Antifungal Locks to Treat Fungal-related Central Line Infections

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the usefulness of antifungal lock therapy with liposomal amphotericin B (Ambisome), in combination with systemic antifungal(s), in patients with catheter-related blood stream infections with fungal organisms, whose catheter has not been removed because of the continuing critical need for central line access. The primary group of potential patients will be those with intestinal insufficiency, including post-op small bowel transplant recipients. The recommendation of the Infectious Disease Society of America (IDSA) is to remove all catheters with fungal infections and treat systemically for 14 days after the last positive culture. However, in certain intestinal failure patients, removal of an infected line might significantly reduce or eliminate intravenous (IV) access and create a life threatening situation. Thus, the investigators' aim is to determine the usefulness of antifungal lock therapy in intestinal failure patients whose catheter has not been removed. The investigators' hope is to salvage central line catheters rather than to remove them.

Detailed Description
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This is a descriptive study in intestinal failure patients with catheter-related blood stream infections (CRBSI) with fungal organisms. At present, the recommendation of the Infectious Disease Society of America (IDSA) is to remove all catheters with fungal infections and treat systemically for 14 days after the last positive culture (2). However, in intestinal failure patients who have limited IV access, removal of a line infected with Candida albicans, although recommended, might significantly reduce intravenous access and create a life threatening situation. Thus, the purpose of this study is to evaluate the use of antifungal lock therapy with liposomal amphotericin B (Ambisome) in combination with systemic antifungal therapy in patients with fungal CRBSI, whose catheter has not been removed because of the continuing critical need for central line access. The research methods are as follows: Study patients will consist of in-patients hospitalized at Children's Hospital of Pittsburgh. From our intestinal failure patients followed by GI, Transplant, and Pediatric Surgical Services, we plan to enroll 25 patients. In addition, other patients with similar concerns regarding limited central venous access with catheter-related candidal bloodstream infection may also be considered for this protocol. The primary group of potential patients in the study will be patients with intestinal insufficiency, including post-op small bowel recipients, whose intravenous access is limited. Thus, when a fungal CRBSI is suspected, retention of the CVC will be highly desirable. Additional subjects potentially eligible for this study would include children with cancer, those status-post bone marrow transplant, etc. who have limited central venous access and have a documented catheter-related bloodstream infection secondary to candida. Once the fungal infection is established, the patient will be approached to participate in the study. The investigator(s) will fully explain the study and its benefits and risks to the patient and/or parent or guardian (if legally appointed for research) and consent and assent will be obtained. Upon enrollment, antifungal therapy will be instituted consisting of both systemic and antifungal lock therapy. A. Ambisome at a dose of 3-5 mg/kg/day (or other appropriate antifungal based upon standard of care) will be administered intravenously B. Antifungal lock therapy with Ambisome will be administered. It consists of the placing up to 2.3 ml (based upon specific catheter types and volumes) of concentrated Ambisome into the infected CVC and allowing it to dwell uninterruptedly for 8 to 12 hours per day. The concentration of Ambisome is 2 mg/ml in sterile water (4). Patients enrolled in the study will receive routine clinical care as in-patients of CHP and be monitored appropriately from an infectious disease perspective including daily blood cultures. Patients will be examined clinically for evidence of fungal-related complications (e.g., septic arthritis, endocarditis, etc.). The duration of antifungal lock therapy (in addition to IV systemic antifungal therapy) will be 10-14 days. After 5 days of antifungal lock therapy, the patient with a persistently positive fungal blood culture will be deemed a failure and antifungal lock therapy will be discontinued. There will be no further antifungal lock therapy permissible via this protocol and data collection for the patient will be completed as soon as possible. The primary service will be responsible for the removal of the line. With successful lock therapy, additional blood cultures through the catheter will be obtained on day 5 and day 30 (or later if subject is still on systemic antifungal agents) post antifungal lock for a test of cure. If a patient has a recurrence of fungal infection on culture on day 5 or day 30 post antifungal lock, pulse field gel electrophoresis will be performed on both the original and new isolate to determine if the fungal organism is the same. If the organism is the same based upon electrophoretic analysis, treatment will be deemed a failure If the organism is not the same, then another source for the infection will be investigated. Since the standard of care would have been to remove the CVC, the primary end point of the study will be the number and percent of patients who successfully received antifungal lock therapy, i.e., those patients with at least 2 negative fungal cultures before the completion of 5 days of antifungal lock therapy and whose CVCs were not removed. Secondary endpoints will include the number of days before the cultures become negative; the development of fungal-related complications (e.g., septic arthritis, endocarditis, etc.); and the development of recurrent candidemia on day 5 and day 30 post antifungal lock therapy. When medically appropriate, subjects may be discharged to complete their Ambisome® lock therapy at home. Instructions/training on how to administer lock therapy will be provided to the parents, guardian, or subject and contact with the research coordinator will be maintained while the patient is at home. A patient registry will be established and offered to all subjects with central line fungal infections treated with Ambisome® locks.

Official Title
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The Use of Antifungal Lock Therapy in Intestinal Failure and Other Patients

Conditions
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Central Line Fungal Infections

Intervention / Treatment
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* Drug: amphotericin B liposomal (Ambisome)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with intestinal insufficiency and central venous access. Culture positive fungal-related CRBSI. Females of childbearing potential will be eligible for the study. Ambisome carries a category B Pregnancy Risk Factor. Since this is a minimal pregnancy risk category, no special precautions will be taken to determine that the patient is not pregnant. HIV serostatus will not be determined for the purpose of participating in this study. Exclusion Criteria: Patients less than 30 days of age Patients greater than 21 years of age

Ages Eligible for Study
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Minimum Age: 30 Days
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antifungal lock-treated patients<br>Intestinal failure and other patients with poor IV access and central line fungal-related infections will receive intravenous systemic antifungal therapy plus the instillation of Ambisome locks into the infected catheter. | Drug: amphotericin B liposomal (Ambisome)<br>* After enrollment, antifungal therapy will be instituted consisting of both systemic and antifungal lock therapy. Systemic therapy will be amphotericin B liposomal (Ambisome) administered IV in a dose of 3-5 mg/kg/day (or other antifungal based upon standard of care) combined with antifungal lock therapy. The antifungal lock therapy consists of placing sufficient amphotericin B liposomal (Ambisome [2 mg/ml]) lock solution into the infected central venous catheter (CVC) and allowing it to dwell uninterruptedly for 8 to 12 hours per day for 10-14 days (largest CVC = 2.3 mL).<br>* Other names: Ambisome;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With 2 Negative Fungal Cultures After 5 Days of Combined Systemic Antifungal and Antifungal Lock Therapy and the CVC Was Not Removed | Records the number of patients with 2 negative fungal cultures after 5 days of combined systemic antifungal and antifungal lock therapy and the CVC was not removed | 5 days of antifungal lock treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Days Before the Infected Central Line Culture Becomes Negative | Records the mean number of days required for the cultures to become negative | 5 days of antifungal lock treatment | 
| The Development of Fungal-related Complications | Records the number of fungal related adverse complications that occurred | Usually 1-28 days | 
| Number of Participants With Negative Cultures on Day 5 and Day 30 During the Test of Cure Period Post Antifungal Lock | Records the number of participants with 2 negative cultures who completed the trial and had (-) test of cure cultures on day 5 and 30 | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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central line fungal infections, antifungal lock therapy, Ambisome lock therapy