Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05793073 |
| Other study ID # |
23Infectio01 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2019 |
| Est. completion date |
May 31, 2022 |
Study information
| Verified date |
March 2023 |
| Source |
Centre Hospitalier Universitaire de Nice |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Febrile neutropenia (FN) is a frequent and serious complication in patients with
hematological malignancies undergoing intensive chemotherapy. The growth of antibiotic
resistance is a major threat in high-risk neutropenic patients given that delay in
introduction of appropriate empirical antibiotic therapy (EAT) in this population is
associated with increased morbidity and mortality.
In 2013, the 4th European Conference on Infections in Leukaemia (ECIL-4) group published new
guidelines, promoting early adaptation of EAT in stable afebrile patients, regardless of
neutrophil count and expected duration of neutropenia. Despite these evidence-based
guidelines, discontinuation and de-escalation strategies are not widely implemented in
hematology departments. However, recent studies have found that early adaptation of EAT is
safe and feasible and could lead to reduced antibiotic consumption.
In response to growing antibiotic resistance and low adherence to ECIL-4 guidelines in the
hematology department in the center of Nice, the investigators have developed and implemented
a multifaceted AMS intervention. This intervention aimed to improve the quality of febrile
neutropenia management and to promote the adoption of early de-escalation and discontinuation
strategies in high-risk neutropenic patients by our hematology team.
The aim of this before-after study was to assess the impact of a multifaceted AMS
intervention, promoting early adaptation of empirical antibiotic therapy, on antibiotic
consumption and clinical outcomes in high-risk neutropenic patients. Secondly, the
investigators sought to assess the applicability and adherence to de-escalation and
discontinuation strategies by the hematology team.
The primary endpoint was total antibiotic use during hospital stay, expressed as days of
therapy (DOT). DOT was defined as the number of days that a patient received antibiotics
regardless of the dose. Secondary endpoints included length of therapy (LOT), antibiotic-free
days (AFD), 30-day mortality, ICU admission, Clostridium difficile infection and duration of
stay. LOT was defined as the number of days that a patient received systemic antibiotic
therapy, irrespective of the number of different antibiotics.
Description:
INTRODUCTION
Febrile neutropenia (FN) is a frequent and serious complication in patients with
hematological malignancies undergoing intensive chemotherapy. FN episodes are responsible for
repeated and prolonged antibiotic therapy, leading to an increased risk of bacterial
antibiotic resistance, Clostridium difficile infections, fungal infections and adverse drug
events. The growth of antibiotic resistance is a major threat in high-risk neutropenic
patients given that delay in introduction of appropriate empirical antibiotic therapy (EAT)
in this population is associated with increased morbidity and mortality.
Excessive and inappropriate antibiotic use are major drivers of the growth of antibiotic
resistance. Antimicrobial stewardship (AMS) interventions have therefore been introduced to
optimize antibiotic use in order to decrease unintended consequences of antibiotic use, such
as growing antibiotic resistance and excessive healthcare costs. AMS interventions often
include various components, such as prescriber education, prospective audit and feedback as
well as clinical decision support at the point-of-care.
In 2013, the 4th European Conference on Infections in Leukaemia (ECIL-4) group published new
guidelines, promoting early adaptation of EAT in stable afebrile patients, regardless of
neutrophil count and expected duration of neutropenia. Despite these evidence-based
guidelines, discontinuation and de-escalation strategies are not widely implemented in
hematology departments. However, recent studies have found that early adaptation of EAT is
safe and feasible and could lead to reduced antibiotic consumption. However, some of these
studies did not use a control group. Furthermore, some of these studies solely investigated
the effets of one aspect of adaptation (i.e. de-escalation or discontinuation) or focused on
specific clinical presentations or patient profiles. One interrupted time series study
investigated the impact of de-escalation and discontinuation strategies on antibiotic
consumption but found no significant difference in total antibiotic consumption.
In response to growing antibiotic resistance and low adherence to ECIL-4 guidelines in the
hematology department in our center, the investigators have developed and implemented a
multifaceted AMS intervention. This intervention aimed to improve the quality of febrile
neutropenia management and to promote the adoption of early de-escalation and discontinuation
strategies in high-risk neutropenic patients by our hematology team.
The aim of this before-after study was to assess the impact of a multifaceted AMS
intervention, promoting early adaptation of empirical antibiotic therapy, on antibiotic
consumption and clinical outcomes in high-risk neutropenic patients. Secondly, the
investigators sought to assess the applicability and adherence to de-escalation and
discontinuation strategies by the hematology team.
METHODS
Study population This study was conducted in the hematology department of a 1800-bed
university teaching hospital in Nice, France during two 6-month periods. The hematology
department is divided into two separate units: a 10-bed intensive care unit with laminar air
flow rooms and a 16-bed conventional hospitalization unit.
During these periods, all patients admitted to the hematology department for intensive
chemotherapy, with chemotherapy-induced neutropenia lasting 7 days or more, who experienced
at least one febrile episode, were eligible for inclusion. Patients were excluded if they
were younger than 18 years old or had chemotherapy-induced neutropenia for less than 7 days
or received corticosteroids.
Design and implementation of AMS intervention The pre-intervention spanned from October 2019
to March 2020. During this period, if EAT was effective (i.e patient remained stable and
apyrexia was obtained), no change to antibiotic regimen was made, discontinuation was not
considered and de-escalation was rarely performed. During this period, the discontinuation of
antibiotic therapy was solely determined by neutrophil recovery.
In early 2021, the investigators started to design a persuasive multifaceted AMS
intervention, aimed to optimize the management of high-risk febrile neutropenia. The
implementation of the intervention started on November 2nd 2021 and the implementation phase
lasted one month. This intervention included the development of new local clinical guidelines
in the form of visual decision algorithms, prompting early de-escalation and discontinuation
of EAT, according to clinical and microbiological criteria. These decision algorithms were
subsequently discussed with the hematology medical team and revised until they were agreed
upon by both teams. These visual decision aids were then displayed in all medical offices of
the hematology department. Educational meetings were held with residents and paramedical
staff during the implementation period, providing an opportunity for all stakeholders to ask
questions and to learn about the adaptation guidelines. Additionally, a patient-level review
of all antibiotic prescriptions was conducted twice a week in the presence of the hematology
medical team and the AMS team. Patient-specific recommendations regarding antibiotic therapy
were provided by the AMS team based on clinical and microbiological data. Moreover, the AMS
team offered day-to-day guidance via a specialist hotline.
The post-intervention phase started in December 2021 and lasted for the subsequent 6 months,
until May 2022. During this period, clinical outcomes and adherence to clinical algorithms
were prospectively assessed and face-to-face meetings were organized by the AMS team to
provide feedback on progress of the intervention and to discuss opportunities for improvement
with the hematology team.
Febrile neutropenia guidelines In November 2021, new clinical guidelines promoting early
adaptation of EAT, based on local microbiological epidemiology, clinical and microbiological
criteria and ECIL-4 guidelines, were introduced.
In line to guidelines, EAT with a beta-lactam agent was started as early as possible after
onset of fever in neutropenic patients. During both periods, carbapenem use was restricted to
patients with prior colonization or infection with ESBL-producing bacteria and in patients
with septic shock. A single injection of aminoglycosides was administered in patients with
sepsis or septic shock. An agent active against resistant Gram-positive (e.g. daptomycin,
vancomycin or linezolid) was added in patients with suspected catheter-related infection,
skin and soft tissue infection or severe mucitis, in patients with prior colonization or
infection with methicillin-resistant Staphylococcus aureus (MRSA) as well as in patients with
septic shock.
Without documented infection, EAT was discontinued after 72 hours in stable patients who had
been afebrile for at least 48 hours, irrespective of neutrophil count or expected duration of
neutropenia. In clinically or microbiologically documented infections, appropriate antibiotic
therapy was continued for at least 7 days and until infection was microbiologically
eradicated and clinical resolution was obtained and fever had resolved for at least 4 days.
If an anti-resistant Gram-positive agent was started based on focal clinical signs, its
stopping was encouraged in stable patients who had been afebrile for at least 48 hours upon
resolution of focal clinical signs. If EAT with carbapenem was started based on prior
colonization or infection with resistant pathogens and no microbiological documentation was
available, de-escalation was encouraged in stable patients who had been afebrile for at least
48 hours. If carbapenem or anti-resistant Gram-positives therapy was started in the context
of septic shock and the patient had stabilized on treatment, without documented infection, no
particular change was encouraged.
Data collection All individual data on the pre-intervention period was retrospectively
collected by the AMS team by manual review of electronic health records (EHRs) while data on
the post-intervention phase was prospectively collected. Data on patient demographics,
comorbidities, hematological malignancies, colonization with multidrug-resistant (MDR)
bacteria (i.e. MRSA or ESBL-producing bacteria), dates and reason for hospital stay, results
of microbiological samples, were collected. All data on antibiotic use were also retrieved
from EHRs and were then double checked for accuracy by the pharmacy department. Clinical
outcomes, such as ICU admission and 30-day mortality, were also collected to assess for
unintended consequences of early adaptation of EAT. The applicability of de-escalation and
discontinuation strategies and clinician adherence to these strategies were also assessed by
the AMS team individually for all FN episodes.
The primary endpoint was total antibiotic use during hospital stay, expressed as days of
therapy (DOT). DOT was defined as the number of days that a patient received antibiotics
regardless of the dose. When a patient received more than one antibiotic, more than one DOT
was counted. Secondary endpoints included length of therapy (LOT), antibiotic-free days
(AFD), 30-day mortality, ICU admission, Clostridium difficile infection and duration of stay.
LOT was defined as the number of days that a patient received systemic antibiotic therapy,
irrespective of the number of different antibiotics [24]. AFD were calculated by the
difference between duration of neutropenia of stay and LOT. If duration of neutropenia was
greater than LOT, AFD was measured as 0. The 30-day mortality was defined as death occurring
within 30 days after the onset of neutropenia.
Statistical analysis Continuous variables are reported as median (interquartile range) and
categorical variables as number (percentage). Continuous variables were compared using the
Student's t-test, or when inappropriate the Mann-Whitney test. Categorical variables were
compared using the Chi-2 test, or when inappropriate the Fisher's exact test. All tests were
two-tailed and p values ≤ 0.05 were considered statistically significant. Univariate and
multivariate logistic regression was performed to identify factors associated with clinician
adherence to de-escalation and discontinuation strategies. Only variables with p values < 0.2
in the univariate analysis were included in the multivariate logistic regression model.
Sample size was calculated using a power of 80% and an α value of 0.05. Based on preliminary
results from our department, the mean DOT was assumed to be 29 days (standard deviation =
13.5 days) and a reduction of DOT by 25 % in the post-intervention period was considered
significant. Based on these assumptions, a sample size of 55 per period was required. The
open-source software R Foundation for Statistical Computing (Vienna, Austria) was used for
statistical analysis.
