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

Obtain a detailed history (an assessment of risk for complications of severe infections):

❑ Infections and inflammation of

❑ Skin and soft-tissues:

❑ Erythema

❑ Intravenous catheter site pain and/or swelling

❑ Nodules

❑ Rash

❑ Swelling

❑ Ulcers

❑ Vesicles

❑ 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

❑ Photophobia

❑ Seizures

❑ Vomiting

❑ Oral cavity and oropharynx:

❑ Dental pain

❑ Mouth ulcers

❑ Neck pain

❑ Lungs (pneumonia):

❑ Dyspnea

❑ Fever (high grade) with sweating, chills, and rigor

❑ Pleuritic chest pain

❑ Productive cough (greenish or yellow sputum)

❑ Rapid and shallow breathing

❑ Abdomen (neutropenic enterocolitis or clostridium difficile colitis):

❑ Diarrhea

❑ Crampy lower abdominal pain

❑ Fever with chills

❑ Nausea

❑ Abdominal distension

❑ Urinary tract (urinary tract infection):

❑ Back, flank or groin pain

❑ Cloudy and foul-smelling urine

❑ Dysuria

❑ Extreme fatigue

❑ Frequent urination

❑ Hematuria

❑ Night sweats

❑ Nocturia

❑ Pain in the midline suprapubic region

❑ Shaking chills and high spiking fever

❑ Vomiting

❑ History of any co-morbid conditions:

❑ Diabetes mellitus

❑ Chronic obstructive lung disease

❑ Any recent exposure to infections
❑ Any current antibiotic prophylaxis
❑ Non infectious causes of fever

❑ Blood transfusions

❑ Uncontrolled cancer

❑ Any recent surgical procedures

❑ Any prior documentation of infections or pathogen colonization

Examine the patient (an assessment of risk for complications of severe infections):

❑ Dehydration
❑ Vital signs:

❑ Blood pressure: Look for hypotension (<90/50 mm Hg)

❑ Pulse rate: Look for tachycardia (>100 beats/min)

❑ Respiratory rate: Look for tachypnea (>20 breaths/min)

❑ Oxygen saturation: Look for decreased oxygen saturation (<90%)

❑ Temperature: Look for a single oral temperature ≥38.3° C (101° F) or a temperature ≥38° C (100.4° F) sustained for over one hour

❑ Signs of infections and inflammation at:

❑ Skin and soft-tissues:

❑ Cellulitis

❑ Ecthyma gangrenosum

❑ Erythema

❑ Erythema multiforme

❑ Erythema, swelling and/or tenderness at sites of previous procedures in skin (example: bone marrow aspiration site)

❑ Furuncles

❑ Intravenous catheter site erythema and/or tenderness

❑ Mucositis

❑ Nodules

❑ Paronychia

❑ Perianal fissures

❑ Pilonidal disease

❑ Rash

❑ Skin lesions with a necrotic center

❑ Ulcers

❑ Vesicles

❑ Central nervous system (meningitis and encephalitis):

❑ Altered sensorium

❑ Brudzinski’s sign

❑ Kernig’s sign

❑ Nuchal rigidity

❑ Personality changes

❑ Oral cavity and oropharynx:

❑ Dental cellulitis

❑ Peritonsillar cellulitis

❑ Mouth ulcers

❑ Lungs (pneumonia):

❑ Bronchial breath sounds

❑ Crackles

❑ Decreased breath sounds

❑ Dullness on percussion

❑ Increased tactile fremitus

❑ Increased volume of whispered (vocal fremitus)

❑ Rales

❑ Rhonchi

❑ Abdomen (neutropenic enterocolitis or clostridium difficile colitis):

❑ Abdominal distension

❑ Abdominal tenderness

❑ Urinary tract (urinary tract infection):

❑ Back or flank tenderness

❑ Discomfort or pain at the urethral meatus

❑ Suprapubic tenderness

❑ Perineum:

❑ Erythema

❑ Tender hemorrhoids

❑ Tenderness on palpation

Don’t do digital rectal examination and rectal temperature recording (increased risk of traumatizing the fragile mucosa and introducing infections)

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

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

❑ 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 clostridium 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

❑ 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

❑ 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

❑ 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

❑ 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

❑ 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