In this episode, I’ll discuss the safety of early antibiotic discontinuation in hematology patients with fever of unknown origin during chemotherapy-induced neutropenia.
The occurrence of fever is very common in patients undergoing intensive chemotherapy treatment for malignant hematological disease. Because these patients are also prone to severe bacterial infection, broad-spectrum antibiotic therapy is instituted when fever first occurs, regardless if there are other signs of infection.
Such scenarios are prime targets for antimicrobial stewardship as empiric therapy for these patients often involves giving carbapenems or fourth-generation anti-pseudomonal cephalosporins for a week or longer.
Observational and retrospective studies have suggested that early discontinuation of antibiotics in select patients appears safe, but Cochrane reviews have called for more randomized trial data before a strong conclusion can be drawn.
Recently published in Lancet was a non-inferiority, open-label, multicentre, randomized trial that sought to clarify the safety of early antibiotic discontinuation in hematology patients with fever of unknown origin during chemotherapy-induced neutropenia.
The study population was comprised of just under 300 patients who were being treated for fever of unknown origin during high-risk neutropenia after receiving intensive chemotherapy or hematopoietic stem-cell transplantation (HSCT) for hematological malignancy.
All patients started out receiving either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Sometime after 48 to 72 hours of therapy, patients were randomized to early discontinuation after 72 hours of antibiotics or extended treatment where the carbapenem was continued for at least 9 days and until being afebrile for 5 days or neutrophil recovery.
The primary endpoint was a composite of treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was set up to look for non-inferiority of early discontinuation vs extended treatment.
In both the intent-to-treat and per-protocol analyses, the rate of the composite outcome was similar between groups and were well within the pre-specified non-inferiority margin of 10%.
The authors concluded:
Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistently febrile in the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating.
The findings of the secondary analysis regarding mortality and adverse events will make implementing early discontinuation from a stewardship perspective challenging, as continued vigilance and monitoring are needed.
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