Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With FUO

Study Overview
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Brief Summary
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A multicenter open-label non-inferiority randomized clinical trial comparing the safety (non-inferiority) of short antibiotic treatment (72 hours) with an anti-pseudomonal carbapenem with regard to treatment failure in comparison with extended treatment (at least 9 days) of high-risk febrile neutropenia in hematology patients receiving standard antimicrobial prophylaxis.

Detailed Description
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Episodes of fever are very common in patients undergoing intensive chemotherapy treatment for malignant hematological disease. More than 80% of patients experience one or more episodes of fever after their first cycle of chemotherapy. Only 20-30% of these patients have a clinically documented focus and mostly include infections of skin, intestinal tract and lung, while at most 10-25% of these patients have microbiologically proven bacteremia during these episodes. Patients with malignant hematological diseases and intensive chemotherapy induced neutropenia are extremely prone to overwhelming bacterial infections. Therefore, empirical antibiotic treatment is initiated at the first occurrence of fever, even if no apparent cause for the fever is evident. Most protocols advice treatment with very broad-spectrum antibiotics, mostly anti-pseudomonal carbapenems or fourth generation anti-pseudomonal cephalosporins. Prolonged continuation of treatment may induce bacterial resistance. In view of the possible emergence of bacterial resistance due to prolonged antibiotic administration, continuation until recovery of neutropenia is suboptimal because it is costly because of longer hospital admissions, higher antibiotics costs and more possible adverse reactions. Recent observational data (Slobbe et al) has showed that in adult hematological patients with febrile neutropenia, discontinuation of empiric antibacterial therapy after three days can be safe if no infectious etiology can be found, even in cases with persistent fever. However no RCT has hitherto been performed to support this observational data. This study compares the safety (non-inferiority) of short treatment (72 hours) versus extended treatment (at least 9 days) with an anti-pseudomonal carbapenem for hematology patients with unexplained high risk febrile neutropenia. We hypothesize that a more restrictive use of broad-spectrum antibiotic use of three days in unexplained fever in neutropenic hematology patients is non-inferior to the present extended use during at least 9 days which would lead to a more restrictive use of antibiotics and less multiresistant strains of bacteria, costs and hospitalization length in the future.

Official Title
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Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With Fever of Unknown Origin: a Randomized Multicenter Non-inferiority Trial.

Conditions
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Febrile Neutropenia, Hematological Malignancy

Intervention / Treatment
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* Drug: Discontinuation of imipenem-cilastatin or meropenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with malignant hematological diseases being treated with cytotoxic chemotherapy or stem cell transplantation; High-risk neutropenia (Absolute neutrophil count (ANC) <0.5x109/L which is expected to last longer than 7 days); Fever (One single measured tympanic membrane temperature of >38.5°C or a temperature of >38.0°C during 2 subsequent measurements separated by at least 2 hours); Age 18 years or older; Written informed consent. Exclusion Criteria: Contraindications to use of imipenem-cilastatin or meropenem such as allergy, previous severe side-effects or previous microbiological cultures with carbapenem-resistant microorganism(s). Corticosteroid use ≥10 mg per day prednisolone or equivalent for more than 3 consecutive day during the previous 7 days. Clinically or microbiologically documented infection. Symptoms of septic shock (systolic blood pressure <90 mm Hg unresponsive to fluid resuscitation and/or oliguria (urine production <500mL/day). Previous enrollment in this study during the same episode of neutropenia. Any critical illness for which Intensive Care Unit treatment is required. Legal incompetency

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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Short treatment<br>Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever. | Drug: Discontinuation of imipenem-cilastatin or meropenem<br>* Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.<br>* Other names: tienam (imipenem-cilastatin);|
| No Intervention: Extended treatment<br>Extended treatment with imipenem-cilastatin or meropenem for at least 6 more days. The treatment with a carbapenem will be continued until patients have been treated for at least 9x24 hours and have been afebrile (tympanic membrane temperature <38.0°C) for at least five consecutive days or until resolution of neutropenia (ANC > 0,5 x10^9/L), whichever comes first. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients with failed treatment | Treatment failure is defined as the occurrence of one of the following events after 3x24 hours and before 9x24hours after treatment initiation with a carbapenem: -A clinically or microbiologically documented carbapenem-sensitive infection; treatment. Recurrence of fever after previous defervescence (tympanic temperature <38.0 °C during 24 hours) which is not attributable to administration of a blood product or to a drug reaction. o In case of clinical doubt whether the fever is of infectious etiology, the recurrence of fever will be considered as failure. | Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation) | 
| Death/ARDS or Septic shock | The occurrence of death, ARDS/respiratory insufficiency, septic shock (systolic blood pressure <90 mmHg and oliguria <500 mL/day) due to any cause. | From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality. |  | 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia | 
| Infection-related mortality. |  | 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia | 
| The length of hospitalization in days. |  | From admission until discharge, with an estimated average of 4 weeks | 
| Treatment strategy failure | Treatment strategy failure is defined as occurrence of any of the following events after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode: Any clinically or microbiologically documented infection. The recurrence of fever after previous defervescence during neutropenia. Death, septic shock or ARDS/respiratory failure due to any cause Adverse drug-related events due to a carbapenem requiring (temporary) interruption of treatment, including but not exclusively: liver and kidney dysfunction, convulsion and allergic reactions. Unexpected re-admission within 30 days after discharge other than for planned chemotherapy or other elective treatment. Antibiotic or antifungal treatment within 30days after discharge other than standard antibiotic prophylaxis. | after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode | 
| The total number of febrile episodes during neutropenia. |  | From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days | 
| Time to defervescence | Fever is defined as one single measured tympanic membrane temperature of >38.5°C or a temperature of >38.0°C during 2 subsequent measurements separated by at least 2 hours. Defervescence is defined as three times a tympanic membrane temperature <37.5 °C with a minimal measurement interval of at least 8 hours | Onset of fever until defervenscence, an expected average of 5 days. | 
| Incidence and prevalence of Clostridium difficile infection |  | Onset of fever until 30 days after the end of neutropenia. | 
| Candida spp. colonization in (surveillance) cultures |  | From onset of fever until 30 days after the end of neutropenia. | 
| Cost of antimicrobial therapy per admission |  | From admission until discharge, with an estimated average of 4 weeks | 
| The percentage of patients with a MASCC-score≥21 and treatment failure (defined as in primary endpoint) |  | From the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days. | 
| The percentage of patients with mucositis and positive blood cultures or short treatment failure. |  | From onset of fever until 30 days after end of neutropenia. | 
| Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)). |  | All previous cultures and cultures performed until 30 days after the end of neutropenia. | 
| The incidence and prevalence of fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia |  | om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days. | 
| Late treatment failure | Defined as primary endpoint. | Between 9x24hours and 14x24hours after onset of treatment with a carbapemen. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fever, neutropenia, febrile neutropenia, carbapenem, imipenem, meropenem, antibiotic stewardship, hematology, oncology