Blood cancers

Caution on aminoglycoside use after study shows increase risk in kids with febrile neutropenia

National guidelines are needed for the management of paediatric febrile neutropenia (FN), according to the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study group.

The call follows a study of aminoglycoside use in children with febrile neutropenia which challenges the empiric use of this class of antibiotics and the variation in hospital-and state-based recommendations.

The study comprised 858 episodes of neutropenia in 462 children with haematological or solid cancers recruited between 2016 and 2018 from across Australia’s eight tertiary paediatric hospitals.

All children had fevers >38.0 C and absolute neutrophil counts (ANC) <1,000 cells/mm3 – 90% were below <500 cells/mm3 – and their median age was 5.8 years.

A total of 255 aminoglycoside prescriptions, mostly amikacin (55%) and gentamicin (41.1%), were recorded. Dosing was based on the local guidelines and ranged from 6–7.5 mg/kg/dose 24 hourly for gentamicin, depending on age and hospital, and 18–22.5 mg/kg/dose 24-hourly for amikacin, depending on age.

Piperacillin-tazobactam was the most commonly prescribed antibiotic overall (60.5%) followed by ceftazidime (24.4%) and flucloxacillin (17.5%).

The observational study, published in PLOS ONE, found aminoglycoside use was associated with unfavourable outcomes.

“The adjusted hazard of the composite unfavourable outcome was 3.81 times higher among patients prescribed empiric aminoglycosides than among those who were not (95% confidence interval, 1.89–7.67),” the study said.

“When individual endpoints among composite outcome were assessed, those prescribed aminoglycosides were more likely to have ICU admission (17/255 vs 7/596; OR 6.08, 95% CI 2.35–17.3) whereas late-onset sepsis, relapse of infection and death were not significantly different, though numbers were small.”

“In those prescribed an aminoglycoside, median hospital length of stay was longer: 10.6 days (IQR 5.6–19.1 days) compared with 4.7 days (IQR 2.7–9.1 days, p = 0.0001).”

The study team said use of aminoglycosides as combination therapy in FN remains controversial, in both adults and children.

Just under half of the children (46.5%) who qualified for aminoglycoside therapy according to local guidelines actually received it – likely reflecting some concern about toxicity or lack of efficacy of the agents compared to β-lactam monotherapy.

The study said their findings provide evidence “against liberal empiric use of aminoglycosides as combination therapy for treatment of FN in an Australian or other low-resistance setting.”

“Further efforts should be directed towards standardising recommendations for paediatric FN nationally, establishing the role for empiric aminoglycosides in this group, if any, and researching barriers and facilitators of efforts to reduce unnecessary variation in antimicrobial therapy for children with cancer,” it concluded.

Co-investigator Dr Gabrielle Haeusler, from the Peter MacCallum Cancer Centre and Royal Children’s Hospital Melbourne, told the limbic that a national standardised approach to paediatric FN care was important.

“The key thing with this paper is it was actually quite surprising that this signal of an increased risk of the composite adverse outcome was seen in patients who received the aminoglycosides.”

“Even when we tried to correct for the things that might have the child be more unwell, they had a bad outcome anyway. It’s an important signal that we have seen that warrants further research.”

Dr Haeusler was a co-author on international guidelines for the management of fever and neutropenia in children with cancer and HSCT recipients.

“While aminoglycosides are not recommended as routine first-line antibiotics, there is a caveat to review local antibiotic resistance rates and if there is concern about increasing resistance to the particular standard first line, it is quite an accepted practice around the world to add in an aminoglycoside into that setting.”

She noted aminoglycosides were already used much more cautiously in adults because of the risk of kidney toxicity which becomes more pronounced in adults.

Adult national consensus guidelines regarding FN were due for update and paediatric-specific guidelines would be wrapped in with that process which had been delayed due to COVID-19.

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