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.