Due to reduced levels of neutrophils in circulation, patients with neutropenia may have an impaired ability to fight infections. It is crucial to monitor patients for signs and symptoms of infection, which may present as fever, chills, or sweats. Other signs and symptoms of infection for patients with FN are provided in Table 1. Fever may be the sole indicator of an underlying infection in patients with chemotherapy-induced neutropenia; other signs and symptoms of inflammation may be absent.
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It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in , we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis.
Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.
What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices.
Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorithmic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been established during the past 40 years, guided and modified by clinical evidence and experience over time. The Infectious Diseases Society of America Fever and Neutropenia Guideline aims to provide a rational summation of these evolving algorithms.
Summarized below are the recommendations made in the guideline update. A detailed description of the methods, background, and evidence summaries that support each of the recommendations can be found in the full text of the guideline. Recommendations Assessment of risk for complications of severe infection should be undertaken at presentation of fever A-II.
Risk assessment may determine the type of empirical antibiotic therapy oral vs intravenous [IV] , venue of treatment inpatient vs outpatient , and duration of antibiotic therapy A-II. Such patients should be initially admitted to the hospital for empirical therapy A-II. All patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients B-I.
Recommendations 5. Laboratory tests should include a complete blood cell CBC count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin A-III.
At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing central venous catheter CVC , if present, and from a peripheral vein site; 2 blood culture sets from separate venipunctures should be sent if no central catheter is present A-III.
Culture specimens from other sites of suspected infection should be obtained as clinically indicated A-III. A chest radiograph is indicated for patients with respiratory signs or symptoms A-III. Recommendations General Considerations 9. Vancomycin or other agents active against aerobic gram-positive cocci is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia A-I.
These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability. Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients B-III. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; they may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria A-I.
Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment A-I. Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used B-III.
Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone A-III. Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection A-III. Recommendations Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data A-II. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen.
If an infection is identified, antibiotics should be adjusted accordingly A-I. If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is no evidence for a gram-positive infection A-II.
Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi A-III.
Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable A-I. An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate A-I. Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured B-III.
If fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-risk patients A-III. Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4—7 days of a broad-spectrum antibacterial regimen and no identified fever source A-II.
Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery C-III. Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered to be roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection.
A systematic strategy for monitoring the development of fluoroquinolone resistance among gram-negative bacilli is recommended A-II. Addition of a gram-positive active agent to fluoroquinolone prophylaxis is generally not recommended A-I.
Recommendations High risk Data are insufficient to recommend a specific empirical antifungal agent for a patient already receiving anti-mold prophylaxis, but switching to a different class of anti-mold antifungal that is given intravenously should be considered B-III.
Preemptive antifungal management is acceptable as an alternative to empirical antifungal therapy in a subset of high-risk neutropenic patients. Those who remain febrile after 4—7 days of broad-spectrum antibiotics but are clinically stable, have no clinical or chest and sinus computed tomography CT signs of fungal infection, have negative serologic assay results for evidence of invasive fungal infection, and have no recovery of fungi such as Candida or Aspergillus species from any body site may have antifungal agents withheld B-II.
Antifungal therapy should be instituted if any of these indicators of possible invasive fungal infection are identified. Low Risk In low-risk patients, the risk of invasive fungal infection is low, and therefore routine use of empirical antifungal therapy is not recommended A-III.
Prophylaxis against Candida infection is recommended in patient groups in whom the risk of invasive candidal infection is substantial, such as allogeneic hematopoietic stem cell transplant HSCT recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia A-I.
Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and caspofungin are all acceptable alternatives.
Prophylaxis against Aspergillus infection in pre-engraftment allogeneic or autologous transplant recipients has not been shown to be efficacious. Yearly influenza vaccination with inactivated vaccine is recommended for all patients being treated for cancer A-II.
Influenza virus infection should be treated with neuraminidase inhibitors if the infecting strain is susceptible A-II. In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive treatment empirically C-III. Recommendation Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine during CVC insertion are recommended for all CVC insertions A-I.
Hand hygiene is the most effective means of preventing transmission of infection in the hospital A-II. Standard barrier precautions should be followed for all patients, and infection-specific isolation should be used for patients with certain signs or symptoms A-III.
Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients B-III. Hospital work exclusion policies should be designed to encourage health care workers HCWs to report their illnesses or exposures A-II.
It updates the IDSA document that was last revised in [ 1 ]. Most patients will have no infectious etiology documented. Substantial fluctuation in the epidemiologic spectrum of bloodstream isolates obtained from febrile neutropenic patients has occurred over the past 40 years. Early in the development of cytotoxic chemotherapy, during the s and s, gram-negative pathogens predominated. Then, during the s and s, gram-positive organisms became more common Table 1 [ 6—7 ] because of increased use of indwelling plastic venous catheters, which can allow for colonization by and entry of gram-positive skin flora [ 1 , 6 ].
Currently, coagulase-negative staphylococci are the most common blood isolates in most centers; Enterobacteriaciae eg, Enterobacter species, Escherichia coli and Klebsiella species and nonfermenting gram-negative rods eg, Pseudomonas aeruginosa and Stenotrophomonas species are isolated less often.
Table 1. Common Bacterial Pathogens in Neutropenic Patients Common gram-positive pathogens Staphylococcus aureus, including methicillin-resistant strains Enterococcus species, including vancomycin-resistant strains Viridans group streptococci.
Guidelines in the Management of Febrile Neutropenia for Clinical Practice