Transcript FN lecture 6 NOV 07

Infections in
Immunocompromised
Host
A focus on Febrile Neutropenia
Historical Background
First description around 1900
 Rare until development of chemotherapy
 In the 1960s: mainly in acute leukemia with profound
neutropenia G-ve sepsis most common with mortality = 90%
 Empirical therapy with synergistic combinations of antibiotics
reduced mortality to + 10 %
 In the1980s: development of chemotherapy for solid tumors
leading to less severe and less protracted neutropenias
 For multiple reasons, replacement of G-ve infections by G+ve
→severity of infections decreases
 FN becomes a heterogeneous syndrome
 Risk-stratification models allow for identification of low risk
patients with additional treatment options
 Increase of fungal sepsis in specific groups of neutropenic patients
leads to widespread use of empirical antifungal agents

Introduction

Immunocompromised Host:
 Patient
with intrinsic or acquired defects in host
defenses
 Increased
risk of infection
 Incidence
is increasing


– HIV/AIDS, organ transplant, and cancer pts
Infection remains the leading cause of autopsydetermined death in neutropenic cancer patients
Introduction

Infectious complications are a major cause of
morbidity and mortality in cancer patients due
to advances in therapeutics of the malignancy.

Cytotoxic chemotherapeutic agents,
immunotherapy, and bone marrow transplant
almost invariably affect bone marrow function.
Introduction

The normal kinetics of blood cell turnover influence
the sequence and sensitivity of each of the formed
elements.

Polymorphonuclear leukocytes (PMNs; T1/2 = 6 to
8 h)

platelets (T1/2 = 5 to 7 days)

red blood cells (RBC; T1/2 ~ 120 days)

have most, less, and least susceptibility to usually
administered cytotoxic agents, respectively.
The Causes and Consequences
of Neutropenic Complications
Chemotherapy
Radiation
Neutropenia
Disease Process
FEBRILE NEUTROPENIA
Complicated Infections
Prolonged Hospitalization
DEATH
Adapted from Lyman GH. Oncology. 2003:17(suppl):8-13.
Introduction

Infections are the most common complication
of neutropenia

Febrile neutropenia is a MEDICAL
EMERGENCY!!!

Typically occurs 7-10d post chemo

Timely/Thorough assessment and antibiotics
are life saving
Introduction

Risk of infection is proportional to severity
and duration of neutropenia

Recovery of ANC is the most important factor
determining the outcome of infectious
complications
Definitions
ANC = (% segs or PMNS + % Bands) x WBC/100
• Neutropenia
– ANC <1000
– ANC <500 – what most treatment guidelines consider
critical
– ANC <100 – risk of infection and death is greatest
• Fever
– Single oral temp > 38.3° C (101° F)
– Temp > 38.0° for > 1 hour (100.4° F)
NCCN Definitions of Neutropenia
and Febrile Neutropenia
Neutropenia
Fever
ANC <500/μL
or
ANC <1000/μL and
a predicted decline to
≤500/μL
over the next 48 h
Oral temperature
>38.3°C (single
reading) or
>38.0°C (>1 h)
fever + neutropenia = febrile neutropenia
ANC example
Example 1
– WBC = 3.6
– 45% Segs
– 10% Bands
ANC = 55% (3600)/100
OR = 0.55 (3600)
= 1980

Example 2
– WBC 3.0
– 38% Neutrophils
ANC = 0.38 (3000)
= 1140

Risk Factors for FN
Patient-related
 Comorbidities
 Age (>65 y)
 Chronic obstructive
pulmonary disease
 Female gender
 Cardiovascular disease
 Poor performance status
 Liver disease
 Poor nutritional status
 Kidney disease
 Decreased immune
function
 Diabetes mellitus
 Conditions associated with
 Low baseline serum
risk of serious infection
hemoglobin level
 Open wounds
 Active tissue infection
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.

Risk Factors for FN

Treatment-related
 Cancer-related
 Type of chemotherapy (high Hematologic
dose cyclophosphamides,
malignancies
anthracyclines)
 Bone marrow
 History of severe neutropenia
involvement with tumor
with similar chemotherapy
 Advanced or
 Preexisting neutropenia or
uncontrolled cancer
lymphocytopenia
 Elevated serum LDH
 Extensive prior chemotherapy
(lymphoma)
 Concurrent or prior radiation
therapy to marrow-containing
LDH = lactate dehydrogenase; RDI = relative dose-intensity.
bone
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
Risk Factors for FN

Altered skin defenses / foreign body
 CVC
 Urinary
/ Foley catheter
 Radiation induced skin damage / cellulitis
 Surgery
 Mechanical ventilation
 Mucositis / Stomatitis

Colonization
 Recovery
of an organism without clinical signs of infection
 Most infection are from bacteria that colonized the GIT,
URT, and Skin
Incidence of Neutropenia and FN per
Tumor Type and Regimen
Neutropenia Risk
Regimen
FN
Other
Docetaxel,
doxorubicin
33%
Grade 3 or 4 neutropenia: 97%
Docetaxel,
doxorubicin,
cyclophosphamide
25%
Grade 4 neutropenia: 88%
Doxorubicin,
paclitaxel
32%
Grade 4 neutropenia: 89%
MVAC
26%
Grade 3 or 4 leukopenia: 62%
Paclitaxel,
carboplatin
21%
Grade 3 or 4 neutropenia: 39%
Breast
Bladder
Regimen
Small Cell Lung
Etoposide, cisplatin
Topotecan, paclitaxel
Non–Small Cell Lung
Carboplatin, paclitaxel
Cisplatin, paclitaxel
Colorectal
Irinotecan
Non-Hodgkin’s
Lymphoma
CHOP
Neutropenia Risk
FN
Other
Fever: 18%
21%
Grade 3 or 4 neutropenia: 85%
Grade 4 neutropenia: 96%
4%
16%
Grade 3 or 4 neutropenia: 63%
Grade 3 or 4 neutropenia: 75%
14%
Grade 3 or 4 neutropenia: 47%48%
Hospitalization:
<age 65: 7.9%
≥age 65:
13.8%5
Grade 3 or 4 leukopenia:
34%-72%
Other immune system defects
 T-lymphocyte and macrophage function (cellmediated immunity)
 Transplant patients receiving immunosuppressive
drugs, HD, HIV
 B-cell function (humoral immunity)
 Underlying disease such as multiple myeloma or
CLL
Etiology of Infection
 Primary site often includes alimentary tract and where
there has been damage to integument
– Site of infection can be documented in only 30% to
40% of febrile episodes


Bacterial infections most common (fungal infections
increasing)
Gram - replaced by Gram + organisms (often
methicillin resistant)
Etiology of Infection
 Check for other causes of fever
 Reaction
to blood products
 chemotherapy
 cell
lyses and the underlying malignancy
Etiology of Infection

Timeline helps narrow the differential

Early:

Bacterial

Gram Positives (staph, strep …)

Gram Negatives (e.coli, klebsiella, Pseudomonas..)

Mixed in 25%

Infrequently anerobes
Etiology of Infection

Late
 Candida
 Aspergillosis
 PCP

(if on steroids)
Varied
 Viral

Herpes family( HSV, EBV, CMV,

RSV, Paraflu etc…
Most Common Organisms

Gram-Positive Cocci and Bacilli
 Most
likely if infected catheter
 60-70%
of documented infections, WHY?

Staphylococcus species

Streptococcus species

Enterococcus faecalis / faecium

Corynebacterium species
Most Common Organisms

Gram-negative Bacilli and Cocci
 E.
coli
 Klebsiella


sp.
Pseudomonas aeruginosa
Fungal infections: usually super infections

Candida sp or other fungi can cause primary
infections
 In
BMT patients and prolonged N > 7 days
Most Common Organisms

Viral
 Mostly


a reactivation of latent infections
Herpes Simplex, Varicella Zoster
CMV in Stem Cell Transplant
Clinical Presentation

Fever is the most important presenting symptom
in a neutropenic patient

60% of neutropenic patients who become febrile
have an established / occult infection

40% of patients based on a documented microbiological
origin

20% of patients based on clinical findings alone
Clinical Presentation

Many normal signs and symptoms of infection may
be absent, WHY?
 Inflammation
may be minimal
⇓
or absent indurations, erythema, and postulation normally
seen in bacterial skin infections
 Pneumonia
without infiltrate, infiltrates may not develop
until ANC > 500
 Meningitis without
 UTI
without pyuria
WBCs in CSF
Clinical Presentation
Most common sites of infection

lung→only fever and dry cough

Skin cellulitis → no pain, heat , erythema,
swelling
Clinical Presentation

Search should be undertaken for subtle signs and
symptoms
 PAIN

at most commonly infected sites
Periodontium

Pharynx

Lower esophagus

Lung

Perineum

Skin

Bone marrow aspiration site

Catheter access sites
Evaluation

Thorough Physical Exam

Cultures
>
2 sets of blood cultures; 1 set from a central
venous access site and a peripheral vein
 Any
lesions suspected of being infected
 Urine
if any S&S of UTI, presence of catheter, or
abnormal U/A
 Stool
cultures if diarrhea present
Evaluation

CXR if s/s of respiratory tract infection or if
outpatient therapy is planned

CBC
 What
would you expect?

SrCr, BUN, and transaminases

Determine high and low risk patients (see
algorithm)
Evaluation: Low/High risk neutropenia
algorithm

Scores >= 21
considered low
risk

Other algorithms
available
Factors that favor low risk

ANC > 100

Duration of neutropenia < 7 days

Resolution of neutropenia expected in < 10 days

Normal CXR

No IV catheter site infection

Normal hepatic and renal function

No appearance of illness
Treatment Algorithm
Outpatient
Inpatient
Treatment

Empiric antibiotic therapy should be administered
promptly
 if
afebrile, but signs and symptoms of infection present
 If
febrile with ANC< 500 or > 500 and predicted to < 500
 Gm

–ve infections have a 91% mortality in the 1st 24-48 hrs
Remove any sources of infection if possible
Treatment

Initial antibiotics
 Must
consider site of infection/ likely pathogen
 Frequency
of isolation
 Antibiogram
of hospital
 Allergies
 Concomitant
 Organ
 Must
treatments
dysfunction
have bactericidal activity
Treatment

Optimal antibacterial spectrum
 Cover
gm-ve bacilli : E.coli, K.pneumonia,
P.aeruginosa + staphylococci, streptococci
 Optimal
regimen remains controversial
Proposed Classification/Management for
FN Patients

High Risk: Prolonged Neutropenia ( > 14 d),
Heme CA or allo BMT, substantial
comorbidity, unstable
 Admit,
IV therapy (usually combination Rx) for duration of
neutropenia; Ampho B empiric Rx for continued fever
Proposed Classification/Management
for FN Patients

Moderate Risk: Neutropenia 7-14 d, auto BMT,
stable, minimal comorbidity
 Initial IV
Rx (monotherapy OK), early discharge with po if
response; Ampho B for cont’d fever (especially if azole prophy)

Low Risk: < 7d neutropenia, solid tumor, stable
 Outpatient IV
or po therapy; azole Rx ok for cont’d fever
Candidates for Outpatient Therapy

Appears stable

< 60 years

ANC > 100

No source identified

Responsive tumor

No comorbidity
 bleeding, 

BP,  CA++, respiratory failure, altered MS
Suspected duration of neutropenia is not a determining
factor (can’t predict at time of febrile presentation)
Oral antibiotics

As initial therapy or as follow up therapy

Oral ciprofloxacin + amoxicillin-clavulanate

May use clindamycin in allergic patients
Monotherapy
Monotherapy does not cover

Coagulase-negative staphylococci
 MRSA
 Enterococcus
(except imipenem covers faecalis)
Monotherapy

Ceftazidime
 3rd
generation cephalosporin/ antipseudomonal
 covers
only some gram + organisms
 May
improve staphylococcal cover with
vancomycin
 Increasing
lactamases
resistance ( K.pneumonia produce β-
Monotherapy

Cefepime
 4th
generation cephalosporin
 FDA
approved as monotherpay for FN
 Low
affinity for β-lactamases
 more
potent than Ceftazidime against gram +
organisms ( ↓ need for vancomycin)
 Above
advantage is lost when high rate of MRSA
Monotherapy

Carbapenems
 Imipenem+
Cilastatin or meropenem
 Broad
spectrum against gm+ve and gm-ve +
anerobes
 Evidence
 Higher
 More
support efficacy
incidence of N/V
expensive
Monotherapy- Summary

Monotherapy is appropriate as initial empiric TX

No evidence to support superiority of one agent

Carbapenems are usually not used due to cost and
potential of resistance of Acinetobacter

Carbapenems reserved who failed initial empiric TX
or have Hx of infection with resistant organisms
Monotherapy- Summary

Ineffective monotherapy
 Monobactams→lacks
gm+ve activity
 Fluoroquinolones →variable
gm+ve activity, used
for prophylaxis
 B-lactam/b-lactamase
inhibitor combinations
Two Drug Therapy

Advantages
 Broad
spectrum
activity
 Potential synergy
 Minimal
emergence
of drug-resistant
strains

Disadvantages
 Lack
of G + activity
when AG + ceftaz is
used
 Additive
toxicities
when AGs are added
Empiric Combinations

Anti-Pseudomonal PCN or 3rd G Cephalosporin +
aminoglycoside
 Most
established combination
 response
 no
rates all around 70%,
advantage of one b-lactam over another
 Disadvantage;
nephrotoxicity, TDM
Empiric Combinations

Double β-lactam; Anti-Pseudomonal PCN + 3rd G
Cephalosporin or Moxalactam
 Similar
response rates
 Limited
experience
 Poorer
 less
response in documented P. aeruginosa
nephrotoxic, high cost
Empiric Combinations

Ciprofloxacin + AG or B-lactam
 Associated

with ↑ gm +ve infections
Cipro activity against P. aeruginosa has ↓ (<70%)
Empiric Vancomycin
Rationale

Previous combinations lack activity against MRSA

Increasing gm+ve pathogens

Should be D/C after 3-5 days if G+ve infection not identified
Disadvantages

Excessive use → Vanco resistant organisms VRE/VRSA

↑ AG nephrotoxicity

Mortality from staphylococcal infections is < 4% in 1st 48 hrs →
can delay adding until pathogen is confirmed.
Indications for Vancomycin
 Clinically suspected catheter/Skin related infection
 Known colonization with resistant G+ve organism/MRSA
 Positive blood culture for G+ve bacteria
 Hypotension / CV impairment
 Severe mucositis in hospitals with high MRSA (HD-Ara-C)
 Quinolone prophylaxis
 Severe Sepsis
 In institution frequently isolating viridans streptococci
Vancomycin Up Front?

PRO
 change
in most common
isolates in F/N
?
Less febrile days overall, and
perhaps less ampho B use
 viridans
streptococci may be
fatal; particular problem with
quinolone prophylaxis and
regimens that induce severe
mucositis

CON
 overall mortality from
documented gm(+)
bacteremia only 5%
 vast
majority of
patients with gm(+)
survive and respond to
addition of Vanco
VRE
Alternatives to Vancomycin

Linezolid
 Oxazolidione
 IV
or oral
 Thrombocytopenia

Quinupristin-dalfopristin
 IV
 High
side effect profile
 High
potential for DI
Drug Allergy

Need to assess type of allergy and determine
risk versus benefit

Know the organisms you need to cover

If unable to use β-lactam

Vanc + Cipro
 Vanc
+ Aztreonam
Modifying Initial Empiric Regimen

Reassess after 3 days to determine efficacy of
regimen
 Fever
status
 Clinical

condition improved or deteriorated
Changes made sooner if condition deteriorates
 Etiologic pathogen
identified
Afebrile within 3-5 days
No Etiology Identified

Continue empiric TX for 7 d

If ANC> 500 for 2 days→ may D/C Abs

D/C Abs after 14 days in prolonged neutropenia
without evidence of infection

ANC< 500 at 7 d with initial ANC< 100 or
mucositis or unstable → continue ABs
Afebrile within 3-5 days
Etiology Identified

Additional antimicrobial or AB dosage adjustment
based on susceptibility tests and serum conc.

If persistently neutropenic→Maintain broadspectrum antibacterial coverage.

If neutropenia resolved →narrow therapy against
organism for appropriate duration
Persistent Fever during 3-5 days
No Etiology Identified
 Check for other causes of fever
 Tumor
lyses
 Nonbacterial infection
 Resistant bacterial infection
 Inadequate serum
and tissue levels of antibiotics
 Slow
response to therapy
 Drug
related fever

Emergence of a second infection/super infection
 Infection
at avascular site
Persistent Fever during 3-5 days
No Etiology Identified

RE-ASSESS patient! If re-assessment reveals
no new cause: 3 options
1) Continue current therapy
2) Change or add antibiotics
3) Add anti-fungal drug with or without
antibiotic change
Persistent Fever during 3-5 days
No Etiology Identified
1.Continue current therapy

Pt remains stable, not deteriorate

Neutropenia expected to resolve within 5 d

Continue Abs 4-5d after recovery of neutropenia

Continue Abs for 14 days with continued neutropenia
and reassess.
Persistent Fever during 3-5 days
No Etiology Identified
2.Modify initial Abs

If there is evidence of disease progression
 Catheter

site drainage, abdominal pain, pulm. Infilt
Add or change ABs
Persistent Fever during 3-5 days
No Etiology Identified
3. Add antifungal

In pts with hematological CA, persistent fever,
neutropenia > 5d of Abs

Up to 1/3 of febrile neutropenic patients who
do not respond to a 1-week course of abx have
systemic fungal infections

Generally must cover Candida and Aspergillus
Adding Amphotericin B

Reliable activity against Candida and Aspergillus

addition of AmphoB appears to improve outcome

Considered DOC for empiric antifungal Tx

Continue until resolution of neutropenia

Persistent neutropenia→ 2 wk course

Documented infection → variable depending on
diagnosis
Amphotericin B

0.7 mg/kg IV qd is the dose used in severe
infections

Rapid titration up to 0.7 mg/kg over 3 days is
used if infection is less severe
Amphotericin B - Toxicities

Infusion Related
 F/C,
N/V, HA, thrombophlebitis, myalgias and
arthralgias
 Premeditation
may reduce these symptoms
(Tylenol, Benadryl)
 Meperidine
can be given for rigors
Amphotericin B - Toxicities

Nephrotoxicity
 80%
of patients develop some type of impairment
 Dose
related
 Potentiated by

other nephrotoxins
Electrolyte Imbalances
⇓
K, ⇓ Mg, ⇓ Ca
Lipid formulations of Ampho B

Similar efficacy

Decreased side effects (infusion related and
nephrotoxicity)

Consider in patients at risk for nephrotoxicity
or with underlying renal dysfunction.

Expensive
Specific criteria for liposomal
Ampho B

Initial Creat > 2.0 and not on dialysis (long-term)

A doubling of serum creatinine and > 2.0 mg/dL

refractory disease after 10 days (or 500 mg) of
AmphoB

High risk patients (i.e. on CsA, tacrolimus, AG,
foscarnet, cis-platinum, ifosfamide;)

severe or persistent infusional AE to AmphoB
Other Agents

Fluconazole

May be used if mold infections (aspergillus sp)
and drug resistant candida sp are uncommon
 Not
for suspected aspergillus or who used FLZ
prophylaxis

Itraconazole
 When
FLZ is not indicated
 Lower
toxicity than AmphoB
Other Agents

Voriconazole
 Increased
activity against aspergillus and nonalbicans candida
 Alternative
 Less
to AmphoB
toxic, easier to administer
Bottom Line, Empiric Therapy

IV lipo-amphotericin and itraconazole FDA approved,
Ampho-B is a standard of care and has most clinical
experience
 Caspofungin

likely to be approved in near future
Data suggest adding ONLY after 96 hours of antibacterials
AND either persistent or recurrent fever at that time
Bottom Line, Empiric Therapy

Ampho B > Caspofungin > L-Ampho B > Itraconazole as
empiric Rx in patients previously receiving fluconazole
prophylaxis
 Voriconazole may
have a role in high risk, long-term prophylaxis
(e.g. Allo BMT with GvHD), or as empiric therapy in high
aspergillus risk patient after initial blood Cxs (-), but not drug of
choice for empiric Rx of Fever/Neutropenia
Antivirals

Empiric use not indicated without evidence of
viral disease

Indicated if clinical or laboratory evidence of
viral disease

Skin lesions due to herpes simplex or varicellazoster
 Heal
the lesions to decrease potential portals of
entry for bacteria and fungi
Case 1


A 66-y.o. woman presents to her physician with
fever, malaise, sore throat, and easy bruisability.
She is diagnosed to have AML. Following induction
chemotherapy, the patient becomes profoundly
neutropenic (ANC≤ 100/mm3).
She is asymptomatic but develops a fever on the 3rd
day of neutropenia. Her PE, which includes oral
mucosa, indwelling vascular catheter site, heart,
lungs, abdomen, and perianal region, is normal
except for an oral temperature of 39°C. A CXR is
normal, and blood cultures are obtained.
Case 1
1. Which one of the following measures is most
appropriate?
A) Obtain additional tests including sputum, throat,
and urine cultures; then initiate treatment with
appropriate empiric antimicrobial therapy
B) Await results of blood cultures and initiate empiric
antimicrobial therapy if clinical deterioration occurs
C) Initiate empiric therapy with imipenem and
vancomycin
D) Initiate empiric therapy with cefepime
E) Initiate empiric therapy with ceftazidime and
tobramycin
Case 1
2.Two sets of blood cultures grow gram-positive cocci
in clusters. The patient appears clinically stable
except for continued fever. What is the most
appropriate next step?
A) Await identification and antibiotic susceptibility of the
organism before modifying antimicrobial therapy
B) Remove the indwelling intravascular catheter
C) Initiate therapy with vancomycin
D) Obtain additional blood cultures via catheter and
peripheral vein
Case 1
3.The gm-+ve cocci in the blood are identified as
MRSA. Despite appropriate management for the
next 6 days, fever persists. Again, the patient
appears stable with no other symptoms or signs
of infection. Repeat blood cultures and CXR are
negative. Which of the following is the best next
step?
A) Change the patient’s antibacterial regimen
B) Continue the same antimicrobial therapy
C) Test for Clostridium difficile toxin in stool and
perform urinalysis and urine culture
D) Administer empiric antifungal therapy
Duration of Therapy
 Neutrophil count is determinant of discontinuation
 Afebrile by days 3 to 5 AND no infection identified
 ANC > 500 x 2 d, stop abx 48 h after afebrile AND ANC >
500
 If ANC < 500 by day 7
 If low risk and doing well, stop antibiotics when afebrile
x 5 to 7 days
 If initially high risk, continue antibiotics
 If an infection documented then titrate abx according
and continue a full course
Duration of Therapy

Persistent Fever

ANC > 500: Stop 4 to 5 days after ANC > 500
and reassess (if no infection ID’d)
 ANC
< 500: Continue for 2 weeks, reassess. If no
disease present and patient stable, discontinue
Transfusion of granulocytes

has no role in the management of febrile neutropenia
 their
exceedingly short half-life
 mechanical fragility
 clinical
syndromes of pulmonary compromise with
leukostasis after their use.
 Instead, colony stimulating factors (CSFs) are used to
augment bone marrow production of PMNs.
Use of CSF

Can significantly shorten the duration of neutropenia

Has not consistently reduced other measures of
febrile morbidity

Not routinely recommended

May be indicated when a worsening course is
predicted and there is an expected long delay in
recovery of marrow
Mechanism Of Action

Granulocyte colony-stimulating factor (G-CSF), is
one of 5 "classic" hematopoietic growth factors that
are involved in the development and functional
activation of hematopoietic elements

These glycoproteins are produced naturally in
lymphocytes and monocytes, and have been
demonstrated to stimulate progenitor cells of different
hematopoietic cell lineages
The 4 other classes of CSFs

granulocyte-macrophage colony-stimulating
factor (GM-CSF; sargramostim)

macrophage colony-stimulating factor (MCSF),

interleukin-3

erythropoietin
Available Myeloid Growth Factors
Filgrastim

Recombinant methionyl
human G-CSF

175 amino acids

Half-life SC = 3.5 hours

Primarily renal clearance
Pegfilgrastim

Covalent conjugate
of recombinant methionyl
human G-CSF and
monomethoxypolyethylene
glycol

175 amino acids

Half-life SC = 15-80 hours

Limited renal clearance;
primarily neutrophilmediated clearance
Available Myeloid Growth Factors
Sargramostim

Recombinant yeast-expressed human GM-CSF

127 amino acids

Half-life = 60 minutes

Indicated only for use following induction chemotherapy in
older adult patients with AML, for myeloid reconstitution
after BMT, and for mobilization of peripheral blood stem cells
for harvest
Administration

do not administer within 24 hrs of chemotherapy

G-CSF or GM-CSF is conventionally started 24 to 72
hrs after completion of chemotherapy and continued
until a PMN count of 1000 is achieved
CSF Prophylaxis for First and All
Subsequent Cycles: NCCN Guidelines
If the patient is receiving:
If the
patient’s
risk for
FN* is:
Treatment with
curative intent or
adjuvant therapy
Treatment to
prolong survival or
improve QOL
Palliative therapy to
manage symptoms or
improve QOL
>20%
(high)
Use CSF
Use CSF
Consider CSF (discuss
high-risk chemotherapy
with patient)
10%-20%
(intermediat
e)
Consider CSF
Consider CSF
Consider CSF (discuss
(discuss high-risk
high-risk chemotherapy
chemotherapy with with patient)
patient)
<10%
(low)
CSF is not
recommended
for most
patients†
CSF is not
recommended
CSF is not
recommended
CSF Prophylaxis for FN Maintenance of
Scheduled Dose Delivery
Filgrastim
 Daily dose of 5 µg/kg until post-nadir ANC recovery
to normal or near-normal levels
 Start 1-3 days after completion of chemotherapy and treat through postnadir recovery
 Pegfilgrastim
 One dose of 6 mg per cycle of treatment
 Start 1-3 days after completion of chemotherapy
 There is evidence to support use for chemotherapy regimens given
every 3 weeks
 Phase 2 studies demonstrate efficacy in chemotherapy regimens given
every 2neutrophil
weeks count.
ANC = absolute

NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
Prophylaxis against Infection

Non-Pharmacologic therapy
 Reverse isolation
 Infection control guidelines
 Avoid fresh fruits and vegetables
 Personal hygiene
Prophylaxis against Infection
Antimicrobial Prophylaxis
 Data
supports efficacy of TMP-SMX, FQs,
fluconazole, and intraconazole to reduce # of
infectious episodes
Prophylaxis against Infection
 Antimicrobial
 No
Prophylaxis
absorbable antibacterial

Theorized to reduce GI colonization

have not showmen consistent efficacy

Lack of compliance

Induce resistance
Prophylaxis against Infection
Antimicrobial Prophylaxis

TMP-SMX
 showen
consistent benefit in reducing bacterial infections
in FN patients
 Effect
on mortality less clear
 Benefit
must be weighed against risk of bone marrow
suppression, hypersensitivity, and emergence of resistance/
super infection
 Should
be strongly considered for patients at risk of PCP;
ALL receiving intensive chemo, AIDS, Allogenic BMT.
Prophylaxis against Infection
Antimicrobial Prophylaxis

Fluoroquinolones
 Equal
or superior to TMP-SMX in preventing gmve infections in FN
 Disadvantages

↑ gm +ve in patients receiving prophylaxis

Emergences of resistant gm-ve bacilli

Does not reduce mortality
Prophylaxis against Infection
Antimicrobial Prophylaxis

A.
Antifungal

In pts receiving chemo for solid tumors antifungal
prophylaxis may not be beneficial and may ↑ risk of super
infection with resistant fungi

Pts with hematological malignancy and BMT may
benefit more due to longer duration of neutropenia
No absorbable antifungal

Some have role in oropharayngeal candidiasis but not
invasive fungal infections
Prophylaxis against Infection
Antifungals
B.
Systemic antifungals

Itraconazole →efficacy in reducing systemic candida

Fluconazole →


↓ superficial and systemic fungal infections in BMT only

Limited spectrum

Inferior to Itraconazole
Amphotericin

Effective but more toxic
Prophylaxis against Infection

Antivirals

Pts seropostive for HS and receiving BMT, Acute
leukemia, or past history of infection→acyclovir
prophylaxis during neutropenia

Pts seropostive for varicella and receiving
BMT→acyclovir prophylaxis during neutropenia

BMT→ganciclovir prophylaxis against CMV
during neutropenia.
Prophylaxis against Infection
 Antimicrobial
Prophylaxis
 Recommendation:

Routine prophylaxis controversial

May not reduce the need for empiric antimicrobials

Concern about emerging drug-resistant bacteria and
fungi

No consistent reduction in mortality