Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults

INTRODUCTION — Intensive cytotoxic chemotherapy can cause severe and sometimes prolonged neutropenia, which may result in hospitalization for treatment of fever or cause potentially fatal infection. Severe prolonged neutropenia is most likely to occur in the pre-engraftment phase of hematopoietic cell transplantation (particularly allogeneic) and in patients undergoing induction chemotherapy for acute leukemia. One approach to reducing infectious complications involves the use of prophylactic antibacterial, antiviral, and antifungal agents in patients at significant risk of such infections.

Because neutropenic patients are unable to mount robust inflammatory responses, serious infection can occur with minimal symptoms and signs. In such patients, fever is often the only sign of infection. Infections in neutropenic patients can progress rapidly, leading to hypotension and/or other life-threatening complications. Thus, empiric therapy with broad-spectrum antibiotics should be initiated promptly in all febrile neutropenic patients (including those receiving antimicrobial prophylaxis) to reduce the risk of serious morbidity and mortality. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

The role of prophylactic antibacterial and antiviral agents in high-risk adults will be reviewed here. Infection control precautions for patients with chemotherapy-induced neutropenia will also be discussed.

Related topic reviews regarding prophylaxis of infection in neutropenic patients include:

●(See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies".)

●(See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

●(See "Prevention of infections in hematopoietic cell transplant recipients".)

●(See "Prevention of viral infections in hematopoietic cell transplant recipients".)

Topic reviews on neutropenic fever syndromes include

●(See "Overview of neutropenic fever syndromes".)

●(See "Risk assessment of adults with chemotherapy-induced neutropenia".)

●(See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

●(See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●(See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

●(See "Fever in children with chemotherapy-induced neutropenia".)

Preventive measures for coronavirus disease 2019 (COVID-19) are discussed separately.

●(See "COVID-19: Vaccines".)

●(See "COVID-19: General approach to infection prevention in the health care setting".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Considerations in patients with cancer".)

DEFINITIONS

Neutropenia — The definition of neutropenia varies from institution to institution, but neutropenia is usually defined as an absolute neutrophil count (ANC) <1500 or 1000 cells/microL, and severe neutropenia is usually defined as an ANC <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL over the next 48 hours [1]. The risk of clinically important infection rises as the neutrophil count falls below 500 cells/microL and is higher in those with a prolonged duration of neutropenia (>7 days). For the purposes of this discussion, we are defining neutropenia as an ANC <500 cells/microL.

The ANC can be calculated by multiplying the total white blood cell count by the percentage of polymorphonuclear cells and bands (calculator 1). (See "Overview of neutropenic fever syndromes", section on 'Neutropenia' and "Overview of neutropenia in children and adolescents", section on 'Definitions and normal values' and "Approach to the adult with unexplained neutropenia", section on 'Definitions and normal values'.)

High risk criteria — It is crucial to assess the risk of serious complications in patients with chemotherapy-induced neutropenia who develop fever (table 1). This risk assessment is also relevant for patients in whom antimicrobial prophylaxis is being considered, since prophylaxis is generally indicated for high-risk patients.

High-risk patients are those who are expected to be neutropenic (ANC <500 cells/microL) for >7 days. Patients with neutropenic fever who have ongoing comorbidities or evidence of significant hepatic or renal dysfunction are also considered to be high risk, regardless of the duration of neutropenia. By contrast, low-risk patients are those in whom the duration of neutropenia (ANC <500 cells/microL) is expected to be less than seven days and who have no comorbidities and no evidence of significant hepatic or renal dysfunction. It is important to note that the presence of comorbidities and hepatic or renal dysfunction are important for determining the approach to empiric therapy in patients with neutropenic fever, whereas only the risk of neutropenia (ANC <500 cells/microL) is used for determining the need for prophylaxis.

Some experts have defined high-risk patients as those expected to have profound neutropenia (ANC ≤100 cells/microL) for >7 days based on experience that such patients are the most likely to have life-threatening complications [1,2]. However, formal studies to clearly differentiate between patients with an ANC <500 cells/microL and ≤100 cells/microL are lacking. For the purposes of this discourse, we will combine these groups.

The risk assessment of patients with neutropenic fever is discussed in greater detail separately. (See "Risk assessment of adults with chemotherapy-induced neutropenia".)

Prolonged neutropenia is most likely to occur in the pre-engraftment phase of hematopoietic cell transplantation (particularly allogeneic) and in patients undergoing induction chemotherapy for acute leukemia. Additional factors, such as oral and gastrointestinal mucositis, also increase the risk of neutropenic fever [3]. The risk associated with these and other factors are summarized in the following table (table 2).

ANTIBACTERIAL PROPHYLAXIS — Antibacterial prophylactic regimens target Pseudomonas aeruginosa and other gram-negative bacilli, since these pathogens are particularly virulent and may cause life-threatening infections. (See "Overview of neutropenic fever syndromes", section on 'Bacterial pathogens'.)

Indications — Many investigators have sought to determine if the administration of prophylactic antibacterial agents has a beneficial effect on clinical outcomes. The fluoroquinolones, levofloxacin (500 or 750 mg orally once daily) and ciprofloxacin (500 to 750 mg orally twice daily), have been studied most extensively, and levofloxacin is favored in patients at increased risk for oral mucositis-related viridans group streptococcal infection [4]. Results have been mixed with respect to effectiveness and have prompted concern about toxicities and antimicrobial resistance [5-7]. At institutions that use fluoroquinolone prophylaxis, systematic monitoring of the prevalence of fluoroquinolone resistance among gram-negative bacilli should be performed.

Based upon the available data, we suggest fluoroquinolone prophylaxis for high-risk neutropenic patients (patients anticipated to have an absolute neutrophil count [ANC] <500 cells/microL for >7 days) who do not have a contraindication to receiving a fluoroquinolone (table 1) [1]. High-risk patients include patients undergoing allogeneic hematopoietic cell transplantation (HCT) and patients receiving induction chemotherapy for acute leukemia [1,4,8]. (See 'High risk criteria' above.)

Antibacterial prophylaxis is sometimes given to an additional category of "intermediate-risk" patients, as discussed below. The decision of whether to give antibacterial prophylaxis to intermediate-risk patients should be made on a case-by-case basis. (See 'Guidelines' below.)

When considering the use of fluoroquinolone prophylaxis, caution is indicated in patients at risk of a prolonged QT interval because QT prolongation is a known toxicity. This is particularly important to consider in patients who may require other QT prolonging agents, such as voriconazole (table 3). Tendon rupture has also been reported with fluoroquinolone use. Further, doses need to be reduced in patients with renal insufficiency. (See "Fluoroquinolones", section on 'QT interval prolongation' and "Fluoroquinolones", section on 'Tendinopathy'.)

Another important consideration when deciding whether or not to give fluoroquinolone prophylaxis involves the risk of promoting resistance among both gram-negative and gram-positive bacteria [7]. In institutions and geographic regions in which there are appreciable rates of fluoroquinolone resistance, the use of these agents for prophylaxis is less likely to be effective [6,9]. In one study, HCT recipients receiving levofloxacin prophylaxis who were colonized with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pre-transplant were more likely to develop bacteremia with ESBL-producing Enterobacteriaceae post-transplant than those who were not colonized [10]. Of 31 patients colonized pre-transplant, 10 (32 percent) developed ESBL-producing Enterobacteriaceae bacteremia during their transplant admission, compared with 1 of 281 patients (0.4 percent) who were not colonized. All bloodstream ESBL-producing Enterobacteriaceae were levofloxacin resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. It is not clear if this single-center experience is representative of other centers and other neutropenic patient populations, but clearly further study is warranted. There has also been concern about the possibility of increasing the risk of Clostridioides difficile infections, although this has not been proven among neutropenic patients receiving fluoroquinolone prophylaxis [7,11]. In a large multicenter randomized trial of levofloxacin prophylaxis among children undergoing chemotherapy for acute leukemia or HCT, no increase in C. difficile infection was observed in those who received levofloxacin prophylaxis compared with those who received no prophylaxis (2.3 versus 5.2 percent) [12]. Practices regarding the use of antibacterial prophylaxis vary from center to center, with some centers avoiding the routine use of fluoroquinolone prophylaxis.

For most patients with chemotherapy-induced neutropenia expected to be of short duration (which includes standard chemotherapy regimens for most solid tumors), we recommend against the use of antibacterial prophylaxis. This is discussed in greater detail separately. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Antibacterial prophylaxis'.)

Timing — The optimal timing for initiating and discontinuing antibacterial prophylaxis has not been adequately studied. When indicated, many clinicians start antibacterial prophylaxis either on the first day of cytotoxic chemotherapy or on the day after the administration of the last dose of the cycle of chemotherapy. It is common to discontinue antibacterial prophylaxis when the neutropenia has resolved or, for patients who become febrile during neutropenia, when an empiric antibacterial regimen is initiated.

Guidelines — Guidelines from the American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (IDSA) recommend consideration of fluoroquinolone prophylaxis in patients at high risk for profound prolonged neutropenia (anticipated ANC ≤100 cells/microL for >7 days) [1]. International guidelines for the prevention of infections in HCT recipients recommend fluoroquinolone prophylaxis in patients anticipated to be neutropenic for seven days or longer [13]. As noted above, our approach differs slightly from ASCO and the IDSA's approach because we consider high-risk patients to be those who are anticipated to have an ANC <500 cells/microL (rather than ≤100 cells/microL) for >7 days (see 'High risk criteria' above). Links to guidelines are provided separately. (See 'Society guideline links' below.)

Combination of a fluoroquinolone plus an antibiotic with enhanced activity against gram-positive organisms is not recommended for prophylaxis. While studies have shown that this approach may reduce infections due to Staphylococcus and Streptococcus spp and reduce the incidence of neutropenic fever, they do not affect infection-related mortality [14]. In addition, increased rates of breakthrough-resistant gram-negative and gram-positive bacterial infections have limited the utility of this approach [6,7,15,16]. (See 'Evidence' below.)

Consensus-based National Comprehensive Cancer Network (NCCN) guidelines suggest strong consideration of fluoroquinolone prophylaxis for high-risk patients: those undergoing allogeneic HCT, neutropenic patients receiving induction chemotherapy for acute leukemia, and any patient in whom the duration of anticipated neutropenia is >10 days [8]. They also suggest consideration of fluoroquinolone prophylaxis in patients in the following intermediate-risk groups:

●Autologous HCT

●Lymphoma

●Chronic lymphocytic leukemia

●Multiple myeloma

●Purine analog therapy

●Anticipated neutropenia 7 to 10 days

The decision of whether to give antibacterial prophylaxis to the NCCN category of intermediate-risk patients should be made on a case-by-case basis. (See 'Intermediate-risk patients' below.)

Evidence

High-risk patients — Fluoroquinolones have been evaluated in many clinical trials of prophylaxis for neutropenic patients because of their broad spectrum of antibacterial activity, favorable safety profiles, and oral bioavailability. Ciprofloxacin and levofloxacin have been studied most extensively. Ciprofloxacin has greater in vitro activity than levofloxacin against P. aeruginosa, but levofloxacin has greater in vitro activity against gram-positive bacteria (eg, alpha-hemolytic streptococci) and is given only once daily compared with twice daily for ciprofloxacin.

The following observations have been noted in meta-analyses of prophylaxis trials in neutropenic patients:

●In a 2012 meta-analysis of 109 randomized trials of afebrile neutropenic patients (most of whom had hematologic malignancies or had undergone HCT, with duration of neutropenia >7 days), antibiotic prophylaxis was associated with lower all-cause mortality when compared with placebo or no treatment (relative risk [RR] 0.66, 95% CI 0.55-0.79) [17]. Antibiotic prophylaxis was also associated with significantly reduced occurrence of fever, fewer clinically documented and microbiologically documented infections, fewer infections due to both gram-positive and gram-negative bacteria, fewer bacteremias, and lower risk of infection-related death.

●An updated systematic review with meta-analysis of fluoroquinolone-based antibacterial chemoprophylaxis in neutropenic patients with hematological malignancies from the European Conference on Infections in Leukemia group on studies (2 randomized-controlled trials and 12 observational studies) published 2006 to 2014 reported fewer febrile episodes (pooled odds ratio [OR] 0.32, 95% CI 0.20-0.50) and fewer bloodstream infections (pooled OR 0.57, 95% CI 0.43-0.74) but no effect upon all-cause mortality (pooled OR 1.01, 95% CI 0.73-1.41) [11].

●Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (RR 0.54, 95% CI 0.40-0.74) as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections [17].

●In a 2006 meta-analysis, the benefit of antibiotic prophylaxis was found to be greater for high-risk patients than for low-risk patients [18]:

•The number of patients needed to treat to prevent one febrile episode was 5 for leukemia or HCT recipients in contrast with 23 for solid tumor or lymphoma patients.

•The number of patients needed to treat to prevent one documented infection was 6 for leukemia or HCT patients versus 13 for solid tumor or lymphoma patients.

•The number needed to treat to prevent one death was 43 for leukemia or HCT patients versus 132 for solid tumor or lymphoma patients [13].

●Fluoroquinolone prophylaxis was associated with trends to higher rates for colonization with resistant bacteria in a 2007 meta-analysis that focused on this issue [19]. In a subsequent retrospective review, fluoroquinolone prophylaxis was specifically associated with the development of meropenem-nonsusceptible P. aeruginosa bacteremia [20].

●Prophylactic antibiotics were associated with an increased risk for adverse events, primarily gastrointestinal toxicities [17].

Trimethoprim-sulfamethoxazole (TMP-SMX) was evaluated in older trials [17], but it is no longer used since it has no activity against P. aeruginosa. In addition, susceptibility to TMP-SMX among a variety of bacterial species has declined worldwide. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Resistance'.)

Intermediate-risk patients — Fluoroquinolone prophylaxis is sometimes used in selected intermediate-risk patients whose treatment regimens generally result in 7 to 10 days of neutropenia (eg, autologous HCT recipients; patients with lymphoma, chronic lymphocytic leukemia, or multiple myeloma; patients receiving a purine analog) [8]. The decision of whether to give antibacterial prophylaxis to intermediate-risk patients should be made on a case-by-case basis. Although several studies have shown benefits in these patients [21,22], the magnitude of benefit is less than with high-risk patients, and a survival benefit has not been definitively demonstrated. One should weigh the benefits versus the risk that wider use in more patients may increase the risk for the emergence of resistance.

Low-risk patients — The evidence regarding antibacterial prophylaxis in low-risk patients is reviewed separately. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Antibacterial prophylaxis'.)

ANTIFUNGAL PROPHYLAXIS

Invasive fungal infections — A relatively high incidence of life-threatening invasive fungal infections (eg, candidemia) among cancer patients and HCT recipients since the late 1980s has prompted interest in antifungal prophylaxis for patients receiving chemotherapy. This 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".)

PCP prophylaxis — Pneumocystis pneumonia (PCP) prophylaxis is used in certain patients, such as allogeneic HCT recipients, selected autologous HCT recipients, and in some patients receiving induction chemotherapy for acute lymphocytic leukemia [8,13]. This is discussed in detail separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Prevention of infections in hematopoietic cell transplant recipients", section on 'Pneumocystis prophylaxis'.)

ANTIVIRAL PROPHYLAXIS

Influenza — Annual immunization with an inactivated influenza vaccine is recommended for all patients being treated for cancer [1]. As the immune response to the influenza vaccine is likely to be impaired in patients receiving chemotherapy, the vaccine is optimally administered at least two weeks before chemotherapy starts or following completion of chemotherapy if the patient is expected to finish chemotherapy early in the influenza season. If neither of these options is possible, we suggest immunizing patients about a week after the start of a chemotherapy cycle. Under these circumstances, the degree of protection must be considered to be suboptimal. The data to support this recommendation are presented separately. (See "Immunizations in adults with cancer", section on 'Influenza vaccine'.)

Annual immunization of all family members and other close contacts is also recommended. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines".)

Chemoprophylaxis to prevent influenza virus is indicated under certain circumstances. This is discussed in greater detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Chemoprophylaxis' and "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

HSV and VZV — Reactivation of herpes simplex virus (HSV)-1 and HSV-2 are important causes of morbidity in patients with acute leukemia and those undergoing HCT. In addition, varicella-zoster virus (VZV) reactivation occurs commonly in HCT recipients who are not receiving prophylaxis. Both HSV and VZV infections can be effectively prevented with antiviral prophylaxis.

Patients who are seropositive for HSV and who are undergoing allogeneic HCT or induction chemotherapy for acute leukemia should receive antiviral prophylaxis with acyclovir (400 or 800 mg orally twice daily) or valacyclovir (500 mg orally twice daily) [13]. HCT recipients who are seropositive for VZV should also receive antiviral prophylaxis. Of these agents, we prefer valacyclovir for VZV prophylaxis given its greater bioavailability and the need for high levels of active acyclovir to inhibit VZV in vitro. If acyclovir is selected, the higher dose should be used (800 mg orally twice daily). These recommendations are based upon randomized trials demonstrating benefit in these populations [23-25]. Patients receiving proteasome inhibitors such as bortezomib, carfilzomib, or ixazomib also are at increased risk of VZV and should receive prophylaxis. (See "Infections in patients with multiple myeloma".)

HSV prophylaxis is usually initiated when induction chemotherapy or the conditioning regimen for HCT is started and continued until recovery of the white blood cell count or resolution of mucositis, whichever occurs later; it can be extended for a longer period in patients with frequent recurrent HSV infections or in those with graft-versus-host disease (GVHD) [4,13,25]. In HCT recipients who are seropositive for VZV, antiviral prophylaxis is typically continued for one year or longer in those with chronic GVHD and/or who require ongoing immunosuppression [13]. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Varicella-zoster virus'.)

CMV — Reactivation of cytomegalovirus (CMV) does not occur commonly in patients with chemotherapy-induced neutropenia, and CMV prophylaxis or pre-emptive therapy is therefore not indicated. In contrast, HCT recipients are at significant risk for CMV reactivation. Strategies for the prevention of CMV disease in HCT recipients are discussed in detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Cytomegalovirus'.)

Hepatitis B — 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 [26]. 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 with a nucleoside reverse transcriptase inhibitor (entecavir or tenofovir) should be given to patients at risk for reactivation and should be continued for at least six months after the completion of chemotherapy [1,26]. This strategy can reduce the risk of reactivation from 24 to 53 percent to 0 to 5 percent [27]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Colony stimulating factors — The IDSA guidelines recommend that the prophylactic use of colony stimulating factors (also known as myeloid growth factors or hematopoietic growth factors), such as granulocyte and granulocyte-macrophage colony stimulating factors, be considered for afebrile patients in whom the anticipated risk of fever and neutropenia is ≥20 percent [4]. Recommendations based on underlying condition or therapies (eg, acute myelogenous leukemia, hematopoietic cell transplantation) are presented separately. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Growth factor support' 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" and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Neutropenia' and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

VACCINATION — Vaccines for the prevention of infection in cancer patients and hematopoietic cell transplant recipients are discussed separately. (See "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients" and "COVID-19: Vaccines" and "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Considerations in patients with cancer", section on 'COVID-19 vaccination'.)

INFECTION CONTROL

General precautions — Several precautions should be taken while caring for neutropenic patients with cancer to prevent transmission of infection in the hospital [4]:

●Hand hygiene should be used; this is the most effective measure for preventing the contact transmission of infection.

●No specific protective gear (eg, gowns, gloves, masks) is required during the routine care of neutropenic patients, but standard barrier precautions should be used for all patients (ie, when contact with body fluids is anticipated), and infection-specific isolation precautions should be used for patients with signs and symptoms of certain infections. (See "Infection prevention: Precautions for preventing transmission of infection" and "Infection control measures for prevention of seasonal influenza".)

●HCT recipients should be placed in private rooms with >12 air exchanges per hour and high-efficiency particulate air (HEPA) filtration.

●Plants and dried or fresh flowers should not be allowed in the hospital rooms of neutropenic patients.

●Hospital work exclusion policies should be created to encourage health care workers and other hospital staff to report their illnesses or exposures.

●Rectal thermometers, enemas, suppositories, and digital rectal examinations are contraindicated. (See "Diagnostic approach to the adult cancer patient with neutropenic fever", section on 'Perianal region'.)

In addition, outpatients with chemotherapy-induced neutropenia should avoid prolonged contact with environments that have high concentrations of airborne fungal spores, such as construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovations [1,28].

Infection control precautions for HCT recipients are discussed in greater detail separately. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Infection control measures'.)

Neutropenic diet — The "neutropenic diet," consisting of "low-bacteria," well-cooked foods, has been the usual approach for decades for neutropenic patients, recognizing that gut mucosal injury makes patients particularly susceptible to serious infection from enteric bacteria. Unfortunately, there has been a paucity of data from clinical trials to evaluate the neutropenic diet. Meta-analyses of randomized trials and observational studies have not demonstrated a reduction in the overall infection rates when comparing neutropenic diets with unrestricted diets [29-32].

A variety of methodologic concerns make definitive conclusions difficult. The ASCO/IDSA guidelines do not endorse the neutropenic diet due to lack of evidence suggesting a benefit for reducing infection rates or all-cause mortality [1,33]. However, one large randomized trial in adult acute myeloid leukemia (AML) patients found more bacteremias in the unrestricted diet group although there was no difference in rates of major infection between the neutropenic diet and unrestricted diet groups [34]. This finding raises a concern that, at least in more intensively treated patients, such as AML patients and HCT recipients, there may be a benefit of the neutropenic diet.

We believe that there is need for more study to determine the optimal strategy for preventing foodborne infection in cancer patients and, until such definitive trials are performed, recommendations are difficult to make. Of note, a survey of United States HCT programs participating in the Blood and Marrow Transplant Clinical Trials Network [35] and a survey of European centers [36] indicates that the majority of HCT centers use a neutropenic diet [34]. One recommendation that is generally agreed upon is adherence to the US Food and Drug Administration food safety guidelines [37].

NEUTROPENIC FEVER MANAGEMENT — Empiric therapy with broad-spectrum antibiotics should be initiated promptly in all febrile neutropenic patients to reduce the risk of serious morbidity and mortality, including patients who have been receiving antimicrobial prophylaxis [4,8].

This is discussed in greater detail separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

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 5^th to 6^th 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 10^th to 12^th 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

●Overview

•Background − Intensive cytotoxic chemotherapy can cause severe and sometimes prolonged neutropenia, which may result in hospitalization for treatment of fever or cause potentially fatal infection. One approach to reducing infectious complications involves the use of prophylactic antibacterial, antiviral, and antifungal agents in patients at significant risk of such infections. (See 'Introduction' above.)

•Risk assessment − It is crucial to assess the risk of serious complications in patients with chemotherapy-induced neutropenia; prophylaxis is generally indicated for high-risk patients, defined as those who are anticipated to have an absolute neutrophil count (ANC) <500 cells/microL for >7 days. (See 'High risk criteria' above.)

●Antibacterial prophylaxis

•High-risk patients − We suggest fluoroquinolone prophylaxis for high-risk neutropenic patients (patients anticipated to have an ANC <500 cells/microL for >7 days) who do not have a contraindication to receiving a fluoroquinolone (Grade 2A). High-risk patients include those undergoing allogeneic hematopoietic cell transplantation (HCT) and those receiving induction chemotherapy for acute leukemia. Levofloxacin (500 or 750 mg orally once daily) and ciprofloxacin (500 or 750 mg orally twice daily) have been studied most extensively, and levofloxacin is favored in patients with increased risk for oral mucositis-related Streptococcus viridans infection. (See 'Indications' above and 'Guidelines' above.)

•Selected intermediate-risk patients − Fluoroquinolone prophylaxis is sometimes used in selected intermediate-risk patients whose treatment regimens generally result in 7 to 10 days of neutropenia (eg, autologous HCT recipients; patients with lymphoma, chronic lymphocytic leukemia, or multiple myeloma; patients receiving a purine analog). The decision of whether to give antibacterial prophylaxis to intermediate-risk patients should be made on a case-by-case basis. (See 'Guidelines' above.)

•Caveats with fluoroquinolone use − There are several potential downsides to using fluoroquinolone prophylaxis, including toxicities and the potential for promoting resistance. Practices regarding the use of antibacterial prophylaxis vary from center to center, with some centers avoiding the routine use of fluoroquinolone prophylaxis. At institutions that use fluoroquinolone prophylaxis, systematic monitoring of the prevalence of fluoroquinolone resistance among gram-negative bacilli should be performed. (See 'Indications' above.)

•Appropriate antibiotic spectrum − For patients who are at risk for neutropenia, we recommend against the addition of a prophylactic antibacterial agent with specific activity against gram-positive organisms (Grade 1B). (See 'Guidelines' above.)

•Short duration neutropenia − For most patients with chemotherapy-induced neutropenia expected to be of short duration (which includes standard chemotherapy regimens for most solid tumors), we recommend against the use of antibacterial prophylaxis (Grade 1B). (See 'Indications' above.)

●Antifungal and antiviral prophylaxis

•Antifungal prophylaxis − Antifungal prophylaxis is used in certain high-risk patients with chemotherapy-induced neutropenia. This 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".)

•Antiviral prophylaxis − We recommend antiviral prophylaxis with acyclovir or valacyclovir for all patients who are seropositive for herpes simplex virus who are undergoing allogeneic HCT or induction chemotherapy for acute leukemia (Grade 1B). We also recommend antiviral prophylaxis for HCT recipients who are seropositive for varicella-zoster virus (Grade 1B). Strategies for the prevention of cytomegalovirus in HCT recipients are discussed separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Varicella-zoster virus' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Cytomegalovirus'.)

●Other measures

•Vaccination − Vaccines for the prevention of infection in cancer patients and HCT recipients are discussed separately. (See "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients" and "COVID-19: Vaccines" and "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Considerations in patients with cancer", section on 'COVID-19 vaccination'.)

•Colony stimulating factors − The prophylactic use of colony stimulating factors, such as granulocyte and granulocyte-macrophage colony stimulating factors, should be considered for afebrile patients in whom the anticipated risk of fever and neutropenia is ≥20 percent. (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".)

•Urgent antibiotic therapy for fever − Empiric therapy with broad-spectrum antibiotics should be initiated promptly in all febrile neutropenic patients, including patients who have been receiving antimicrobial prophylaxis, to reduce the risk of serious morbidity and mortality. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)