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\begin{document}

\title{Antibiotic use in Greek Pediatric Hematology-Oncology and Bone Marrow
Transplantation units}



\author[1]{Elpis Mantadakis}%
\author[2]{Ioannis  Kopsidas}%
\author[3]{Susan Coffin}%
\author[4]{Gabriel Dimitriou }%
\author[4]{Despoina  Gkentzi}%
\author[5]{Emmanuel Hatzipantelis}%
\author[6]{Aikaterini Kaisari}%
\author[7]{Antonis Kattamis}%
\author[2]{Eleni  Kourkouni}%
\author[8]{Smaragda Papachristidou}%
\author[9]{Eugenia Papakonstantinou}%
\author[10]{Sophia Polychronopoulou}%
\author[11]{Emmanuel Roilides}%
\author[12]{Nikos Spyridis}%
\author[13]{Sotirios  Tsiodras}%
\author[14]{Maria Tsolia}%
\author[15]{Grammatiki-Christina Tsopela}%
\author[16]{Theoklis  Zaoutis}%
\author[17]{Athanasios Tragiannidis}%
\affil[1]{Democritus University of Thrace}%
\affil[2]{Center for Clinical Epidemiology and Outcomes Research (CLEO), Athens, Greece}%
\affil[3]{The Children's Hospital of Philadelphia}%
\affil[4]{Patras Medical School, University General Hospital of Patras, Patra, Greece}%
\affil[5]{Aristotle University of Thessaloniki Faculty of Health Sciences}%
\affil[6]{Agia Sofia Children's Hospital}%
\affil[7]{Aghia Sophia Children's Hospital}%
\affil[8]{Oncology Department, "P \& A Kyriakou" Children's Hospital, Athens, Greece}%
\affil[9]{Ippokratio General Hospital}%
\affil[10]{Agia Sophia Childrens' Hospital}%
\affil[11]{ippokratio }%
\affil[12]{Infectious Diseases Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens (NKUA), Athens, Greece}%
\affil[13]{4th Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece}%
\affil[14]{Aglaia Kiriakou Children's Hospital}%
\affil[15]{Center for Clinical Epidemiology and Outcomes Research (CLEO)}%
\affil[16]{Center for Clinical Epidemiology and Outcomes Research (CLEO) / Infectious Diseases Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens (NKUA), Athens, Greece}%
\affil[17]{ARISTOTLE UNIVERSITY OF THESSALONIKI}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Pediatric hematology-oncology (PHO) and bone marrow
transplantation (BMT) units have high use of antimicrobials. Objectives:
To survey antimicrobials used in Greek PHO and BMT units before and
after an intervention involving education on the 2017 clinical practice
guidelines (CPG) for the management of febrile neutropenia in children
with cancer and hematopoietic stem cell transplant recipients. Methods:
Antibiotic prescribing practices were prospectively recorded between
June 2016 and November 2017. In December 2017, education for the CPG
took place and antibiotic prescribing practices were followed for one
more year. For antibiotic stewardship, days of therapy and length of
therapy were calculated. Results: Five of six PHO units and the single
pediatric BMT unit covering \textgreater{}92\% of children with
hematologic and oncologic diseases in Greece participated.
Administration of [?] 4 antibiotics simultaneously and of antibiotics with
overlapping activity for [?] 2 days was significantly more common in PHO
units located in general compared to pediatric hospitals. Use of at
least one antifungal was recorded in approximately 47\% of the patients
before and after the intervention. De-escalation and/or discontinuation
of antibiotics on day 6 of initial treatment increased significantly
from 43\% to 53.5\% (p=0.032). Although the number of patients requiring
support in the intensive care unit for sepsis did not change, a
significant drop was noted in all-cause mortality after the intervention
(p=0.008). Conclusion: Our surveillance was able to accurately document
the antibiotic prescribing practices of Greek PHO and BMT units.
Moreover, it identified areas in immediate need for improvement in
antibiotic stewardship.%
\end{abstract}%



\sloppy


\textbf{Antibiotic use in Greek Pediatric Hematology Oncology and Bone
Marrow Transplantation units}

\textbf{Authors}

Elpis Mantadakis, Ioannis Kopsidas, Susan Coffin, Gabriel Dimitriou,
Despoina Gkentzi, Emmanouel Hatzipantelis, Aikaterini Kaisari, Antonis
Kattamis, Eleni Kourkouni, Smaragda Papachristidou, Evgenia
Papakonstantinou, Sophia Polychronopoulou, Emmanuel Roilides, Nikos
Spyridis, Sotirios Tsiodras, Maria N. Tsolia. Grammatiki-Christina
Tsopela, Theoklis Zaoutis, Athanasios Tragiannidis

\textbf{Affiliations}

Elpis Mantadakis, Democritus University of Thrace Faculty of Medicine,
University General Hospital of Alexandroupolis, Alexandroupolis, Greece

Ioannis Kopsidas, Center for Clinical Epidemiology and Outcomes Research
(CLEO), Athens, Greece

Susan Coffin, Division of Infectious Diseases and Center for Pediatric
Clinical Effectiveness, Children's Hospital of Philadelphia,
Philadelphia, USA

Gabriel Dimitriou, Patras Medical School, University General Hospital of
Patras, Patra, Greece

Despoina Gkentzi, Patras Medical School, University General Hospital of
Patras, Patra, Greece

Emmanouel Hatzipantelis, Children \& Adolescent Hematology-Oncology
Unit, 2\textsuperscript{nd} Pediatric Department, School of Medicine,
Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece

Aikaterini Kaisari, Stem Cell Transplant Unit, Aghia Sophia Children's
Hospital, Athens, Greece

Antonis Kattamis, First Department of Pediatrics, National and
Kapodistrian University of Athens, Aghia Sophia Children's Hospital,
Athens, Greece

Eleni Kourkouni, Center for Clinical Epidemiology and Outcomes Research
(CLEO), Athens, Greece

Smaragda Papachristidou, Oncology Department, ''P \& A Kyriakou''
Children's Hospital, Athens, Greece

Evgenia Papakonstantinou, Department~of Pediatric Oncology,
Hipppokration General Hospital,~Thessaloniki, Greece

Sophia Polychronopoulou, Department of Pediatric Hematology-Oncology
(T.A.O.), Aghia Sophia Children's Hospital, Athens, Greece

Emmanuel Roilides, Third Department of Pediatrics, Aristotle University
of Thessaloniki, Hipppokration General Hospital, Thessaloniki, Greece

Nikos Spyridis, Infectious Diseases Unit,
2\textsuperscript{nd}Department of Pediatrics, National and Kapodistrian
University of Athens (NKUA), Athens, Greece

Sotirios Tsiodras, 4\textsuperscript{th} Department of Internal
Medicine, National and Kapodistrian University of Athens, Attikon
Hospital, Athens, Greece

Maria N. Tsolia, Infectious Diseases Unit,
2\textsuperscript{nd}Department of Pediatrics, National and Kapodistrian
University of Athens (NKUA), Athens, Greece

Grammatiki-Christina Tsopela, Center for Clinical Epidemiology and
Outcomes Research (CLEO), Athens, Greece

Theoklis Zaoutis, Center for Clinical Epidemiology and Outcomes Research
(CLEO) / Infectious Diseases Unit, 2\textsuperscript{nd} Department of
Pediatrics, National and Kapodistrian University of Athens (NKUA),
Athens, Greece

Athanasios Tragiannidis, Children \& Adolescent Hematology-Oncology
Unit, 2\textsuperscript{nd} Department of Pediatrics, School of
Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

\textbf{Corresponding Author}

Elpis Mantadakis, MD, PhD

Professor of Pediatrics-Pediatric Hematology/ Oncology

Department of Pediatrics

University General Hospital of Alexandroupolis

6\textsuperscript{th} Kilometer Alexandroupolis-Makris

68100 Alexandroupolis, Thrace, Greece

Tel: +30-25513-51411, Fax: +30-25510-30340

E-mail: emantada@med.duth.gr

\textbf{Word Count for Abstract:} 250

\textbf{Word Count for Main Text:} 3,396

\textbf{Number of} Tables: 5, Figures: 1

\textbf{Running title} : Antibiotic use in Greek PHO and BMT units

\textbf{Keywords:} Antimicrobial stewardship; surveillance; quality
improvement; pediatric hematology oncology

\textbf{List of abbreviations}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviation} & \textbf{Meaning}\tabularnewline
\midrule
\endhead
ANC & Absolute Neutrophil Count\tabularnewline
ASP & Antibiotic Stewardship Program\tabularnewline
BMT & Bone Marrow Transplantation\tabularnewline
CLEO & Center for Clinical Epidemiology and Outcomes
Research\tabularnewline
CPG & Clinical Practice Guideline\tabularnewline
DOT & Days of Therapy\tabularnewline
FN & Febrile neutropenia\tabularnewline
HSCT & Hematopoietic Stem Cell Transplantation\tabularnewline
ICU & Intensive Care Unit\tabularnewline
IDSA & Infectious Diseases Society of America\tabularnewline
IFD & Invasive Fungal Disease\tabularnewline
IQR & Interquartile range\tabularnewline
LOT & Length of Therapy\tabularnewline
PHIG & Preventing Hospital Infections in Greece\tabularnewline
PHO & Pediatric Hematology-Oncology\tabularnewline
TMP/SMX & Trimethoprim/sulfamethoxazole (cotrimoxazole)\tabularnewline
\bottomrule
\end{longtable}

\textbf{ABSTRACT Background:} Pediatric hematology-oncology (PHO) and
bone marrow transplantation (BMT) units have high use of
antimicrobials.\textbf{Procedure:} To survey antimicrobials used in
Greek PHO and BMT units before and after an intervention involving
education on the 2017 clinical practice guidelines (CPG) for the
management of febrile neutropenia in children with cancer and
hematopoietic stem cell transplant recipients. Antibiotic prescribing
practices were prospectively recorded between June 2016 and November
2017. In December 2017, education for the CPG took place and antibiotic
prescribing practices were followed for one more year. For antibiotic
stewardship, days of therapy and length of therapy were
calculated.\textbf{Results:} Five of six PHO units and the single
pediatric BMT unit covering \textgreater{}92\% of children with
hematologic and oncologic diseases in Greece participated.
Administration of [?] 4 antibiotics simultaneously and of antibiotics with
overlapping activity for [?] 2 days was significantly more common in PHO
units located in general compared to pediatric hospitals. Use of at
least one antifungal was recorded in approximately 47\% of the patients
before and after the intervention. De-escalation and/or discontinuation
of antibiotics on day 6 of initial treatment increased significantly
from 43\% to 53.5\% (\emph{p} =0.032). Although the number of patients
requiring support in the intensive care unit for sepsis did not change,
a significant drop was noted in all-cause mortality after the
intervention (\emph{p} =0.008).

\textbf{Conclusions} : Our surveillance was able to accurately document
the antibiotic prescribing practices of Greek PHO and BMT units.
Moreover, it identified areas in immediate need for improvement in
antibiotic stewardship.

\textbf{Introduction}

The overuse of antimicrobials, the emergence of antimicrobial resistance
worldwide, and increasing health-care associated costs have shown the
importance of maximizing the application of antibiotic stewardship
programs (ASP) in order to maintain the efficacy of currently existing
antibiotics along with substantial cost
savings.\textsuperscript{1,2}This issue is particularly important when
it comes to children with cancer, who frequently require antibiotics
during periods of febrile neutropenia (FN) associated with the
administration of cytotoxic chemotherapy or with their underlying
disease.\textsuperscript{3,4} FN is a condition where evidence-based
antibiotic prescribing is not frequently followed, as shown by a
retrospective cohort study of audits performed during an
ASP.\textsuperscript{1}

In pediatric hematology-oncology (PHO) units, evidence-based use of
antibiotics and antibiotic de-escalation strategies have the potential
to decrease unnecessarily prolonged use of broad-spectrum antimicrobial
agents,\textsuperscript{5} but such measures have not been studied
extensively, especially on a national level.\textsuperscript{6} Studies
in both adults and children have shown that in hematology-oncology
units, antibiotic de-escalation and discontinuation can be safely
implemented, i.e., without increasing the number of infectious deaths or
Intensive Care Unit (ICU) admissions.\textsuperscript{7-10} For example,
an open-label, randomized, controlled phase 4 clinical trial in six
academic hospitals in Spain showed that in adults with hematological
malignancies, high-risk FN and negative blood cultures, empirical
antimicrobial therapy can be safely discontinued after 72 hours of
apyrexia and clinical recovery irrespective of the absolute neutrophil
count (ANC).\textsuperscript{11}

In Greece, nearly 300 pediatric oncology patients aged 0 to 14 years are
diagnosed annually, out of a national population of approximately 11
million people. Additionally, approximately 12 children with
non-malignant diseases such as immunodeficiencies, homozygous
beta-thalassemia, aplastic anemia, and other conditions require
hematopoietic stem cell transplantation (HSCT) annually. Currently,
there are six PHO units located in Greece: three units in Athens; two
units in Thessaloniki, and one unit in Heraklion, Crete. In addition,
there is a single pediatric bone marrow transplantation (BMT) unit
located in Athens. The two PHO units in Thessaloniki and the PHO unit in
Crete are in general university hospitals, while all units in Athens,
including the BMT unit are in Aghia Sophia Children's Hospital and P.
and A. Kyriakou Children's Hospital.

The Center for Clinical Epidemiology and Outcomes Research (CLEO) is an
non-governmental, not-profit organization in Greece that surveils the
most common hospital-acquired infections, with emphasis on improving
prevention strategies and promoting and monitoring the judicious use of
antibiotics.\textsuperscript{12} Since 2016, as part of the project
Preventing Hospital Infections in Greece (PHIG), CLEO has been
monitoring the use of antimicrobials in Greek PHO units with the goals
of promoting the implementation of evidence-based insertion and
maintenance bundles for central lines and encouraging implementation of
international evidence-based guidelines for management of FN in children
with cancer and HSCT recipients.\textsuperscript{13}

The goal of this study is to describe the use of antibiotics in
hospitalized children with cancer or children requiring HSCT in Greece
and to evaluate the impact of a simple multifaceted intervention on
prescribing practices. The results of PHIG intervention regarding
central line-associated bloodstream infections will be the subject of a
separate report.

\textbf{Patients and Methods}

In end of June 2016, 5 out of 6 Greek PHO units and the country's single
pediatric BMT unit participated in this collaborative, and prospectively
recorded the first 15 children per month admitted to their units, who
required the initiation of new antibiotics for treatment or prophylaxis.
Ethics approval was obtained from the institutional review boards of all
participating hospitals. Individual informed consent was not considered
necessary to be obtained in any of the hospitals.

\emph{Data collection}

Children receiving only prophylactic antibiotics were included, while
children who were already on intravenous antibiotics for a previous
infection the day before the initiation of the new antibiotic regimen
were excluded. Administration of any antifungal therapy in a child with
FN was recorded as empirical therapy. No pediatric patient was recorded
twice within the same month, and the form was completed for the first
seven days of antibiotic administration.

Data recorded included age and sex, presence of central lines, type of
underlying disease (hematologic malignancy, solid tumor, or other
disease), ANC and its relation to the first day of antibiotic therapy,
antibiotics used and their indication (empirical or targeted therapy,
perioperative or other prophylaxis), cultures obtained, and pathogens
isolated, presence or absence of invasive fungal disease (IFD), and
clinical outcome (hospital discharge, ICU admission, or death).

In December 2017, a meeting between CLEO representatives and the
directors of all PHO units took place, where baseline data analysis was
presented along with the main conclusions. Finally, the goal of
implementing the recently updated at that time clinical practice
guidelines (CPG) for the management of FN in children with cancer and
HSCT recipients by the International Pediatric Fever and Neutropenia
Guideline Panel was also discussed.\textsuperscript{13} The timeframe
and the goals of the PHIG intervention are shown in \textbf{Figure 1} .
For FN, the definition of the Infectious Diseases Society of America
(IDSA) was used.\textsuperscript{17}

\emph{PHIG intervention}

The surveillance of antibiotic use and the educational intervention
about the implementation of the CPG started in December 2017 for five of
the units; one started in March 2018 due to local resource restrictions,
while one of the units participated in data collection only during the
pre-intervention period (June 2016 to December 2017) due to limited
resources. The same demographic and clinical data were recorded in the
post-intervention two-year period (January 2018 to December 2019), to
compare antimicrobial use before and after implementation of the
guidelines for the management of FN in children with cancer and HSCT
recipients.\textsuperscript{13}

\emph{Data analysis}

For the purposes of antibiotic stewardship, we calculated days of
therapy (DOT) and length of therapy (LOT).\textsuperscript{18,19} One
DOT represents the administration of a single antibiotic on a given
calendar day, even if multiple doses are given on that day. LOT is the
number of days a patient is receiving antibiotics regardless of the
number of different agents administered. We compared administration of [?]
4 antibiotics simultaneously, use of antibiotics with overlapping
antimicrobial activity for [?]2 days, de-escalation/discontinuation with
negative cultures by day 6, start of antibiotics without obtaining
cultures, antibiotic initiation without a clear source or fever and with
ANC\textgreater{}500/\selectlanguage{greek}μ\selectlanguage{english}l, use of standard versus other non-standard
regimens for empirical therapy (defined as cephalosporins without
anti-\emph{Pseudomonas} activity such as ceftriaxone and cefotaxime,
ceftazidime monotherapy, colistin, metronidazole, and others), early use
of antifungals before day 4 of fever, number of patients admitted for
sepsis to ICU, and number of deaths before and after PHIG intervention.
In all participating units, a feedback report was sent every six months
throughout the study period to inform them about their specific progress
with respect to implementation of the CPG.

Statistical analysis

Nominal variables are presented with absolute and relative (\%)
frequencies, whereas continuous variables are presented with medians and
interquartile ranges (IQR). To evaluate differences between units and
the effect of intervention, chi-square tests of independence and
Mann-Whitney U tests were performed, as appropriate. Stratified analysis
by unit and type of unit (PHO units located in pediatric compared to
general hospitals) was also performed. All reported \emph{p} values were
based on two-sided tests, and statistical significance was set
at\emph{p} \textless{}0.05. All statistical analyses were performed with
STATA v.13.0 software (StataCorp., College Station, TX, USA).

\textbf{Results}

\emph{Cohort characteristics}

Demographic (age, gender), and clinical characteristics (underlying
disease) of recorded cases by PHO unit and location in a pediatric or
general hospital are shown in \textbf{Table 1} . Patients hospitalized
in PHO units located in general hospitals were significantly younger
than patients hospitalized in PHO units located in pediatric hospitals
{[}(pediatric hospitals: median 7.5 years (IQR 3.6-12.3) versus general
hospitals: median 5.4 years (IQR 3.1-8.5), \emph{p} =0.001{]}. In
addition, significantly more female patients were hospitalized in PHO
units located in general hospitals.

\emph{Antibiotic use}

Patient and antibiotic days, LOT per 1000 patient days, DOT/LOT ratios,
and most commonly used antibiotics during the study period by PHO unit
and by type of hospital (pediatric versus general) are shown
in\textbf{Table 2.} Ceftazidime was commonly used in PHO units located
in general hospitals, while piperacillin/tazobactam monotherapy was
commonly used in the BMT unit. After intervention, ceftazidime use
decreased in the two PHO units located in general hospitals (from 19\%
to just 1.1\%) and remained low in units located in pediatric hospitals
throughout the surveillance period (0.2\% before and 0.4\% after
intervention). Regarding the use of glycopeptides, their use remained
high and essentially unchanged after intervention. More specifically,
their use was 30.4\%, both prior to and after the intervention in PHO
units located in general hospitals, and slightly increased after the
intervention from 24.9\% to 27.2\% in PHO units located in pediatric
hospitals.

\emph{Redundant antibiotic use}

Results of PHIG intervention in relation to other study goals are
summarized in \textbf{Table 3.} Overall, the administration of [?] 4
antibiotics simultaneously remained unchanged at 4.1\% before and after
the intervention. However, it changed from 2.2\% to 0.9\% in units
located in pediatric hospitals and from 8.2\% to 11.2\% in units located
in general hospitals. Both the pre- and post-comparison of the
simultaneous use of [?] 4 antibiotics between units by type of hospital
was highly significant (\emph{p} =0.001 for both). The overall
administration of antibiotics with overlapping activity for [?]2 days did
not change significantly (4.5\% before and 5.4\% after the
intervention,\emph{p} =0.39). It decreased from 3.5\% to 2.1\% in units
located in pediatric hospitals, while it increased from 6.7\% to 12.5\%
in units located in general hospitals. Again, the pre- and
post-intervention comparison of the administration of antibiotics with
overlapping activity for [?]2 days between units by type of hospital was
highly significant (\emph{p} =0.034 and \emph{p} =0.001, respectively).

\emph{Antibiotic use for FN}

Antibiotic use on day one of FN before and after PHIG intervention is
shown in \textbf{Table 4} . Major differences in practice existed
between different PHO units prior to intervention. In units 1 and 2,
triple antibiotic therapy (i.e., an antipseudomonal beta-lactam, a
second Gram negative agent and a Gram-positive agent) was commonly
practiced; in the BMT unit monotherapy with an antipseudomonal
beta-lactam was more commonly used; in unit 5, double Gram-negative
coverage was used; and in unit 6, triple antibiotic therapy and other
non-standard regimens were frequently used. Significant improvements in
appropriateness of antibiotic prescribing were noted after the
intervention (\emph{p} =0.005). For all units combined, antibiotic
therapy was started without obtaining cultures less frequently after the
intervention (9.8\% versus 14.1\% before, \emph{p} =0.006). This
practice was more frequent in PHO units located in general compared to
pediatric hospitals before (25.5\% compared to 9\%) and after
intervention (18.2\% compared to 5.8\%), and this difference was highly
significant (\emph{p} =0.001 for both comparisons).

\emph{}

\emph{De-escalation of antibiotic therapy}

In cases of negative blood cultures in patients receiving antibiotics
with Gram-positive coverage and/or a second antibiotic with
Gram-negative coverage, de-escalation and/or discontinuation of
antibiotics on day 6 in all units significantly increased from 43\% to
53.5\% (\emph{p} =0.032). More specifically, it increased from 53.1\% to
60.2\% in units located in pediatric hospitals and from just 15.1\% to
28.3\% in units located in general hospitals.

Antibiotic initiation without a clear infectious source or fever and
with ANC\textgreater{}500/\selectlanguage{greek}μ\selectlanguage{english}l occurred during the pre-and
post-intervention period in 4.1\% and 3\% of antibiotic courses,
respectively (\emph{p} =0.198). In PHO units located in pediatric
hospitals, it tended to drop from 3.7\% to 3\% and in PHO units located
in general hospitals from 5\% to 3\%.

\emph{Use of non-standard antibiotic regimens}

The overall use of non-standard antibiotic regimens was not
significantly different after the intervention (11.9\% before versus
12.7\% after). However, it was significantly more frequent in PHO units
located in general versus pediatric hospitals prior to intervention
(\emph{p} =0.001) and remained so post-intervention (\emph{p} =0.001).
Triple antibiotic therapy decreased in units 1 and 2, monotherapy with
an antipseudomonal beta-lactam decreased in the BMT unit, and triple
antibiotic therapy and non-standard antibiotic combinations decreased in
unit 6.

\emph{Antifungal use}

Use of antifungals in PHO units before and after PHIG intervention is
shown in \textbf{Table 5} . Overall, 47.4\% of patients before and
46.9\% after the intervention received at least one antifungal (\emph{p}
=0.893). Almost all patients treated in the BMT unit were receiving at
least one antifungal at the time of data collection. Almost two thirds
of children treated in units located in general hospitals were receiving
at least one antifungal compared to approximately one fourth of patients
treated in units located in pediatric hospitals. In unit 6, antifungal
use significantly increased after intervention (\emph{p} =0.044).
Overall, use of at least one antifungal was significantly more common in
PHO units located in general versus pediatric hospitals before the
intervention (66\% compared to 40.9\%,\emph{p} =0.001) and remained so
after the intervention (73\% compared to 36.2\%, \emph{p} =0.001).

\emph{Outcomes (ICU admissions and deaths)}

The number of patients requiring ICU support for sepsis did not change
significantly (18 or 2.13\% before intervention compared to 23 or 2.33\%
after intervention, \emph{p} =0.781), while a significant drop was noted
in the recorded number of deaths in all PHO units combined (36 deaths or
4.29\% before intervention compared to 21 deaths or 2.13\% after
intervention, \emph{p} =0.008).

\textbf{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 \textgreater{}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.\textsuperscript{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 \emph{Pseudomonas aeruginosa} with decreased
susceptibility to ceftazidime.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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,\textsuperscript{26} a systematic
review of randomized trials showed that monotherapy for high-risk FN is
an effective strategy.\textsuperscript{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\textgreater{}500/\selectlanguage{greek}μ\selectlanguage{english}l, 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,\textsuperscript{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,\textsuperscript{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.\textsuperscript{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.

\textbf{CONCLUSION}

In this study, we performed surveillance of antibiotic prescribing
practices in hospitalized children with cancer and HSCT recipients in
Greece. Our surveillance data allowed comparisons among units,
identified areas necessitating improvement and provided useful
information on antibiotic prescribing to physicians in each PHO unit. 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. Ideally, future
accurate capturing of unit-specific antibiotic susceptibility data for
all bacterial pathogens is needed along with more dedicated personnel
exclusively involved with antibiotic stewardship. Finally, further
research in this area is required to reduce the use of broad-spectrum
antimicrobials and antifungals safely and substantially in this
susceptible patient population.

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/FIGURE-1/FIGURE-1}

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