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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