ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications

Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications
Literature review current through: Jan 2024.
This topic last updated: Feb 21, 2022.

INTRODUCTION — Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces. Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients [1], an elevated body temperature may be the earliest and only sign of infection. It is critical to recognize neutropenic fever and associated sepsis syndromes early and to initiate empiric systemic antibacterial therapy promptly to avoid progression to a severe sepsis syndrome and possibly death.

Guidelines have been developed for the prevention and management of fever in neutropenic patients with cancer [2-6]. The recommendations below are generally in keeping with the 2010 Infectious Diseases Society of America (IDSA) guidelines [2] and the 2018 American Society of Clinical Oncology (ASCO) and IDSA guidelines [7,8]. Links to guidelines are provided separately. (See 'Society guideline links' below.)

The treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications will be reviewed here. The treatment and prevention of neutropenic fever in adults at high risk for complications are discussed separately. An overview of neutropenic fever syndromes, the risk assessment of patients with neutropenic fever, the diagnostic approach to patients presenting with neutropenic fever, and the use of colony-stimulating factors in patients with chemotherapy-induced neutropenia are also discussed elsewhere. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prevention of infections in hematopoietic cell transplant recipients" and "Overview of neutropenic fever syndromes" and "Risk assessment of adults with chemotherapy-induced neutropenia" and "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Neutropenic fever in children is also presented separately. (See "Fever in children with chemotherapy-induced neutropenia".)

DEFINITIONS

Fever — Fever in neutropenic patients is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period [2]. The definition of fever and appropriate methods for measuring body temperature are discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Fever' and "Overview of neutropenic fever syndromes", section on 'Temperature measurement'.)

Risk of serious complications — The initial clinical evaluation focuses on assessing the risk of serious complications. This risk assessment dictates the approach to therapy, including the need for inpatient admission, intravenous antibiotics, and prolonged hospitalization. The factors that are associated with serious complications are summarized in the following table (table 1) and are discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Risk of serious complications' and "Risk assessment of adults with chemotherapy-induced neutropenia".)

EPIDEMIOLOGY — The majority of infections in patients with neutropenic fever are due to the patient's endogenous microflora. The following table lists the range of pathogens found in both high-risk and low-risk patients with chemotherapy-induced neutropenia (table 2). In a single-center study of 863 ambulatory cancer patients with solid tumors or hematologic malignancies, the majority (90 percent) of whom had Multinational Association of Supportive Care in Cancer (MASCC) scores ≥21 attending a tertiary care emergency department for 1001 neutropenic fever episodes, unexplained fevers accounted for 67 percent of the episodes, clinically documented infections for 21 percent (with respiratory tract infections accounting for about two-thirds of these), and microbiologically documented infections for 12 percent (where bacteremic infections accounted for 6 percent and nonbacteremic infections for 6 percent) [9]. Enteric gram-negative bacilli accounted for 52 percent of the bloodstream infections, Pseudomonas aeruginosa for 12 percent, and gram-positive cocci for 34 percent.

In another study, the most common bloodstream isolates in low-risk patients were gram-positive cocci in almost one half (49 percent) of the cases, with the majority being due to coagulase-negative staphylococci or Staphylococcus aureus (table 2) [10]. Just over one-third (36 percent) of bloodstream isolates were gram-negative bacilli, of which just over one half (52 percent) were due to members of the family Enterobacteriaceae (Escherichia coli, Klebsiella spp, and Enterobacter spp), and the remainder were due to nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp, and Haemophilus influenzae.

The use of antibacterial chemoprophylaxis strategies such as the fluoroquinolones intended to target gram-negative bacilli may select for resistant organisms such as gram-positive cocci. A related major concern is that increasing rates of antibacterial resistance have been observed among patients (including neutropenic patients) with health care-associated bacterial infections [11-13]. Examples of prevalent resistant bacteria include fluoroquinolone-resistant E. coli and P. aeruginosa, carbapenem-resistant Enterobacteriaceae, methicillin-resistant S. aureus, and vancomycin-resistant enterococci. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Vancomycin-resistant enterococci: Epidemiology, prevention, and control" and "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection", section on 'Antimicrobial resistance'.)

Characteristics among low-risk febrile neutropenic patients that may be associated with a higher risk for bacteremic infection include initial hypotension, the presence of a clinical focus of infection, a temperature ≥39°C (102.2°F), the presence of a central venous access device, a C-reactive protein of ≥100 mg/L (10 mg/dL), and an absolute neutrophil count (ANC) <100 cells/microL [14]. Characteristics among bacteremic patients that are predictive of mortality include the presence of acute kidney injury, health care-associated infection, age ≥65 years, an ANC <100 cells/microL, and a Charlson comorbidity index of ≥4 [15].

Fungal infections are uncommon in low-risk patients with neutropenic fever; however, the incidence of invasive fungal infection (eg, invasive aspergillosis, cryptococcosis, and pneumocystosis) among neutropenic ibrutinib recipients may be higher than expected. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors'.)

Reactivation of herpes simplex virus and varicella-zoster virus, also relatively uncommon in low-risk patients, may also be more frequent in patients with renal cell carcinoma receiving mTOR inhibitors (sirolimus, everolimus) [16].

During the pandemic, coronavirus disease 2019 is always a possibility. While immunocompromised patients do not appear to be at higher risk for its acquisition, they are at higher risk for more severe disease. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness' and "COVID-19: Considerations in patients with cancer".)

Further, treatment with immune-augmenting checkpoint inhibitors (PD-1: nivolumab or pembrolizumab; PDL-1 inhibitors: atezolizumab, avelumab, or durvalumab; CTLA-4 inhibitor: ipilimumab) for such malignancies as advanced melanoma, advanced non-small cell lung cancer, advanced renal cell carcinoma, advanced uroepithelial cancer, Merkel cell carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, and head or renal cell carcinoma may produce immune-related adverse effects (skin, gastrointestinal, liver, endocrine organs) that must be discriminated from infections. The immunosuppressive regimens (eg, glucocorticoids, infliximab) required to control these immune-related adverse events may themselves predispose to opportunistic infections.

The epidemiology of infections in patients with neutropenic fever is discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Epidemiology'.)

INITIAL ASSESSMENT — In patients presenting with neutropenic fever, a reliable method for obtaining body temperature must be used, and a mechanism for estimating the absolute neutrophil count (ANC) is mandatory. The temperature should be taken using oral or tympanic thermometry. (See "Overview of neutropenic fever syndromes", section on 'Temperature measurement'.)

Risk of neutropenia — Patients and their families should be instructed by their hematologist or oncologist to inform health care providers in the triage setting about recent chemotherapy, and providers in the triage setting should ask cancer patients who do not offer this information about recent chemotherapy. The ANC can be estimated based upon the timing of the febrile episode following the first dose of the current cytotoxic chemotherapy or from a laboratory-based measurement of the ANC from a complete blood count (calculator 1). Knowledge that the ANC is expected to reach its nadir of <500 cells/microL a median of 12 to 14 days from day 1 of chemotherapy can guide the clinician to the correct index of suspicion regarding the likelihood of neutropenia before the availability of complete blood count results.

Over 70 percent of cancer recipients who develop systemic therapy-related complications present to emergency triage facilities within four to six weeks of systemic anticancer treatment [17]. The use of a sensitive but nonspecific historical indicator, receipt of systemic anticancer therapy within the preceding six weeks, has been advocated for use in emergency triage departments to identify patients who are likely to be neutropenic [18].

In general, the likelihood of a neutropenic fever episode appears highest among patients receiving intensive cytotoxic therapy for acute leukemia (85 to 95 percent) and lowest among solid tumor patients receiving intermittent cyclical chemotherapy for prostate cancer (approximately 1 percent), breast cancer (approximately 4 percent), colorectal cancer (approximately 5 percent), and lung cancer (approximately 10 percent) (table 3) [8]. The neutropenic fever event rates for lymphoma treatment recipients appear to be intermediate between the two (approximately 20 percent).

High risk versus low risk — As discussed above, it is crucial to assess the risk for serious complications in patients with neutropenic fever, since this assessment will dictate the approach to therapy, including the need for inpatient admission and intravenous antibiotics, and the likelihood of prolonged hospitalization. (See 'Risk of serious complications' above.)

Risk of sepsis — Although the signs and symptoms of infection may be significantly muted in neutropenic patients [1,19], an early part of the clinical assessment at triage should include an examination for evidence of a systemic inflammatory response syndrome and a determination of the criteria for sepsis, severe sepsis, or septic shock (algorithm 1) [18]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions'.)

Patients presenting with evidence of new organ dysfunction (altered mental status, hypotension, hypoxia, or oliguria) should be managed emergently for severe sepsis. The following algorithm provides a suggested time-dependent care pathway for neutropenic cancer patients presenting at an emergency triage facility based upon historical and observational clinical criteria assessable at presentation (algorithm 1). Patients with evidence for septic shock should be managed in a critical care hospital environment. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Diagnostic evaluation — The diagnostic evaluation of patients presenting with neutropenic fever should be obtained promptly. The diagnostic approach is summarized in the following table (table 4) and is discussed in detail separately. (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

During the coronavirus disease 2019 pandemic, all patients should be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Enhanced infection control measures and personal protective equipment (eg, respirator use, face shields or eye protection, gowns, gloves) are recommended to limit transmission while excluding infection. (See "COVID-19: General approach to infection prevention in the health care setting".)

EMPIRIC THERAPY

General principles — Fever in a neutropenic patient should be considered a medical emergency. Assessment by a physician should occur soon (eg, within 15 minutes) after triage for patients presenting with neutropenic fever within six weeks of having received chemotherapy for malignancy [7]. Broad-spectrum antibacterials should be given as soon as possible (within 60 minutes of triage) and at full doses, adjusted for renal and/or hepatic function. In addition, the diagnostic evaluation should be obtained quickly. (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

The aim of empiric therapy is to cover the spectrum of the most likely and most virulent pathogens that may rapidly cause serious or life-threatening infection in neutropenic patients (table 2) [2]. The following general principles apply:

Antibiotics are usually administered empirically but should always include appropriate coverage for suspected or known infections. Even when the pathogen is known, the antibiotic regimen should provide broad-spectrum empiric coverage for the possibility of copathogens, unlike the treatment strategy adopted in many immunocompetent hosts.

Initial antibiotic selection should be guided by the patient's history, allergies, symptoms, signs, recent or concurrent antibiotic use and culture data, and awareness of the susceptibility patterns of institutional nosocomial pathogens [20].

Ideally, antibiotics should be bactericidal and should be administered through alternate ports of central venous catheters, if present.

Clinical response and culture and susceptibility results should be monitored closely; therapy should be adjusted in a timely fashion in response to this information [21].

Timing of antibiotics — In all febrile neutropenic patients, empiric broad-spectrum antibacterial therapy targeting aerobic gram-negative bacilli and microaerophilic gram-positive cocci should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed [18,22]. Antimicrobial therapy should be administered within 60 minutes of presentation (algorithm 1) [7,18,23,24]. Some investigators have argued that initial empiric antimicrobial therapy should be administered within 30 minutes [25]; we agree that antibiotics should be given as early as possible. This is discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Timing of antibiotics'.)

Spectrum of coverage — Although gram-positive bacteria are the most frequent pathogens identified during neutropenic fever episodes, it is important to cover broadly for aerobic gram-negative pathogens because of their virulence and association with severe sepsis syndromes [26,27]. Furthermore, gram-negative organisms continue to cause the majority of infections in sites outside of the bloodstream (eg, respiratory tract, biliary tract, gastrointestinal tract, urinary tract, and skin) [28], and a rising number of infections are polymicrobial [26,27,29]. Clinicians need to be aware of the current microbiology surveillance data from their own institution, which can vary widely from center to center and over time [20,26]. The decision about the optimal spectrum of coverage for an individual patient must take into account the impact of antibacterial prophylaxis when such strategies have been employed.

Antibiotic resistance in patients with neutropenic fever is discussed in detail separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Antibiotic resistance'.)

Initial regimen — The initial regimen and site of care (inpatient versus outpatient) depends on whether the patient is at high risk or low risk for medical complications (table 1) (see 'Risk of serious complications' above):

All patients who are considered to be high risk require hospital admission for intravenous (IV) antibiotics and often require a prolonged length of stay. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

In contrast, patients who clearly meet all criteria for being low risk can be given oral antibiotics as outpatients, following either a brief period of observation or a short hospital admission. (See 'Site of care' below.)

Our preferred empiric oral antibacterial regimen for low-risk patients not receiving fluoroquinolone-based prophylaxis and who are not known to be colonized by extended-spectrum beta-lactamase-producing gram-negative bacilli involves a combination of ciprofloxacin 750 mg orally twice daily and a beta-lactam agent, such as amoxicillin-clavulanate (500 mg/125 mg orally three times daily or 875 mg/125 mg orally twice daily) [2,7,30]. Levofloxacin 750 mg orally once daily can be used as an alternative to ciprofloxacin (in combination with amoxicillin-clavulanate), but we favor the ciprofloxacin-containing regimen because the added gram-positive activity of levofloxacin compared with ciprofloxacin is not necessary when amoxicillin-clavulanate is used [7].

Another alternative is to give monotherapy with either levofloxacin or moxifloxacin (400 mg orally once daily) [30,31], but we generally reserve these options for patients who are allergic to penicillin and who also cannot take a cephalosporin. Of the three fluoroquinolones, ciprofloxacin has the best activity against P. aeruginosa, but levofloxacin generally has adequate anti-Pseudomonas activity when dosed at 750 mg daily. Moxifloxacin is less active against P. aeruginosa than ciprofloxacin and levofloxacin.

For patients who have a history of penicillin hypersensitivity, another option is to give clindamycin (300 mg four times daily) in place of amoxicillin-clavulanic acid or, if a cephalosporin is deemed to be safe, to give cefixime (400 mg once daily) [2]. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

Patients receiving fluoroquinolone-based antibacterial prophylaxis should not receive a fluoroquinolone-based initial empiric antibacterial therapy [2,32]. Such patients should receive one of the IV regimens recommended for high-risk patients in order to provide adequate activity against P. aeruginosa (algorithm 2); the fluoroquinolones are the only oral antibiotics with activity against P. aeruginosa. In patients with known colonization or prior infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae or fluoroquinolone-resistant organisms, outpatient fluoroquinolone-based antibacterial therapy may not be appropriate and hospitalization for IV carbapenem-based therapy should be considered. This strategy may also be appropriate in hospitals with high prevalence of these resistant organisms. (See 'Epidemiology' above.)

It is reasonable to give an IV antibiotic regimen on an outpatient basis provided that the patient meets all the criteria for being at low risk for complications. Empiric IV regimens for neutropenic fever are discussed in detail separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Initial regimen'.)

In two trials of low-risk in patients with neutropenic fever, oral ciprofloxacin plus amoxicillin-clavulanate had similar efficacy to IV regimens [33,34]. In one of these trials, treatment was successful without the need for modifications in 71 percent of episodes in those who received an oral regimen, compared with 67 percent of episodes in those who received IV ceftazidime [33]. In a meta-analysis of 22 trials that compared oral antibiotics with IV antibiotics in patients with neutropenic fever, both the mortality rate and the treatment failure rate were similar in both groups [35]. Gastrointestinal adverse events were more common in those who received oral antibiotics.

In a randomized trial, patients with neutropenic fever who were considered to be at low risk for complications were assigned to receive either moxifloxacin monotherapy or combination therapy with ciprofloxacin plus amoxicillin-clavulanate [30]. A successful response was defined as defervescence and improvement in clinical status during study drug treatment, remaining free of relapsing infection, and having no documented infection caused by bacteria with in vitro resistance to the study drugs. Among the 333 patients included in the intention-to-treat analysis, a successful response was observed in an equivalent percentage of patients in each group (80 versus 82 percent for moxifloxacin and ciprofloxacin-amoxicillin-clavulanate, respectively). Survival was also similar in both groups (99 percent each). However, the findings in this study may not apply to regions that have high local rates of Pseudomonas infections and/or fluoroquinolone-resistant Enterobacteriaceae [36].

Site of care — As stated above, patients who meet all criteria for being at low risk for complications of neutropenic fever can be treated as outpatients, following either a brief period of observation or a short hospital admission (see 'Risk of serious complications' above). The initial therapy for neutropenic patients who are being considered for outpatient management and who have evidence of a systemic inflammatory response syndrome (SIRS) or a sepsis syndrome (SIRS plus a clinical focus of infection) should be administered under observation to ascertain tolerance and ensure timeliness of administration of the first dose. We favor monitoring patients for at least four hours after the initial dose of antibiotics before sending them home [2,7]. Most studies have observed patients in the hospital for the first 24 hours of empiric therapy, although in some studies patients were discharged as early as six hours after the initial dose of antibiotics was administered [37].

Hospitalized low-risk patients who are initially given IV antibiotics and who are stable and have responded to therapy, especially those classified as having unexplained neutropenic fever, may be switched to an oral regimen and discharged [7]. In such patients, plans should be made for outpatient follow-up and monitoring.

The benefits of outpatient oral therapy include reduced cost [38], lack of need for IV access, and improved patient acceptance [2,37]. Not only outpatient oral therapy but also outpatient IV therapy are less costly than inpatient IV therapy [39]. In a survey of physician members of the American Society of Clinical Oncology, outpatient antibiotics were used by 82 percent of respondents for selected low-risk patients with neutropenic fever [40].

A 2019 Cochrane meta-analysis of six randomized trials comparing inpatient and outpatient treatment for low-risk adult cancer patients with neutropenic fever found no clear evidence of different rates of treatment failure, mortality, or adverse drug reactions based on the site of care [41].

Readmission rates for outpatients managed with oral fluoroquinolone-based initial empiric antibacterial therapy have been reported to be in the range of 3 to 10 percent [42-45].

Monitoring — Defervescence of fever and resolution of foci of infection present at baseline have been the primary outcomes sought by medical teams treating patients with neutropenic fever syndromes. The observed median times to defervescence for patients with neutropenic fever at high risk and low risk for medical complications have been five days and two days, respectively [2].

Febrile neutropenic patients should be monitored frequently in clinic or at home for at least the initial three days following presentation with neutropenic fever [7]. Features to monitor include vital signs (blood pressure, heart rate, respiratory rate, and temperature), performance status (the clinical burden of the neutropenic fever syndrome), and the ability to achieve adequate oral intake in the presence of oral or gastrointestinal mucositis. Attention to fluid and electrolyte management is important given the dehydrating effects of fever, vomiting, and/or diarrhea. Temporarily holding administration of systemic chemotherapy should be considered during the management of the sepsis syndrome until the patient stabilizes.

After the initial few days, patients should continue to be monitored with frequent (up to daily) telephone contact to verify resolution of fever. Patients should also have frequent clinic visits. The absolute neutrophil count (ANC) and platelet count should be monitored to evaluate for myeloid reconstitution.

Patients deemed eligible for outpatient management must be able to access medical care 24 hours daily, seven days per week, and should be able to reach the medical facility within one hour should the clinical condition worsen. Patients should be admitted to the hospital for IV antimicrobial therapy if they develop fever recrudescence, new signs or symptoms of infection, an inability to tolerate oral antibiotics, or if diagnostic tests identify species not susceptible to the initial empiric regimen [2,7]. Persistence of fever beyond the expected median time to defervescence of two to three days should mandate a reassessment and consideration of modification of the initial empiric regimen and hospital admission. Persistent fever alone in a stable patient unaccompanied by any other signs or symptoms of progressive or new infection is not in itself a circumstance that warrants regimen modification [2,32]. The need to modify the regimen should be driven by clinical and/or microbiologic evidence for resistant organisms and evidence of ongoing and progressive infection.

Duration — The duration of antibacterial therapy for patients with clinically or microbiologically documented infections depends upon the clinical syndrome and pathogen. In general, antibacterial therapy is continued until myeloid reconstitution, defined by recovery of the ANC to ≥500 cells/microL (calculator 1).

The duration of treatment for unexplained fevers is largely a function of response to treatment, defined by defervescence and myeloid reconstitution. A trial of empiric oral antibacterial therapy in low-risk febrile neutropenic patients showed that more than half of the patients had defervesced by day 2 of treatment [30]. In clinical trials, sustained defervescence has been defined as an afebrile period of four to five days among high-risk patients and 48 to 72 hours for low-risk patients [2]. Accordingly, the duration of antibacterial therapy in low-risk patients with negative blood cultures has been based upon documentation of at least two afebrile days after the ANC has recovered. Among patients in whom the ANC has not recovered to >500 cells/microL, antibacterial therapy should be continued until the patient has been afebrile for five to seven days [32].

Most documented infections, such as pneumonia or bloodstream infection, require 10 to 14 days of therapy, which may extend well beyond the time of myeloid reconstitution [2].

Colony-stimulating factors — Colony-stimulating factors (CSFs; also known as myeloid growth factors or hematopoietic growth factors), such as granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF), are generally not recommended for the management of patients with established fever and neutropenia, with some exceptions. In contrast, the use of CSFs as primary prophylaxis has reduced the incidence of febrile neutropenia, infection-related mortality, and preserved anticancer relative dose intensity [46]. These issues are discussed in detail separately. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Neutropenic fever'.)

MYELOID RECONSTITUTION SYNDROME — Clinicians should be aware of the myeloid reconstitution syndrome, a circumstance in which there may be onset or progression of an inflammatory focus defined clinically or radiologically temporally related to neutrophil recovery [47]. Because such processes may appear in the context of a persistent neutropenic fever syndrome, the likelihood of superinfection must be considered with respect to the antimicrobial spectrum of the patient's current empiric antibacterial therapy and the microbiologic differential diagnosis applicable to those circumstances. (See "Overview of neutropenic fever syndromes", section on 'Neutropenic fever syndromes'.)

OUTCOMES — The efficacy of the treatment of patients with neutropenic fever syndromes has improved greatly, as demonstrated by a progressive decline in mortality rates since the prompt initiation of empiric coverage was implemented in the 1970s [28,48,49]. Studies from the 1960s, before the routine use of empiric therapy, documented mortality rates of 90 percent in neutropenic patients with bacteremia caused by gram-negative bacilli [50,51]. In contrast, in a study of 41,779 adults with cancer who were hospitalized with neutropenic fever in the United States between 1995 and 2000, the in-hospital mortality was 9.5 percent [52]. The mortality rate depended upon the underlying malignancy: 8 percent in patients with solid tumors, 8.9 percent in patients with lymphoma, and 14.3 percent in patients with leukemia. The number of major comorbid conditions also significantly affected the mortality rate. Patients without any comorbidities had a 2.6 percent risk of dying, compared with 10.3 percent in patients with one comorbidity, 21.4 percent in patients with two comorbidities, 38.6 percent in patients with three comorbidities, and 50.6 percent in patients with four comorbidities.

Factors that influence the risk of treatment failure are discussed separately. (See "Risk assessment of adults with chemotherapy-induced neutropenia", section on 'Risk of treatment failure'.)

PREVENTION — Effective infection prevention strategies for low-risk neutropenic patients have focused upon the most common pathogens causing the infections, including pyogenic bacteria, viruses, and fungi. The risk for developing a neutropenic fever syndrome and experiencing serious complications should be evaluated in consultation with an infectious diseases specialist, considering patient-related, disease-related, and treatment-related factors. (See "Risk assessment of adults with chemotherapy-induced neutropenia".)

Antibacterial prophylaxis — Fluoroquinolone-based antibacterial prophylaxis has been effective in reducing febrile events and invasive gram-negative infections in high-risk neutropenic patients (table 1) [53-55]. Although randomized controlled studies in low-risk patients have demonstrated some protective effects [56], the number of low-risk patients requiring treatment in order to prevent one infection has been high [57]. Given the increased costs, drug-related adverse effects, susceptibility to superinfection (such as Clostridioides difficile infection [58]), and selection for antimicrobial resistance [55,59-61], we do not recommend the routine use of antibacterial prophylaxis for low-risk patients for whom the duration of neutropenia (absolute neutrophil count [ANC] <500 cells/microL) is anticipated to be seven days or fewer. This approach is consistent with that of the Infectious Diseases Society of America (IDSA) and the American Society of Clinical Oncology (ASCO) [8]. (See 'Risk of serious complications' above.)

Patients with solid tumors who are receiving conventional chemotherapy are generally considered to be at low risk for complications of neutropenia and therefore do not require antibacterial prophylaxis.

Antibacterial prophylaxis for high-risk neutropenic patients is discussed in detail separately. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

Antifungal prophylaxis — The risk for invasive fungal infection due to opportunistic yeasts, such as Candida spp, or molds, such as Aspergillus spp, is very low among patients for whom the anticipated duration of neutropenia (ANC <500 cells/microL) is anticipated to be seven days or fewer. Accordingly, antifungal prophylaxis for patients with solid tumors or lymphoma undergoing conventional chemotherapy with or without concomitant immunotherapies is not recommended [2,8]. As described above for antibacterial prophylaxis, this approach is consistent with that of the IDSA and ASCO [8]. (See 'Risk of serious complications' above.)

Antifungal prophylaxis in high-risk patients is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

Pneumocystis prophylaxis — Most low-risk cancer patients do not require prophylaxis against Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP). The indications for PCP prophylaxis are discussed in detail separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Antiviral prophylaxis — Several preventive measures can be used to prevent viral infections in neutropenic patients. Hand hygiene and cough etiquette remain the most important methods for preventing the spread of respiratory virus infections in ambulatory low-risk cancer patients [8]. (See "Infection prevention: Precautions for preventing transmission of infection" and "Infection control in the outpatient setting".)

HSV and VZV — Antiviral prophylaxis against herpes simplex virus (HSV) and varicella-zoster virus (VZV) is generally not used in low-risk neutropenic patients since the rate of reactivation of these viruses is low in such patients. In contrast, antiviral prophylaxis with activity against HSV and VZV is used routinely in high-risk neutropenic patients (eg, patients receiving induction chemotherapy for acute leukemia, hematopoietic cell transplant recipients). This is discussed in detail separately. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'HSV and VZV'.)

Influenza — Prevention of influenza virus should be considered well in advance of the development of neutropenia. Annual immunization with an inactivated influenza vaccine is recommended for all patients being treated for cancer [2,62]. Although the optimal timing for such immunization has not been established, the vaccine is generally administered >2 weeks before chemotherapy starts or, when circumstances dictate, between chemotherapy cycles and at least seven days after the last cycle [2]. Annual immunization of all family members and other close contacts is also recommended. (See "Seasonal influenza vaccination in adults" and "Immunizations in adults with cancer", section on 'Influenza vaccine'.)

Chemoprophylaxis to prevent influenza virus is indicated under certain circumstances. This is discussed in greater detail separately. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

Hepatitis B — Solid tumor and lymphoma patients receiving chemotherapy who have a history of previous hepatitis B virus infection are at risk of reactivation with a flare of hepatitis that may potentially result in hepatic failure [63]. Patients with elevated circulating hepatitis B deoxyribonucleic acid (DNA) or detectable levels of circulating hepatitis B surface antigen (HBsAg) are at particular risk. Those who have been infected and cleared the virus from the circulation and developed antibody to HBsAg or to hepatitis B core antigen are also at risk. Antiviral prophylaxis should be considered for such patients at risk for reactivation; when used, antiviral prophylaxis should be started one week before chemotherapy begins and continued for at least six months after the completion of chemotherapy [8,63]. This strategy can reduce the risk for reactivation from 24 to 53 percent to 0 to 5 percent [64]. The choice of agent is discussed in detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

COVID-19 prevention

Vaccination − Vaccination against SARS-CoV-2 is recommended for all immunocompromised patients who lack contraindications. The timing of vaccination and number of required doses is discussed separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Considerations in patients with cancer".)

Because the immune response to vaccination may be blunted in these patients, continued personal measures to minimize SARS-CoV-2 exposure (eg, wearing masks, careful hand hygiene, and physical distancing) is recommended regardless of vaccination status. Household and other close contacts of immunocompromised patients should be vaccinated. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

Pre-exposure prophylaxis − Because patients with cancer are at high risk for poor outcomes from coronavirus disease 2019 (COVID-19) infection due to immune suppression and because they may not mount effective responses to vaccination, we offer and try to obtain pre-exposure prophylaxis against SARS-COV-2 for cancer patients actively receiving immunosuppressive therapy or those with moderate to severe residual immunocompromise after completion of treatment. In the United States, tixagevimab-cilgevimab has been authorized for emergency use for individuals 12 years or older (weighing at least 40 kg). (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)

Postexposure prophylaxis – Many cancer patients are eligible for postexposure prophylaxis because of their immunosuppressed status; however, available monoclonal antibodies have limited activity against the Omicron variant and thus are not being routinely used. (See "COVID-19: Epidemiology, virology, and prevention", section on 'No role for post-exposure prophylaxis'.)

Colony-stimulating factors — The use of colony-stimulating factors (CSFs) as primary prophylaxis has reduced the incidence of febrile neutropenia, infection-related mortality, and preserved anticancer relative dose intensity [46]. Guidelines from the Infectious Diseases Society of America [2], the European Society of Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) [65] recommend primary CSF prophylaxis be considered for patients in whom the anticipated risk of chemotherapy-induced fever and neutropenia is ≥20 percent. These issues are discussed in detail separately. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Neutropenic fever'.)

In the setting of the COVID-19 pandemic, ASCO, ESMO, and the National Comprehensive Cancer Network have expanded the recommendations for primary CSF prophylaxis to include recipients of cytotoxic regimens with an intermediate risk (>10 percent) for febrile neutropenia [6]. (See "COVID-19: Considerations in patients with cancer" and "Society guideline links: COVID-19 – Hematology care (including hematologic malignancies and transplantation)".)

Infection control precautions — Infection control precautions for patients who are hospitalized with neutropenic fever and infection control precautions for COVID-19 are discussed separately. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'General precautions'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neutropenic fever in adults with cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Neutropenia and fever in people being treated for cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS — The recommendations below apply to patients who are at low risk for complications of neutropenic fever. The treatment and prevention of neutropenic fever in high-risk patients are discussed separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

Overview

Early recognition of neutropenic fever − Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces. Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients, an elevated body temperature may be the earliest and only sign of infection. It is critical to recognize neutropenic fever early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death. (See 'Introduction' above.)

Risk of serious complications − It is crucial that there be an assessment of the risk of serious complications in patients with neutropenic fever, since this assessment will dictate the approach to therapy, including the need for inpatient admission and intravenous (IV) antibiotics, and the likelihood of prolonged hospitalization. Low-risk patients are those in whom the duration of severe neutropenia (absolute neutrophil count [ANC] <500 cells/microL) is expected to be seven days or fewer and those with no comorbidities or evidence of significant hepatic or renal dysfunction. Most patients receiving chemotherapy for solid tumors are considered to be low risk. (See 'Risk of serious complications' above.)

Common infections in low-risk patients − The most common bloodstream isolates in low-risk patients are gram-positive cocci (in almost one-half the cases), with the majority being due to coagulase-negative staphylococci or Staphylococcus aureus. Just over one-third of bloodstream isolates are due to gram-negative bacilli. Fungal infections are uncommon in low-risk patients with neutropenic fever. Reactivation of herpes simplex virus and varicella-zoster virus is also rare in low-risk patients. The following table lists the range of pathogens found in both high-risk and low-risk patients with chemotherapy-induced neutropenia (table 2). (See 'Epidemiology' above.)

COVID-19 − During the pandemic, SARS-CoV-2 is possible diagnosis even among vaccinated patients. (See "COVID-19: Considerations in patients with cancer".)

Initial assessment

Febrile neutropenia as a medical emergency − Fever in a neutropenic patient should be considered a medical emergency. Empiric broad-spectrum antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed. (See 'General principles' above and 'Timing of antibiotics' above.)

Prompt empiric antibiotic treatment − All patients who have received systemic anticancer therapy within the previous six weeks and who present to an emergency department with a systemic inflammatory response syndrome should be presumed to have a neutropenic sepsis syndrome until proven otherwise. Empiric broad-spectrum antimicrobial therapy should be administered within 60 minutes of presentation for patients presenting with neutropenic fever and a sepsis syndrome, severe sepsis, or septic shock (algorithm 1). Some investigators have argued that initial empiric antimicrobial therapy should be administered within 30 minutes; we agree that antibiotics should be given as early as possible. (See 'Risk of neutropenia' above and 'Timing of antibiotics' above.)

Evaluation − The diagnostic evaluation should be obtained promptly and should include testing for SARS-CoV-2 during the pandemic (table 4). (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

Empiric therapy

Intravenous therapy for hospitalized patients − All patients who are considered to be high risk require hospital admission for intravenous antibiotics. (See 'Initial regimen' above.)

Empiric regimen selection − Although gram-positive bacteria are the most frequent pathogens identified during neutropenic fever episodes, it is important to cover broadly for gram-negative pathogens because of their virulence and association with sepsis. For the initial empiric oral antibacterial regimen for low-risk patients with neutropenic fever, we recommend a combination of ciprofloxacin 750 mg orally twice daily and amoxicillin-clavulanic acid (500 mg/125 mg orally three times daily or 1000 mg/250 mg orally twice daily) (Grade 1B). Patients receiving fluoroquinolone-based antibacterial prophylaxis should not receive a fluoroquinolone-based initial empiric antibacterial therapy. In patients with known colonization or prior infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae or fluoroquinolone-resistant organisms, outpatient fluoroquinolone-based antibacterial therapy may not be appropriate and hospitalization for intravenous carbapenem-based therapy should be considered. This strategy may also be appropriate in hospitals with a high prevalence of these resistant organisms. (See 'Initial regimen' above.)

Outpatient treatment criteria − Patients who meet all criteria for being at low risk for complications of neutropenic fever can be treated as outpatients, following either a brief period of observation or a short hospital admission. We favor monitoring patients for at least four hours after the initial dose of antibiotics before sending them home. (See 'Site of care' above.)

Close monitoring of outpatients − Patients deemed eligible for outpatient management must be able to access medical care 24 hours daily, seven days per week, and should be able to reach the medical facility within one hour should the clinical condition worsen. Fever recrudescence or new signs of infection should mandate admission to the hospital for intravenous antibacterial therapy. (See 'Monitoring' above.)

Prevention

Antibacterial prophylaxis − We do not recommend antibacterial prophylaxis for low-risk patients (eg, patients with solid tumors who are receiving conventional chemotherapy) for whom the duration of neutropenia (ANC <500 cells/microL) is anticipated to be seven days or fewer (Grade 1B). (See 'Antibacterial prophylaxis' above.)

Antifungal prophylaxis − We do not recommend antifungal prophylaxis for low-risk patients for whom the anticipated duration of neutropenia (ANC <500 cells/microL) is anticipated to be seven days or fewer (Grade 1B). (See 'Antifungal prophylaxis' above.)

COVID-19 vaccination − Vaccination against SARS-CoV-2 is recommended for all immunocompromised patients who lack contraindications. The timing of vaccination and number of required doses is discussed separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Considerations in patients with cancer".)

COVID-19 prevention − Pre- and postexposure prophylaxis for COVID-19 is also discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis' and "COVID-19: Epidemiology, virology, and prevention", section on 'No role for post-exposure prophylaxis'.)

  1. Sickles EA, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Arch Intern Med 1975; 135:715.
  2. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.
  3. Infectious Diseases Society of Taiwan, Hematology Society of Taiwan, Medical Foundation in Memory Dr. Deh-Lin Cheng, et al. Guidelines for the use of antimicrobial agents in patients with febrile neutropenia in Taiwan. J Microbiol Immunol Infect 2005; 38:455.
  4. Weissinger F, Auner HW, Bertz H, et al. Antimicrobial therapy of febrile complications after high-dose chemotherapy and autologous hematopoietic stem cell transplantation--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2012; 91:1161.
  5. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2018. http://www.nccn.org (Accessed on August 01, 2018).
  6. Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol 2016; 27:v111.
  7. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol 2018; 36:1443.
  8. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol 2018; 36:3043.
  9. Ko BS, Ahn S, Lee YS, et al. Impact of time to antibiotics on outcomes of chemotherapy-induced febrile neutropenia. Support Care Cancer 2015; 23:2799.
  10. Kamana M, Escalante C, Mullen CA, et al. Bacterial infections in low-risk, febrile neutropenic patients. Cancer 2005; 104:422.
  11. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013; 34:1.
  12. Satlin MJ, Calfee DP, Chen L, et al. Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies. Leuk Lymphoma 2013; 54:799.
  13. Bow EJ. There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy. J Antimicrob Chemother 2013; 68:492.
  14. Ha YE, Song JH, Kang WK, et al. Clinical factors predicting bacteremia in low-risk febrile neutropenia after anti-cancer chemotherapy. Support Care Cancer 2011; 19:1761.
  15. Tumbarello M, Trecarichi EM, Caira M, et al. Derivation and validation of a scoring system to identify patients with bacteremia and hematological malignancies at higher risk for mortality. PLoS One 2012; 7:e51612.
  16. Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect 2018; 24 Suppl 2:S53.
  17. McKenzie H, Hayes L, White K, et al. Chemotherapy outpatients' unplanned presentations to hospital: a retrospective study. Support Care Cancer 2011; 19:963.
  18. Bell MS, Scullen P, McParlan D, et al. Neutropenic sepsis guidelines. Northern Ireland Cancer Network, Belfast 2010. p. 1-11.
  19. Sickles EA, Young VM, Greene WH, Wiernik PH. Pneumonia in acute leukemia. Ann Intern Med 1973; 79:528.
  20. Sepkowitz KA. Treatment of patients with hematologic neoplasm, fever, and neutropenia. Clin Infect Dis 2005; 40 Suppl 4:S253.
  21. Lazarus HM, Creger RJ, Gerson SL. Infectious emergencies in oncology patients. Semin Oncol 1989; 16:543.
  22. Link H, Böhme A, Cornely OA, et al. Antimicrobial therapy of unexplained fever in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society). Ann Hematol 2003; 82 Suppl 2:S105.
  23. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296.
  24. Chemotherapy services in England: Ensuring quality and safety. National Chemotherapy Advisory Group, London 2009.
  25. Rosa RG, Goldani LZ. Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother 2014; 58:3799.
  26. Rolston KV. Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. Clin Infect Dis 2005; 40 Suppl 4:S246.
  27. Viscoli C, Castagnola E. Planned progressive antimicrobial therapy in neutropenic patients. Br J Haematol 1998; 102:879.
  28. Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis 2005; 40 Suppl 4:S240.
  29. Pagano L, Caira M, Nosari A, et al. Etiology of febrile episodes in patients with acute myeloid leukemia: results from the Hema e-Chart Registry. Arch Intern Med 2011; 171:1502.
  30. Kern WV, Marchetti O, Drgona L, et al. Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy--EORTC infectious diseases group trial XV. J Clin Oncol 2013; 31:1149.
  31. Cornely OA, Wicke T, Seifert H, et al. Once-daily oral levofloxacin monotherapy versus piperacillin/tazobactam three times a day: a randomized controlled multicenter trial in patients with febrile neutropenia. Int J Hematol 2004; 79:74.
  32. de Naurois J, Novitzky-Basso I, Gill MJ, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010; 21 Suppl 5:v252.
  33. Freifeld A, Marchigiani D, Walsh T, et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999; 341:305.
  34. Kern WV, Cometta A, De Bock R, et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1999; 341:312.
  35. Vidal L, Ben Dor I, Paul M, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst Rev 2013; :CD003992.
  36. Slavin MA, Thursky KA. Outpatient therapy for fever and neutropenia is safe but implementation is the key. J Clin Oncol 2013; 31:1128.
  37. Freifeld AG, Sepkowitz KA. No place like home? Outpatient management of patients with febrile neutropenia and low risk. J Clin Oncol 2011; 29:3952.
  38. Elting LS, Lu C, Escalante CP, et al. Outcomes and cost of outpatient or inpatient management of 712 patients with febrile neutropenia. J Clin Oncol 2008; 26:606.
  39. Hendricks AM, Loggers ET, Talcott JA. Costs of home versus inpatient treatment for fever and neutropenia: analysis of a multicenter randomized trial. J Clin Oncol 2011; 29:3984.
  40. Freifeld A, Sankaranarayanan J, Ullrich F, Sun J. Clinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA. Support Care Cancer 2008; 16:181.
  41. Rivas-Ruiz R, Villasis-Keever M, Miranda-Novales G, et al. Outpatient treatment for people with cancer who develop a low-risk febrile neutropaenic event. Cochrane Database Syst Rev 2019; 3:CD009031.
  42. Innes HE, Smith DB, O'Reilly SM, et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study. Br J Cancer 2003; 89:43.
  43. Innes H, Billingham L, Gaunt C, et al. Management of febrile neutropenia in the United Kingdom: time for a national trial? Br J Cancer 2005; 93:1324.
  44. Girmenia C, Russo E, Carmosino I, et al. Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia. Ann Hematol 2007; 86:263.
  45. Sebban C, Dussart S, Fuhrmann C, et al. Oral moxifloxacin or intravenous ceftriaxone for the treatment of low-risk neutropenic fever in cancer patients suitable for early hospital discharge. Support Care Cancer 2008; 16:1017.
  46. Wang L, Baser O, Kutikova L, et al. The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer 2015; 23:3131.
  47. Bow EJ. Neutropenic fever syndromes in patients undergoing cytotoxic therapy for acute leukemia and myelodysplastic syndromes. Semin Hematol 2009; 46:259.
  48. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med 1971; 284:1061.
  49. Klastersky J, Cappel R, Debusscher L. Evaluation of gentamicin with carbenicillin in infections due to gram-negative bacilli. Curr Ther Res Clin Exp 1971; 13:174.
  50. Klastersky J. The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Why empirical therapy? J Antimicrob Chemother 2009; 63 Suppl 1:i14.
  51. Gram-negative bacteremia, clinical, laboratory and therapeutic observations. Arch Intern Med 1962; 110:856.
  52. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006; 106:2258.
  53. Bow EJ. Point: fluoroquinolone-based antibacterial chemoprophylaxis in neutropenic cancer patients works for defined outcomes in defined populations, but must be used wisely. J Natl Compr Canc Netw 2004; 2:433.
  54. Bow EJ. Prophylaxis. In: Managing Infections in Patients with Hematological Malignancies, Kleinberg M (Ed), Humana Press, 2009. p.259.
  55. Egan G, Robinson PD, Martinez JPD, et al. Efficacy of antibiotic prophylaxis in patients with cancer and hematopoietic stem cell transplantation recipients: A systematic review of randomized trials. Cancer Med 2019; 8:4536.
  56. Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005; 353:988.
  57. Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med 2005; 353:1052.
  58. Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254.
  59. Kern WV, Andriof E, Oethinger M, et al. Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center. Antimicrob Agents Chemother 1994; 38:681.
  60. Carratalá J, Fernández-Sevilla A, Tubau F, et al. Emergence of quinolone-resistant Escherichia coli bacteremia in neutropenic patients with cancer who have received prophylactic norfloxacin. Clin Infect Dis 1995; 20:557.
  61. Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis 2011; 24:545.
  62. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013; 31:794.
  63. Lubel JS, Angus PW. Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: diagnosis and management. J Gastroenterol Hepatol 2010; 25:864.
  64. Firpi RJ, Nelson DR. Viral hepatitis: manifestations and management strategy. Hematology Am Soc Hematol Educ Program 2006; :375.
  65. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 33:3199.
Topic 13951 Version 41.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟