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Febrile Neutropenia

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Anti-Infective Agents

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Anti-Bacterial Agents

Antibiotics, Antitubercular

Discontinuation of empirical antibiotics, despite neutrophil count below 0.5x10⁹ cells/L, after 48 hours of apyrexia and clinical stability.

A child is considered clinically stable when there is resolution of all symptoms and signs of infection, and normalization of vital signs including heart rate, respiratory rate, oxygen saturation, blood pressure, and daily diuresis.

Discontinuation of antibiotics when neutrophil count is equal to or above 0.5x10⁹ cells/L, and the child is afebrile and clinical stable OR the child has received 10 days of antibiotics and have been afebrile and clinically stable for 7 days

Termination of empirical antibiotics for febrile neutropenia based on clinical parameters, regardless of neutrophile count.

Early termination of empirical antibiotics

Nadja Vissing, MD, PhD

Ulrikka Nygaard, MD, PhD

Birgitte Klug Albertsen, MD PhD

Nadja Vissing, MD PhD

Peder Skov Wehner, MD PhD

The study is a nationwide, multicenter, open label, randomized controlled trial.

A target population of 220 children in treatment for cancer with neutropenic fever and a neutrophil count below 0.5 × 10⁹ cells/L with expected duration for more than 7 days will be recruited during the first 48 hours of antibiotic treatment (24 months inclusion period). They will be randomized 1:1 as follows:

* Experimental group: Discontinuation of antibiotics, despite neutrophil count below 0.5 × 10⁹ cells/L, after 48 hours of apyrexia and clinical stability
* Control group: Discontinuation of antibiotics when neutrophil count is equal to or above 0.5 × 10⁹ cells/L and the child is afebrile and clinically stable (up to maximum of 14 days after apyrexia and clinical stability).

Primary endpoint is the number of days without antibiotic treatment in 28 days after treatment initiation. Secondary endpoints are crude mortality, severe adverse events, days with relapsing fever, and alterations of the microbiome.

BACKGROUND: In children with cancer, infections are a major cause of morbidity and mortality due to chemotherapy-related immunosuppression, comprising up to 70% of all treatment-related deaths. The relationship between neutropenia and life-threatening infection has been well established, and any signs of infection including fever has to be treated promptly with broad spectrum antibiotics. However, the duration of antibiotic therapy in pediatric cancer patients with febrile neutropenia without a known source is unknown. Traditionally, antibiotic therapy is continued until neutrophil recovery, due to fear of relapse of infection potentially as life-threatening sepsis, but scientific evidence supporting this strategy is limited. It has been debated that the strategy may be over-cautious, leading to unnecessarily prolonged antibiotic treatments with important side effects, including extended hospital admissions, adverse drug events, super-infection with fungi and multi-resistant bacteria, and thus affecting the children on both short and long term.

Studies in adults have shown that withdrawal of empirical antimicrobial therapy based on clinical assessment, despite severe neutropenia, can reduce antibiotic treatment significantly without compromising patient safety. This approach is warranted in children with cancer, but no randomized studies have been conducted in high risk children with prolonged neutropenia. A few studies have documented that early discontinuation of empirical antibiotics in low-risk children with short-lasting neutropenia is safe, but as stressed by recent international guidelines, the question of optimal duration of empirical antibiotics for high-risk children with prolonged bone marrow suppression continues to be a major research gap.

HYPOTHESIS: Empirical antibiotic therapy of febrile neutropenia can safely be discontinued after 48 hours of apyrexia and clinical stability, despite severe neutropenia, in high-risk children with expected prolonged neutropenia.

AIM: To establish evidence-based treatment strategies for children with febrile neutropenia by performing a randomized controlled trial investigating the efficacy and safety of early termination of empirical antibiotic therapy.

METHODS: Children treated at one of the 4 pediatric oncology departments in Denmark who are admitted with neutropenic fever will be evaluated according to current routines, including complete physical examination, assessment of severity signs and source, blood samples (biochemistry and hematology), blood cultures (collected from the central venous catheter), and additional samples from infected sites as clinically indicated. After obtaining cultures, empiric antibiotic therapy for neutropenic fever is started. The type of antibiotics will depend on current local guideline. Children who remain febrile despite empirical antibiotic therapy will be treated and investigated according to local and international guidelines.

Eligible subjects will be screened and included as described.

Included subjects will be followed for 28 days after initiation of empirical antibiotic treatment or until neutrophile recovery, whichever is longest.

They will be assessed at the following protocolled time points:

1. At 48 hours of apyrexia
2. At recovery of neutropenia
3. At 28 (±2) days (final assessment)
4. In the event of relapsing fever after the initial 48 hours of apyrexia during the follow-up period.

Each assessment will include a clinical interview, targeted physical examination and review of patient chart including biochemistry and hematology. A fecal and a pharyngeal swap will be collected and stored at the final assessment.

Children receiving antibiotics with no additional need for in-hospital treatment can receive their antibiotic treatment by continuous infusion on a portable pump and discharged to outpatient therapy, according to local department guidelines.

STATISTICS: The number of days free of antibiotics will be compared between the groups by linear regression analysis. A multivariate linear regression analysis will be carried out adjusting for age, gender, neutropenia duration, and underlying malignant disease and other significant risk factors.

Secondary outcomes will be compared by a non-inferiority assumption with an inferiority margin of 10%. All tests will be two-sided, with p values of 0.05 considered significant. An interim analysis will be conducted when 50% of the patients have been recruited to assess the safety of the study. A worst-case imputation method will be used for missing data in an exploratory sensitivity analysis.

Patients receiving empirical antibiotic treatment due to high risk neutropenic fever will be randomly assigned 1:1 to one of two groups regimens. Randomization can occur from 36 hours after initiation of antibiotics until 48 hours of apyrexia and clinical stability. The allocated treatment regimen is followed from randomization until neutrophil recovery, also in case of relapsing fever after termination of antibiotic treatment.

A participant can be randomized more than once, but only one time during each episode of neutropenia, i.e. bone marrow recovery and subsequent chemotherapy treatment must have taken place before a new randomization can occur.

Early Termination of Empirical Antibiotics in Febrile Neutropenia in Children With Cancer

Early Termination of Empirical Antibiotics in High-risk Febrile Neutropenia in Children With Cancer: an Open-label, Randomised, Controlled Trial

Number of days without antibiotic treatment

Alterations in gut microbiome composition measured by bacterial whole genome sequencing on fecal samples collected at 28 days after randomisation.

Kjeld Schmiegelow

Professor in Paediatrics

Neoplasms

Hematologic Neoplasms

Tazobactam

Ceftolozane

Ceftolozane, tazobactam drug combination

beta-Lactamase Inhibitors

Enzyme Inhibitors

Eligible patients will be started on empiric ceftolozane-tazobactam in addition to standard care.

Empiric Ceftolozane-tazobactam IV 3g over 1 hour every 8 hours. The dose will be reduced to 1.5g 8 hourly in patients with CrCl of 30-50 ml/min, and to 750mg every 8 hours in those with CrCl of 15-29 ml/min. Patients on hemodialysis will receive 2.25g loading dose followed by 450mg every 8 hours.

Ceftolozane-tazobactam IV

Ali S. Omrani, FRCP

Patients with blood cancers and those who received a bone marrow transplant frequently have low circulating white blood cell countS. Fever in patients with low white blood cell count requires early appropriate antibiotic treatment to prevent complications including death. Bacteria have increasingly become more resistant to existing antibiotic options. Ceftolozane-tazobactam is a newer type of antibiotic that has been shown to be safe and effective in infections caused by several types of resistant bacteria that can cause serious infections in individuals with low blood count. This study aims to examine the effectiveness of this antibiotic in these types of patients.

Patients with blood cancer and those who have received a bone transplant will be offered the option to join this study if they develop unexplained fever. If informed consent is granted, they will receive ceftolozane-tazobactam on top of the usual care that such patients receive. The patients will then be followed very closely to check their response to the treatment and if they develop any untoward events. The study will include 164 patients over an estimated 2 year period.

The study is funded by Merck \& Co, the company that manufactures the study antibiotic. However, Merck \& Co. will not be involved in the actual running of the study, the collection of the study results or their analysis and interpretation. The study protocol has been reviewed and approved by an independent research oversight committee.

The role of early appropriate empiric anti-bacterial therapy in reducing morbidity and mortality in patients with prolonged neutropenia has long being documented. The National Center for Cancer Care and Research (NCCCR) antibiograms for recent years showed increasing rates of ESBL-producing E. coli and K. pneumoniae, as well as reduced susceptibility of P. aeruginosa isolates to piperacillin-tazobactam. Ceftolozane-tazobactam is a newer β-lactam-β-lactamase inhibitor combination with a broad in-vitro spectrum that includes ESBL and AmpC-producing Enterobacterales, as well as multidrug resistant P. aeruginosa. The clinical efficacy and safety of ceftolozane-tazobactam was demonstrated in registrational randomized clinical trials in multiple settings. However, clinical experience with ceftolozane-tazobactam in patients with hematological malignancy or HSCT is very limited. The aim of this study is to explore the potential role of ceftolozane-tazobactam as empiric treatment for hematology patients with neutropenic fever of unknown origin.

The primary objective is to assess the efficacy of ceftolozane-tazobactam as empiric anti-bacterial therapy for neutropenic fever in patients with hematological malignancy or HSCT.

The study will be a prospective, non-comparative, single-arm, single center, open-label interventional study. Patients admitted to NCCCR with a malignant hematological diagnosis and/or HSCT will be screened daily for possible inclusion in the study. Participants will receive empiric therapy with ceftolozane-tazobactam intravenously. All remaining care will be consistent with standard clinical care for patients with neutropenic fever. The Primary endpoint will be treatment success at 72 hours of ceftolozane-tazobactam therapy without modification of anti-bacterial therapy. Treatment success is defined as a composite of defervescence, resolution of any baseline clinical signs of infection, microbiological eradication of any baseline bacterial pathogen, and no modification of anti-bacterial therapy by addition of or switch to an agent with microbiological activity against Enterobacterales or P. aeruginosa (except the addition of sulfamethoxazole-trimethoprim for P. jiroveci prophylaxis).

The study will be conducted in full conformance with principles of the "Declaration of Helsinki", Good Clinical Practice (GCP), and within the laws and regulations of Ministry of Public Health in Qatar. Participation will be subject to written informed consent. The study is sponsored by Hamad Medical Corporation. Funding and medication supply is provided by Merck \& Co (MSD) through its Investigator Initiated Studies Program. MSD will not have any role in data collection, data analysis or driving study conclusions.

The study will be a prospective, non-comparative, single-arm, single center, open-label interventional study.

CEFtolozane-Tazobactam for the Empiric Anti-bacterial Treatment of Neutropenic Fever in Hematology Patients

CEFtolozane-Tazobactam for the Empiric Anti-bacterial Treatment of Neutropenic Fever in Hematology Patients; a Single-arm, Single-center, Open-label Clinical Trial (CEF-10 Study)

Treatment success is defined as a composite of defervescence, resolution of any baseline clinical signs of infection, microbiological eradication of any baseline bacterial pathogen, and no modification of anti-bacterial therapy by addition of or switch to an agent with microbiological activity against Enterobacterales or P. aeruginosa (except the addition of sulfamethoxazole-trimethoprim for P. jiroveci prophylaxis).

Treatment success is defined as a composite of defervescence, resolution of any baseline clinical signs of infection, microbiological eradication of any baseline bacterial pathogen, and no modification of anti-bacterial therapy by addition of or switch to an agent with microbiological activity against Enterobacterales or P. aeruginosa (except the addition of sulfamethoxazole-trimethoprim for P. jiroveci prophylaxis)

Counted from the first oral temperature of \<38oC which is sustained for ≥48 hours

Survival for 30 days from initiation of therapy

Merck Sharp & Dohme LLC

Hamad Medical Corporation

Infections

Inflammation

Communicable Diseases

Virus Diseases

Disease Attributes

70 children with cancer and a positive blood culture.

50 children with cancer and no positive blood culture.

Whole transcriptome profiling using RNA sequencing

RNA expression signature

Lotte M. Smedegaard, M.D.

The aim is to investigate if RNA expression signature can discriminate bacterial from viral infection or non-infectious inflammation in children with cancer.

Earlier studies in immunocompetent children have shown promising results, but studies in immunocompromised children are lacking.

We aim to include 300 febrile episodes in children with cancer. The samples will be analysed by RNA sequencing. If succesfull, this method can help prevent unnecessary antibiotic treatment, reduce hospital admissions, side effects and antimicrobial resistance and improve quality of life for children during cancer treatment.

Children with cancer are at high risk of invasive bacterial infections particularly during neutropenia. Febrile neutropenia is an early sign of a potentially fatal infection requiring broad-spectrum empiric antibiotics. However, the majority of children do not have a bacterial infection, but still receive antibiotics, since current tests cannot distinguish causes of fever. A number of transcriptomic studies of immunocompetent patients show that host leukocyte patterns of activated RNA can discriminate bacterial infection from non-infectious inflammation with high accuracy, but studies in immunocomprised patients are few.

Methods

A prospective non-interventional observational multicentre study including febrile childhood cancer patients during 24 months at all Danish Pediatric Oncology Departments (Rigshospitalet, Aarhus, Odense and Aalborg University Hospitals). Leukocyte RNA expression will be analysed in whole blood samples by RNA sequencing adjusted for low RNA input. 300 febrile episodes will be included, and predictive host RNA signatures will be identified in a discovery cohort and assessed in a validation cohort. Further, to explore the transcriptome in non-febrile children with neutropenia, we include a control group of 15 children with cancer and no fever.

Time frame Inclusion of children: 1st of June 2019 to 31st of May 2021 Analysis of samples (RNA sequencing): 1st of June 2021 - 1st of December 2021

Perspective

The study will create a base for a randomised trial regarding implementation of RNA signature versus normal procedure in handling febrile children with cancer. This can lead to the development of a targeted RNA-expression analytical platform that can prevent unnecessary antibiotic treatment in the majority of children with febrile neutropenia. This will reduce hospital admissions, side effects, antimicrobial resistance and improve quality of life during cancer treatment. The results can be extrapolated to the adult patients with cancer, who are often treated with prophylactic antibiotics, which complicate finding the infectious agent. Additionally, the test may be applied in other immunosuppressed children with infections.

All children will have 2.5 ml whole blood drawn into a PaxGene RNA (Qiagen®) tube along with routine blood tests. Only RNA is extracted

Host RNA Signature in Children With Cancer and Infection

Host RNA Signature to Discriminate Bacterial From Viral Infection and Non-specific Inflammation in Children With Cancer

To detect specific RNA signatures in whole blood in children with febrile neutropenia

An investigation of the change in RNA expression over time during an infection period

To test RNA signatures from genes published in other studies eg. the genes IFI44L and FAM89A

To investigate potential differences in RNA signatures in patients with gram positive versus gram negative bacteria

To compare RNA signatures in febrile neutropenic and non-neutropenic children with a positive blood culture

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Early Termination of Empirical Antibiotics in Febrile Neutropenia in Children With Cancer	NCT04637464	Neutropenia, Fe... Pediatric Cance...	Early terminati...	- 18 Years	Rigshospitalet, Denmark
CEFtolozane-Tazobactam for the Empiric Anti-bacterial Treatment of Neutropenic Fever in Hematology Patients	NCT05061654	Neutropenia, Fe... Hematologic Can...	Ceftolozane-taz...	18 Years -	Hamad Medical Corporation
Host RNA Signature in Children With Cancer and Infection	NCT04669418	Childhood Cance... Infection Neutropenia, Fe...	RNA expression ...	- 17 Years	Rigshospitalet, Denmark

Spots Global Cancer Trial Database for neutropenia, febrile