lock solutions for 10 days. As in the previous groups, at the end of day 10, the concentration of vancomycin, teicoplanin and daptomycin will be performed by HPLC. The concentration of linezolid and tigecycline will be assessed by LC-MS. All data obtained will be registered. At this point the study will be finished.


Secondary Outcome Measures:
  • Antimicrobial activity of antibiotics in lock solutions at the end of lock time assigned. [ Time Frame: 1, 3, 5, 7, and 10 days ] [ Designated as safety issue: Yes ]
    Antibiotic antimicrobial activity will be assessed by a biological assay using an American type culture collection (ATCC) strain of Micrococcus spp. The results will show values of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill curves.

  • Anticoagulant activity of heparin in antibiotic lock solutions at the end of lock time assigned. [ Time Frame: 1, 3, 5, 7 and 10 days ] [ Designated as safety issue: Yes ]
    Anticoagulant activity of heparin will be assessed by activated partial thromboplastin time. Activated partial thromboplastin time (APPT) values are given in seconds.


Estimated Enrollment: 125
Study Start Date: May 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Vancomycin
Vancomycin antibiotic-lock solution: 10 mg vancomycin + sodium heparin 100 IU/ml + sodium chloride to reach a final volume of 5 ml. The final concentration of vancomycin in the solution is 2 mg/ml.
Drug: Administration of vancomycin in antibiotic lock solution
The patients will be randomized in 5 arms of antibiotic lock solution (ALS) (vancomycin 2 mg/ml, teicoplanin 10 mg/ml, linezolid 1,8 mg/ml, daptomycin 5 mg/ml and tigecycline 4,5 mg/ml). Each arm will be stratified in subsequent subgroups of 5 patients according to the length of time of ALS inside the port (1,3,5,7,10 days). At the end of lock time, 4 ml of the ALS will be withdrawn. The concentration of the antibiotic will be assessed by HPLC or LC-MS. The cutt-off value for antibiotic concentration is 1 mg/ml. A confirmed concentration media value > 1 mg/ml in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in case of reaching antibiotic concentration < 1 mg/ml.
Other Names:
  • vancomycin: vancomicina sala 500 mg vial.
  • sodium heparin 1%, 5000 IU/5ml.
  • sodium chloride 0,9% 10 ml vial.
Experimental: Teicoplanin
Teicoplanin antibiotic-lock solution: 50 mg teicoplanin + sodium heparin 100 IU/ml + sodium chloride to reach a final volume of 5 ml. The final concentration of teicoplanin in the solution is 10 mg/ml.
Drug: Administration of teicoplanin in antibiotic lock solution
The patients will be randomized in 5 arms of antibiotic lock solution (ALS) (vancomycin 2 mg/ml, teicoplanin 10 mg/ml, linezolid 1,8 mg/ml, daptomycin 5 mg/ml and tigecycline 4,5 mg/ml). Each arm will be stratified in subsequent subgroups of 5 patients according to the length of time of ALS inside the port (1,3,5,7,10 days). At the end of lock time, 4 ml of the ALS will be withdrawn. The concentration of the antibiotic will be assessed by HPLC or LC-MS. The cutt-off value for antibiotic concentration is 1 mg/ml. A confirmed concentration media value > 1 mg/ml in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in case of reaching antibiotic concentration < 1 mg/ml.
Other Names:
  • teicoplanin: targocid 200 mg vial.
  • sodium heparin 1%, 5000 IU/5ml.
  • sodium chloride 0,9% 10 ml vial.
Experimental: Linezolid
Linezolid antibiotic-lock solution: 9 mg of the linezolid vial + sodium heparin 100 IU/ml + sodium chloride to reach a final volume of 5 ml. The final concentration of linezolid in the solution is 1,8 mg/ml.
Drug: Administration of linezolid in antibiotic lock solution
The patients will be randomized in 5 arms of antibiotic lock solution (ALS) (vancomycin 2 mg/ml, teicoplanin 10 mg/ml, linezolid 1,8 mg/ml, daptomycin 5 mg/ml and tigecycline 4,5 mg/ml). Each arm will be stratified in subsequent subgroups of 5 patients according to the length of time of ALS inside the port (1,3,5,7,10 days). At the end of lock time, 4 ml of the ALS will be withdrawn. The concentration of the antibiotic will be assessed by HPLC or LC-MS. The cutt-off value for antibiotic concentration is 1 mg/ml. A confirmed concentration media value > 1 mg/ml in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in case of reaching antibiotic concentration < 1 mg/ml.
Other Names:
  • linezolid: zyloxid 2 mg/ml, 300 ml vial.
  • sodium heparin 1%, 5000 IU/5ml.
  • sodium chloride 0,9% 10 ml vial.
Experimental: Daptomycin
Daptomycin antibiotic-lock solution: 25 mg daptomycin + sodium heparin 100 IU/ml + lactated ringer´s solution to reach a final volume of 5 ml. The final concentration of daptomycin in the solution is 5 mg/ml.
Drug: Administration of daptomycin in antibiotic lock solution
The patients will be randomized in 5 arms of antibiotic lock solution (ALS) (vancomycin 2 mg/ml, teicoplanin 10 mg/ml, linezolid 1,8 mg/ml, daptomycin 5 mg/ml and tigecycline 4,5 mg/ml). Each arm will be stratified in subsequent subgroups of 5 patients according to the length of time of ALS inside the port (1,3,5,7,10 days). At the end of lock time, 4 ml of the ALS will be withdrawn. The concentration of the antibiotic will be assessed by HPLC or LC-MS. The cutt-off value for antibiotic concentration is 1 mg/ml. A confirmed concentration media value > 1 mg/ml in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in case of reaching antibiotic concentration < 1 mg/ml.
Other Names:
  • daptomycin: cubicin 350 mg vial.
  • sodium heparin 1%, 5000 IU/5ml.
  • lactated ringer´s solution 500 ml viaflo.
Experimental: Tigecycline
Tigecycline antibiotic-lock solution: 22,5 mg of the tigecycline vial + sodium heparin 100 IU/ml. Final volume 5 ml. The final concentration of tigecycline in the solution is 4,5 mg/ml.
Drug: Administration of tigecycline in antibiotic lock solution
The patients will be randomized in 5 arms of antibiotic lock solution (ALS) (vancomycin 2 mg/ml, teicoplanin 10 mg/ml, linezolid 1,8 mg/ml, daptomycin 5 mg/ml and tigecycline 4,5 mg/ml). Each arm will be stratified in subsequent subgroups of 5 patients according to the length of time of ALS inside the port (1,3,5,7,10 days). At the end of lock time, 4 ml of the ALS will be withdrawn. The concentration of the antibiotic will be assessed by HPLC or LC-MS. The cutt-off value for antibiotic concentration is 1 mg/ml. A confirmed concentration media value > 1 mg/ml in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in case of reaching antibiotic concentration < 1 mg/ml.
Other Names:
  • tigecycline: tygacil 50 mg vial.
  • sodium chloride 0,9% 10 ml vial.
  • sodium heparin 1%, 5000 IU/5ml.

Detailed Description:

Primary Objective: To know in vivo concentration of vancomycin, teicoplanin, linezolid, daptomycin and tigecycline in antibiotic lock solutions during the time. Secondary Objectives: 1) To define antimicrobial activity of teicoplanin, linezolid, daptomycin and tigecycline in antibiotic lock solutions and to compare them with vancomycin activity in antibiotic lock solutions against gram positive cocci. 2) To know if heparin used in the antibiotic lock solutions keeps its anticoagulant activity. Methods: Pilot clinical trial that will include 125 patients with a recently implanted intravenous access port. Patients with inclusion criteria that previously had signed the consent form, will be randomized into 5 groups (vancomycin, teicoplanin, linezolid, daptomycin and tigecycline). In each study arm, the patients will be stratified in subsequent subgroups of 5 patients according to the length of time of lock solution inside the port. At the end of each period of time assigned for lock solutions (subgroups of 1, 3, 5, 7 and 10 days) the antibiotic concentration will be determined by high precision liquid chromatography (HPLC). The cutt-off value for antibiotic media concentration is 1 mg/ml. A confirmed antibiotic concentration media value > 1 mg/ml extracted from the ports in the subgroups of 1 day lock will allow continuing with the other subgroups from 3 to 10 days. Any of the arms of the study could be interrupted any time from day 1 to day 10 in the event of reaching an antibiotic concentration < 1 mg/ml in the lock solution. If the cut-off media concentration goal is not achieved, it would not be necessary to expose more patients to prolonged periods of antibiotic lock solution.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Intravenous access port recently inserted (≤ 3 days of insertion).
  • Intravenous access port inserted more than 3 days before informed consent form signing patient. In this case, a blood sample from the catheter will be drawn for blood culture before administration of the antibiotic lock solution.
  • Informed Consent Form Signed.

Exclusion Criteria:

  • Patients with confirmed or suspected local or systemic infection related to the catheter.
  • Reported allergy or intolerance to the antibiotic employed for study lock solutions.
  • Patients receiving oral, intravenous or intramuscular antibiotic treatment at the moment of inclusion in the clinical trial.
  • Patients receiving oral, intravenous or subcutaneous anticoagulant treatment, in a higher dose than the one used for venous thrombosis prophylaxis at the moment of inclusion in the clinical trial.
  • Patients younger than 18 years old.
  • Pregnant women or women in nursing period.
  • Personal incapacity to subscribe the informed consent to participate in the clinical trial.

Patient Replacement Criteria:

All patients and/or their legal representatives will be inform that they can leave the clinical trial in whenever they wish to do it, without prejudice to their medical attention.

Also, according to the criteria of the principal investigator, a patient could be separated from the clinical trial. The reasons to separate a patient from the study and replace him/her are:

  • Severe adverse reaction that could threat the life of the patient.
  • Resolution of the patient or from his/her legal representative to abandon the study.
  • No attend to the extraction visit date.
  • Development of clinical inconveniences that may indicate to abandon the study in behalf of the patient.
  • While antibiotic lock solution is within the port, manipulation or use of the port for administration of any kind of medication or fluid.
  • Impossibility to extract 4 ml of the antibiotic lock solution from the port.
  • Impossibility to extract 5 ml of peripheral blood sample at the moment of extraction of the antibiotic lock solution.
  • Use of any of the prohibited medications during the antibiotic lock solution is inside the port.
  • Intentionally wish of the patient in abandoning the study before or after antibiotic lock solution has been administered, or while the antibiotic lock solution is inside the port.

All patients who abandon the study or would be separated from the study for the exposed reasons, will be replaced for new candidates who fulfil the inclusion criteria and have signed the informed consent form.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01592032

Contacts
Contact: JOSE L DEL POZO, MD, Ph. D. 34948255400 ext 5117 jldelpozo@unav.es
Contact: CESAR E BUSTOS, MD 34948255400 ext 5113 cbustos@unav.es

Locations
Spain
Clinica Universidad de Navarra Recruiting
Pamplona, Navarra, Spain, 31008
Contact: JOSE L DEL POZO, MD, Ph.D.    +34948255400 ext 5117    jldelpozo@unav.es   
Contact: CESAR E BUSTOS, MD    +34948255400 ext 5113    cbustos@unav.es   
Principal Investigator: JOSE L DEL POZO, MD. PhD.         
Sub-Investigator: CESAR E BUSTOS, MD         
Sub-Investigator: AITZIBER AGUINAGA, Pharm. D.         
Sub-Investigator: JOSE R YUSTE, MD. PhD.         
Sub-Investigator: JOSE R AZANZA, MD. PhD.         
Sponsors and Collaborators
Clinica Universidad de Navarra, Universidad de Navarra
University of Navarrra Hospital (Clinica Universitaria)
Investigators
Principal Investigator: JOSE L DEL POZO, MD. Ph. D. Clinica Universidad de Navarra
Study Chair: CESAR E BUSTOS, MD. Clinica Universidad de Navarra
Study Chair: AITZIBER AGUINAGA, Pharm. D. Clinica Universidad de Navarra
Study Chair: JOSE R YUSTE, MD. Ph.D. Clinica Universidad de Navarra
Study Chair: JOSE R AZANZA, MD. Ph.D. Clinica Universidad de Navarra
  More Information

Publications:

Responsible Party: José Luis del Pozo, Medical Doctor, Ph. D., Clinica Universidad de Navarra, Universidad de Navarra
ClinicalTrials.gov Identifier: NCT01592032     History of Changes
Other Study ID Numbers: CAS110775, 2010-023814-29
Study First Received: April 24, 2012
Last Updated: December 17, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Clinica Universidad de Navarra, Universidad de Navarra:
Antibiotic-lock technique.
In vivo antibiotic concentration.
Antimicrobial activity.

Additional relevant MeSH terms:
Infection
Communicable Diseases
Bacteremia
Catheter-Related Infections
Bacterial Infections
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Pharmaceutical Solutions
Anti-Bacterial Agents
Vancomycin
Daptomycin
Tigecycline
Minocycline
Teicoplanin
Antibiotics, Antitubercular
Calcium heparin
Heparin
Linezolid
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Anticoagulants
Hematologic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on September 18, 2014