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Saima Abbas M.

D
Infectious Diseases
Fellow-PGY5

Why is this an Oncologic


emergency ??

Infection + ABX +
Immune system = cure
Normal Gross
Anatomy
Skin Integrity
Intact mucous
membranes
Intact ciliary
function
Absence of
Foreign Bodies

Innate Immunity
( PMN,
Macrophages, NK
cells, Mast cells and
basophils)
Complement
Adaptive immunity
T cells CD 4 and CD 8
B cells

Case 1
July 10th 2009 - NF 1
You are paged at 5:00am by the nurse
taking care of Mr. Thomas on 4 AB
He spiked a fever of 38 C (100.4F) one
hour ago.
-There is no order for Tylenol.

~ You check your Hem Oncology List .


Per sign out:
The patient was recently diagnosed with
AML is S/P chemotherapy and is stable.
You can
Order Tylenol and take the next page.
OR..

OR
Am I missing febrile
Neutropenia???

If you are alert, you think

What are the facts you


need to know?

Does 38 C define febrile neutropenia?

Whats his Absolute Neutrophil Count?

Any transfusion in the last 6 hours?

Definition of Fever in FN
A single oral temp 38.3 C
(101 F)
or

A temperature of 38 C
(100.4 F) on two occasions
separated by 1 hour

You request her to repeat the


temperature and she reports 38. 2 C
(100.8 F)

Dont be tricked

If temperature 37 38 C , repeat
temperature in 1 hour to see if the
above criteria for treatment are met

Clinical signs of septicemia

Good history of fever detected by


patient before admission and afebrile
when you evaluate the patient.

Definition of Neutropenia

ANC 500/mm3 or

1000/mm3 and predicted

decline to 500/mm
~ Clin Inf Dis, 2002;34:730-51

ANC : Mr. Thomas

WBC 0.7

Segs = 38%

Bands = 2%

Absolute Neutrophil Count


(Total # of WBC) x (% of Neutrophils) =
ANC
Take the percent of neutrophils (may
also be polys or segs) + percent bands
Convert percent to a decimal by
dividing by 100 (Example 40% = 40/100
= 0.40) (*move the decimal 2 points to
the left)
Multiply this number by the total White
Blood Cells (WBC)

Calculation

Neutropenia

Normal ANC 1500 to 8000 cells/mm


Neutropenia: ANC < 1500 cells / mm3
Mild Neutropenia: 1000-1500 cells / mm3
Moderate Neutropenia: 500-999 cells /
mm3
Severe Neutropenia: < 500 cells / mm3
Profound Neutropenia: <100 cells/ mm

When Does Neutropenia


Occur?

Most chemotherapy agents/protocols


cause neutropenia nadir at 10-14 days
But can see anytime from a few days
after chemotherapy to up to 4-6
weeks later depending on the agents
used

Risk of Infection as Absolute Neutrophil Count


Declines

Epidemiology

Up to 60% febrile neutropenia


episodes = infection
(microbiological or clinical)

~20% patients with ANC <100


cells/mm with febrile neutropenia
episodes have bacteremias.

Epidemiology
--NEJM, 1971;284:1061
Retrospective data have shown that
~ 50 % of Pseudomonas Aeruginosa Bacteremia
result in death within 72 hours when ANC is < 1000
Early trials aimed at Pseudomonas showed that

Carbapenicillin /Gentamicin decreased Mortality by


33 %
~Journal of Infectious diseases, 1978;147:14

Epidemiology

Viscoli et al, Clin Inf Dis;40:S240-5

Changing etiology of bacteremia


IATG-EORTC 1973-2000 trials of febrile neutropenia
Gram positive
dominant since mid
1980s

Gram negative resurgence

1) More intensive
chemoTx
Mucositis
2) In-dwelling catheters
Cutaneous-IV portal
3) Selective antiBx
pressure
Fluoroquinolones
Co-trimoxazole
4) Antacids
Promote orooesophageal
colonisation with
GPC

Duration of Neutropenia

< 7 days LOW risk

7 to 14 days INTERMEDIATE RISK

> 14 days HIGH RISK

Duration Of Neutropenia
1988,Rubin and

< 7 days of neutropenia


~ response rates to initial antimicrobial
therapy was 95%, compared to only
32% in patients with more than 14
days of neutropenia ( <.001)
~ patients with intermediate durations of
neutropenia between 7 and
14 days had response rates of 79%

colleagues

Common Microbes
Gram-positive cocci
and bacilli
Staph. aureus
Staphylococcus
epidermidis
Enterococcus
faecalis/faecium
Corynebacterium
species

Gram-negative
bacilli and cocci
Escherichia coli
Klebsiella species
Pseudomonas
aeruginosa
FUNGI
Candida- Non albicans
emerging
Aspergillus >> in HSCT

Initial evaluation
Ensure Hemodynamic Stability and No NEW
ORGAN DYSFUNCTION
History
Underlying disease, remission and transplant status-

spleen +/Chemotherapy
Drug history (steroids, any previous antibiotics)
Allergies

Focused Review of systems


Transfusions
Can cause fevers

Lines or in-dwelling hardware

THINK Strep.
Pneumoniae
Neisseria meningitidis
Hemophilus Influenzae

Splenectomy

Exam (be prepared to find


no signs of inflammation)

HEENT Look in the mouth any oral


sores periodontium, the pharynx
Lungs
Abdomen for tenderness- RLQ (signs of
Typhilitis)
Perineum including the anus -No rectal
exam !

Skin Exam- Ask the


patient for any area of
Skin
tenderness?
Bone marrow aspirations sites,

vascular catheter access sites

and tissue around the nails

Rashes (Drug eruptions/herpes zoster


reactivation / Petechial rashes all are
common in these patients)

Febrile neutropenia
Investigation

Complete Blood Count (with Differential)


-White cells, haemoglobin, platelets

Biochemistry
-Electrolytes, urea, creatinine, Liver function

Microbiology
-Blood cultures (peripheral and all central line lumens)
-Oral ulcers or sores send swabs ( Viral Cx and fungal Cx )
-Exit site swabs
-Wound swabs
-Urine Cultures (SSx/Foley Catheter) [- pyuria ?? UA]
-Stool Cultures and CDiff Toxin/PCR

Radiology
-Chest Xray +/- CT abdomen/pelvis

Lumbar puncture

Examination of CSF specimens is not


recommended as a routine procedure
but should be considered if a CNS
infection is suspected and
thrombocytopenia is absent or
manageable.

Skin lesions

Aspiration or biopsy of skin lesions


suspected of being infected should be
performed for cytologic testing, Gram
staining, and culture

IMAGING in FN

CXR if Symptomatic or if out pt Rx


considered
High resolution CT Chest Indicated ONLY
if persistent fevers with pulmonary
symptoms after initiation of empiric Abx
CTA if suspect PE
CT abdomen for Necrotizing Enterocolitis
or Typhilitis
CT brain R/o ICH / MRI of the spine or
brain - more for evaluation of metastatic
disease than FN

Stratify risk of
complications
1. Neutropenia

with severity of neutropenia (< 50/mm 3)


with duration of neutropenia (>7 days)

2.Bacteremia
Gram negative > gram positive

3.Underlying malignancy and status


Acute Leukemia
Relapsed disease
Solid malignancies: Local effects eg obstruction,

invasion

4.Co-morbidities, age >60

HIGH risk Patients


Prolonged Neutropenia (>14 days)
Haematological malignancy/ Allogenic HSCT
Myelosuppresive chemotherapy
Concurrent chemotherapy and radiotherapy
Age >60
Co-morbidities eg. Diabetes, poor nutritional status.
Bone marrow involvement of cancer
Delayed surgical healing or open wounds
Significant mucositis
Unstable (eg hypotensive, oliguric)
On steroid dose >20mg prednisone daily
Recent hospitalization for infection

a Concomitant condition of significance (e.g.,shock, hypoxia, pneumonia,


or other deep organ infection, vomiting, or diarrhea).

Risk model
Model 2
(Klatersky et al MASCC 2000 J Clin Onc)

No or Mild symptoms
Moderate symptoms
No Hypotension
No COPD
Solid tumour /
Haem malignancy
(no fungal infection)
Outpatient
No dehydration
Age <60 yrs
LOW RISK=score>20

5
3
5
4
4
3
3
2

ORAL vs IV

For patients who are low risk for


developing infection-related
complications during the course of
neutropenia,
~ Oral ciprofloxacin plus
amoxicillin/clavulanate
~ Oral ciprofloxacin plus clindamycin
for PCN allergy


If EMPIRIC
inpatientANTIMICROBIAL
and high risk

THERAPY after Blood


Cultures.
Must be initiated within 1
hour

THREE approaches for IV


EMPIRIC therapy

IV MONO THERAPY

IV DUAL THERAPY

COMBINATION THERAPY
Mono or dual therapy + VANCOMYCIN

Monotherapy IV
1.

Extended spectrum Antipseudomonal


Cephalosporins

2.

Carbapenem

3.

Cefepime
Ceftazidime
Imipenem Cilastatin
Meropenem

Anti Pseudomonal PCN

Piperacillin- Tazobactam
Ticarcillin- Clavulanic acid

DUAL therapy
1.

an aminoglycoside
plus
an antipseudomonal penicillin
(with or without a beta-lactamase
inhibitor)
or
an extended-spectrum
antipseudomonal cephalosporin,

Dual therapy
(2) ciprofloxacin plus an
antipseudomonal penicillin.

Indications
Unstable patient
H/O P. aeruginosa colonization or
Invasive disease

5 Indications for
Vancomycin

1. clinically suspected serious catheter-related


infections
2. known colonization with penicillin- and
cephalosporin-resistant pneumococci or MRSA,
3. positive results of blood culture for gram-positive
4.

hypotension or other evidence of cardiovascular


impairment

5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole

vancomycin resistant
enterococcus

Linezolid

Daptomycin (avoid for pneumonia)

Quinopristin- Dalfopristin

PCN allergy
NON ANAPHYLACTIC
If not allergic to cephalosporins
~ Cefepime
ANAPHYLACTIC and allergic to
cephalosporins~Aztreonam +/- Aminoglycoside or a FQ

+/- Vancomycin if indicated

MAINTAIN BROAD
SPECTRUM ACTIVITY
FOR A MINIMUM OF 7
DAYS OR UNTIL ANC
>500

Antibiotic stopping guide


IDSA, Clin Infect Disease, 2002

Minimum 1 week of therapy if

Afebrile by day 3
Neutrophils >500/mm3 (2 consecutive days)
Cultures negative
Low risk patient, uncomplicated course

> 1 week of therapy based if


Temps slow to settle (>3 days)
Continue for 4-5 days after neutrophil recovery (>500/mm3 )

Minimum 2 weeks
Bacteraemia, deep tissue infection
After 2 weeks if remains neutropenic (< 500/mm3), BUT afebrile, no

disease focus, mucous membranes, skin intact, no catheter site


infection, no invasive procedures or ablative therapy planned
cease antibiotics and observe

When temperatures do
not go away

Non-bacterial infection (eg fungal, viral)


Bacterial resistance to first line therapy (MRSA,
VRE)
Slow response to drug in use
Superinfection
Inadequate dose
Drug fever
Cell wall deficient bacteria (eg Mycoplasma,
Chlamydia)
Infection at an avascular site (abscess or catheter)
Disease-related fever

Antifungals

Easy to Initiate/ Difficult to stop


Aggressive search for Fungal Infections
Pulmonary Aspergillosis/Sinusitis /
Hepatic Candidiasis
CT Chest and Abdomen
CT Sinuses
Cultures of suspicious skin lesions

ANTI FUNGALS
AMPHO B IV drug of choice for high
risk patients
Alternative options
FLUCONAZOLE
ITRACONAZOLE
ECHINOCANDINS
Voriconazole is NOT FDA approved for
empiric therapy for persistent fevers in
FN

Fluconazole ~ candida
Fluconazole
acceptable if NO
Moulds and Resistant
Candida
( C. Krusei and C.
glabrata )
Uncommon.

Low risk patients

DO NOT Use
Fluconazole if
Evidence of Sinusitis
or
Radiographic
evidence of Evidence
of Pulmonary
disease
If patient has
received Fluconazole
prophylaxis before.

Itraconazole
In a recent controlled study of 384
neutropenic patients with cancer,
itraconazole and amphotericin B were
equivalent in efficacy as empirical
antifungal therapy.
FOR BOARDS use AmphoB OR
Itraconazole- hopefully should not ask
you to choose between Itraconazole and
Ampho B

Antibiotic Prophylaxis
for Afebrile
Use of antibiotic prophylaxis is not routine because
Neutropenic
Patients
of emerging antibiotic resistance
**, except for

Trimethoprim-sulfamethoxazole to prevent
Pneumocystis carinii pneumonitis.
Antifungal prophylaxis with fluconazole
Antiviral prophylaxis with acyclovir or ganciclovir
are warranted for patients undergoing allogenic
hematopoietic stem cell transplantation.
** CID
40:1087&1094,2005
NEJM 353:977,988&1052,2005

Use of Antiviral Drugs

Antiviral drugs are not recommended for


routine use unless clinical or laboratory
evidence of viral infection is evident.

Granulocyte Transfusions
Granulocyte transfusions are not
recommended for routine use.

Use of Colony-Stimulating Factors


Use of colony-stimulating factors is not
routine but should be
considered in certain cases with
predicted worsening of course.

Role of G-CSF

Studies of G-CSF used in febrile


neutropenia show:
Length of neutropenia but generally not

hospitalization
No mortality advantage

Generally not recommended


Exception may be those in high risk

group esp. if unstable

Updates not for BOARDS


but for clinical practice

JAC 57:176,2006
A meta analysis of 33 RCTs until Feb
2005 on Antipseudomonal B lactams as
MONOtherapies showed that
~CEFEPIME increases 30 day all cause
mortality
~ Carbapenems were associated with
increased Pseudomembranous colitis.

Special Situations

Neutropenic Enterocolitis
or Typhilitis

Inflammatory process involving colon


and/or small bowel
ischemia, necrosis, bacteremia
( translocation from gut) hemorrhage,
and perforation.
Fever and abdominal pain ( typically
RLQ).
Bowel wall thickening on
ultrasonography or CT imaging.

Treatment
( 50-70% mortality)

Initial conservative management


bowel rest,
intravenous fluids,
TPN,
broad-spectrum antibiotics
and normalization of neutrophil counts.

Surgical intervention
obstruction, perforation, persistent gastrointestinal

bleeding despite correction of thrombocytopenia


and coagulopathy, and clinical deterioration.

Consider Pseudomonal and Clostridial


coverage in Empiric therapy

Clostridium Septicum
Clostridium Sordelli
Cover with PEN G ,AMP,
Clindamycin*
Broad Spectrum Abx ( carbapenem )
include Metronidazole if unsure of
Cdiff
* resistance of Clostridia to clindamycin
reported.

H/O leukemia and


prolonged antibiotic
therapy

Angioinvasive
Aspergillosis

Confirm with Biopsy


Aggressive Antifungal Therapy
Voriconazole (Drug of Choice)
Caspofungin FDA approved for Ampho and

Voriconazole refractory Aspergillus.

Case 1- Mr. Thomas

June 20th 2009 diagnosed AML


June 21st 2009 R subclavian
Hickman placed and Chemotherapy
initiated
Remission Induction S/P 7+ 3 regimen
Cytarabine (Ara C) and Daunorubicin
June 28th 2009 - last dose of
chemotherapy.
July 10th 2009 - Febrile Neutropenia
ANC 280 ANC < 500 last 2 days

Experiences chills with CVC flushing


and erythema and tenderness is noted
over the hickman exit site.
Allergies NKDA
Labs Pancytopenic
LFTS ok Creatinine 1.0

What is the best next


step?
1- Cefepime or Zosyn IV stat
2- Vancomycin IV stat

3- CXR
4- Blood cultures-central and peripheral
5- Fluconazole IV stat

Cefepime and Vancomycin are


initiated
Blood cultures are +
for MRSE 2/2.
Pt becomes afebrile
day 4 of ABX.
Surveillance Blood
cultures are
Negative. Patient is
stable.
ANC = 300 by DAY
4

A
B
C

What will you do


next?
Stop Cefepime
Add G- CSF
Continue Cepepime
until ANC > 500 or a
minimum of 7 days.
Continue
Vancomycin for a
total of 7 days.

Remember for boards

Do not order CT scan in a neutropenic


patient with a normal CXR.
In clinical practice if patient remains
febrile for 3 to 5 days then the next step
is HRCT. ( 50 % of patients with +
imaging have a normal CXR)

Conclusions

Febrile Neutropenia is a serious


complication of chemotherapy
Be vigilant for febrile neutropenia in
chemotherapy patients
Be vigilant for infection even when no
fever
Initiate EMPIRIC antibiotics immediately.
Several treatment options depending on
risk stratification.