Antibiotic Stewardship in Suspected Neutropenic Fever (ASTERIC Trial)

1 Background and Rationale

1.1 Background

Burden of neutropenic fever Neutropenic fever (NF), or febrile neutropenia, is characterised by a high body temperature and low absolute neutrophil count (ANC) after myelosuppressive cancer treatment. It occurs in patients with early-stage and metastatic solid tumours, non-leukaemic haematological cancers and acute leukaemia. The crude mortality rate varies from 3 to 18%. In the United States (US), each year, 7.83 per 1,000 cancer patients are hospitalised with NF. The mean direct hospitalisation costs of managing NF vary from EUR3,950 [about HKD$ 34,000] to US$19,110 [about HKD$150,000] per patient.

Aetiology

NF can have infectious and non-infectious causes. Although 30 - 50% cases appear clinically to be infections only 20 - 30% have microbiologically documented infections. Bloodstream infections, bacterial translocations from the respiratory tract and perianal region, and from the central venous catheter are major sources.

Fever may be the only manifestation of infection during neutropenia because the typical signs of inflammation are obscured. Neutropenia usually results from myelosuppressive cancer treatments, pre-engraftment phases of haematopoietic stem cell transplantation (HSCT), bone marrow failure and/or defective neutrophil maturation.

Neutropenic Fever

NF is defined by 1) a single oral temperature ≥38.3ºC (101ºF), or a sustained temperature ≥38.0ºC (100.4ºF) over 1 hour; and 2) an ANC <1.0 x 10^9/L ("moderate" neutropenia). Neutropenia is classified as "severe", "profound" or "protracted" if the ANC is 0.5 x 10^9/L, <0.1 x 10^9/L, or lasts for more than one week, respectively. This definition only applies to oncological and haematological patients.

In Hong Kong

Local public emergency departments (EDs) have standard operating procedures and guidelines for managing NF. In line with international guidelines the target time from ED registration to antibiotic administration (door-to-antibiotic time, DTA time) is one hour disregarding ANC. The clinical pathways for suspected NF (sNF) expedites medical consultation, septic workup, and early prescription of ultra-broad spectrum antibiotics (UBSAs) such as Meropenem or Piperacillin/ Tazobactam. After implementing clinical pathways in local EDs, DTA times have shortened.

However, over 80% patients presenting to Hong Kong's Queen Mary Hospital with sNF have an ANC>1x10^9/L, do not have NF, do not require UBSAs and possibly do not require hospital admission. Widespread, inappropriate use of UBSAs may contribute to the emergence of antimicrobial resistance (AMR) and multi-drug resistance strains (MDR). Thus, there is a need for prudent, pragmatic, personalised antibiotic stewardship and appropriate de-escalation.

Antibiotic stewardship for cancer patients

As cancer patients are frequently prescribed antibiotics, they are more vulnerable to MDR, and are in special need of antibiotic stewardship. UBSAs are often started empirically in the ED for patients with sNF, assuming infection by drug-resistant bacteria. However, clinicians infrequently de-escalate once antibiotics have been started. Prolonged exposure to parenteral broad-spectrum antibiotic (BSA) impose risks of nosocomial infection and injection site complications. There is also evidence that meeting the one hour target does not improve outcomes but using appropriate antibiotic regimes does.

Research Gap and Unmet Clinical Need

Evidence-based practices are slow to be implemented into routine care. Implementation science seeks to narrow the research-to practice gap by identifying barriers and facilitators to effective implementation and designing strategies to achieve desired implementation outcomes. Most patients with sNF receive UBSAs. Yet <20% have confirmed NF and 16% have a confirmed microbe. Therefore, it is likely that antibiotics are being used inappropriately. There are knowledge gaps on methods for rapidly delivering ANC results in the acute setting; microbiological patterns (AMR and MDR rates); service, implementation and client outcomes; a lack of understanding on physician and nursing attitudes, perceptions and practice; a lack of good evidence on the real-world effectiveness, safety, and cost-implications of good prescribing practice (antibiotic stewardship and de-escalation); and a need for evidence-based education in patients with sNF. Implementation science supports translational medicine research to practice gaps. It identifies barriers and facilitators to effective implementation and designs evolving strategies to achieve desired service, implementation and client outcomes. This proposal addresses these issues.

1.2 Treatment Strategies

There is good evidence that patients with NF presenting to hospital benefit from early UBSA/BSA treatment and this is reflected in current guidelines. There is also good evidence that patients with NF and a high Multinational Association for Supportive Care in Cancer (MASCC) Risk Index do not need to be admitted to hospital. However, some healthcare settings have adopted a one hour limit on starting BSA/UBSA treatment and admit all patients to hospital. As ANC results are not usually available within one hour, more than 80% sNF may be treated unnecessarily with inappropriate antibiotics. Consequently, there is a need for implementation studies to identify barriers and facilitators of care, and to optimise early management.

There is currently little clinical evidence for the early management of sNF patients presenting to hospital. Early BSA/UBSA is recommended for patients with NF but the evidence for a strict one hour target for the first dose of antibiotics in patients with sNF has little evidence base. Most protocols would not recommend starting antibiotics where they are not necessary.

All patients with sNF will receive SoC during the first period in the participating hospitals. Later, hospitals will switch to the ASTERIC. Initially randomisation will be between hospitals to determine the time that each hospital will convert to the new protocol:

Period 1, Before: Although there is evidence that early treatment of sNF with UBSAs is safe, a high proportion of patients receive antibiotics unnecessarily. Thus, there is uncertainty over implementing personalised care and strategies to optimises antibiotic stewardship.

Period 2, After: The ASTERIC protocol seeks to safely optimise personalised care.

Inclusion criteria

• ≥18 years
• Tympanic temperature ≥38.3ºC within 24 hours before ED registration
• Last chemotherapy or targeted therapy within 6 weeks for any solid tumour, or in any period following therapies against leukaemia, lymphoma, myelodysplastic syndrome, aplastic anaemia, multiple myeloma, or recipient of HSCT.

Exclusion criteria

• The decision on how far to apply or deviate from a protocol rests with the clinician. Patients would be excluded from follow up if were unable or unwilling to provide informed consent for data access