Discussion

We prospectively recorded inpatient antibiotic use in pediatric oncology patients and HSCT recipients hospitalized in 5 of the 6 PHO units and in the single BMT unit in Greece. These units treat >92% of children with hematologic and oncologic diseases in the country, so these data can be considered highly representative of the whole country. The distribution of underlying diseases differed significantly by unit, likely because patients with diagnoses other than hematologic malignancies and solid tumors were almost exclusively treated in hospitals in Athens, predominantly in the BMT unit.

The first goal of this study was to document the use of antibiotics in PHO units throughout Greece. The second goal was to educate the medical personnel of all PHO units on the evidence-based management of febrile neutropenia in children with cancer and HSCT recipients, according to the updated international CPG on febrile neutropenia. ^{Reference Lehrnbecher, Robinson and Fisher13} For the latter goal, feedback reports were sent regularly to all participants to inform them about their specific progress.

In our study, LOT per 1,000 patient days slightly decreased after the intervention from 517 to 501. During the same period, we noted a highly significant decrease in the number of deaths in all PHO units combined. The number of patients requiring ICU support for sepsis did not change significantly despite the overall decreased use of antibiotics. The fact that ICU admissions did not increase despite the use of fewer antibiotics is a strong indication that our intervention was safe. However, improved care and increased expertise resulting from the implementation of oncology protocols are other possible reasons for the drop in overall mortality.

The use of ceftazidime decreased after the intervention. Notably, most Greek hospitals harbor multidrug-resistant Pseudomonas aeruginosa with decreased susceptibility to ceftazidime. ^{Reference Feretzakis, Loupelis and Sakagianni20,Reference Maraki, Mantadakis and Nioti21} The goal of decreasing the use of glycopeptides was not achieved; their use represented 25%–30% of antibiotic DOT before and after the intervention. This failure is indicative of the difficulties frequently encountered in the practical implementation of evidence-based antibiotic guidelines. Established and unproven practices are difficult to modify, especially from physicians without adequate training in antibiotic stewardship.

Based on IDSA and the Society for Healthcare Epidemiology of America guidelines, ^{Reference Dellit, Owens and McGowan22} these data are insufficient to recommend combination antibiotic therapy as routine to prevent the emergence of resistance, although empirical combination therapy is important for critically ill patients at risk of infection with multidrug-resistant pathogens. In addition, de-escalation and/or discontinuation of empirical antimicrobial therapy based on culture results, and the elimination of redundant combination therapy, are highly recommended and can result in decreased antimicrobial exposure and substantial cost savings. ^{Reference Dellit, Owens and McGowan22} As a result, a goal of the PHIG intervention was to minimize redundant combination antibiotic therapy. This goal was partially achieved: the administration of ≥4 antibiotics simultaneously and of redundant combination therapy decreased in units in children’s hospitals but increased in units in general hospitals. The reasons for the remarkable improvement in antibiotic use in unit 2 are unclear, although the availability of adequate medical personnel likely played a role.

Overall, the reasons for these inconsistent changes are uncertain. We speculate that the involvement of pediatric infectious disease specialists was higher in units in children’s hospitals. Another possible explanation is that on-call physicians treating patients with febrile neutropenia in general hospitals are more likely to choose more aggressive antibiotic therapies than those needed for lower-risk patients with febrile neutropenia. The latter was shown to be the case in the management of adults with febrile neutropenia in an urban tertiary-care teaching hospital in the United States that provides emergency and inpatient services to a large comprehensive cancer center. ^{Reference Baugh, Wang and Caterino23} It could be argued that unit antibiograms show higher rates of resistance in units situated within general hospitals compared to units in children’s hospitals. However, to our knowledge, no such data exist because PHO units are not typically located within general hospitals outside Greece. Another possible explanation is that general hospitals likely harbor more drug-resistant bacteria, necessitating more aggressive empirical antibiotic therapy, as had been previously shown for uropathogens. ^{Reference Boggan and Navar-Boggan24,Reference Mantadakis, Tsalkidis and Panopoulou25}

Notably, the BMT unit used more piperacillin-tazobactam monotherapy, an evidence-based strategy, compared to any of the PHO units. Although the risk of infections in allogeneic HSCT patients is higher than in PHO patients and their outcomes tend to be worse, ^{Reference Styczynski, Czyzewski and Wysocki26} a review of randomized trials showed that monotherapy for high-risk febrile neutropenia is an effective strategy. ^{Reference Robinson, Lehrnbecher and Phillips27}

The prompt de-escalation and/or discontinuation in cases of negative blood cultures increased in all units but remained low after the intervention. Regarding antibiotic initiation without a clear infectious source or fever and with ANC >500/μL, no significant change was noted after intervention, but this practice was relatively rare to begin with.

The use of antifungals on days 1–4 of fever is contrary to international guidelines, ^{Reference Lehrnbecher, Robinson and Fisher13,Reference Groll, Castagnola and Cesaro28,29} but almost 66% of children treated in units in general hospitals received at least one antifungal compared to ∼25% of patients treated in units in pediatric hospitals. This practice did not change significantly after the intervention. Such early use of antifungals (ie, prior to day 4 of febrile neutropenia) is unjustified. Apart from children with acute myeloid leukemia, refractory, or relapsed acute lymphoblastic leukemia, Burkitt lymphoma, and exposure to high-dose corticosteroids, ^{Reference Alexander, Wade and Hibberd30–Reference Fisher, Robinson and Lehrnbecher32} most children with cancer do not require prophylaxis or therapy with antifungal agents. A multicenter randomized controlled trial in Italy showed that empirical antifungal therapy was of no advantage in terms of survival without fever and invasive fungal disease in children who were defined as low risk for systemic fungal disease. ^{Reference Caselli, Cesaro and Ziino33}

Our study had several strengths and limitations. This was the first study to prospectively collect data regarding antibiotic use in Greek PHO units. Although one PHO unit did not participate and another did not collect data during the postintervention period, our data are representative of the inpatient antibiotic prescribing practices for children with cancer and HSCT recipients treated in specialized units in Greece. One limitation of the study is that only hospital-wide and not unit-specific antibiotic susceptibility data for bacterial pathogens were available. Hence, we could only speculate about the reasons for the considerably different antibiotic prescribing practices among units. Lower susceptibility rates of microbial pathogens may be the reason for the more aggressive use of antibiotics in general hospitals with PHO units, but this issue needs further research. Finally, we were unable to separate all-cause from infectious mortality.

In conclusion, we used surveillance data to describe prescribing practices in Greek PHO and BMT units. We implemented a simple intervention that was associated with improved prescribing practices. We also identified areas necessitating improvement. As a next step, an active intervention with designated antibiotic stewardship physicians and prospective audit-and-feedback recommendations at each Greek PHO unit is needed.