This document provides information on febrile neutropenia, including: - It is a common and serious complication of cancer chemotherapy, especially in those with hematologic malignancies. - Initial evaluation of febrile neutropenic patients includes assessing infection risk factors and sites, as well as collecting blood and other cultures. - High-risk patients require intravenous empirical antibiotic therapy in the hospital, while low-risk patients may be treated orally or as outpatients. - Empirical therapy typically involves a broad-spectrum beta-lactam with coverage against pseudomonas, with vancomycin or other anti-gram positive coverage only added if clinically indicated. Therapy is continued until marrow recovery from neutropenia

1. FEBRILE NEUTROPENIA
Ajay Kumar Yadav
PGY3 Medicine
IOM-TUTH, Kathmandu
2075/05/20

2. LAYOUT
• Introduction
• Risk assessment
• Initial evaluation
• Prophylaxis : Antibacterial + Antifungal + Antiviral
• Empirical Therapy
• CLABSI
• Environmental precautions

3. INTRODUCTION
• One of the most frequent and serious complications of cancer chemotherapy .
• Fever occurs in 10%–50% of pts. with solid tumors and around 80% of those with
hematologic malignancies.
• Clinically documented infections occur in 20%–30% of febrile episodes.
• Resistant Gram Positive Pathogens s/a MRSA and VRE and fluconazole-resistant Candida
strains (e.g. Candida krusei and Candida glabrata) have become more common
• Fungi are rarely identified as the cause of first fever early in the course of neutropenia;
rather, they are encountered after the first week of prolonged neutropenia and empirical
antibiotic therapy

4. DEFINITION
• Fever
• Fever is defined as a single oral temperature measurement of >38.3 C (101F) or a
temperature of >38.0 C (100.4F) sustained over a 1-h period.
• Neutropenia
• Neutropenia is defined as an ANC of < 500 cells/cu mm or an ANC that is expected to
decrease to < 500 cell/cu mm during the next 48 h.
IDSA 2010 Guidelines for Febrile Neutropenia
• Febrile Neutropenia
• Febrile neutropenia (FN) is defined as an oral temperature of >38.3°C or two consecutive
readings of >38.0°C for 2 h and ANC of <0.5 × 109/l, or expected to fall below 0.5 × 109/l.
ESMO Clinical Practice Guidelines 2016

5. Cont..
• Profound neutropenia is an ANC < 100 cells/micro.
• Functional neutropenia
• Refers to patients whose hematologic malignancy results in qualitative
defects (impaired phagocytosis and killing of pathogens) of circulating
neutrophils.
• Should also be considered to be at increased risk for infection, despite a
‘‘normal’’ neutrophil count.

6. NEUTROPENIA Vs CHEMOTHERAPY
• Clear relationship between the severity of neutropenia and the intensity of
chemotherapy.
• Currently, the different regimens are classified as
• High risk (>20%)
• Intermediate risk (10%–20%)
• Low risk (<10%) of FN

7. COMMON BACTERIAL PATHOGENS IN
NEUTROPENIC PATIENTS
Common Bacterial Pathogens in Neutropenic Patients
Common Gram Positive Pathogens Common Gram Negative Pathogens
Coagulase-negative staphylococci
Staphylococcus aureus, including MRSA
Enterococcus species, including VRE
Streptococci viridians
Streptococcus pneumoniae
Streptococcus pyogenes
Escherichia coli
Klebsiella species
Enterobacter species
Pseudomonas aeruginosa
Citrobacter species
Acinetobacter species

8. MORTALITY AND LINKS
• Overall, bacteremia can be detected in ∼20% of patients with FN.
• Mortality rate is 18% in Gram-negative and 5% in Gram-positive bacteremia.
• Mortality is lower than 5% if the MASCC score is ≥21, but possibly as high as 40%
if the MASCC score is <15 .

9. RISK ASSESSMENT

10. What is the role of risk assessment ?
• Determine type of antibiotic therapy (Oral Vs IV )
• Venue of treatment ( Inpatient Vs Outpatient )
• Duration of antibiotic therapy

11. MASCC SCORE

12. HIGH RISK PATIENTS
• MASCC score < 21
• Profound neutropenia (ANC <100 cells/mm3 ) anticipated to extend > 7 days
• Presence of any co-morbid medical problems including but not limited to:
• Hemodynamic instability
• Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea
• Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea
• Neurologic or mental-status changes of new onset
• Intravascular catheter infection, especially catheter tunnel infection
• New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease
• Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal
insufficiency (defined as CrCl of < 30 mL/min).

13. LOW RISK PATIENTS
• MASCC score > 21
• Expected to be neutropenic (ANC < 500 cells/cu mm) for ≤ 7 days
• No active co-morbidities.
• No evidence of significant hepatic or renal insufficiency.

15. INITIAL EVALUATION

16. INITIAL EVALUATION
• Note the presence of indwelling IV catheters ( peripheral and central ).
• S/S suggesting an infection focus:
• Respiratory system
• Gastrointestinal tract
• Skin
• Perineal region/genitourinary discharges
• Oropharynx
• Central nervous system
• Knowledge of previous positive microbiology results by checking clinical records

17. INVESTIGATIONS
Routine investigations Further investigations (profound/prolonged
neutropenia/following allografts)
 CBC , RFT , LFT
 Coagulation screen
 CRP
 Blood cultures (minimum of two sets)
including cultures from indwelling IV
catheter
 Urinalysis and culture
 Sputum microscopy and culture
 Stool microscopy and culture
 Skin lesion (aspirate/biopsy/swab)
 Chest radiograph
 HRCT (if pyrexia despite 72 h of appropriate
antibiotics)
 BAL

18. • At least 2 sets of blood cultures are recommended, with a set collected
simultaneously from each lumen of an existing CVC, if present, and from a
peripheral vein site.
• 2 blood culture sets from separate venipunctures should be sent if no central
catheter is present.
• A ‘‘set’’ consists of 1 venipuncture or catheter access draw of ≈20 mL of blood
divided into 1 aerobic and 1 anaerobic blood culture bottle

19. EMPIRICAL ANTIBIOTIC THERAPY

20. EMPIRICAL THERAPY
• High-risk patients
 Require hospitalization for IV empirical antibiotic therapy.
 Monotherapy with an anti-pseudomonal b-lactam agent, such as cefepime, ceftazidime, a
carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended.
 Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added for
management of complications (eg,hypotension and pneumonia) or if antimicrobial resistance is
suspected or proven.
 Vancomycin (or other agents active against aerobic gram positive cocci) is not recommended as a
standard part of the initial antibiotic regimen for fever and neutropenia.

21. When to add antibiotics active against GPOs
to the empirical regimen?
IDSA clinical guidelines 2010 on febrile neutropenia

22. Cont..
• Most penicillin-allergic pts tolerate cephalosporins, but those with a h/o type 1 HSR s/b
treated with a combination that avoids b-lactams and carbapenems, such as ciprofloxacin
plus clindamycin or aztreonam plus vancomycin.
• Afebrile neutropenic pts who have new s/s suggestive of infection should be evaluated
and treated as high-risk pts.
• Low-risk pts should receive initial oral or IV empirical antibiotic doses in a clinic or
hospital setting.
• Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral
empirical treatment

23. Cont..
• Patients receiving fluoroquinolone prophylaxis should not receive oral empirical
therapy with a fluoroquinolone.
• Hospital re-admission or continued stay in the hospital is required for persistent
fever or s/s of worsening infection

24. IDSA clinical guidelines 2010 on febrile neutropenia

25. WHEN TO MODIFY THERAPY ?
• Modifications to initial empirical therapy may be considered
• Antibiotic resistant organisms, particularly if the patient’s condition is unstable or
• Positive blood culture results suspicious for resistant bacteria.
• MRSA: Consider early addition of vancomycin, linezolid, or daptomycin.
• VRE: Consider early addition of linezolid or daptomycin.
• ESBLs: Consider early use of a carbapenem.
• KPCs: Consider early use of polymyxin-colistin or tigecycline.

26. Cont..
• Modifications to the initial antibiotic regimen s/b guided by clinical and
microbiologic data.
• Unexplained persistent fever in a patient whose condition is otherwise stable
rarely requires an empirical change to the initial antibiotic regimen. If an infection
is identified, antibiotics should be adjusted accordingly.
• Documented clinical and/or microbiological infections should be treated with
antibiotics appropriate for the site and for the susceptibilities of any isolated
organisms.

27. Cont..
• If vancomycin or other coverage for GPOs was started initially, it may be stopped after 2
days if there is no evidence for a gram-positive infection.
• Pts who remain hemodynamically unstable after initial doses with standard agents for
neutropenic fever should have their antimicrobial regimen broadened to include
coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi.
• An IV-to-oral switch in antibiotic regimen may be made if pts are clinically stable and GI
absorption is felt to be adequate.
• Empirical antifungal coverage should be considered in high-risk patients who have
persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no
identified fever source

28. IDSA clinical guidelines 2010 on febrile neutropenia

29. PERSISTENT FEVER
• Persistent fever is an episode of fever during neutropenia that does not resolve
after 5 days of broad-spectrum antibacterial agents.
• The median time to defervescence following the initiation of empiric antibiotics
in patients with hematological malignancies is five days, in contrast with only two
days for patients with solid tumors.

30. IDSA clinical guidelines 2010 on febrile neutropenia

31. How Long Should Empirical Antibiotic Therapy
be Given?
• In pts with clinically or microbiologically documented infections, the duration of
therapy is dictated by the particular organism and site; appropriate antibiotics
should continue for at least the duration of neutropenia (until ANC >500
cells/mm3) or longer if clinically necessary.
• In patients with unexplained fever, it is recommended that the initial regimen be
continued until there are clear signs of marrow recovery; the traditional endpoint
is an increasing ANC that exceeds 500 cells/mm3.
• Alternatively, if an appropriate treatment course has been completed and all s/s
of a documented infection have resolved, pts who remain neutropenic may
resume oral fluoroquinolone prophylaxis until marrow recovery

32. ANTIBIOTIC PROPHYLAXIS

33. ANTIBIOTIC PROPHYLAXIS
• Fluoroquinolone prophylaxis s/b considered for high-risk pts with expected
durations of prolonged and profound neutropenia (ANC <100 cells/mm3 for > 7
days).
• There were no significant differences between fluoroquinolone prophylaxis and
TMP-SMX prophylaxis with regard to death from all causes or infection; however,
fluoroquinolone prophylaxis was associated with fewer side effects.
• Addition of a gram-positive active agent to fluoroquinolone prophylaxis is
generally NOT recommended.
• Antibacterial prophylaxis is NOT routinely recommended for low-risk patients
who are anticipated to remain neutropenic for < 7 days.

34. ANTIFUNGAL EMPIRICAL
THERAPY AND PROPHYLAXIS

35. ROLE OF ANTIFUNGAL EMPIRICAL THERAPY
• Empirical antifungal therapy and investigation for IFI s/b considered for pts with
persistent or recurrent fever after 4–7 days of antibiotics and whose overall
duration of neutropenia is expected to be >7 days.
• Aspergillus has surpassed Candida as a cause of IFI.
• In low-risk patients, the risk of invasive fungal infection is low, and therefore
routine use of empirical antifungal therapy is not recommended.

36. ANTIFUNGAL PROPHYLAXIS
• Prophylaxis against Candida infections is recommended in pts in whom the risk of
invasive candida infections is substantial, such as allogeneic HSCT recipients or
those undergoing intensive remission-induction or salvage induction
chemotherapy for acute leukemia.
 Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and
caspofungin are all acceptable alternatives.
 Fluconazole : prevents infection with all species of Candida except for C. krusei or
C. glabrata ; no activity against Aspergillus or other molds.

37. Cont..
• Prophylaxis against invasive Aspergillus infections with s/b considered for
selected pts >13 years of age who are undergoing intensive chemotherapy for
AML/MDS in whom the risk of invasive aspergillosis without prophylaxis is
substantial.
 Itraconazole ,Voriconazole , Posaconazole and AMB are equal alternatives.
 The NCCN Guidelines panel advises that prophylaxis with posaconazole,
itraconazole and voriconazole s/b avoided in pts receiving vinca alkaloid-based
regimens.
 Only agent effective against invasive Mucor mycosis : AMB

38. ANTIVIRAL PROPHYLAXIS

39. • HSV-seropositive patients undergoing allogeneic HSCT or leukemia induction
therapy should receive acyclovir antiviral prophylaxis.
• Antiviral treatment for HSV or VZV is only indicated if there is clinical or
laboratory evidence of active viral disease

40. CENTRAL LINE ASSOCIATED
BLOODSTREAM INFECTIONS(CLABSI)

41. CLABSI
• Differential Time to Positivity(DTP) >120 min of qualitative blood cultures
performed on specimens simultaneously drawn from the CVC and a vein suggests
a CLABSI.
• For CLABSI caused by S. aureus, P. aeruginosa, fungi, or mycobacteria, catheter
removal is recommended in addition to systemic antimicrobial therapy for at least
14 days.
• Catheter removal is also recommended for tunnel infection or port pocket site
infection, septic thrombosis, endocarditis, sepsis with hemodynamic instability, or
bloodstream infection that persists despite > 72 h of therapy with appropriate
antibiotics

42. CLABSI cont..
• For documented CLABSI caused by coagulase negative staphylococci, the catheter may
be retained using systemic therapy with or without antibiotic lock therapy.
• Prolonged treatment (4–6 weeks) is recommended for complicated CLABSI, defined as
the presence of deep tissue infection, endocarditis, septic thrombosis , or persistent
bacteremia or fungemia occurring > 72 h after catheter removal in a patient who has
received appropriate antimicrobials for S. aureus.
• Vancomycin should be administered through the line when possible to cover GPO.
• Teicoplanin is a useful alternative as it can be administered once daily as a line lock.

43. ROLE OF G-CSF
ESMO clinical guidelines 2016 for febrile neutropenia

44. ENVIRONMENTAL PRECAUTIONS

45. • Hand hygiene is the most effective means of preventing transmission of infection
in the hospital.
• Standard barrier precautions s/b followed for all patients.
• Plants and dried or fresh flowers should not be allowed in the rooms of
hospitalized neutropenic patients

46. REFERENCE
• Management of febrile neutropenia: ESMO Clinical Practice Guidelines 2016.
• Treatment of Febrile Neutropenia and Prophylaxis in Hematologic Malignancies:
A Critical Review and Update 2014.
• Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic
Patients with Cancer: 2010 Update by the Infectious Diseases Society of America.
• Blood journal 2017: How I treat febrile neutropenia?
• NCCN ,ASCO guidelines on febrile neutropenia

47. THANK YOU