Febrile neutropenia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Synonyms and keywords: FN, febrile leukopenia, neutropenic fever, neutropenic fever syndrome, neutropenic sepsis

Overview

Febrile neutropenia is defined as one oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) for over one hour. Neutropenia is defined as an absolute neutrophil count (ANC) <500 cells/mm³ or an ANC that is expected to become less than 500 cells/mm³ over the next 48 hours. Profound neutropenia is defined as an ANC <100 cells/mm³. Patients with functional neutropenia have a qualitative abnormality of neutrophil functions despite a normal or elevated ANC, as seen in hematological malignancy, and are at increased risk of infections similarly to patients with low ANC.

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Life threatening cause 1
• Life threatening cause 2
• Life threatening cause 3

Common Causes

• Common cause 1
• Common cause 2
• Common cause 3
• Common cause 4
• Common cause 5

Management

Day 1: Initial Management of Patients With Febrile Neutropenia

Characterize the clinical and laboratory findings: ❑ Fever in cancer patients who are on chemotherapy ❑ Single oral temperature ≥38.3° C (101° F) or ❑ Temperature ≥38° C (100.4° F) sustained for over one hour with ❑ Reduced absolute neutrophil count (ANC) ❑ ANC <500 cells/mm3 or ❑ ANC that is expected to decrease to <500 cells/mm3 in the next 48 hours

Consider the diagnosis of febrile neutropenia POTENTIALLY LIFE THREATENING

Obtain a detailed history (an assessment of risk for complications of severe infections): ❑ History suggestive of infections and inflammation of ❑ Skin and soft-tissues: ❑ Erythema ❑ Intravenous catheter site pain and/or swelling ❑ Nodules ❑ Rash ❑ Swelling ❑ Ulcers ❑ Vesicles ❑ Lungs (pneumonia): ❑ Dyspnea ❑ Fever (high grade) with sweating, chills, and rigor ❑ Pleuritic chest pain ❑ Productive cough (greenish or yellow sputum) ❑ Rapid and shallow breathing ❑ Central nervous system (meningitis and encephalitis): ❑ Altered mental status ❑ Behavioral or personality change ❑ Clumsiness and unsteady gait ❑ Decreased levels of consciousness. ❑ Delirium ❑ Headache ❑ Irritability ❑ Lethargy ❑ Neck stiffness ❑ Phonophobia (inability to tolerate loud noises) ❑ Photophobia (inability to tolerate bright light) ❑ Seizures ❑ Vomiting ❑ Urinary tract ❑ ❑ History of any co-morbid conditions ❑ Diabetes mellitus ❑ Chronic obstructive lung disease ❑ History of any recent exposure to infections ❑ History of any current antibiotic prophylaxis ❑ History of non infectious causes of fever (example: administration of blood products) ❑ History of recent surgical procedures ❑ History of prior documentation of infections or pathogen colonization

Examine the patient (an assessment of risk for complications of severe infections): Vital signs: ❑ Decreased oxygen saturation ❑ Hypotension < 90 mm Hg ❑ Tachycardia > 125 beats/min ❑ Tachypnea ❑ Search for signs of infections and inflammation at ❑ Skin and soft-tissues: ❑ Cellulitis ❑ Dental or peritonsillar cellulitis ❑ Ecthyma gangrenosum ❑ Erythema ❑ Erythema multiforme ❑ Furuncles ❑ Mucositis ❑ Nodules ❑ Paronychia ❑ Perianal fissures ❑ Pilonidal disease ❑ Rash ❑ Skin lesions with a necrotic center ❑ Ulcers ❑ Vesicles ❑ Entry and exit sites of catheters in skin ❑ Sites of previous procedures in skin (example: bone marrow aspiration site) ❑ Oropharynx (including perioduntum) ❑ Lungs (pnuemonia): ❑ Bronchial breath sounds ❑ Crackles ❑ Decreased breath sounds ❑ Dullness on percussion ❑ Increased tactile fremitus ❑ Increased volume of whispered (vocal fremitus) ❑ Rales ❑ Rhonchi ❑ Central nervous system (meningitis and encephalitis): ❑ Altered sensorium ❑ Brudzinski's sign ❑ Kernig's sign ❑ Nuchal rigidity ❑ Personality changes ❑ Alimentary tract ❑ Perineum

Order laboratory tests (routine): ❑ CBC with ❑ Differential leukocyte count ❑ Platelet count ❑ BMP ❑ AST ❑ ALT ❑ Total bilirubin ❑ Blood cultures (at least 2 sets) Central catheter 1st set 2nd set ❑ Present ❑ From each lumen of existing central catheters ❑ From a peripheral vein site ❑ Absent ❑ From one separate venipuncture ❑ From another separate venipuncture ❑ Urinalysis Order additional tests (not routine and order if clinically indicated): Tests Clinical indications ❑ Urine culture ❑ Urinary tract infection ❑ Urinary catheter in place ❑ Abnormal findings on urinalysis ❑ Chest X-ray ❑ Respiratory tract infection ❑ CT head ❑ CNS infection ❑ CT sinuses ❑ Sinus infection ❑ CT abdomen ❑ Infection of abdominal organs ❑ CT pelvis ❑ Infection of pelvic organs ❑ Stool for clostridium difficile toxin assay ❑ Diarrhea ❑ Stool for bacterial pathogen cultures or for ova and parasite ❑ Diarrhea following a history of recent travel ❑ CSF analysis and culture ❑ Meningitis ❑ Skin aspiration or biopsy for cytological testing, gram staining, and culture ❑ Skin infection ❑ Sputum analysis ❑ Productive cough ❑ Bronchoalveolar lavage and analysis ❑ Infiltrations on chest imaging with an uncertain etiology ❑ Nasal wash or bronchoalveolar lavage and assays for viral detection ❑ Respiratory infection during an outbreak or during winter

Do a risk assessment using MASCC risk Index: (MANDATORY) Characteristic Score ❑ No or mild symptoms in patients following an episode of febrile neutropenia ❑ 5 ❑ Absence of hypotension with a systolic blood pressure >90 mmHg ❑ 5 ❑ No chronic obstructive pulmonary disease (active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators) ❑ 4 ❑ Solid tumor or hematologic malignancy with no previously demonstrated fungal infection or empirically treated suspected fungal infection ❑ 4 ❑ Absence of dehydration that requires parenteral fluids ❑ 3 ❑ Moderate symptoms in patients following an episode of febrile neutropenia ❑ 3 ❑ Outpatient status ❑ 3 ❑ Age <60 years ❑ 2

Low risk patients: ❑ MASCC score ≥21 or ❑ Expected brief neutropenia (≤7 days) and/or ❑ Clinically stable and/or ❑ Absence of comorbidities (neurological changes, gastrointestinal symptoms, underlying chronic lung disease, intravascular catheter infection, hemodynamic instability, hepatic insufficiency, or renal insufficiency)

High risk patients: ❑ MASCC score <21 or ❑ Expected prolonged neutropenia (>7 days) and ❑ Profound neutropenia (ANC≤100 cells mm3) and/or ❑ Clinically unstable (unbearable pain, altered mental status, or hypotension) and/or ❑ Presence of comorbidities (neurological changes, gastrointestinal symptoms, underlying chronic lung disease, intravascular catheter infection, hemodynamic instability, hepatic insufficiency, or renal insufficiency) Patients who do not strictly fulfill the criteria for being at low risk Afebrile neutropenic patients with new signs or symptoms suggestive of infection

Administer oral or IV empirical broad-spectrum antibiotic therapy (URGENT): ❑ Ciprofloxacin + Amoxicillin-clavulanate ❑ In clinic or hospital setting ❑ Observe for 4-24 hours after drug administration

Hospitalize the patient

Consider continuing with inpatient IV broad-spectrum antibiotics: ❑ Inability to tolerate oral medications ❑ Unavailabilty of telephone, transportation to hospital, caregiver ❑ Identified infections requiring IV antibiotics ❑ Patient is clinically unstable ❑ Patient and physician decision

Administer IV empirical antipseudomonal antibiotic monotherapy (URGENT): ❑ Cefepime or ❑ Piperacillin-tazobactam or ❑ Meropenem or ❑ Imipenem-cilastatin

Inpatient monitoring: Monitor for recovery, adverse drug effects, secondary infections and development of drug-resistance with ❑ Daily review of systems ❑ Daily physical examination ❑ Cultures of specimens from suspicious sites ❑ Focused imaging studies

Consider discharge with outpatient oral broad-spectrum antibiotics: ❑ Ability to tolerate oral medications ❑ Availabilty of telephone, transportation to hospital, caregiver ❑ Fulminant infections are excluded ❑ Patient is clinically stable ❑ Patient and physician decision

Add vancomycin to the initial empirical antibiotic monotherapy for: ❑ Suspected Catheter related infection ❑ Suspected skin and soft tissue infection ❑ Suspected pneumonia ❑ Hemodynamic instability ❑ Positive gram-positive bacterial blood culture (that is available before the final identification and susceptibility test) ❑ Colonization with MRSA, VRE, or penicillin-resistant streptococcus pneumoniae ❑ Severe mucositis (following fluoroquinolone prophylaxis and use of ceftazidime as empirical therapy) Consider modifying the initial empirical antibiotic monotherapy for: ❑ Suspected antimicrobial resistance: ❑ Patient is unstable ❑ Patient's positive blood culture is suspicious for a resistant bacteria ❑ Patient has/had treatment in a hospital with high rates of endemicity ❑ Patient had previous history of any infection or colonization with an organism or ❑ Proven antimicrobial resistance where the blood cultures are positive for resistant bacteria For Add ❑ MRSA ❑ Vancomycin or ❑ Linezolid or ❑ Daptomycin ❑ VRE ❑ Linezolid or ❑ Daptomycin ❑ ESBLs ❑ Carbapenem ❑ KPCs ❑ Polymyxin-colistin or ❑ Tigecycline

Outpatient monitoring: ❑ Monitor for recovery, adverse drug effects, secondary infections and development of drug-resistance with ❑ Daily review of systems ❑ Daily physical examination ❑ Cultures of specimens from suspicious sites ❑ Focused imaging studies ❑ Ensure 24 hours a day and 7 days a week access to the appropriate medical care ❑ Consider re-admission for IV broad-spectrum antibiotics in case of ❑ Persisting fever ❑ Recurrent fever ❑ New signs of infection ❑ Decreasing neutrophil counts

Days 2 to 4: Management of Low Risk Patients With Febrile Neutropenia After Day 1 Management

Low risk patients

Unexplained fever after day 1

Clinically or microbiologically documented infection during day 1

❑ Persistent or recurrent fever and/or ❑ Clinically unstable

❑ Responding to initial empirical therapy and/or ❑ Cultures negative

Modify antibiotics according to culture results and/or infection site: Culture results and/or infection site Modified regimen ❑ Gram-negative bacteremia ❑ Administer a combination of ❑ Beta-lactam or ❑ Carbapenem plus ❑ Aminoglycosides or ❑ Fluoroquinolones and ❑ Switch to a monotherapy with a beta-lactam agent once the susceptibilities are known ❑ Gram-positive bacteremia or skin and soft-tissue infections ❑ Administer ❑ Vancomycin or ❑ Linezolid or ❑ Daptomycin and ❑ Adjust regimen based on susceptibility of pathogen ❑ Pneumonia ❑ Administer a combination of ❑ Beta-lactam or ❑ Carbapenem plus ❑ Aminoglycosides or ❑ Antipseudomonal fluoroquinolones and ❑ If MRSA suspected add ❑ Vancomycin or ❑ Linezolid and ❑ Adjust regimen based on susceptibility of pathogens and clinical progress ❑ HSV or candida esophagitis ❑ Administer acyclovir and/or fluconazole ❑ Neutropenic enterocolitis ❑ Adminsiter ❑ Monotherapy: Piperacillin-tazobactam or carbapenem or ❑ Combination therapy: Anti-pseudomonal cephalosporin plus metronidazole

Inpatient management: ❑ Hospitalize the patients who are on outpatient broad-spectrum antibiotics ❑ Continue the patients who are on inpatient IV broad-spectrum antibiotics with inpatient management Order: ❑ A new set of blood cultures ❑ Stool sample for C. difficile antigen and toxin assay (if diarrhea is present) ❑ Abdominal CT (if abdominal pain and diarrhea is present) ❑ Other symptom related diagnostic tests Consider noninfectious causess: ❑ Drug related fever ❑ Thrombophlebitis ❑ Underlying cancer ❑ Resorption of blood from a large hematoma

Continue the initial oral or IV broad-spectrum antibiotics until: ❑ ANC is >500 cells/mm3 and rising Outpatient management: ❑ Consider discharging patients with oral broad-spectrum antibiotics ❑ Ability to tolerate oral medications ❑ Availabilty of telephone, transportation to hospital, caregiver ❑ Fulminant infections are excluded ❑ Patient is clinically stable ❑ Patient and physician decision ❑ Monitor the patients for recovery, adverse drug effects, secondary infections and development of drug-resistance with ❑ Daily review of systems ❑ Daily physical examination ❑ Cultures of specimens from suspicious sites ❑ Focused imaging studies ❑ Ensure 24 hours a day and 7 days a week access to the appropriate medical care ❑ Consider re-admission of patients in case of ❑ Persisting fever ❑ Recurrent fever ❑ New signs of infection ❑ Decreasing neutrophil counts

Modify antibiotics according to culture results and/or infection site: Culture results and/or infection site Modified regimen ❑ Drug-resistant gram-negative bacteria ❑ Drug-resistant gram-positive bacteria ❑ Drug-resistant anaerobes ❑ Change from initial cephalosporin to ❑ Imipenem or ❑ Meropenem ❑ If initially on vancomycin add ❑ Aminoglycoside or ❑ Ciprofloxacin or ❑ Aztreonam ❑ Suspected systemic inflammatory response syndrome ❑ Add fluconazole ❑ Clostridium difficile ❑ Add ❑ Oral vancomycin or ❑ Oral metronidazole ❑ Neutropenic enterocolitis ❑ Adminsiter ❑ Monotherapy: Piperacillin-tazobactam or carbapenem or ❑ Combination therapy: Anti-pseudomonal cephalosporin plus metronidazole

Responding

Not responding

❑ Continue antibiotics ❑ For 7-14 days as appropriate for documented infection or ❑ Until ANC >500 cells/mm3 and rising and ❑ Consider resuming oral fluoroquinolone prophylaxis until ANC >500 cells/mm3 and rising in patients ❑ Who remain neutropenic after completion of appropriate treatment ❑ Who's signs and symptoms of a documented infection has resolved

❑ Consider re-examination and re-imaging studies (CT, MRI) for new or worsening sites of infection ❑ Consider culturing, biopsy, or draining sites of worsening infection ❑ Consider reviewing antibiotic coverage for adequacy of dosing and spectrum ❑ Consider adding empirical antifungal therapy ❑ Broaden antimicrobial coverage for hemodynamic instability

Days 2 to 4: Management of High Risk Patients With Febrile Neutropenia After Day 1 Management

High risk patients

Unexplained fever after day 1

Clinically or microbiologically documented infection during day 1

❑ Persistent or recurrent fever and/or ❑ Clinically stable

❑ Responding to initial empirical therapy and/or ❑ Cultures negative

Modify antibiotics according to culture results and/or infection site: Culture results and/or infection site Modified regimen ❑ Gram-negative bacteremia ❑ Administer a combination of ❑ Beta-lactam or ❑ Carbapenem plus ❑ Aminoglycosides or ❑ Fluoroquinolones and ❑ Switch to a monotherapy with a beta-lactam agent once the susceptibilities are known ❑ Gram-positive bacteremia or skin and soft-tissue infections ❑ Administer ❑ Vancomycin or ❑ Linezolid or ❑ Daptomycin and ❑ Adjust regimen based on susceptibility of pathogen ❑ Pneumonia ❑ Administer a combination of ❑ Beta-lactam or ❑ Carbapenem plus ❑ Aminoglycosides or ❑ Antipseudomonal fluoroquinolones and ❑ If MRSA suspected add ❑ Vancomycin or ❑ Linezolid and ❑ Adjust regimen based on susceptibility of pathogens and clinical progress ❑ HSV or candida esophagitis ❑ Administer acyclovir and/or fluconazole ❑ Neutropenic enterocolitis ❑ Adminsiter ❑ Monotherapy: Piperacillin-tazobactam or carbapenem or ❑ Combination therapy: Anti-pseudomonal cephalosporin plus metronidazole

❑ Assess for infection sites ❑ Include CT of the chest and sinuses to assess for invasive fungal infection

Continue antibiotics until ANC >500 cells/mm3 and rising

❑ No changes in empirical antibiotics ❑ Consider continuing the empirical antibiotic therapy until ANC >500 cells/mm3 and rising ❑ Consider modifying the empirical antibiotic coverage based on the clinical or microbiologic evidence of infections (including anti-fungal agents) ❑ Consider starting fluoroquinolone prophylaxis for the remaining duration of neutropenia if afebrile for 4-5 days ❑ Levofloxacin or ❑ Ciprofloxacin ❑ Consider switching from inpatient to outpatient oral or IV antibiotic regimens if the patients fever has subsided, combined with careful daily follow up

Recurrent fever during persistent neutropenia

Responding

Not responding

❑ Continue antibiotics ❑ For 7-14 days as appropriate for documented infection or ❑ Until ANC >500 cells/mm3 and rising and ❑ Consider starting oral fluoroquinolone prophylaxis (levofloxacin or ciprofloxacin) until ANC >500 cells/mm3 and rising in patients ❑ Who remain neutropenic after completion of appropriate treatment ❑ Who's signs and symptoms of a documented infection has resolved

❑ Consider re-examination and re-imaging studies (CT, MRI) for new or worsening sites of infection ❑ Consider culturing, biopsy, or draining sites of worsening infection ❑ Consider reviewing antibiotic coverage for adequacy of dosing and spectrum ❑ Consider adding empirical antifungal (antiyeast or antimold) therapy ❑ Broaden antimicrobial coverage for hemodynamic instability

After Day 4: Management of High Risk Patients With Febrile Neutropenia

High risk patients with prolonged (>4 days) fever

❑ Daily review of systems ❑ Daily physical examination ❑ Blood cultures (repeat on limited basis) ❑ Cultures for any suspected sites of infection

Unexplained fever after day 4: ❑ Clinically stable ❑ ANC rising (myeloid recovery imminent)

Unexplained fever after day 4: ❑ Clinically stable ❑ ANC not rising (myeloid recovery not imminent) ❑ Consider CT scan sinuses and lungs

Clinically or microbiologically documented infection during days 1-4: ❑ Clinically unstable ❑ Worsening symptoms and signs of infection

❑ Observe the patient ❑ No changes in the antimicrobial regimen unless signs of new infection ❑ Clinical or ❑ Microbiologic or ❑ Radiological

Patients receiving antiyeast (candida) prophylaxis: ❑ Fluconazole or ❑ Itraconazole or ❑ Voriconazole or ❑ Posaconazole or ❑ Micafungin or ❑ Caspofungin For: ❑ Allogeneic hematopoietic stem cell transplantation or ❑ Intensive remission-induction or salvage induction chemotherapy following acute leukemia

Patients receiving antimold (aspergillosis, zygomycosis, fusariosis) prophylaxis: ❑ Posaconazole For: ❑ Intensive chemotherapy following acute myeloid leukemia or myelodysplastic syndrome with an age >13 years or ❑ Prior invasive aspergillosis or ❑ Anticipated prolonged neutropenic periods (>2 weeks) or ❑ Prolonged period of neutropenia prior to hematopoietic stem cell transplantation

❑ Consider re-examination and re-imaging studies (CT, MRI) for new or worsening sites of infection ❑ Consider culturing, biopsy, or draining sites of worsening infection ❑ Consider reviewing antibiotic coverage for adequacy of dosing and spectrum ❑ Consider adding empirical antifungal therapy ❑ Broaden antimicrobial coverage for hemodynamic instability

Preemptive antifungal management: Order: ❑ CT chest and sinuses ❑ Macronodules with or without halo sign ❑ Cavitary lesions ❑ Serial serum b-(1-3)-D glucan test for ❑ Candida species ❑ Aspergillus species ❑ Pneumocystis species ❑ Fusarium species ❑ Serial serum galactomannan test for ❑ Aspergillus species Administer appropriate antifungal therapy if: ❑ Clinically unstable and/or ❑ Clinical or chest and sinus CT signs of fungal infection and/or ❑ Positive serologic assay results for evidence of invasive fungal infection and/or ❑ Recovery of fungi (eg. candida or aspergillus species) from any body site Withhold existing antifungal therapy if: ❑ Clinically stable and/or ❑ No clinical or chest and sinus CT signs of fungal infection and/or ❑ Negative serologic assay results for evidence of invasive fungal infection and/or ❑ No fungi (eg. candida or aspergillus species) recovered from any body site

Add antimold therapy to the empirical antiyeast therapy: ❑ Echinocandin or ❑ Voriconazole or ❑ Amphotericin B preparation

Consider switching to a different class of antimold agent

Do's

• Modify the antibiotic regimens depending on the clinical picture and the epidemiology of infections in the area and the hospital where the patient is being treated at.

Don'ts

• Don't measure the temperature of the patient in the axillary area because it is not as specific as if it was taken orally.
• Don't measure the temperature of the patient rectally to avoid contaminating the skin and soft tissues of the rectal area.

References

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