Early de-escalation of antibiotics in febrile neutropenia: not so fast?

A fixed, short duration of three days antimicrobial therapy rather than extended treatment is feasible in patients with haematological malignancy and unexplained fever during chemotherapy-induced neutropenia.

An open-label clinical trial randomised 292 adult inpatients with high-risk neutropenia and new onset fever during intensive chemotherapy or HSCT to either the fixed 3-day of a carbapenum or 9-14 day extended treatment.

In the short treatment group, the carbapenem was discontinued at 72 hours irrespective of the presence of fever. In the extended treatment group, the carbapenem was continued until neutrophil recovery (≥0·5 × 10⁹/L) or a total treatment duration of 216 hrs, whichever came first. If the participant was not afebrile for 5 consecutive days at day 9, treatment duration was extended until the criterion was met, up to a maximum of 14 days.

The study, published in Lancet Haematology, found treatment failure such as fever recurrence occurred in 19% of the short treatment group and in 15% of the extended treatment group (adjusted risk difference [ARD)] 4·0% [90% CI –1·7% to 9·7%]; p=0·25), meeting the criteria for non inferiority.

The reasons for recurrent fever were mostly unknown (83%), pneumonia (12%) and Gram-negative bacteraemia (5%).

The researchers said restrictive antimicrobial use has several advantages.

“Prolonged exposure to antibiotics in particular drives the development of antimicrobial resistance and selection of resistant microorganisms, which are often more difficult to treat with an increased risk of complications,” they said.

However they noted a higher rate of all serious adverse events (16% v 10%; p<0.0001) including higher rates of unanticipated readmissions (12% v 7%; p<0.006) and a higher mortality rate (3% v 1%; p<0.0001) in the short duration group.

“The higher rate of serious adverse events and the higher overall and infection related mortality after neutrophil recovery in the short treatment group is a concerning and not well understood finding that could prevent a safe introduction of short term treatment in general practice.”

“Therefore, we do not recommend this strategy in patients with ongoing fever after 3 days of empirical antibiotic therapy.”

“However, mortality and other serious adverse events generally occurred late, after the end of neutropenia, and were not judged to be directly caused by infections with carbapenem susceptible bacteria, but rather by progressive leukaemia, candidaemia, and complications of intestinal mucositis.”

A Comment article in the journal by Dr Benjamin Teh said while shorter courses of broad-spectrum antibiotics for neutropenic fever were supported by an increasing amount of evidence, adoption in clinical practice remained poor.

“Only 40–50% of cancer centres have protocols in place for de-escalation or cessation of antibiotics and resolution of fever for at least 48 h is the most common clinical threshold used,” he said.

Dr Teh, from the department of infectious diseases at the Peter MacCallum Cancer Centre, said patients at low risk for complications from neutropenic fever would benefit most from early cessation of antibiotic therapy.

“In combination with fever resolution, this will enhance clinical confidence for early antibiotic cessation.”

“New research incorporating the use of immune profiles, biomarkers, and rapid diagnostic assays will advance personalised use of shorter courses of antibiotic therapy for the management of neutropenic fever,” he said.

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