Updated Pediatric Fever and Neutropenia Guideline Puts Focus on Sepsis, Antibacterial Administration

Thomas Lehrnbecher, MD

The International Pediatric Fever and Neutropenia Guideline Pane have released an updated febrile neutropenic clinical practice guideline, supported by data from 10 recently published clinical trials.¹

Two key changes were incorporated from the 2017 guideline to the 2023 update. For patients who are clinically well and afebrile, empiric antibacterial therapy can be discontinued if their blood cultures remain low risk with negative blood cultures at 48 hours despite no evidence of marrow recovery. Secondly, for patients who are high risk and are not receiving antimold prophylaxis, preemptive antifungal therapy is advised.

The panel also updated their good practice statement in support of febrile neutropenic clinical practice guideline consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients.

“With this new good practice statement, the panel recognized the urgent need for early recognition of sepsis and expeditious administration of empiric antibacterial therapy to improve survival for patients with invasive infection,” they wrote. “Antibacterial therapy should be administered as soon as possible, while other measures to stabilize the patient are taken and should ideally occur much sooner than 1 hour after presentation. Administration of clinical practice guideline-consistent empiric antibacterial therapy is important to ensure appropriate microbial coverage against potential pathogens.”

Fever and neutropenia are among the most common complications of cancer treatment. Moreover, the management of pediatric febrile neutropenia continues to be heterogenous across and within centers. Clinical practice guidelines can help reduce this heterogeneity.

The original guideline on febrile neutropenia management in pediatric patients was published in 2012 and updated in 2017, when a total of 69 randomized clinical trials were used to inform the practice guidelines.² The 2023 update includes an additional 10 new randomized clinical trials. The panel consisted of representatives across pediatric oncology, pediatric infectious disease, nursing, pharmacy, 1 patient advocate, and 2 CPG methodologists, from a total of 10 different countries.

Change No. 1: Ongoing Management: Cessation of Treatment

• B4. In both patients with high-risk and low-risk febrile neutropenia who have been clinically well and afebrile for at least 24 hours, discontinue empiric antibacterial therapy if blood cultures remain negative at 48 hours if there is evidence of marrow recovery (strong recommendation, low-quality evidence).
• B5. In patients with low-risk febrile neutropenia who have been clinically well and afebrile for at least 24 hours, consider discontinuation of empiric antibacterial therapy if blood cultures remain negative at 48 hours despite no evidence of marrow recovery (conditional recommendation, moderate-quality evidence)

In 2017, the recommendation was to consider disconnection at 72 hours, rather than 48 hours. The study authors noted that the definition of marrow recovery is still elusive.

The updated systemic review included data from 2 studies which assessed empiric antibacterial therapy discontinuation in patients. The first of these studies evaluated patients with low-risk febrile neutropenia without marrow recovery who had been afebrile for 24 hours. These patients were randomly assigned to either discontinue antibacterial therapy or continue treatment, with either oral amoxicillin-clavulanic acid or levofloxacin.³ Therapy cessation was deemed noninferior to antibacterial therapy continuation in terms of treatment success. The second study assessed both high-risk and low-risk patients with febrile neutropenia.⁴ These patients had documented respiratory virus infection with no evidence of bacterial infection. They were randomly assigned to continue or discontinue antibacterial therapy at 48 hours following a favorable evolution. No significant difference in uneventful febrile neutropenia resolution was identified.

Change No. 2: Empiric Antifungal Therapy: Treatment

• C4. In invasive fungal disease (IFD) high-risk patients with prolonged (≥ 96 hours) febrile neutropenia unresponsive to broad-spectrum antibacterial therapy, initiate caspofungin or liposomal amphotericin B for empiric antifungal therapy unless a pre-emptive antifungal therapy approach is chosen (strong recommendation, high-quality evidence).
• C5. In nonhematopoietic cell transplant (HCT) IFD high-risk patients not receiving antimold prophylaxis with prolonged (≥ 96 hours) febrile neutropenia unresponsive to broad-spectrum antibacterial therapy, consider a preemptive antifungal therapy approach by deferring empiric antifungal therapy and initiating antifungal therapy only if evaluation suggests or indicates IFD (conditional recommendation, moderate-quality evidence).
• C6. In IFD low-risk patients with prolonged (≥ 96 hours) febrile neutropenia, consider withholding empiric antifungal therapy (conditional recommendation, low-quality evidence).

Previously, the recommendation was to initiative caspofungin or liposomal amphotericin B for empiric antifungal therapy was considered strong. This recommendation was based on 3 randomized control trials, which showed that these 2 treatments had similar efficacy, and liposomal amphotericin B was less nephrotoxic than conventional amphotericin B.²

A new trial randomly assigned patients with both high-risk and prolonged febrile neutropenia to receive preemptive antifungal therapy instead of empiric antifungal therapy.⁵ Those who were assigned to preemptive therapy underwent evaluation with repeat blood cultures, serum galactomannan, chest and sinus CT, and abdominal ultrasound. Only those with evidence of IFD received antifungal therapy. In this study, preemptive therapy was associated with a reduced median duration of antifungal therapy (6 days vs 11 days; P < .001), and no significant difference in the prevalence of IFD was identified (9 of 71 vs 9 of 73, respectively; P = .92). This study was published before the 2017 clinical practice guidelines, and, as such, its IFD evaluation recommendations differed from the guideline. According to the panel, IFD evaluation should follow recommendations CS and C3, even if a preemptive strategy is chosen.

References

1. Lehrnbecher T, Robinson PD, Ammann RA. Guideline for the management of fever and neutropenia in pediatric patients with cancer and hematopoietic cell transplantation recipients: 2023 update. J Clin Oncol. 2023;41(9):1774-1785. doi:10.1200/JCO.22.02224
2. Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update. J Clin Oncol. 2017; 35(18):2082-2094. doi:10.1200/JCO.2016.71.7017
3. Kumar A, Biswas B, Chopra A, et al. Early discontinuation versus continuation of antimicrobial therapy in low risk pediatric cancer patients with febrile neutropenia, before recovery of counts: a randomized controlled trial (DALFEN study). Indian J Pediatr. 2021;88(3):240-245. doi:10.1007/s12098-020-03377-x
4. Santolaya ME, Alvarez AM, Acuna M, et al. Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial. Clin Microbiol Infect. 2017; 23(3):173-178. doi:10.1016/j.cmi.2016.11.001
5. Santolaya ME, Alvarez AM, Acuña M, et al. Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial. J Antimicrob Chemother. 2018;73:2860-2866. doi:10.1093/jac/dky244