Discussion
We prospectively recorded the inpatient antibiotic use of pediatric oncology patients and HSCT recipients hospitalized in five of six PHO and one BMT units in Greece. These six units treat >92% of children with hematologic and oncologic diseases in the country, hence the resulting data are highly representative of the country as a whole. The distribution of underlying diseases was significantly different by unit, and this is mainly because patients with diagnoses other than hematologic malignancies and solid tumors were almost exclusively treated in units located in Athens, predominantly 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 FN in children with cancer and HSCT recipients, as updated in 2017 by the International Pediatric Fever and Neutropenia Guidelines.13
In this study, LOT per 1000 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, while the number of patients requiring ICU support for sepsis did not change significantly. In short, although the recorded changes in antibiotic prescribing practices were not always appropriate, there was a significant drop in the number of deaths during the surveillance period. However, it is unclear to what extent this can be attributed to our intervention. Better care and gain of expertise with the implementation of current international disease-specific oncology protocols may be the main reason for the drop in overall mortality.
The use of ceftazidime dropped after intervention, especially in units located in general hospitals. It is of note that most Greek hospitals harbor multi-resistant Pseudomonas aeruginosa with decreased susceptibility to ceftazidime.20,21 The goal of decreasing the use of glycopeptides was not achieved, as vancomycin and teicoplanin use represented 25-30% of antibiotic DOT before and after the intervention.
The IDSA and the Society for Healthcare Epidemiology of America have published guidelines for developing an institutional program to enhance antimicrobial stewardship.22 Based on these guidelines, there are insufficient data 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.22 As a result, a goal of the PHIG intervention was to minimize redundant combination antibiotic therapy. This goal was partially achieved. More specifically, administration of ≥ 4 antibiotics simultaneously and redundant combination therapy decreased in units located in pediatric hospitals but increased in units located in general hospitals.
The reasons for these inconsistent changes are unclear. We speculate that involvement of pediatric infectious diseases specialists was likely higher in units located in children’s hospitals. Another possible explanation is that on-call physicians treating patients with FN in general hospitals are more likely to choose more aggressive antibiotic therapies than those needed for lower-risk patients with FN. The latter was shown to be the case in the management of adult patients with FN in an urban tertiary-care teaching hospital in United States that provides emergency and inpatient services to a large comprehensive cancer center.23 It could be argued that unit antibiograms show higher rates of resistance in units situated within general hospitals compared to ones in pediatric hospitals. However, to our knowledge no such data exist, as PHO units are not typically located within general hospitals outside Greece. A final possible explanation is that general hospitals likely harbor more resistant bacteria, necessitating more aggressive empirical antibiotic therapy. In fact, this is something that has been shown for uropathogens in USA and Greece.24,25
Of note, the BMT unit used more piperacillin/tazobactam monotherapy, an evidence-based strategy, than 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,26 a systematic review of randomized trials showed that monotherapy for high-risk FN is an effective strategy.27
The prompt de-escalation and/or discontinuation in case of negative blood cultures increased in all units but remained low after intervention to just 28.3% in units located in general hospitals. Regarding antibiotic initiation without a clear infectious source or fever and with ANC>500/μl, no significant change was noted after the intervention, but this practice, which is not recommended, was relatively rare to begin with.
The use of antifungals on days 1-4 of fever is contrary to international guidelines published by major scientific societies and organizations,13,28,29; but almost two thirds of children treated in units located in general hospitals received at least one antifungal compared to approximately one fourth of patients treated in units located in pediatric hospitals, and this practice did not change much after intervention. We believe that apart from HSCT patients, such widespread and early use of antifungals, i.e., prior to day 4 of FN, is unjustified. Apart from children with acute myeloid leukemia, high-risk acute lymphoblastic leukemia (i.e., with refractory or relapsed disease), Burkitt lymphoma, and exposure to high-dose corticosteroids,30-32 none of whom were overrepresented in our sample, 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 IFD in children who were defined as low risk for systemic fungal disease.33
Our study has strengths, but also has several limitations. This was the first study to prospectively collect a large amount of data regarding antibiotic use in Greek PHO units. The limited resources for stewardship programs in almost all units involved did not prevent us from accurately documenting antibiotic prescribing practices in children with cancer and HSCT recipients. Although one PHO unit did not participate, and another did not collect data during the post-intervention 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 in the participating units during the surveillance period. Hence, we can 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 PHO located in general hospitals, but this issue needs further research. Finally, lack of antimicrobial dosing data is another limitation of our study, as is the limited duration of data collection for each patient, and the inability to separate all-cause from infectious mortality.