Safety and efficacy of step‐down to oral outpatient treatment versus inpatient antimicrobial treatment in pediatric cancer patients with febrile neutropenia: A noninferiority multicenter randomized clinical trial

Abstract

Background It has been suggested that low‐risk febrile neutropenia (FN) episodes can be treated in a step‐down manner in the outpatient setting. This recommendation has been limited to implementation in middle‐income countries due to concerns about infrastructure and lack of trained personnel. We aimed to determine whether early step‐down to oral antimicrobial outpatient treatment is not inferior in safety and efficacy to inpatient intravenous treatment in children with low‐risk FN. Procedure A noninferiority randomized controlled clinical trial was conducted in three hospitals in Mexico City. Low‐risk FN was identified in children younger than 18 years. After 48 to 72 hours of intravenous treatment, children were randomly allocated to receive outpatient oral treatment (experimental arm, cefixime) or to continue inpatient treatment (standard of care, cefepime). Daily monitoring was performed until neutropenia resolution. The presence of any unfavorable clinical outcome was the endpoint of interest. We performed a noninferiority test for comparison of proportions. Results We identified 1237 FN episodes; 117 cases were randomized: 60 to the outpatient group and 57 for continued inpatient treatment. Of the FN episodes, 100% in the outpatient group and 93% in the inpatient group had a favorable outcome (P < 0.001). The mean duration of antibiotics was 4.1 days (SD 2.5; 95% CI, 3.4‐4.8 days) in the outpatient group and 4.4 days (SD 2.5; 95% CI, 3.7‐5.0 days) in the inpatient group (P = 0.70). Conclusions In our population, step‐down oral outpatient treatment of low‐risk FN was as safe and effective as inpatient intravenous treatment. Clinical Trials Identifier: NCT04000711.

Diagnosis and Management of Febrile Neutropenia in Pediatric Oncology Patients—A Systematic Review

“…When each study was analyzed individually, however, only two of them [ 12 , 24 ] listed Gram-positive bacteria as being the primary pathogen of their MDI, while all the rest described Gram-negative bacteria to be the leading cause of the infections, with Gram-positive pathogens taking up the second place. The third place was occupied by fungi in all but one study [ 14 ], where there were more fungi identified as Gram-positive bacteria. This can be seen in Figure 3 .…”

“…Either way, prompt empiric broad-spectrum antibiotic administration is collectively recommended by the FN guidelines and professional medical societies [ 11 , 12 , 13 ]. The increased duration until antibiotic administration is initiated has been associated, in the pediatric setting, with higher rates of sepsis and higher rates of intensive care admission and death, thus prompting the term “golden hour” as the recommended timeframe between FN patient presentation to the start of the antibiotic administration [ 7 , 14 ].…”

Step‐down and move forward

“…7 Thus, not erring on the side of safety (including local peculiarities, such as distance from home to the next point of care) leaves only 10-20% of all patients eligible. 1,8 How to move forward? The local standards for blood culture diagnostic should be updated and optimized.…”

“…To the Editor: We thank Avilés‐Robles et al 1 for their interesting study, addressing the safety and efficacy of step‐down to oral outpatient treatment versus inpatient antimicrobial treatment in pediatric cancer patients (pCP) with febrile neutropenia (FN). This study from Mexico City adds very important data to carefully adjust the current standard of clinical practice.…”

“…Defining low risk in pCPs with FN still lacks international consensus 7 . Thus, not erring on the side of safety (including local peculiarities, such as distance from home to the next point of care) leaves only 10‐20% of all patients eligible 1,8 …”