Early discontinuation of antibiotics has been recommended in hematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety has been debated. A recent study1 provides clarity.
This non-inferiority, open-label, multicenter, randomized study was conducted in six hospitals in the Netherlands. Adult patients (≥ 18 years) treated with intensive chemotherapy or haematopoietic stem cell transplantation (HSCT) for a haematological malignancy, and who had fever of unknown origin during high-risk neutropenia (<0.5 × 109/L expected for ≥ 7 days) were eligible. After the onset of fever, patients received 500 mg intravenous imipenem-cilastatin four times daily or 1000 mg intravenous meropenem three times daily. Between 48 hours and 72 hours of treatment, participants were randomly (1:1) assigned to a short-term (72 hours [60-84]; short treatment group) or extended term (≥9 days to fever for 5 days or recovery of neutrophils; extended treatment group) to receive a carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or 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 designed to assess the non-inferiority of the short treatment compared to the comprehensive treatment, with a non-inferiority margin of 10%.
Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not increase treatment failure. This study supports short-term treatment if patients have a fever after 3 days of carbapenem treatment. However, because secondary analyzes suggested that serious adverse events and all-cause mortality were more frequent in patients with persistent fever in the short-term treatment group, vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who deteriorate is warranted.
Comment Nick de Jonge, hematologist, Amsterdam UMC
“Hematology patients with fever are given a lot of antibiotics because of the risk of serious infections. However, there is a lot of attention for the possibility of stopping this earlier, because no infection is seen in a third to half of the cases. This prevents unnecessary antibiotic administration and resistance. In many hospitals, stopping earlier is already the standard. And this study supports the idea that it can be done safely. We have even gone a step further than the European ECIL4 guideline, by stopping in its stop arm after three days regardless of the presence of fever. This was also done in an earlier Rotterdam retrospective study in 2009, and it turned out to be safe there too. However, we felt it was important to confirm this outcome in a randomized trial.
Antibiotic culture
Beforehand, we conducted a survey among colleagues: half of the hospitals stopped taking carbapenem after three days, the other half only after nine days. It was striking that due to antibiotic culture in various centers there was reluctance among hematologists to implement the other treatment: many colleagues were convinced that they were right. A perfect subject for a study.
Unexpected outcome
Stopping after three days was found to be safe, but we did see that patients who still had a fever at the time and who were receiving stem cell therapy scored worse in terms of adverse events and all-cause mortality, but not infections. This was unrelated to the infection. We were unable to explain the reason for this unexpected outcome on the basis of the data. An unproven hypothesis is that the patient is more likely to go back to antibiotic prophylaxis, which disrupts the microbiome. In these cases, too, we find it acceptable to stop earlier, but with the advice that intensive diagnostics should be carried out in the event of persistent fever and that the antibiotic spectrum should be broadened in unstable patients. Our study results can be directly applied in Dutch practice and contribute to reducing the use of reserve antibiotics.”
Bron:
De Jonge N, Sikkens J, Zweegman S, et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open label, multicentre, randomized trial. Lancet Haematol. 2022;S2352-3026(22)00145-4.
–
