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most recent guidelines for management of febrile neutropenia in children with cancer
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Febrile neutropenia in pediatric malignancies.
Mohammed El ShazlyLecturer ass. Clinical OncologyAlexandria Faculty of Medicine.
Definitions
Pathophysiology
Etiology
Assessment and evaluation
Management.
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
Pathophysiology Innate
immunity
Adaptive immunity
Physiologic response
to infection
PathophysiologyINNATE IMMUNITY
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.
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
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.
PathophysiologyPHYSIOLOGIC COMPENSATION TO INFECTION
Lung RLD
Heart cardiomyopathy
Cranial irradiation pituitary dysfunction
Etiology
When a source is identified, 85% to 90% of the pathogens are either gram-positive or gram-negative bacteria.
RISK FACTORS
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.
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.
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.
Management
Patient characteristics
Clinical presentation
Local infrastructure to support different models of care, drug availability ,cost and local epidemiology including patterns of resistance
Management
Management
Empiric broad-spectrum antibiotics
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 ).
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
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.
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.
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
Sharon C.-A. Chen, Monica A. Slavin and Tania C. Sorrell.Echinocandin Antifungal Drugs in Fungal Infections. Drugs 2011; 71 (1): 11-41
Challenges
Escalation of antibiotics….?
optimum duration for antibiotic adminstration in high risk patients pizzo ’79.
Optimum antifungal treatment.
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