Korte versus lange behandeling met een carbapenem voor onverklaarde koorts tijdens hoog risico neutropenie bij hematologische patiënten: een gerandomiseerde non-inferiority studie.

Randomized clinical trial aimed at investigating whether the duration of empiric antibacterial therapy in patients with hematologic malignancies and unexplained neutropenic fever can be safely reduced. A multicenter randomized clinical non-inferiority trial comparing safety of short (3 days) vs extended treatment (9 or more days) with an anti-pseudomonal carbapenem for hematology patients receiving standard antimicrobial prophylaxis is proposed.

Short empirical treatment with a anti-pseudomonal carbapenem in hematology patients with unexplained fever during neutropenia is non-inferior to extended treatment with regard to treatment failure.

The investigational treatment protocol will end after any of the following events:

1. End of the neutropenic episode (ANC <0.5*109/L)

2. Diagnosis of a clinically, microbiologically documented infection after randomization.

3. In case the patient shows symptoms of septic shock (systolic blood pressure <90mm Hg unresponsive to fluid resuscitation and/or oliguria <5mL/kg/hour)

4. Death due to any cause.

5. Lack of patient compliance or withdrawal of informed consent (especially refusal to continue treatment according to protocol).

6. Major protocol violation

7. Contra-indication to administer imipenem-cilastatin or meropenem due to allergy, side effects or carbapenem-resistant microorganism(s) in a microbiological culture.

8. Recurrence of fever after defervescence after randomization.

TREATMENT:

Patients will be included in the first 3x24hours hours after the start of antibiotic treatment and will receive standard diagnostic investigations and empirical treatment with imipenem-cilastatin 500mg QID or meropenem 1000mg TID during this period. If, intensive clinical, radiological and microbiological evaluation yields no explanation for fever, patients are eligible for randomization between 2x24 hours and 3x24hours after start of empirical antibiotic treatment. Patients will be randomized into two groups.



INFORMED CONSENT AND RANDOMISATION:

Within 72hours after onset of fever every eligible patient will be asked for informed consent. Each consenting patient is then randomized to either the short treatment arm or the extended treatment arm. This will be the start of the investigational treatment protocol.



EARLY DISCONTINUATION ARM:

In the short treatment group, imipenem-cilastatin or meropenem will be discontinued after 3x24 hours irrespective of presence of fever. If fever has resolved by this time, no further action will be undertaken. If fever persists after 3x24hours, antifungal treatment with voriconazole (or anidulafungin in case of azole-resistant fungi in surveillance cultures) will then be started after 4x24 hours and will be continued until recovery of neutropenia (ANC >0.5*109/L).



EXTENDED TREATMENT ARM:

In the extended treatment arm, the duration of imipenem-cilastatin or meropenem treatment depends on the presence of fever. Patients who are afebrile after 3x24hours after appearance of fever will continue for at least 6 more days. If fever persists after 3x24hours, antifungal treatment with voriconazole (or anidulafungin in case of azole-resistant fungi in surveillance cultures) will then be started after 4x24 hours and will be continued until recovery of neutropenia (ANC >0.5*109/L). 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 <37,5°C) for at least five consecutive days or until resolution of neutropenia (ANC > 0,5 x109/L), whichever comes first.