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MANAGEMENT OF FEBRILE NEUTROPENIA

Management
ANTIBIOTICS Antifungals Colony stimulating factors: G-CSF

Antivirals

For good Antibiotics prescribing


Obtain all necessary cultures before prescribing drugs. Choose narrow spectrum (bactericidal if possible). Use the cheapest, safest, most effective. Prescribe full, or adequate dose for short period.

Empirical administration of broad spectrum

antibiotics at the onset of fever is the accepted standard approach for FN in cancer patient
Disadvantages:
Colonization by hospital-acquired organisms

(fungal) Emergence of resistant strains. Exposure to adverse effects. Increasing cost

Antibiotic prophylaxis
CONTROVERSIAL?? Antimicrobial resistance and lack of mortality benefits.

Trimethoprim/sulfamethoxazole is sometimes used to prevent bacterial infectuion in patient expected to be severly neutropenic.

IDSA and NCCN 2009 Guideline

IDSA (infectious disease society of America) AND NCCN (National Comprehensi ve Cancer network)

Monotherapy Imipenem

Meropenem
Tazocin Cefepime

Ceftazidime
Dualtherapy Aminoglycoside plus antipseudomonal penicillin

Aminoglycoside plus any of the above


Triple therapy Add Vancomycin for selected patients

Duration of therapy:

At least 3-5 days is usually required to

determine efficacy of the initial regimen


WITHIN 3-5 DAYS OF TREATMENT:

If organism identified

may change

antibitotics to minimize cost and SEs, but must maintain Broad spectrum coverage to prevent bacteremia. Continue Rx for 7 days, until culture ve, no signs & symptoms.

Initial Empiric Antibiotics Recommended choices


Monotherapy versus Combination therapy??

MONOTHERAPY
ADVANTAGES:
Ease of administration. Less drug interaction. Lower cost & toxicity. less need for drug monitoring.

DISADVATAGES:
No synergism potential .

Increased cost of newer, broad spectrum drugs.


May not cover all bacterial pathogens.

COMBINATION THERAPY
ADVANTAGES:
Increased bactericidal activity Synergism Broader antibacterial spectrum Limits emergence of resistance

DISADVATAGES:
Drug toxicities Drug interactions Potential cost increase Administration time

SQUH Guideline (2009)


Monotherapy Carbapenem (Imipenem or meropenem) = 47.6% Prefered by hematology 4th generation Cephalosporin (Cefepime) = 40% peadiatrics Tazocin = 12.3% oncology 3rd generation cephalosporin (Ceftazidime) --- not used Pseudomonas resistance dual therapy Aminoglycoside (Amikacin, gentamycin) plus Tazocin = 80% Aminoglycoside (Amikacin) plus any of the above Tribal therapy

Percentage taken from Nada AlRawas thesis Prescribing pattern of antimicrobial agents for chemotherapyinduced FN in patients with hematological malignancies in SQUH

Inhibitor of cell wall synthesis B-Lactams Vancomycin

Inhibitor of protein synthesis Aminoglycoside

Inhibitor of nucleic acid function or synthesis Fluoroquinolon es

1. Imipenem
intravenous -lactam antibiotic. (subgroup of carbapenems). acts as an antimicrobial through inhibiting cell wall synthesis. broad spectrum of activity against aerobic and anaerobic Gram positive

as well as Gram negative bacteria


(e.coli, acinetobacter, coagulase-negative staphylococcus, pseudomonas

aeruginosa)

It is not active against MRSA.

Rapidly degraded by the renal enzyme dehydropeptidase 1 when

administered alone, and is always co-administered with cilastatin to prevent this inactivation (Imipenem/cilastatin)
SIDE EFFECTS: nausea and vomiting, diarrhea, hypersensitivity

reactions, skin rashes.


CAUTION: Pregnancy and breastfeeding , pencillin allergy and renal

2. Cefipime
4th generation cephalosporin (class of -lactam

antibiotics).
bactericidal and have the same mode of action as other

beta-lactam antibiotics.
true broad-spectrum activity but inactive against

enterococci and MRSA.


(staphylococcus aureus, e. coli. Klebsiella pneumonia)

SIDE EFFECTS: diarrhea, nausea, headache, allergic

reactions and local pain.


CONTRAINDICATIONS: hypersensitivity

3. Tazocin
An injectable antibacterial combination consisting of antibiotic piperacillin

sodium and the b-lactamase inhibitor tazobactam sodium.


presumptive therapy --- prior to identification of causative organisms because

of its broad spectrum of bactericidal activity patients with systemic and/or local bacterial infections.
Given with aminoglycoside e.g. Gentamycin----- synergistic effect
(strept, e. coli, coagulase-negative staphy, klebsiella pneumonia,)

SIDE EFFECT: Diarrhoea, vomiting, nausea, rash, erythema

Bleeding manifestations. Neuromuscular excitability or convulsions (Toxicity)


CAUTION: Patients allergic to any of the penicillins and/or cephalosporins or

b-lactamase inhibitors ---- fatal hypersensitivity (anaphylactic) reactions

Cont,
Dosage adjustments are recommended for renal

impairment. Safety and efficacy in children below the age of 12 have not been established. Can be used in pregnancy (only if clearly needed) and elderly but not nursing mothers.

4. Amikacin, Gentamycin
An aminoglycoside (bactericidal antibiotic).

Works by binding the 30S subunit of the bacterial ribosome,

interrupting protein synthesis.


Mainly aerobic multidrug resistant Gram negative bacteria such

as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter and some gram-positive.


combined with a beta-lactam antibiotic for empiric therapy.

Why IV not Oral??


ototoxic and nephrotoxic <<<< major problem in clinical use.

5. Vancomycin
is a glycopeptide antibiotic --- It inhibits cell wall

synthesis
reserved as a drug of "last resort", used only after

treatment with other antibiotics had failed.


Treatment of serious, life-threatening infections by

Gram-positive bacteria and against multiple drug resistant organisms (MRSA, MRSE ) and antibiotic resistant colitis
ADVERSE EFFECTS: local pain, thrombophlebitis.

Cont,
Intravenous vs oral administration?? Administered via iv slow infusion Note: rapid infusion lead to shock and red man syndrome due to histamine release
Recommended for the these situations:

Suspected serious catheter infections Significant mucositis. Known colonization with organisms resistant

to other antibiotics (MRSA) Persistent fever.

Assessment at 48 hours

ANC < 500 / uL

ANC > 500/ uL

Febrile: Check culture & sensitivity data, examine for new focus of infection/ progression of previous infection, change gram negative cover/ add gram positive cover according to results. Afebrile: Consider early discontinuat ion / change to oral antibiotics/ discharge Febrile: Consider other cause of fever, consider occult fungal infection, consider venous access device related

Afebrile:

Continue same antibiotics

Assessment at 96 hours

ANC < 500 / uL

ANC > 500/ uL

Afebrile: Febrile: Afebrile: Add Amphotericine B 1 mg/kg diluted in 500 cc 5DW over 4 hours Febrile: Consider early discontinuati on / change to oral antibiotics/ discharge

Continue same antibiotics

Consider other cause of fever

Discontinuation of antibiotics ANC > 500 / uL

afebrile, no clinical focus identified, no bacteria isolated: Stop after total antibiotics duration of 5-7 days

febrile:
Identify the clinical focus / positive culture & treat appropriately

Lets practice:
66 YEARS OLD WHITE MALE WITH A HISTORY OF CHRONIC LYMPHOCYTIC LEUKEMIA TRANSFORMED TO A DIFFUSE LARGE CELL LYMPHOMA PRESENTED TO THE HOSPITAL WITH FEVER. EIGHT DAYS BEFORE PRESENTATION, HE RECEIVED CYCLOPHOSPHAMIDE, VINCRISTINE AND PREDNISONE CHEMOTHERAPY PLUS RITUXIMAB.

What is the risk stratification? Most commonly prescribed regimen: Persistent fever for 2-4 days or aggravated clinical symptoms for 1-2 days are considered as??

The most common approach would be ???


Fever persisted after 5-7 d despite antibiotic therapy?? When to discontinue antimicrobial??

Regarding the initiation, continuation or discontinuation of therapy for the potential failure, you need to consider:
Is adequate antimicrobial therapy being

Is the isolated organism the etiologic agent?

provided? Is the needed concentration of antimicrobial agent reaching the site of infection? Have resistant pathogen emerged? Is a persistent fever due to underlying disease, abscess formation, iatrogenic complication, a drug reaction, or another process?

Common bacterial pathogens in neutropenic patients.


Gram +ve bacteria Gram ve Bacteria

Streptococcus species Enterobacter species

Coagulase-negative Escherichia coli staph Enterococcus species Pseudomonas aeruginosa Bacillus species Klebsiella species
Corynebacterium species Proteus mirabilis