Management of children with non-chemotherapy-induced neutropenia and fever

INTRODUCTION — Children with fever and neutropenia should be evaluated promptly because fever may be the first manifestation of a life-threatening infection. The risk of infection in children with non-chemotherapy-induced neutropenia varies with the underlying cause of neutropenia (table 1).

The management of children with non-chemotherapy-induced neutropenia and fever is reviewed here. The conditions that cause neutropenia in children, the risk of infection in and evaluation of children with non-chemotherapy-induced neutropenia and fever, and the evaluation and management children with chemotherapy-induced neutropenia and fever are discussed separately.

●(See "Overview of neutropenia in children and adolescents".)

●(See "Evaluation of children with non-chemotherapy-induced neutropenia and fever".)

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

DEFINITIONS

●Neutropenia – In patients with non-chemotherapy-induced neutropenia, neutropenia is generally defined as an absolute neutrophil count (ANC) <1500 cells/microL. The ANC is calculated using the following formula (calculator 1):

•ANC = total white blood cell count (cells/microL) x (percent polymorphonuclear cells + percent bands) ÷ 100

Increased risk of infection, primarily bacterial infection in those with only granulocyte-line deficiency, becomes apparent when the ANC is <1000 cells/microL and rises as the ANC falls. (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Definitions'.)

●Fever – In neutropenic patients, fever is defined as a single oral temperature ≥38.3°C (101°F), a temperature ≥38°C (100.4°F) for longer than one hour, or two elevations >38°C (100.4°F) during a 12-hour period [1-3].

The measurement and interpretation of temperature in children with non-chemotherapy-induced neutropenia are discussed separately. (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Definitions'.)

●Complicated febrile illness – Complicated febrile illness is defined by one or more of the following:

•Hemodynamic instability

•Gastrointestinal symptoms:

-Abdominal pain

-Nausea

-Vomiting

-Diarrhea

•New-onset neurologic signs or mental status changes

•Intravascular catheter infection (especially catheter tunnel infection)

•Underlying chronic lung disease (eg, in children with dyskeratosis congenita or cartilage-hair hypoplasia)

•New pulmonary infiltrate or hypoxemia

•Skin or soft tissue infection at any site

•Sinus tenderness or other findings of upper respiratory tract infection

RISK-BASED MANAGEMENT APPROACH — The management of children with non-chemotherapy-induced neutropenia and fever varies with their risk of infection (table 1). (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Risk categorization'.)

Given the lack of comparative clinical studies in children of non-chemotherapy-induced neutropenia, our approach is largely extrapolated from controlled clinical trials and guidelines for neutropenia and fever in children with cancer or hematopoietic cell transplant [3,4].

Low risk — We consider the following children with neutropenia and fever to be at low risk of serious infection (table 1) (see "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Low risk'):

●Children with transient neutropenia – Otherwise healthy, well-appearing children with transient isolated neutropenia (eg, presumed to be related to an intercurrent infection; associated with medications such as antibiotics).

Well-appearing children with transient, isolated neutropenia and fever usually are managed in the same manner as children without neutropenia, typically in the outpatient setting (unless the neutropenia was detected during hospitalization). In most cases, the neutropenia is associated with a presumed viral infection and resolves within one to two weeks [5-9].

Management includes:

•Oral antibiotics as indicated if the child has or develops localized bacterial infection (eg, acute otitis media, skin infection).

•Follow-up with blood counts, usually within a few weeks, to ensure that the neutropenia resolves. Neutropenia that is discovered during the course of an infection may be the initial presentation of chronic neutropenia or hematologic malignancy [6,10-12].

●Children with chronic autoimmune neutropenia – Children with chronic autoimmune neutropenia (also known as chronic idiopathic neutropenia and chronic benign neutropenia) have a low risk of infection. They typically present with mild infections (eg, upper respiratory tract infection, otitis media, skin infection) but may (very rarely) develop serious bacterial infections (eg, pneumonia, meningitis, sepsis).

Management includes:

•Oral antibiotics as indicated for suspected bacterial infections in children with adequate bone marrow reserves, although hospitalization and parenteral antibiotics are usually warranted for skin and soft tissue infections.

•Hospitalization and parenteral antibiotics for children with a complicated febrile illness (table 2).

•Individualized management for children with a history of complicated febrile illness.

Low-to-moderate risk — We consider the children with cyclic neutropenia to be at low-to-moderate risk of serious infection if they are well appearing (table 1):

The management of children at low-to-moderate risk varies with clinical findings (table 1):

●Those who have superficial skin infection, upper respiratory infections, may be treated in the outpatient setting with oral antibiotics (as clinically indicated) and close outpatient follow-up [13].

●Those who have gingivitis or oral ulcers usually are treated symptomatically (eg, with topical therapies, including topical anesthetics and maintenance of mouth hygiene).

In addition, children with cyclic neutropenia and oral ulcers or gingivitis generally are treated with granulocyte colony-stimulating factor to raise the absolute neutrophil count. (See "Cyclic neutropenia", section on 'Management'.)

●Those who have a complicated febrile illness (table 2) generally warrant hospitalization for broad-spectrum parenteral antibiotics. Complicated febrile illness should prompt consideration of a more serious form of neutropenia; it is very rare in children with conditions associated with low-to-moderate risk (table 1), although clostridial sepsis may occur in children with cyclic neutropenia.

●Those with a past history of complicated febrile illness are managed on a case-by-case basis.

●Those with cyclic neutropenia and a fever pattern that is uncharacteristic or mucocutaneous lesions that are atypical for their neutrophil nadir are managed on a case-by-case basis.

●Those with cyclic neutropenia and abdominal pain are hospitalized for parenteral antibiotic therapy [2]. (See 'Gastrointestinal symptoms' below.)

The choice of antibiotics for hospitalized children varies with the clinical presentation. (See 'Suggested initial regimens' below.)

High risk — We consider the following children with non-chemotherapy-induced neutropenia to be at high risk of serious infection (table 1):

●Those who are ill appearing (eg, listless, confused, clinically deteriorating), whether or not they are febrile.

●Well- or ill-appearing children with severe congenital neutropenia and fever. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

●Well- or ill-appearing children with acquired or inherited aplastic anemia (eg, Fanconi anemia, Shwachman-Diamond syndrome) and fever.

●Well- or ill-appearing children with other bone marrow failure syndromes (eg, cartilage-hair hypoplasia, reticular dysgenesis).

The cornerstone of treatment for the child with neutropenia who is high risk for serious infection is hospitalization for prompt initiation of empiric broad-spectrum parenteral antibiotic therapy pending results of blood cultures or cultures of specimens related to their symptomatic presentation. (See 'Suggested initial regimens' below.)

ANTIMICROBIAL THERAPY FOR HOSPITALIZED CHILDREN

Spectrum of activity — Empiric antibiotic therapy for children with non-chemotherapy-induced neutropenia and fever should be active against a broad spectrum of potential gram-positive and gram-negative pathogens (eg, Pseudomonas aeruginosa) [14].

Clinical factors that may influence the antimicrobial spectrum include (see 'Suggested initial regimens' below):

●Patient's clinical status (eg, hemodynamic stability, site of symptoms, decreased or decreasing glomerular filtration rate [GFR] or hepatic dysfunction)

●Drug allergies (if any)

●Cause and presentation of previous life-threatening infection(s)

●Prophylactic antimicrobials (if the child is receiving prophylactic antimicrobials, the antimicrobial agent that is used for prophylaxis is avoided in the treatment regimen)

●Previous colonization with resistant bacteria (eg, methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant Enterococcus; extended-spectrum beta-lactamase [ESBL]-producing gram-negative organisms, including Klebsiella pneumoniae; carbapenemase-producing bacteria)

●The types of bacterial isolates found in the institution and the community

●Local antibiotic susceptibility patterns

Suggested initial regimens

Uncomplicated febrile illness — For uncomplicated febrile illness (table 2) in hospitalized children with non-chemotherapy-induced neutropenia (table 1), we suggest empiric monotherapy with a broad-spectrum antipseudomonal agent (table 3).

Acceptable empiric monotherapy regimens include one of the following (the doses must be adjusted for decreased or decreasing GFR):

●Cefepime – 50 mg/kg (to a maximum of 2 g per dose) intravenously (IV) every eight hours

●A carbapenem (eg, meropenem):

•Meropenem (for children ≥3 months of age) 20 mg/kg IV every eight hours (maximum of 1 g per dose)

●Piperacillin-tazobactam (dosed according to the piperacillin component):

•<2 months of age – 80 mg/kg IV every six hours

•2 to 9 months of age – 80 mg/kg IV every eight hours

•>9 months of age

-Body weight <40 kg – 100 mg/kg IV every six to eight hours (maximum of 16 g per day)

-Body weight ≥40 kg – 3 g IV every six hours; this regimen aims to optimize drug levels for organisms with higher minimum inhibitory concentrations (MICs) [15]

●Ceftazidime 50 mg/kg IV every eight hours (maximum dose 2 g) is another option for children at low-to-moderate risk (table 1) who are hospitalized because of a past history of complicated febrile illness. Ceftazidime is no longer recommended for high-risk patients because of its decreased activity against many gram-negative pathogens and weak activity against viridans streptococci.

Randomized trials and meta-analyses of randomized trials have demonstrated that monotherapy with such broad-spectrum antibiotics as cefepime, meropenem, or piperacillin-tazobactam is as efficacious as combination therapy for the empiric treatment of most febrile neutropenic patients [16-21].

Signs of sepsis — For children with non-chemotherapy-induced neutropenia and signs of sepsis (eg, hypotension, unexplained tachycardia and/or widened pulse pressure, mental status changes, respiratory dysfunction), consultation with an expert in pediatric critical care and infectious diseases is suggested, and the empiric regimen is individualized according to institutional clinical practice guidelines and clinical features, including previous culture results, concern for multidrug-resistant organisms, local culture yields, and resistance patterns [22]. As examples:

●For children with no history of multidrug-resistant organisms, we provide broad-spectrum antipseudomonal therapy with cefepime.

●For children with a history of multidrug-resistant organisms, we provide broad-spectrum antipseudomonal therapy with meropenem or a novel beta-lactamase inhibitor combination (eg, ceftazidime-avibactam, ceftolozane-tazobactam).

●For children with a history of or concern for carbapenem-resistant Enterobacterales, we provide broad-spectrum therapy with a novel beta-lactamase inhibitor combination (eg, ceftazidime-avibactam).

Gastrointestinal symptoms — For the hemodynamically stable child with neutropenia and abdominal symptoms, particularly abdominal pain or blood per rectum, we suggest that empiric therapy include activity against anaerobes.

●Abdominal symptoms – Acceptable empiric regimens include one of the following (the doses must be adjusted for renal dysfunction) (table 3) [3,23]:

•Meropenem (for children ≥3 months of age) 20 mg/kg IV every eight hours (maximum of 1 g per dose)

•Piperacillin-tazobactam (dosed according to the piperacillin component)

-<2 months of age – 80 mg/kg IV every six hours

-2 to 9 months of age – 80 mg/kg IV every eight hours

->9 months of age – Body weight <40 kg: 100 mg/kg IV every six to eight hours (maximum of 16 g per day); body weight ≥40 kg: 3 g IV every 6 hours; this regimen aims to optimize drug levels for organisms with higher MICs

•Combination therapy with cefepime 50 mg/kg (to a maximum of 2 g per dose) IV every eight hours and metronidazole 10 to 13.3 mg/kg (to a maximum of 500 mg per dose) IV every eight hours

●Suspected Clostridioides difficile – For children with suspected C. difficile, we suggest combination therapy with a broad-spectrum antipseudomonal agent (eg, piperacillin-tazobactam, meropenem, cefepime with metronidazole) plus therapy for C. difficile, pending results of C. difficile testing. The therapy for C. difficile varies with the clinical scenario and is discussed separately. (See "Clostridioides difficile infection in children: Treatment and outcome".)

Other indications for combination therapy — Extrapolating from guidelines for patients with chemotherapy-induced neutropenia and fever [3,4,24], we suggest increasing gram-positive coverage, typically by adding one of the following agents to broad-spectrum antipseudomonal therapy (eg, piperacillin-tazobactam, meropenem, or cefepime), in the clinical scenarios listed below (table 3).

●Radiographically documented pneumonia – Add vancomycin if MRSA is suspected (table 4).

●Evidence of meningitis or new onset of neurologic signs and symptoms suggestive of meningitis – Add vancomycin (table 4) to broad-spectrum antipseudomonal therapy with cefepime or meropenem; if meropenem is used as the broad-spectrum antipseudomonal agent, use the dose for central nervous system infections: 40 mg/kg IV every eight hours (maximum of 2 g per dose).

●Clinically suspected central venous catheter site infection (eg, chills or rigors with infusion through the catheter and signs of infection around the catheter entry or exit site) – Add vancomycin (table 4) to broad-spectrum antipseudomonal therapy [25]. Alternatives to vancomycin include ceftaroline or daptomycin, although these agents are not used routinely.

●For any of the following, add vancomycin (table 4), clindamycin (if the rates of clindamycin-resistant S. aureus in the community is acceptably low and the child is not receiving meropenem or piperacillin-tazobactam), or linezolid (if the child is known to be colonized with or has a history of infection with vancomycin-resistant gram-positive organisms; linezolid should be used with caution because it has been associated with neutropenia) [3,26]:

•Skin or soft tissue infection at any site (eg, cellulitis) [27]

•Known colonization with MRSA or penicillin- and cephalosporin-resistant Streptococcus pneumoniae or previous history of infection with penicillin-resistant streptococci [28]

•High prevalence of MRSA infections in the community

When broadening gram-positive coverage, the combination of vancomycin and piperacillin-tazobactam should be avoided because of the increased risk of acute kidney injury [29,30]. Kidney function should be monitored in children receiving vancomycin.

The routine use of empiric vancomycin or other agents with gram-positive activity for febrile neutropenia is discouraged to decrease colonization or infection with multidrug-resistant organisms, such as vancomycin-resistant enterococci, and to prevent complications of overuse, such as C. difficile colitis. In addition, although up to two-thirds of bacterial bloodstream isolates in febrile neutropenic cancer patients are gram-positive cocci (frequently coagulase-negative staphylococci resistant to beta-lactams, except ceftaroline), in randomized trials, the morbidity and mortality were similar for cancer patients with fever and neutropenia who were treated with and without vancomycin in the initial antibiotic regimen [31].

Ongoing antimicrobial therapy — Modification of the initial empiric antimicrobial regimen may be necessary in children with clinical worsening or instability, documented infection, or persistent unexplained fever.

Clinical worsening or instability — Children who worsen or become unstable at any point during antimicrobial therapy should undergo reevaluation for new or worsening sites of infection. Reevaluation includes thorough physical examination and imaging or repeat imaging, as well as culture, biopsy, or drainage of sites of worsening or potential new infection (assessing for bacterial, viral, and fungal pathogens). (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Evaluation'.)

Antimicrobial therapy should be reviewed for adequacy of dosing and spectrum.

For children with hemodynamic instability and no identified source of fever, antimicrobial therapy should be broadened (eg, to increase activity against gram-positive, gram-negative, resistant, and potentially anaerobic bacteria). Appropriate regimens vary with the clinical scenario, local susceptibility data, and institutional formulary.

Positive blood culture

●Isolation of gram-negative bacteria pending identification and susceptibility – The antimicrobial regimen should be adjusted when susceptibility results are available. There is no need to add another agent with activity against gram-negative organisms if the patient is stable. In a retrospective review of 879 children with gram-negative bacteremia, compared with beta-lactam monotherapy, combination beta-lactam/aminoglycoside therapy that continued after susceptibility results were available was not associated with improved 30-day mortality (approximately 7 percent in both groups) but was associated with increased rates of nephrotoxicity (25 versus 10 percent) [32].

●Isolation of gram-positive bacteria pending identification and susceptibility – Add vancomycin; alternative agents include ceftaroline and daptomycin if the patient is known to be colonized with or previously infected with vancomycin-resistant gram-positive organisms. The modified antimicrobial regimen should be adjusted when susceptibility results are available.

Other documented infection — For children with documented infection at any point during treatment, antimicrobial therapy is modified according to culture and susceptibility results and/or site of infection [3]. Infection may be documented microbiologically (eg, positive culture) or clinically (eg, cellulitis or pneumonia without isolated pathogen).

No documented infection — For clinically stable children with no documented infection after 48 hours of antimicrobial therapy and resolution of fever, we recommend discontinuing antimicrobial agents and monitor clinically given the potential harms of ongoing therapy without a documented infection (eg, nephrotoxicity, colonization or infection with resistant pathogens) [4]. For clinically stable children with no documented infection at 48 hours of antimicrobial therapy who remain febrile, we recommend continuing antipseudomonal therapy (eg, cefepime, meropenem, piperacillin-tazobactam) while evaluating for a source of infection.

We make further modifications to the empiric antibiotic regimen only if clinical status changes (eg, clinical worsening, documented infection, as described above). We generally do not alter the antibiotic regimen for persistent fever or recurrence of fever after initial defervescence without additional changes in clinical status, although the addition of antifungal therapy may be warranted.

Addition of antifungal therapy — For children with non-chemotherapy-induced neutropenia who have remained febrile and severely or profoundly neutropenic and have no indicators of count recovery after four to five days of broad-spectrum antibiotics, we suggest that antifungal therapy be added to the empiric antibiotic regimen, as is standard of care in chemotherapy-induced neutropenia.

Patients with persistent fever and neutropenia despite empiric antibacterial therapy may have a clinically occult fungal infection [3,4]. Addition of antifungal therapy is particularly important for patients with severe aplastic anemia, for whom invasive fungal infections, especially Aspergillus, are a major cause of death [14,33]. (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Aplastic anemia'.)

There is little evidence to guide the choice of empiric antifungal agents for children with non-chemotherapy-induced neutropenia. Although antifungal agents are better studied in children with chemotherapy-induced neutropenia, comparative evidence of efficacy and safety is limited [34,35]. (See "Fever in children with chemotherapy-induced neutropenia", section on 'Addition of antifungal therapy'.)

Given the limited evidence, the choice of empiric antifungal agent for children with non-chemotherapy-induced neutropenia is influenced by age and potential adverse effects.

●Conventional amphotericin B (amphotericin B deoxycholate) is active against a broad-spectrum of fungi and is a reasonable initial therapy for neonates and young infants.

●We generally prefer lipid formulations of amphotericin or an echinocandin that is active against yeasts and Aspergillus spp (eg, micafungin) for older infants and children.

Alternative antifungal agents include other echinocandins (eg, caspofungin, micafungin) and triazole derivatives (eg, voriconazole, posaconazole). We generally avoid fluconazole because it is not active against Aspergillus spp. Of the triazoles, posaconazole and isavuconazole have additional coverage against Zygomycetes and other filamentous fungi. (See "Mucormycosis (zygomycosis)".)

Duration of therapy

●Identified source of infection – For children with an identified source of infection, the duration of antimicrobial therapy is determined by the site of infection (eg, pneumonia, cellulitis), the clinical response (including resolution of fever), and the pathogen identified. Antimicrobial agents that do not target the pathogenic organism can be stopped at this stage.

●Unknown source of fever – When the source of the fever remains unknown, empiric antibiotic therapy (with the exception of agents that were added for additional gram-positive or gram-negative activity) usually is continued until fever resolves and, in certain cases, until bone marrow production of granulocytes has recovered. In select patients, empiric antibiotic therapy may be transferred to an ambulatory setting after an initial period of 48 hours [3,4,13]. (See 'No documented infection' above.)

For children with aplastic anemia and other forms of stable chronic neutropenia, the indeterminate duration of neutropenia complicates the decision about the course of antibiotics. We generally continue antibiotics for a total of 14 days. Results of a sentinel study of infection in patients with aplastic anemia suggest that empiric antibiotic therapy should continue for 10 to 14 days, followed by careful observation [14]. The duration of antifungal therapy, if initiated, requires careful consideration because of the high risk of Aspergillus infection. Consultation with experts in pediatric hematology and infectious diseases is suggested.

GRANULOCYTE COLONY-STIMULATING FACTOR — Decisions regarding initiation of granulocyte colony-stimulating factor (G-CSF; filgrastim, lenograstim) in children with non-chemotherapy-induced neutropenia and complicated febrile illness requiring hospitalization are individualized. Previous infectious history of the patient, especially history of prior serious infection, needs to be considered. Such children should be treated in specialized centers by clinicians with expertise in the use of G-CSF. (See "Introduction to recombinant hematopoietic growth factors".)

The benefits of initiation of G-CSF in children with non-chemotherapy-induced neutropenia and fever are unproven. Limited data suggest that prophylactic treatment with G-CSF may be beneficial in reducing episodes of fever and infection in children with cyclic neutropenia and congenital neutropenia [36,37]. The prophylactic use of G-CSF in the treatment of each of these disorders is discussed in detail separately. (See "Immune neutropenia", section on 'Chronic idiopathic neutropenia' and "Cyclic neutropenia", section on 'Management' and "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

ENVIRONMENTAL PRECAUTIONS — Environmental precautions may reduce the risk of hospital-acquired infection in neutropenic patients who are admitted to the hospital for treatment of fever. Environmental precautions may include [3]:

●All persons should perform hand hygiene before entering and after leaving the patient's room

●Oral hygiene (toothbrushing at least twice per day; oral rinses; dental flossing once per day if it can be performed without trauma)

●Daily showers or baths

●Daily inspection of skin sites that may be portals of infection (eg, perineum, sites of intravascular access)

●Perineal hygiene (gentle but thorough cleaning after bowel movements; thorough drying of the perineum after urination)

●Avoidance of tampons

●Avoidance of rectal procedures (eg, thermometry, enemas, suppositories, examinations)

●Prohibition of plants and dried or fresh flowers in the patient's room (may contain molds)

Although a "neutropenic diet" (eg, well-cooked foods; avoidance of prepared luncheon meats) has been recommended, it does not provide any benefit over adherence to the US Food and Drug Administration food safety guidelines [38,39] and may be nutritionally insufficient [40]. Adherence to a neutropenic diet is therefore not recommended.

SUMMARY AND RECOMMENDATIONS

●Definitions – Neutropenia is generally defined as an absolute neutrophil count (ANC) <1500 cells/microL (calculator 1). Increased risk of infection becomes apparent when the ANC is <1000 cells/microL and rises as the ANC falls. In neutropenic patients, fever is defined as a single oral temperature ≥38.3°C (101°F), a temperature ≥38°C (100.4°F) for longer than one hour, or two elevations >38°C (100.4°F) during a 12-hour period. (See 'Definitions' above.)

●Risk-based management approach – Our approach to the management of children with non-chemotherapy-induced neutropenia and fever varies with their risk of infection and is summarized in the table (table 1). (See 'Risk-based management approach' above.)

●Initial antimicrobial therapy – Initial antimicrobial therapy for children hospitalized with non-chemotherapy-induced neutropenia varies with the clinical findings.

•For children with uncomplicated febrile illness (table 2), we suggest initial broad-spectrum monotherapy with an antipseudomonal antibiotic (eg, cefepime, meropenem, piperacillin-tazobactam) rather than combination therapy (Grade 2B). (See 'Uncomplicated febrile illness' above.)

•For children with signs of sepsis (eg, hypotension, unexplained tachycardia and/or widened pulse pressure, mental status changes, respiratory dysfunction), consultation with an expert in pediatric critical care and infectious diseases is suggested, and the empiric regimen is individualized according to institutional clinical practice guidelines, clinical features, including previous culture results, concern for multidrug resistant organisms, and local resistance patterns. (See 'Signs of sepsis' above.)

•For children with abdominal symptoms, particularly abdominal pain or blood per rectum, we suggest an antibiotic regimen with activity against anaerobes (Grade 2C). Acceptable regimens include monotherapy with piperacillin-tazobactam or meropenem or combination therapy with cefepime and metronidazole. (See 'Gastrointestinal symptoms' above.)

•Other indications for combination therapy and suggested regimens are provided in the table (table 3). (See 'Other indications for combination therapy' above.)

●Ongoing antimicrobial therapy – Modification of the initial empiric antibiotic regimen may be necessary in children with clinical worsening, instability, or development of documented infection (eg, positive blood culture). (See 'Clinical worsening or instability' above and 'Positive blood culture' above and 'Other documented infection' above.)

For clinically stable children with no documented infection after 48 hours of antimicrobial therapy and resolution of fever, we discontinue antimicrobial therapy. For clinically stable children with no documented infection at 48 hours of antimicrobial therapy who remain febrile, we generally continue antipseudomonal therapy (eg, cefepime, meropenem, piperacillin-tazobactam) while evaluating for a source of infection. (See 'No documented infection' above.)

We suggest that antifungal therapy be initiated in children who remain febrile and profoundly neutropenic after four days of broad-spectrum antibiotics (Grade 2C). (See 'Addition of antifungal therapy' above.)

●Duration of antimicrobial therapy – The duration of antimicrobial therapy is determined by the site of infection (eg, pneumonia, cellulitis), the clinical response (including resolution of fever), and the pathogen identified. When the source of the fever remains unknown, empiric antibiotic therapy (with the exception of agents that were added for additional gram-positive or gram-negative activity) usually is continued until clinical response (eg, resolution of fever) and, in certain cases, until bone marrow production of granulocytes has recovered. (See 'Duration of therapy' above.)