Linezolid in the Treatment of Hemodialysis Patients With Catheter-Related Gram-Positive Bloodstream Infections

Study Overview
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Brief Summary
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This study will treat hemodialysis patients who have a central catheter that is thought to be infected with a specific bacteria (Gram positive bacteria).

Detailed Description
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Pfizer suspended enrollment on 21 August 2006 as a precautionary measure in light of the mortality imbalance seen in a similar study, and terminated the study on April 6, 2007 due to factors affecting the timeline to completion, such as slow enrollment and inclusion of sufficient evaluable subjects.

Official Title
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Linezolid vs Vancomycin/Cefazolin in the Treatment of Hemodialysis Patients With Catheter-Related Gram-Positive Bloodstream Infections

Conditions
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Bacteremia, Gram-Positive Bacterial Infections

Intervention / Treatment
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* Drug: Cefazolin IV
* Drug: Linezolid IV
* Drug: Vancomycin (IV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for this study, a patient must provide informed consent and must meet all of the following criteria. No study procedures, including any baseline tests, should be performed until the patient (or parent/legally acceptable representative, if appropriate) legally signs the informed consent form. Male or female, 18 years of age or older and >= 40 kg body weight End-stage renal disease patients on hemodialysis with: A) Signs and symptoms of a localized catheter-related infection (eg tenderness and/or pain, erythema, swelling, purulent exudates within 2 cm of entry site); OR B) A body temperature of >= 38.0 C or < 36.0 C (oral equivalent); OR C) A Gram-positive blood culture. If the Gram-positive isolate is S. aureus, it must be cultured from at least 1 culture bottle from either the peripheral set or the catheter set of culture bottles. For all other Gram-positive pathogens (eg, coagulase-negative staphylococci), isolates need to be cultured from at least 2 culture bottles of which one must be from the peripheral set. There must be no other obvious source of the bacteremia Presence of at least one of the following systemic signs of infection (may be obtained up to 24 hours prior to baseline): *Hypotension, defined as systolic blood pressure <90 mmHg or its reduction by >= 40 mmHg from the patient's baseline, in the absence of other causes for hypotension; *Tachycardia defined as a pulse rate > 90 beats per minute; *Tachypnea defined as a respiratory rate > 20 breaths per minute or PACO2 <32 torr; *White blood count >10,000 cells/mm3 or < 4,000 cells/mm3, or with a differential count showing >10% band neutrophil forms. Patients on hemodialysis with tunneled or nontunneled catheters including antibiotic coated hemodialysis catheters. Patients may have more than one concurrent catheter. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures Exclusion Criteria: Patients presenting with any of the following will not be included in this study: Catheter-related bloodstream infections caused by Gram-negative bacteria, fungi, mixed cultures of Gram negative bacteria and Gram positive bacteria or mixed cultures of Gram positive/negative bacteria and fungi Patients with evidence of other infections resulting in bacteremia, such as clinical or radiographic signs of osteomyelitis, endocarditis, skin/skin structure infection, pneumonia, urinary tract infection, joint infection, intraabdominal infection, septic thrombophlebitis or other infection Patients in whom the infected catheter cannot be removed Patients with permanent intravascular devices such as artificial vascular grafts, implantable pacemakers or defibrillators; intra-aortic balloon pumps, and left ventricular assist device; intravascular transplants such as prosthetic cardiac valves; or non-intravascular devices such as peritoneal dialysis catheters; or neurosurgical devices such as ventriculo-peritoneal shunts, intra-cranial pressure monitors, or epidural catheters, prosthetic cardiac valves, prosthetic vascular grafts, or other internal prosthesis Females of child-bearing potential who are unable or unwilling to take adequate contraceptive precautions, have a positive pregnancy result within 24 hours prior to study entry, are known to be pregnant, or are currently breastfeeding an infant Identification of a pathogen resistant to linezolid or vancomycin Patients who are unlikely to survive through the treatment period and evaluation Administration of a glycopeptide antibiotic within 5 days prior to enrollment. Administration of other potentially effective systemic Gram-positive antibiotics for more than 48 hours within 72 hours prior to enrollment unless the pathogen showed drug resistance Previous enrollment in this protocol Hypersensitivity to linezolid, vancomycin, gentamicin or one of their excipients (or aztreonam if non-bacteremic Gram-negative coverage is required) Concurrent use of another investigational medication or use within 30 days of study entry Patients with pressor and fluid-resistant hemodynamic compromise or pulmonary embolism

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Cefazolin IV|nan|
|Drug: Linezolid IV|nan|
|Drug: Vancomycin (IV)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Microbiological response assessed at participant level. Eradication = baseline isolate not present in repeat culture from the original infection site; Presumed Eradication = clinical response of cure based on Sponsor's (Sp) assessment, culture data not available for participants; Persistence = baseline isolate present in repeat culture from the original infection site; Presumed Persistence = culture data not available for participants with a clinical response of failure based on Sp assessment. | Short term follow-up (STFU) visit for TOC (2 to 3 weeks after the last dose of study medication) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Outcome Based on Sponsor's (Sp) and Investigator's (Ir) Assessment | Ir assessment Cure: clinical signs/symptoms of infection (SSx) resolved and no reoccurrence; Improvement: Moderate resolution of SSx, no additional antibiotic needed; Failure: persistence/progression of baseline SSx, new clinical findings; Indeterminate: circumstances precluding above classification. Sp assessment Failure: concomitant antibiotic after day 3 up to/including Ir assessment day at TOC/upper limit of TOC window (if no Ir assessment at TOC), no Ir assessment at end of treatment (EOT) and TOC; Indeterminate: Sp assessment cured/ improved at EOT, no Ir assessment at TOC/indeterminate. | EOT (within 72 hours after last dose of study medication), STFU visit for TOC (2 to 3 weeks after the last dose of study medication), Long term follow-up (LTFU) visit (6 to 8 weeks after the last dose of study medication) | 
| Number of Participants With Complications During Therapy | Late metastatic sequelae associated with Gram positive bacterial infections: abdominal abscess, brain abscess, meningitis, septic arthritis, osteomyelitis, endocarditis, empyema, spinal epidural abscess, intracerebral epidural abscess, septic phlebitis and septic thrombophlebitis. | LTFU visit (6 to 8 weeks after the last dose of study medication) | 
| Percentage of Pathogens Eradicated | Eradication included Documented or Presumed Eradication of the given pathogen. Percentage of pathogen eradicated was calculated as number of pathogens eradicated divided by number of pathogens eradicated or persisted multiplied by 100. | STFU visit for TOC (2 to 3 weeks after the last dose of study medication), LTFU visit (6 to 8 weeks after the last dose of study medication) | 
| Percentage of Participants With Eradication of Staphylococcus Aureus Nasal Colonization | Eradication was defined as the absence of the original baseline nasal Staphylococcus aureus isolated in nasal swab culture. | STFU visit for TOC (2 to 3 weeks after the last dose of study medication), LTFU visit (6 to 8 weeks after the last dose of study medication) |