Journal Club Presentation
Management of Patients with Fever and Neutropenia Through the Arc of Time
Pizzo, P.A. (2019). Management of Patients With Fever and Neutropenia Through the Arc of Time: A Narrative Review. Annals of Internal Medicine, [Epub ahead of print]. doi: 10.7326/M18-3192
Jennifer Handy, NP March 18, 2019 Introduction
This article is an overview of how treatment principles related to the management of fever and neutropenia have responded to changes in the patient’s at risk, the microbes responsible and the tools for their treatment, while still being sustained over the arc of time.
Bodey and Colleagues’ seminal study in 1966 – -Fever in a patient with neutropenia is associated with potentially life threatening infection especially in patients receiving cytotoxic chemotherapy. -Neutropenic patients – disease/treatment related breaches to immune system/host defense barriers (Susceptible to bacterial, viral, fungal, parasitic infections) -Prompt immediate empirical broad spectrum antibiotics Treatment Advances
Cancer treatment therapies have increased survival rates across the continuum. -Survival rates for childhood cancers have increased from <10% to nearly 90%
Targeted therapies to reduce complications of cytotoxic chemotherapy
1998: Tyrosine Kinase Inhibitor. First targeted therapy for the treatment of Chronic myelogenous leukemia
Other Targeted therapies focus on Immunotherapeutic agents/Host modifying agents that boost the host’s immune system/altering risk for infection. -monoclonal antibodies, hematopoietic cytokines (erythropoietin, granulocyte colony-stimulating factor – reduce neutropenia from 6 days to 1 day – reduce incidence of infection and complications by 50% but not mortality.)
Though, Cytotoxic Chemotherapy is still the mainstay of most cancer treatment regimens The Role of the Microbiome in Risk for Infection and Modulation of Host Defenses
1970’s-1980’s: Observed that nearly 80% of the microorganisms associated with infection in the febrile neutropenic patient came from endogenous microbial flora 1970’s: Observed shift from the “normal” gram-positive, anaerobic environment of oral and gastrointestinal microflora when a patient is first diagnosed with cancer To predominately gram negative organisms after initiation of therapies which altered balance of aerobes and anaerobes. Gut microbiome – anaerobes produce a protective barrier (Inhibit colonization by new aerobes) -Can influence response to treatments such as chemotherapy -Composition of gut microbiota can Increase/decrease risk for fever/neutropenia/infection. (i.e. Proteobacteria in children with ALL before chemo was associated with development of fever and neutropenia) When and Where to Initiate Antibiotics and Which Ones Should be Administered
Initiation of Empiric broad spectrum antibiotics within 1 hour of fever onset in the chemotherapy induced neutropenic patient – Standard of care since 1966
Since 1966, An unresolved question that researchers have sought to answer: 1) How to differentiate patients with life threatening infection from those whose fever might not be of infectious cause. 2) Which patients require longer versus short antibiotic courses
Despite advances in diagnostic testing (i.e. inflammatory markers, immunodiagnostics, imaging) their usefulness in identifying serious infections are limited.
Blood cultures and physical exam - standard diagnostic tools for 50 years. 1990: The International Immunocompromised Host Society – Guidelines for how clinical trials were conducted on the antibiotic management of neutropenic patients Coincided with the first guidelines for antibiotic therapy in febrile neutropenic patients (Updated 2002, 2011) with many of their recommendations that remain relevant today. When and Where to Initiate Antibiotics and Which Ones Should be Administered, continued
1960’s-1970’s: No single antibiotic could provide broad coverage against gram positive and gram negative aerobes and anaerobes
Combo: 1st Gen Cephalosporin + Aminoglycoside + PCN
Goal: achieving high bactericidal levels d/t Gram negative bacteria esp. Pseudomonas were dominant 1980’s: Advances in antibiotic therapy in an effort to reduce toxicity (Limit Aminoglycosides/Vanc)
Major advances: 3rd and 4th Gen Cephalosporins, Carbapenems, Fluoroquinolones
Predominant bacterial pathogens shifted: Gram positive organisms (Staph aureus, MRSA, coagulase-negative staph) 1980-1990’s: Monotherapy considered an option d/t broad spectrum coverage/including pseudomonas
Limited by drug resistance
Fluoroquinolones: Used as antibiotic prophylaxis against neutropenic infection
Limited to patients who are likely to have profound neutropenia (neutrophil count <100 cells per microliter for >7 days When and How Should the Initial Antibiotics be Modified?
A response to an antibiotic regimen WITHOUT modifications should be determined at 72 hours, again at day 5. And reasons for regimen modification (if required) should be stated
Reasons for modifying initial empiric therapy
Persistent fever (With or without clinical deterioration)
A new microbiological finding (With or without clinical deterioration)
Evidence of clinical progression of a presumed infection
Adverse event/intolerance to drug Duration of Antibiotic Therapy in Patients With Unexplained Fever or Defined Infection
Patients Whose Neutrophils Recover or Who Become Afebrile
Multiple studies have show that antibiotics can be withdrawn with resolution of fever and/or neutropenia, with patients followed closely
1993: Study by Bechanan: Discontinuing empiric antibiotics were considered safe when patient showed signs of hematologic recovery (increasing neutrophils if though not yet >500 cells/microliter).
2018: ANTIBIOSTOP study showed similar results. Early discontinuation of empirical antibacterial therapy in febrile neutropenia
2017: Study by Aguilar, et al.: Patient’s who were considered “high risk” Neutropenia >7days,to continue/discontinue antibiotics if they were clinically stable and afebrile after 72 hours of treatment. Found no difference in adverse consequences in groups that had discontinued antibiotics Duration of Antibiotic Therapy in Patients With Unexplained Fever or Defined Infection, continued.
Patients Who Remain Febrile and Neutropenic
Discontinuing empiric antibiotics is not recommended in patients who remain persistently febrile AND neutropenic
High-risk patients with persistent fever AND neutropenia, continued antibiotic therapy along with empirical antifungal therapy starting 4-7 days after initiation of antibiotic therapy is recommended
1982: Studies have shown benefit of adding empiric antifungal therapy if fever and neutropenia persisted for 7 or more days
Researchers have tried to define which patients are most likely to benefit. But unable to identify. But d/t reduction of morbidity/mortality with the use of antifungal therapy, their use has been recommended. Duration of Antibiotic Therapy in Patients With Unexplained Fever or Defined Infection, continued. The Management of Specific Infections
When an infection is identified.
Still up for debate:
Narrowing antimicrobial therapy to target the identified infection versus continuing the broader therapy in the setting of immunodeficiency
Defined duration of treatment (7-10 days) versus continued treatment up until neutropenia and all signs of infection resolve Approach to Therapy Low-Risk versus High-Risk Patients
Low-Risk Patients: Severely Neutropenic (ANC <500 cells/microL) for ≤7 days MASCC Score ≥21 or a CISNE score of 0 No comorbidities or evidence of significant hepatic or renal dysfuction This group of patients has been well studied in randomized trials and has been shown to be at low risk for serious complications High-Risk patients: Severely Neutropenic (ANC <500 cells/microL) for >7 days MASCC Score <21 or a CISNE score of ≥3 (Intermediate CISNE scores (1 or 2) may require clinicians to judge the relative safety of outpatient oral therapy versus hospitalization for parenteral antibacterial therapy. ) Patients with neutropenic fever who have ongoing comorbidities or evidence of significant hepatic or renal dysfunction are also considered to be high risk for medical complications, regardless of the duration of neutropenia.
https://www.uptodate.com/contents/overview-of-neutropenic-fever-syndromes
Future Directions
Neutropenic fever in patients having cancer therapy has been a focus of investigation over the past 5 decades
In the early days of cancer treatment, Infectious complications were the leading cause of death.
Although the risk for infection is still notable, infection related morbidity and mortality have decreased
Many early approaches to management of febrile neutropenic patients remain relevant today, suggesting that some interventions endure over the arc of time
Future research will focus on the questions that remain unresolved.
Continuing to seek cancer treatments that results in less cytotoxicity and immunodeficiency.
New ways of modulating the immune system to lessen the complications of cancer treatment, neutropenia, fever and infection. Thank you!