08/10/2020

NEUTROPENIC FEVER
1. DEFINTION OF NEUTROPENIC FEVER
A. Fever
i. Single temperature: ≥ 38.8°C (101°F)
ii. Temperature 38.0°C (100.4°F) for at least 1 hour
B. Neutropenia
i. Reduction in the number of circulation granulocytes or neutrophils which predisposes the host
to infections
ii. Absolute neutrophil count
1. ANC <500 cells/ mm 3
2. ANC <1000 cells/ mm 3 expected to drop below 500 cells/ mm 3 in 48 hours
3. Calculating ANC=WBC X (% neutrophils/segs/bands ÷ 100)
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a. Normal ANC= 3000-7000 neutrophils/mm
b. Mild: ANC= 500-1000/mm 3
c. Moderate: ANC= 100-500/mm 3
d. Severe: AND< 100/mm 3

2. PROPHYLAXIS
ANTIBIOTICS ANTIFUNGALS ANTIVIRALS
CONSIDER FOR: CONSIDER FOR: CONSIDER FOR:
- Allogenic HSCT - Allogenic HSCT - Allogenic HSCT
- Acute Leukemia - Autologous HSCT - Autologous HSCT
- Profound neutropenia >7 days - Acute Leukemia
undergoing induction

AGENT: AGENT: AGENT:

- Ciprofloxacin - Fluconazole - Acyclovir
- Sulfamethoxazole/trimethopri - Voriconazole - Valacyclovir
m - Posaconazole - Letermovir

3. EVALUATION OF THE NEUTROPENIC PATIET

A. Clinical presentation
i. Fever- most important clinical finding; sometimes the only manifestation
ii. Signs and symptoms of infection may be absent in the neutropenic patient immunocompromised
secondary to muted immune response
1. Cough, sputum production, purulence, dysuria, dyspnea…
B. Clinical assessment
i. History and physical exam
ii. Laboratory assessment:
1. CBC with differential
iii. Microbiology/diagnostics:
 1. Blood cultures- 2 sets from 1 different site
a. Complete this prior to antibiotic administration
2. Culture any visible potential sites of infection
a. Skin lesions, catheter drains…
3. Urinalysis and urine culture*
4. Chest radiography*
*If clinically appropriate based on patient presentation and symptoms

4. COMMON PATHOGENS

GRAM POSITIVE: GRAM NEGATIVE:

- Staph epi - E. coli
- Staph aureus - Klebsiella
BACTERIA - Strep viridans - Enterobacter
L - Strep pneumoniae
- Pseudomonas
- Enterococcus
- Serratia
- Citrobacter
- Acinetobacter

- C. albicans - HSV
- C. krusei - Varicella
- C. tropicalis - CMV
FUNGAL VIRAL
- C. glabrata
- Aspergillus

5. EMPIRIC THERAPY
A. Initiate at the onset of fever or at the first signs of infection or within 1 hour of arrival
B. Selection considerations
i. Patient specific factors:
1. Renal/hepatic function
2. History of infections
3. Drug allergies
4. Presence of risk factors
5. Concurrent drugs (i.e. nephrotoxicity)
ii. Institutional variations:
1. Patterns of resistance/microbial susceptibility
C. Patient evaluation
LOW RISK PATIENTS HIGH RISK PATIENTS
- Outpatient status at time of fever - Inpatient status at time of fever
- Anticipated short duration of neutropenia (<7 - Anticipated long duration of severe neutropenia
days) - Significant medical comorbidity or clinic unstable
- No acute comorbid illness - Uncontrolled/progressive cancer
- Good performance status (ECOG 0-1) - Renal or hepatic insufficiency
- No renal/hepatic insufficiency Agents:
Agents: - Cefepime
- Ciprofloxacin PO + Amoxicillin/clavulanate PO - Meropenem
- Levofloxacin PO - Piperacillin/tazobactam

*Every patient will be initiated on vancomycin + an antipseudomonal agent. De-escalation after ~48 hours as

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 indicated except for GCT.

6. ANTIBACTERIAL AGENTS: GRAM-POSITIVE ACITIVITY

A. Vancomycin- 15mg/kg IV Q12H
i. Spectrum:
1. Gram positive organisms, with the exception of VRE
ii. Pearls:
1. Not recommended as standard part of initial regimen unless certain risk factors present
2. TDM
B. Linezolid- 600mg PO/IV Q12H
i. Spectrum:
1. Gram positive organisms including VRE
ii. Pearls:
1. Hematologic toxicity with prolonged use (thrombocytopenia most commonly)
2. Serotonin syndrome risk
3. ADR considerations: lactic acidosis, myelosuppression, and peripheral/optic neuropathy
C. Daptomycin- 6mg/kg/d IV
i. Spectrum:
1. Gram positive organisms including VRE
ii. Pearls:
1. Weekly CPK to monitor for rhabdomyolysis

7. ANTIBACTERIAL AGENTS: ANTI-PSEUDONOMAL

A. Cefepime- 2g IV Q8H infused over 30 minutes
i. Spectrum:
1. Activity against most gram positive and negative organisms
2. Not active against most anaerobes or enterococcus
B. Meropenem- 1g IV Q8H infused over 30 minutes
i. Spectrum:
1. Activity against most gram positive, negatives and anaerobic organisms
2. Preferred against ESBL
3. Consider increased incident of carbapenem-resistant gram-negative rod infections
ii. Pearls:
1. May lower seizure threshold in patients with CNS malignancies or infection or with renal
insufficiency
C. Piperacillin/tazobactam- 3.375g IV Q8H infused over 4H
i. Spectrum:
1. Activity against most gram positive, negative and anaerobic organisms

8. ANTIBACTERIAL AGENTS: OTHERS

A. Aminoglycosides- Consider extended interval dosing
i. Gentamicin, Tobramycin, and Amikacin
ii. Spectrum:
1. Activity primarily against gram-negative organism
iii. Pearls:
1. Addition for seriously ill or hemodynamically unstable patients

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 B. Ciprofloxacin- 500-750mg PO Q12H or 400mg IV Q8-12H
i. Spectrum:
1. Activity against gram positive and atypical organisms
2. No anaerobic activity
ii. Pearls:
1. Avoid in empiric therapy if patient was recently treated with FQ prophylaxis
2. Increasing gram-negative resistance
3. Prolonged QTc internal
4. BBW considerations
C. Trimethoprim/sulfamethoxazole- 15mg/kg/day in divided doses Q6-8H
i. Spectrum:
1. Activity against P jurovecii
a. PJP prophylaxis
ii. Pearls:
1. Monitor for renal insufficiency, myelosuppression, hepatotoxicity and hyperkalemia
2. Interaction with methotrexate

9. ANTIFUNGAL AGENTS: AZOLES

A. Fluconazole- 400mg IV/PO QD
i. Spectrum:
1. C. glabrata is associated with variable resistance
2. C. krusei is intrinsically resistant
3. Inactive against molds
a. Aspergillus and zygomycetes
ii. Pearls:
1. Prolonged QTc internal
B. Posaconazole- loading dose 300mg PO/IV Q12H on day 1 then maintenance dose 300mg QD
i. Spectrum:
1. Active against candida, aspergillus and some zygomycetes species
ii. Pearls:
1. Tablet is better absorbed & should be taken with food
2. PPIs decrease plasma concentration
3. Hepatic function monitoring before and during treatment
4. TDM
C. Voriconazole- loading 6mg/kg IV or 400mg PO Q12H X 2 doses on day 1 then 4mg/kg IV or
100-200mg PO Q12H
i. Spectrum:
1. Active against candida, aspergillus and some rarer molds
2. Poor activity against zygomycetes
ii. Pearls:
1. Visual disturbance and hallucinations
2. Possibility of long-term metabolic irregularities
3. TDM

10. ANTIFUNGAL AGENTS: ECHINOCANDINS

A. Micafungin- 100-150mg IV QD
i. Spectrum:

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 1. C. auris may be resistant to echinocandins
2. Not reliable coverage for cryptococcus, zygomycetes…
ii. Pearls:
1. Excellent safety profile
2. Poor CNS and eye penetration

11. ANTIVIRAL AGENTS

A. Acyclovir- 400mg PO BID
i. Spectrum:
1. HSV/VZV
B. Valganciclovir- 900mg QD (CMV prophylaxis); 900mg PO BID X 2 weeks and until negative
(CMV preemptive treatment)
i. Spectrum:
1. HSV/VZV
2. CMV
ii. Pearls:
1. Potential bone marrow suppression
C. Letermovir- 480mg PO/IV QD
i. Spectrum:
1. CMV
ii. Pearls:
1. 50% dose reduction if co-administered with cyclosporine
2. Has not been studied for treatment therapy

12. ASSESSING EMPIRIC THERAPY

A. Monitoring:
i. Reassess in 3-5 days
ii. In unexplained fever, initial regimen should be continued until ANC>500 and afebrile for 2 days
B. Changing empiric regimen:
i. Should be guided by clinical pattern and cultures
ii. Modification of initial antibiotic regimen is not needed for persistent fever alone
iii. If vancomycin or other gram-positive coverage was started initially, it should be stopped after 2-
3 days of no evidence of gram-positive infection.
iv. Clinical instability after 4-7 days of broad-spectrum antibiotics would warrant investigation into
nonbacterial sources of infection
1. i.e. add micafungin
REFERENCES:
1. National Comprehensive Cancer Network (NCCN). Prevention and Treatment of Cancer-Related Infections. Accessed August 2020.
2. Infectious Diseases Society of America (IDSA) Clinical Practice Guideline: Antimicrobial
Agents in Neutropenic Patients with Cancer. Clinical Infectious Diseases.