febrile neutropenia in pediatric malignancies
DESCRIPTION
most recent guidelines for management of febrile neutropenia in children with cancerTRANSCRIPT
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Febrile neutropenia in pediatric malignancies.
Mohammed El ShazlyLecturer ass. Clinical OncologyAlexandria Faculty of Medicine.
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Definitions
Pathophysiology
Etiology
Assessment and evaluation
Management.
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Definitions
Fever: single oral 38.3 degree Celsius, or two consecutive temp greater than 38.0 in a 12 hour period lasting at least an hour.
Neutropenia: ANC <500/mm3 , <1000/mm3 before reaching the nadir.1
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Pathophysiology Innate
immunity
Adaptive immunity
Physiologic response
to infection
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PathophysiologyINNATE IMMUNITY
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Pathophysiology INNATE IMMUNITY Mucocuatenous barrier Local tumor invasion, Surgical removal of lesions, Radiation therapy, Graftversus-host disease (GVHD), Mucositis caused by cytotoxic chemotherapy Agents (eg, methotrexate, high-dose cytosine
arabinoside, and etoposide) , Indwelling surgical devices, Frequent blood draws compromise the
epidermal barrier.
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Pathophysiology INNATE IMMUNITY Phagocytic cells
qualitative
quantitative
1)Severity of neutropenia, 2)Rate of ANC decline (rapidly falling rate imposes a greater risk than chronic neutropenia 3)duration of neutropenia.
Impaired chemo attractant responsiveness, Bactericidal killing,and superoxide production
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Pathophysiology ADAPTIVE IMMUNITY
B and T cell populations responsible For regulating the humoral and cell-
mediated host response.
B cellsT cells
• Defective immunoglobulin synthesis
• Hypogammaglobulinemia
impairing the cellular immune response
Increase susceptibility to infection
Bacterial esp. encapsulated, fungal, and viral organisms, intracellular organisms.
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PathophysiologyPHYSIOLOGIC COMPENSATION TO INFECTION
Lung RLD
Heart cardiomyopathy
Cranial irradiation pituitary dysfunction
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Etiology
When a source is identified, 85% to 90% of the pathogens are either gram-positive or gram-negative bacteria.
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RISK FACTORS
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ASSESSMENT AND EVALUATIONHistory
Neutropenic patient has a decreased response to inflammation.
Symptoms e.g. pain on defecation.
Exposures e.g. home, school.
CVAD
Medications
Immunization status.
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ASSESSMENT AND EVALUATIONPhysical examination
Vital signs T, RR, HR, B.P, Wt, pulse oximetery, Cappillary filling time.
HEENT mucosal integrity , moisture, discoloration.
Chesttachypnea
Abd pancreatitis, typhilitis
Surgical sites CVAD, VP shunt, biopsy site.
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ASSESSMENT AND EVALUATIONLaboratory tests
CBC with manual diff.
Blood Culture from CVC and peripheral.
CXR if indicated
Culture from any catheter
Clean catch or mid stream urine sample is available.
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Management
Patient characteristics
Clinical presentation
Local infrastructure to support different models of care, drug availability ,cost and local epidemiology including patterns of resistance
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Management
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Management
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Empiric broad-spectrum antibiotics
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In neutropenic IFD high-risk children, initiate empiric antifungal treatment for persistent or recurrent fever of unclear etiology that is unresponsive to prolonged (> 96 hours) broad-spectrum antibacterial agents (1C; strong recommendation). In neutropenic IFD low-risk children, consider empiric antifungal therapy in the setting of persistent FN (2C; weak recommendation).
Use either caspofungin or liposomal amphotericin B (L-AmB) for empiric antifungal therapy (1A; strong recommendation ).
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Echinocandin mechanism of action involves a target specific for fungus
• Echinocandin is a noncompetitive inhibitor of 1,3--D-glucan synthase
-D-glucan is essential to fungal cell wall integrity
¾ Enzyme is present in fungal, but not mammalian cells
¾ Without it, fungal cells are osmotically fragile and easily lysed
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Intravenousonly
Echoncandin metabolism and elimination differ from each other
OATP=Organic anion-transporting polypeptide.
Biliaryelimination
Urine
Caspofungin
Micafungin COMT
OATP-1B1N-acetylation
Anidulafungin Slo
w
ch
em
ical
deg
rad
ati
on
COMT=Catechol-O-methyltransferase.
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Echinocandins have different complex metabolism and interaction profile
Caspofungin Micafungin Anidulafungin
Hepatic metabolism?
Yes (N-acetylation)
Yes (Arylsulfatase and
catechol-O-methyltransferase;
some CYP3A hydroxylation)
No
CYP3A4 inhibitor?
No, but interact with Inducers Weak No
DrugInteractions?
Cyclosporine; TacrolimusRifampin; Efavirenz;
Nevirapine; Phenytoin; Dexamethasone;Carbamazepine
SirolimusNifedipine No known interactions
Dose adjustments?
Yes Moderate to severe
hepatic insufficiencyand/or
With CYP inducers
No No
Cancidas [Summary of Product Characteristics]. Hoddesdon, Hertfordshire, UK: Merck Sharp & Dohme Limited; 2007.Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006.Ecalta [Summary of Product Characteristics]. Sandwich, Kent; UK: Pfizer Limited; June 2007. DRAFT.
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Comparison of major properties and key pharmacokinetic parameters of echinocandins in adults
Sharon C.-A. Chen, Monica A. Slavin and Tania C. Sorrell.Echinocandin Antifungal Drugs in Fungal Infections. Drugs 2011; 71 (1): 11-41
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Sharon C.-A. Chen, Monica A. Slavin and Tania C. Sorrell.Echinocandin Antifungal Drugs in Fungal Infections. Drugs 2011; 71 (1): 11-41
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Challenges
Escalation of antibiotics….?
optimum duration for antibiotic adminstration in high risk patients pizzo ’79.
Optimum antifungal treatment.
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