Complications related to Treatment of

Leukemia ‘Fever and Neutropenia’

Aziza Shad, MDLombardi Cancer CenterGeorgetown University HospitalWashington DC

Mortality Associated with Infection during

Neutropenia

0

20

40

60

80

100

1950 1960 1970 1980 1990 2000

Empirical therapy

Mort

al it

y r

ate

Factors involved in decreasing mortality

•Empirical antibiotic therapy

•Supportive care strategies

• Infection control strategies

Principles of Empiric Antibiotic Therapy

1. Recognition of commonly occurring pathogens, link between specific pathogens and specific sites, drug and/or tumor, tumor-related barrier breakdown

2. Broad coverage directed against the most common pathogenic organisms

Principles of Empiric Antibiotic Therapy

3. Prevention of development of multi-resistant organisms

4. Hold the fort until the underlying lesion is corrected by the return of neutrophils

Definitions

• Fever: single oral temperature of > 38.3 °C (101 °F) or > 38 °C (100.4 °F) for more than 1 hour.

• Neutropenia: ANC <500cells/mm3 or ANC <1000 cells/mm3 with a predicted decrease to <500 cells/mm3

CID 2002, 34:730-751

Recognition of potential pathogens

Evaluation of the host

• Diminished inflammatory response alters usual signs and symptoms of infection

• Fever may be the earliest warning sign

• Absence of fever in patient with localizing signs, even if subtle, may point to infection

Cancer

Treatment

Nutritional status

Microbialflora

Humoral + cellular immunity

Phagocytic defenses

REsystem

Skin + mucosalbarriers

Recognition of potential pathogens

Mouth: gingiva, dentition, buccal mucosa--gram+ anaerobes/HSV/ Candida

Skin: BMA/B, LP, venipuncture sites, tissue around nails - gram+/ fungal / Pseudomonas/VZV

Abdomen/perianal area:enterococci/gram-/anaerobes

Central Catheter:gram+/-

Pulmonary: bacteria, PCP, virus, fungi

Diarrhea: C. difficile

Even with a comprehensive evaluation, an infectious etiology is demonstrated in 50 to 70% of cases

Recognition of potential pathogens

• All efforts should be made in order to identify a pathogen

• Focal findings should be investigated + cultures should be sent when possible

• If no focus send BC/UC

• Determine whether vancomycin is needed

Evaluation of the host

Blood Cultures

If CVC is present culture all ports - 33% oftimes only one port is positive

Peripheral blood cultures when CVC is present is controversial and may not contribute to the management of the pediatric patient

Blood cultures should be sent at least daily if patient remains febrile

Broad coverage against the most common

organisms85-90% of isolated pathogens during new

fever in a neutropenic patient are bacteria

Gram + and Gram - bacteria. Endogenous flora / nosocomial flora

The relative distribution of these organisms vary among institutions

Antibiotic sensitivity patterns vary among institutions

Bacterial Causes during F/N

I ndustrialized Countries

Gram- positive cocci and bacilli *60- 70% of isolates Staphylococcus spp

Coagulase –negative Coagulase-positive Streptococcus spp Enterococcus spp Corynebacterium spp

Developing Countries

Gram- positive cocci and bacilli Staphylococcus spp

Coagulase-positive Coagulase-negative

Gram- negative cocci and bacilli Escherichia coli Klebsiella spp Pseudomonas aeruginosa

Gram- negative cocci and bacilli *60- 70% of isolates

Pseudomonas aeruginosa Escherichia coli Klebsiella spp

Anaerobes Bacteroides spp Clostridium spp Fusobacterium spp Peptococcus/ peptostreptococcus spp Veilonella spp

Bacterial Causes during F/N

Use of central vascular devices Nutritional status Intestinal Parasitosis Infection control strategies 60 % of hospital-acquired infections are caused by

drug resistant microbes in industrialized countries this is many times unknown in developing countries

Disparities between Nations: potential explanations

Emergence of Antimicrobial Resistant Bacteria

Hospital-acquired

Community-acquired

1950 1960 1970 1980 1990

S. aureus

Gram - rods

Enterococcus spp

S pneumoniae

H. influenzae

N. gonorrhoeae

M. catarrhalis

Shigella spp

Emergence of Antimicrobial Resistant Bacteria

Gram-positive cocci

• The most recent of which are VRE• MRSA are no longer confined to hospital wards• 90 % of strains of S.aureus are resistant to

penicillin• Prevalence of DRSP shows geographic variation

30- 40%

Emergence of Antimicrobial Resistant Bacteria

Gram-negative bacilli

• ESBL are enzymes that mediate resistance to third generation cephalosporins and monobactams but do not affect cephamycins or carbapenems

• Common ESBL producers are E. coli, Klebsiella spp, P.aeruginosa and enterobacteria

Cause more indolent infectionsThe most common isolates (CNS, VRE, Corynebacterium jk)

Cause acute infections that progress rapidly S.aureus, S.viridans, pneumococcus also

Cause usually superinfections

M onotherapyCef t az id ime

Cef epime or

Car bapenems

T wo Drugs+ A minoglycos ide

or

2 lac t ams

Vancomycinnot needed

Vancomycin plusCephs / car bap

+/ -

aminoglycos ide

Vancomycinneeded

ff ff ff ff ff ff ff ff ff ff ff ff ff

Child with Fever + N eutropeniaff ff ff ff ff ff ff ff ff ff ff ff ff ff ff

Reassess after 3-5 days

• BC gram + cocci in clusters• Known MRSA colonization• CVL tunnel infection• Suspected sepsis• Substantial mucosal damage• Prophylaxis with quinolones• Sudden increase in temp >40°C

Selection of initial antibiotic therapy

Antibiotic Enteric Gram –P. Aeruginosa

CPS/CNS

Entero cocci

Strepto- cocci

Anaerobes

CeftazidimeCefoperazone

+++ ++/- - - -

Cefepime +++ ++/- - + +

ImipenemMeropenem

+++ +++/+

+++ +++ +++

Quinolones +++ +++/+

+++ + +++

AztreonamAminoglycoside

+++ -/- - - -

Ticar/TazoPiper/clavul

+++ +++/+

+++ + +++

Antibiotic Enteric Gram –P. Aeruginosa

CPS/CNS

Entero cocci

Strepto- cocci

Anaerobes

CeftazidimeCefoperazone

+++ ++/- - - -

Cefepime +++ ++/- - + +

ImipenemMeropenem

+++ +++/+

+++ +++ +++

Quinolones +++ +++/+

+++ + +++

AztreonamAminoglycoside

+++ -/- - - -

Ticar/TazoPiper/clavul

Higher incidence of C. diff colitis/ N+V/ seizures

Good efficacy

More gram positive infections detected

Good efficacy and tolerance

Usually in prophylaxis during neutropenia in high risk patients

Use in lactams allergy – only in combinationToxicity – use only in combination

Limited experience – interfere with Aspergillus antigen detection

Reassessment – Afebrile patient

ConsiderPO ant ibiot ics

Low Risk

Cont inue sameI V ant ibiot ics

H igh r isk

N o et iology

A dj usttherapy

Et iology ident ifi ed

ff ff ff ff ff ff ff ff ff ff ff ff ffA f ebr ile within the fi rst 3- 5 days of t reatment

ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff

Sequential Oral antibiotics

• Limited experience

• Significant cost reduction

• Only for low-risk patients

• Less tolerance (GI toxicity)

• Antibiotic Regimens:

Ciprofloxacin Cipro + amoxi-clavulanic

Factors that favor a Low Risk for severe infections during Neutropenia

ANC > 100 cells/mm3 AMC >100 cells/mm3 Normal CXR Nearly normal renal and lever function tests Duration of neutropenia < 10 days No CVL infection Malignancy in remission Peak temperature <39 °C No neurological or mental status changes No abdominal pain No appearance of illness No co-morbidity complications

Lab

ora

tory

Clin

ical

Reassessment – Febrile Patient

I f no changein pat ientcondit ion

D/ C vanco

Cont inue sameA nt ibiot ics

CoverES BL T ype 1 lactamase

I f progressivedisease

I f cr iter ia f orVancomycin

Change A nt ibiot ics A dd ant if ungaldrug

ff ff ff ff ff ff ff ff ff ff ff ff ffFebrile f or the fi rst 3- 5 days of t reatment

O r new onset f ever

• Review all cultures

• Meticulous Physical exam

• CXR- Image any organ suspected of having infection (CT/US)

• Status of CVL/PIV or venipuncture site

• Pursue biopsy / culture of affected areas / BAL

• Send Aspergillus galactomannan

S ubsequent T herapy

Days 3- 7

I nit ial T herapy

Day 1

I nit ial Evaluat ion

ttt

Approach to the febrileneutropenic patient

Summary

History - Physical examCXR-UC-BCbp + cx of suspicious lesions

Empiric broad spectrum antibiotics

Documented infection

Fever unknown origin

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Factors involved in decreasing mortality

•Supportive care strategies

• Infection control strategies