Title: ADULT GUIDELINES FOR THE MANAGEMENT OF NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY

Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
Dates:
Owner: Department of Medicine: Divisions of Hematology/Oncology & Infectious Disease,
Departments of Laboratory Medicine, Clinical Services, and Pharmacy/Lenz
Originated: 1/02; Location/File name: COF/Oncology; Reviewed: 1/10
Approving Committee/Physician: P&T Committee: 5/07; Revised: 1/10; Revised 2/13; Revised 8/13; Revised 2/14
** These guidelines do not purport to reflect all relevant medical considerations and are not intended to replace
patient-specific clinical judgment. **
I. PRINCIPLES:
A. Neutropenia is defined as a circulating neutrophil count < 0.5 K/cumm or a predicted decrease to < 0.5 K/cumm. The
risk of infection varies inversely with the absolute neutrophil count. In addition, infection is nearly certain when the
neutrophil count is < 0.1 K/cumm for more than a few days. At any given neutrophil count, patients with rapidly declining
neutrophil count after chemotherapy (e.g. absent marrow precursors) are at much greater risk than patients with rising
neutrophil counts.
B. Fever is considered an oral temperature > 38.3°C (101°F) or > 38°C (100.4°F) for > 1 hour. Fever is often the only sign
of infection in a neutropenic patient since many of the classic signs of local infection (purulent discharge, swelling, pain,
infiltrate on x-ray, sputum production, etc.) result from the accumulation of neutrophils. Therefore, fever in a neutropenic
patient is assumed to represent infection until proven otherwise. Fortunately, neutropenic patients with a true infection
often have fevers.
C. Infection in a neutropenic patient is a medical emergency. 20 – 30% of febrile neutropenic patients are bacteremic with
the first fever. Therefore, prompt evaluation of the patient and rapid institution of empiric antibiotic therapy is mandatory.
The house officer must examine the patient, obtain appropriate cultures, and verify that antibiotics are given (not just
ordered) within 2 hours of the initial fever.
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
D. Patients should be classified into low-risk and high-risk categories to determine appropriate antibiotic treatment (refer
to Section III for antibiotic selection). Low-risk patients may receive treatment in an inpatient or outpatient setting. Highrisk patients must be admitted to the hospital for IV antibiotics.
1. Low-risk:
 Outpatient status at time of development of fever
 No associated acute comorbid illness, independently indicating inpatient treatment or close observation
 Anticipated short duration of severe neutropenia (≤ 0.1 K/cumm for < 7 days)
 Good performance status (ECOG 0-1)
 No hepatic insufficiency
 No renal insufficiency
 OR
 A score of 21 or greater on the MASCC Risk Index
 NOTE: any patient that does not strictly fulfill criteria for being low-risk should be treated as a high-risk
patient
2. High-risk:
 Inpatient status at time of development of fever
 Significant medical comorbidity or clinically unstable
 Anticipated prolonged severe neutropenia (≤ 0.1 K/cumm for > 7 days)
 Hepatic insufficiency (aminotransferase 5 times UNL)
 Renal insufficiency (CrCl < 30 mL/min)
 Uncontrolled/progressive cancer
 Pneumonia or other complex infections at clinical presentation
 Received alemtuzumab
 Mucositis grade 3-4
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS



Patients post hematopoietic stem cell transplantation on immunosuppressive therapy regardless if not
neutropenic
OR
MASCC Risk Index score of less than 21
E. Multinational Association for Supportive Care in Cancer (MASCC) Scoring System
1. The maximum value of the score is 26. Scores below 21 are high risk.
The MASCC Risk-Index Score
Characteristics
Weight
Burden of febrile neutropenia with no or mild symptoms* 5
No hypotension (systolic blood pressure > 90 mmHg)
5
No chronic obstructive pulmonary disease
4
Solid tumor or hematologic malignancy with no previous 4
fungal infection
No dehydration requiring parenteral fluids
3
Burden of febrile neutropenia with moderate symptoms
3
Outpatient status
3
Age < 60 years
2
*Burden of febrile neutropenia: Refers to the general clinical status of the patients as influenced by the febrile
neutropenic episode. It should be evaluated on the following scale: no or mild symptoms (score of 5); moderate
symptoms (score of 3); severe symptoms or moribund (score of 0).
F. Most infecting organisms in hospitalized neutropenic patients are acquired from the hospital environment; therefore,
institutional antibiotic susceptibility determines the choice of empiric antibiotics. Certain principles apply universally:
1. Empirically treat for those organisms that can cause rapid death from cardiovascular collapse (Pseudomonas
aeruginosa and other aerobic gram negative organisms).
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
2. Use broad-spectrum antibiotics in effective bactericidal doses.
G. The duration of neutropenia is a critical determinant of successful infection treatment. Almost all appropriately treated
patients recover if the duration of neutropenia can be predicted from the underlying disease and/or therapy. The only
“safe” time to stop antibiotics is after recovery of the neutrophil count and resolution of all signs of infection. Do not stop
antibiotics in a neutropenic patient without consulting the attending physician (see Section III.C.).
H. Many febrile neutropenic episodes (up to 70%) will have no documented pathogen or site of infection; however, at least
half of such episodes will progress to serious infections if antibiotics are stopped prematurely.
II. PRACTICE:
A. Attempt to reduce acquisition of resistant hospital pathogens in neutropenic patients by using the following precautions:
1. Single-bed room (“protective isolation”)
2. Limitation of visitors
3. No live plants
4. Meticulous skin care (especially IV catheter sites)
5. Foley catheters, rectal thermometers, and suppositories should be avoided
6. No blade razors
7. Additional precautions per Infection Control policies
B. Avoid routine use of antipyretics and corticosteroids so that temperature trends and response to antibiotics can be
monitored. Acetaminophen may be used for discomfort associated with fever. Note: allogeneic stem cell transplant
patients may receive corticosteroids for graft-versus-host disease prophylaxis.
C. Examine the patient frequently. Perform a goal-directed history and physical paying special attention to the most
common sites of infection in neutropenic patients:
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
1. Upper and lower respiratory tract
2. Periodontium, oropharynx, and esophagus
3. Skin, IV sites, and perineum
4. Anus/rectum (inspect carefully; gentle digital exam if indicated)
5. Urinary tract
D. Evaluate fever immediately. The most important aspect of the fever work-up is the examination of the patient. Do not
simply order cultures and antibiotics without examining the patient.
1. Assess the patient for signs/symptoms of sepsis
2. Examine the areas noted above and all symptomatic areas
3. Laboratory/radiology testing (see next page)
E. Obtain cultures prior to starting antibiotics for the first fever. Re-culture patients every 48 hours if still febrile but no
clinical change. Otherwise obtain cultures as clinically indicated (e.g. signs and symptoms of sepsis).
1. Blood cultures x 2 (1 central if applicable and 1 peripheral) for routine culture
2. Culture other symptomatic sites (e.g. urine, throat, skin, etc.)
3. If diarrhea present, send stool for C. difficile PCR
(a) If inpatient < 3 days, send stool for routine culture (Salmonella, Shigella, and Campylobacter)
F. Signs & Symptoms of sepsis (any one or more of the following signs):
1. Hyperpyrexia: oral temperature > 40°C (104°F)
2. Hypothermia: oral temperature < 36°C (96°F)
3. Chills not associated with transfusions or medications (e.g. IVIG, amphotericin B)
4. Hypotension: BP change > 30% or SPB < 90 mmHg
5. Hypoxemia: O2 saturation < 90% or > 5% change from baseline
6. Moderate/severe end organ dysfunction (increased Scr or LFTs)
7. Altered mental status
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
G. Signs & Symptoms of a line infection:
1. Pain, erythema, tenderness at site of an indwelling catheter, or fever during the use of a catheter
2. Note: purulent discharge at site is usually not present in a neutropenic patient with a line infection
H. Institute therapy promptly (within 2 hours of fever; refer to Section III for antibiotic selection).
I. Obtain a baseline chest X-ray (preferably PA and lateral) and any other radiologic exam after cultures are obtained and
antibiotics started.
J. Re-evaluate the patient daily (or more often if clinically indicated) for localizing signs of infection and for response to
therapy. Unless the patient’s clinical status changes allow at least 48 hours prior to modifying antibiotics.
K. Be alert for re-appearance of fever in a patient who initially defervesces. This may indicate superinfection with resistant
bacteria or with fungi. Consult the attending physician and / or infections diseases for advice in managing superinfection.
*** Special Considerations
A. Patients receiving purine analogues (e.g. fludarabine, cladribine, pentostatin):
1. Febrile patients who have received purine analogs (whether or not neutropenic) are at risk for Listeriosis. In
these patients, consider adding empiric coverage for Listeria (e.g. ampicillin and gentamicin).
2. Patients who have received purine analogues are also at risk for other opportunistic infections (e.g.
Pneumocystis carinii pneumonia/PCP). Consider appropriate prophylaxis.
III. ANTIBIOTIC USE:
A. Initiate empiric antibiotic therapy at the time of first fever (oral temperature > 38.3°C (101°F) or > 38°C (100.4°F) for
> 1 hour).
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
a. The initial preferred antibiotics are as follows for high-risk patients:
1. All adult patients should receive cefepime (Maxipime®). If a patient has an anaphylactic reaction to
penicillins or beta-lactams, then initiate aztreonam (Azactam®) and tobramycin (Nebcin®) instead of
cefepime.
2. For patients who have a positive blood culture for gram-positive bacteria, before final identification and
susceptibility are available, history of MRSA infection/colonization or penicillin-resistant Streptococcus
pneumonia, skin or soft-tissue infection at any site, clinically suspected catheter-related infection,
hemodynamic instability or other s/s of sepsis start vancomycin (Vancocin®) with a 25-30 mg/kg load
based on actual body weight followed by 15 mg/kg with the dosing interval based on renal function.
3. Adult patients receiving a fluoroquinolone (e.g. ciprofloxacin (Cipro®), levofloxacin (Levaquin®)) after
allogeneic transplant (< 60 days from transplant) should continue on the fluouroquinolone and have
vancomycin added to this therapy. Other patients should have the fluoroquinolone discontinued when
vancomycin is added.
a. For patients who have a VRE positive surveillance culture, initiate daptomycin (Cubicin®) at
8mg/kg IV with an appropriate interval based on renal function. Draw serum CK level x 1 STAT
prior to initiating daptomycin. Note that daptomycin is inactivated by surfactant in the lungs and
should be used cautiously in patients with pneumonia (Note: VRE pneumonia is rare). Patients
with a positive CXR should have linezolid (Zyvox®) added to daptomycin. Note that prolonged
administration of linezolid may cause myelosuppression. If patients have no positive cultures 72
hours after the initiation of vancomycin or daptomycin (+ / - linezolid), discontinue the respective
antibiotic even if febrile.
b. The initial preferred antibiotics are as follows for low-risk patients:
1. IV options (may be received at home)
i.
Cefepime (Maxipime®)
ii.
Meropenem (Merrem®)
iii.
Piperacillin/tazobactam (Zosyn®)
2. PO options (may be received at home)
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
Combination of ciprofloxacin (Cipro®) and amoxicillin/clavulanate (Augmentin®) is oral regimen of
choice.
ii.
If the patient has a penicillin allergy then a combination of ciprofloxacin and clindamycin should be
used.
***Refer to appendix for dosing recommendations in patients with organ dysfunction or page Adult Clinical Pharmacist for
assistance.
i.
B. Additional treatment options may be added if high-risk patients do not respond to empiric therapy as noted previously.
1. Tobramycin may be added to any patient with signs/symptoms of sepsis if not already in the treatment plan.
2. Patients with persistent fevers on antibacterials or reappearance of fever after initial defervesce on antibiotics
should be started on broad-spectrum antifungal therapy. Adult patients should receive voriconazole (Vfend®) with
the appropriate loading dose and maintenance dose. Patients intolerant to voriconazole may receive amphotericin
b (AmBisome®). (See Appendix for dosing schedules).
C. If patient has been on cefepime or other broad-spectrum antibiotics at the time of fever, consider use of carbapenem to
cover multidrug resistant gram-negative organisms.
D. Fully review cultures and consult with attending before discontinuing antibiotics before or after engraftment post stem
cell transplant or after recovery from neutropenia.
1. Discontinue antibiotics and observe if ANC > 0.5 K/cumm, and patient is afebrile.
2. Consider discontinuation of antibiotics or changing to an oral regimen if high-risk patient is afebrile X 72 hours after
≥ 7 days of IV antibiotics, yet the ANC remains < 0.5 K/cumm. This approach should only be considered for
patients with intact mucous membranes and skin (e.g. no mucositis, bleeding sites, ulcerations), and no invasive
procedures pending. Appropriate oral antibiotics include a combination of ciprofloxacin (Cipro®) and
amoxicillin/clavulanate (Augmentin®).
3. Consider discontinuation of antibiotics if ANC is > 0.5 K/cumm X 2 days and the patient remains febrile.
4. Treat any positive cultures for an appropriate time period.
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Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
E. Low-risk patients should be observed for 2-12 hours before allowed to move to home-based management.
F. Low-risk patients should be admitted to the hospital after 2-4 days of empiric treatment if a persistent fever is present
and clinically unstable in order to receive IV antibiotics.
APPENDIX:
Drug
Amoxicillin/clavulanate
(Augmentin®)
Amphotericin B
(AmBisome®)
Aztreonam (Azactam®)
Dosing
875 mg PO Q12H or 500 mg
PO Q8H
5 mg/kg IV Q24H
Dose adjustments
CrCl < 10 mL/min: give normal dose
Q24H
No adjustments needed
Comments
2 gm IV Q6H
CrCl < 30 mL/min: 1 gram IV Q6H
Consult pharmacists for dosing assistance in
HD patients
Cefepime (Maxipime®)
2 gm IV Q8H
Ciprofloxacin (Cipro®)
500 mg - 750 mg PO Q12H
or 400 mg IV Q8-12H
Clindamycin (Clinda®)
Daptomycin (Cubicin®)
600 mg PO Q8H
8-10 mg/kg IV Q24H
Imipenem (Primaxin®)
Linezolid (Zyvox®)
Meropenem (Merrem®)
Piperacillin/Tazobactam
(Zosyn®)
500 mg IV Q6H
600 mg IV or PO Q12H
1 gm IV Q8H
4.5 gm IV Q8H
CrCl 30-60 mL/min: 2 gm IV Q12H;
CrCl 11-29 mL/min: 2 gm IV Q24H
HD: 1gm q24H given after HD on
HD days
CrCl < 30 mL/min: give normal dose
Q24H
HD: give normal dose Q24H after
HD on HD days
No adjustments needed
CrCl < 30 mL/min or on HD: give
normal dose Q48H
CrCl < 50 mL/min: 500 mg IV Q12H
No adjustments needed
CrCl < 30 mL/min: 500 mg IV Q12H
CrCl < 30 mL/min: 4.5 gm IV Q12H
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Obtain baseline CPK, and then follow weekly
Use during meropenem shortage
Prolonged infusion over 4 hours
Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
Drug
Tobramycin (Nebcin®)
Dosing
2.5 mg/kg IV Q12H (round to
the nearest 20mg)
Dose adjustments
CrCl < 50 mL/min: consult
Pharm.D. specialist or adult clinical
pharmacist on call for dosing
assistance
Vancomycin (Vancocin®)
Load with 25-30 mg/kg IV X1
(consult Pharm.D. on call for
doses > 2 gm); then 12H later
start 15 mg/kg IV Q12H
(round to the nearest 250mg)
Treatment dosing: 6 mg/kg IV
Q12H load X 2; then 4 mg/kg
PO or IV Q12H after loading
dose. Prophylactic dosing:
200 mg PO Q12H
CrCl < 50 mL/min: consult
Pharm.D. specialist or adult clinical
pharmacist on call for dosing
assistance
Voriconazole (Vfend®)
CrCl < 50 mL/min: use PO dosing if
possible
FORMULAS:
Ideal Body Weight (IBW; for adults):
IBW = (inches over 5 feet x 2.3) + 50 kg for males or 45.5 kg for females
Dosing Body Weight (DBW; for adults >20% IBW):
DBW: IBW + 0.4 x (ABW – IBW)
Creatinine Clearance (CrCl; for adults):
CrCl in mL/min (Cockcroft-Gault):
Males= (140 - age) x IBW
72 x SCr
Females = Multiply above by 0.85
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Comments
Base dosing on adjusted body weight if
actual is >120% if their ideal body weight. If
actual is <ideal, use actual weight. Obtain
peak and trough around 4th dose.
(Goal: peak 10-12 μg/mL; trough <1 μg/mL)
Base dosing on actual weight. Order trough
level prior to 4th dose if continuing beyond 72
hours. (Goal: trough 10-20 μg/mL)
Order baseline serum galactomannen if
suspecting aspergillosis. For hepatic
dysfunction, consult adult clinical pharmacist
on call for dosing assistance.
Title: ADULT GUIDELINES FOR THE MANAGEMENT OF
NEUTROPENIC INFECTIONS IN HEMATOLOGY/ONCOLOGY
AND STEM CELL TRANSPLANT PATIENTS
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