Dr ANKUR NANDAN VARSHNEYSenior Resident

Department of Medical Oncology

Safdurjung Hospital

NEUTROPENIA

Absolute Neutrophil Count (ANC) < 500.

ANC < 1000 and a predicted decline to < = 500 over next 48 hours.

Profound neutropenia ANC < 100.

FEBRILE NEUTROPENIA Single Oral Temperature >= 38.3* C or 101*F

>= 38* C or 100.4 * F for > 1 hour

Active infection : clinically Severe mucositis, abdominal pain, perirectal pain.

Febrile Neutropenia Importance

Common toxicity of chemotherapy 25- 40%. The most common patient groups were those with breast (27%), lung (16%), ovarian (13%) and esophageal (13%) cancers.

Compromises clinical outcomes Prolonged hospital stay Increased diagnostic and treatment costs Delayed chemotherapy courses Chemotherapy dose reductions Deteoriation in Quality of Life Increased mortality

Schelenz S et al. Annals of Oncology November 2, 2011

Increased Infections Absence of Granulocytes

Disruption of Integumentary, mucosal and muco-ciliary barriers

Shifts of inherent microbial flora

PREVENTION

Prophylaxis

General measures :

Handwashing by all before dealing with pts

Skin care of neutropenic pts ( preventing Staph. aureues ).

Avoiding of fresh flowers and food with high bacterial contents

Teeth should be brushed daily

PROPHYLAXIS : MYELOID GROWTH FACTORS

Colony Stimulating Factors

Reduce risk, severity and duration of FN

Two types

1. Granulocyte Colony Stimulating Factors (GCSF)

2. Granulocyte Macrophage Colony Stimulating Factors (GM- CSF)

MCSF, IL-3 not approved yet

Granulocyte Colony Stimulating Factors

Filgrastim

( wide spectrum, stem cell transplant, chronic neutropenia )

Pegfilgrastim

Tbo-filgrastim

( only in solid organ malignancy associated)

Lenograstim ( not in USA)

Granulocyte Macrophage Colony Stimulating Factors (GM- CSF)

Sargramostim

1. Induction in AML

2. Stem cell transplant

When to give ? Patient factor

Chemotherapy1. High dose

2. Dose dense

3. Standard Dose

Curative intent vs Palliative

Underlying Disease

Patient factors Age > 65

Previous chemo or radiotherapy

Pre-existing neutropenia

Bone marrow involvement

Poor performance status

HIV

Renal or liver dysfunction

Prior infection

Risk Assessment Done prior to first cycle

Administration Only by subcutaneous route

Not given with concurrent chemo or radiotherapy

Filgrastim:

To be started next day after completion of chemotherapy or up to 3- 4 days.

Continued until ANC recovers to near normal

Dose 5 mcg/kg, may be rounded to near normal vial size

PegFilgrastim:

Single dose 6mg/cycle.

Should be given on day after completion of chemotherapy ( categ 1)

Can be given on same day of chemotherapy in Long-distance patients, Longer duration of neutropenia

Side effects Musculoskeletal pain

Allergic reaction to skin

ARDS

Alveolar hemorrhage

Splenic rupture

Sickle cell crisis

Pulmonary toxicity

Increased risk of AML/MDS

Therapeutic use

Poor Clinical Outcome Sepsis

Age > 65

Profound Neutropenia

Neutropenia > 10 days

Pneumonia

Invasive fungal infection

Prior FN/ Hospitalization

Is GCSF alone sufficient ? Underlying Malignancy

Disease status

Duration of neutropenia

Prior Chemotherapy

Intensity of Immunosuppressive therapy

Prophylactic antibiotics : Fluoroquinolone prophylaxis

But

1. Prophylaxis not associated with reduction in bacteremia due to Gram positive pathogens

2. Quinolone resistance may emerge

3. Prophylaxis with quinolones associated with Clostridium difficile diarrhea and colitis

LEVOFLOXACIN is the preferred drug. ( 2014 update )

THERAPEUTIC

Reasons to worry Symptoms and signs of inflammation may be minimal

or absent in the severely neutropenic patient, especially if accompanied by anemia

Diminished or absent induration, erythema, and pustules in response to bacterial infection leave the patient with a cutaneous infection without typical cellulitis

Pulmonary infection without discrete infiltrate on a radiograph

meningitis without pleocytosis in the CSF

urinary tract infection without pyuria

Multinational Association for Supportive Care (MASCC) index

Scores 21 or more are at low risk of complications.

Limitation Does not consider duration of severe neutropenia.

Profound neutropenia > 7 days is always high risk.

Primary sites in INPATIENTS Alimentary tract

Sinuses

Lungs

Skin

Catheter site

Initial Empirical treatment

Vancomycin not routinely recommended for empiric therapy

Use should be limited to specific indications:

1. clinically suspected serious catheter-related infection

2. known colonization with MRSA or pcn/ceph-resistant pneumococci

3. gram-positive bacteremia pending further C&S

4. hypotension or other cardiovascular impairment

5. soft-tissue infection

6. risk factors for viridans strep bacteremia (severe mucositis)

DAILY FOLLOW UP Site specific history and examination

Daily analysis of laboratory/ culture reports to document decrease in bacteremia.

Document fever trends

Drug-related toxicity

Empiric Anti-Fungal To be started after 4 or more days of fever plus persistent

neutropenia.

Ampho B is considered as gold standard, being wide spectrum.

Recently capsofungin has also been approved but iv voriconazole not recomended.

Orally, fluconazole good alternative but no activity against molds.

CT scan and blood culture are recommended.

Serum galactomannan and beta glucan assay have varied results in various studies.

DURATION OF THERAPY1. Skin/soft tissue: 7-14 days

2. Sinusitis: 10-21 days

3. Bacterial pneumonia: 10-21 days

4. Uncomplicated bacteremia:

a) Gram negative: 10-14 days

b) Gram positive: 7-14 days

S.aureus: at least 2 weeks after first negative blood culture and normal TEE

Yeast: ≥2 weeks after first negative blood culture

mold (aspergillus etc): min 12 weeks

Viral:

a) HSV/VZV: 7-10 days

b) Influenza: ≥5 days.

DRUGS REVIEW

IV Therapy Comparison

Piperacillin-tazobactam Broad spectrum gram(-), gram(+) & anaerobic coverage Use for intra-abdominal source Not recommended for meningitis (poor CSF penetration)

Imipenem-cilastin Broad spectrum gram(-), gram(+) & anaerobic and ESBL

coverage Use for intra-abdominal source Risk of seizures in CNS malignancy or renal impairment

Meropenem Broad spectrum gram(-), gram(+) & anaerobic and ESBL

coverage Use for intra-abdominal source Preferred for meningitis/CNS infection

Ceftazidime Poor gram(+) activity Breakthrough streptococcal infections No activity against anaerobes, enterococcus Good CSF penetration

Aminoglycosides Gram(-) coverage, synergy with beta-lactams against S.aureus

and Enterococcus Nephrotoxicity, ototoxicity

Ciprofloxacin Gram(-) and atypical bacterial coverage No anaerobic coverage, less gram(+) activity than other options Good clinical studies as empirical PO or IV therapy Avoid in patients recently treated with quinolone prophylaxis

Anti- fungalsNCCN recommends:

Add fluconazole if no prior azole antifungal prophylaxis,

low risk for invasive aspergillosis and

low rates of azole-resistant Candida.

Dosing: 150 mg PO x1 dose for vaginal candidiasis

200 mg PO daily x14 days for candidal pyelonephritis

800 mg x1 then 400 mg daily x14 days from first negative culture for candidiasis (not recommended if received prophylaxis)

400 mg PO daily prophylaxis for neutropenic patients

NCCN Recommends Add voriconazole, liposomal amphotericin B or an echinocandin

if already exposed to an azole or known to be colonized with non-albicans Candida.

Voriconazole 6 mg/kg IV q12h x2 doses then 4 mg/kg IV/PO q12h Liposomal Amphotericin 3-5 mg/kg IV daily Caspofungin 70 mg IV x1 then 50 mg IV daily; 70 mg IV daily for

aspergillosis

Continue until neutropenia has resolved, or for at least 14 days in patients with a demonstrated fungal infection.

Antiviral drugs

No indication for empirical use of antiviral agents

Treat HSV or VZV lesions

Consider acyclovir (famiciclovir or valacyclovir) for suppression of HSV (hematologic malignancy)

In BMT consider need to treat CMV with ganciclovir or foscarnet

Anti- viral drugs

Oral vesicular lesions: HSV

Esophageal lesions: HSV, CMV

Skin lesions: VZV

Pneumonia: Influenza

CNS symptoms: HSV

Acyclovir: Mucocutaneous HSV: 5 mg/kg IV Q8h Single dermatomal VZV: 800 mg PO 5x/day or 5 mg/kg IV Q8h Disseminated VZV or HSV: 10 mg/kg IV Q8h

Valacyclovir: HSV or VZV treatment: 1g PO Q8h

Ganciclovir: CMV treatment: 5 mg/kg IV Q12h x2 weeks then 5 mg/kg IV Q24h x2-4 weeks

Foscarnet: Acyclovir-resistant HSV: 40 mg/kg IV Q8h CMV treatment: 90 mg/kg IV Q12h x2 weeks then 120 mg/kg IV Q24h x2-4 weeks

Oseltamivir: Influenza: 75 mg PO Q12h

(reduced doses required in renal impairment)

CNS Symptoms CT +/- MRI LP recommended

Empiric therapy: Anti-pseudomonal penicillin that enters CSF (ceftazidime,

meropenem) Vancomycin as first choice, especially if neurosurgical. Ampicillin unless using meropenem Adjuvant dexamethasone is recommended For encephalitis add high dose acyclovir For suspected Abscess, add metronidazole Among anti-fungal, voriconazole must be cautiously used. Use cotrimoxazole, if suspect toxoplasma and nocardia

PneumoniaAdditional Tests: Chest radiographs+ blood culturesputum culturesNasal wash for respiratory virusesLegionella urine antigen testConsider BAL

If high risk consider addingCT chest to define infiltrates

Include coverage for: anti-pseudomonal drug must be given atypical bacteria with azithromycin/ fluroquinolones P.jirovecii with Septran MRSA with vancomycin or linezolid adding antiviral therapy (influenza outbreak) mold-active antifungal (voriconazole or liposomal amphotericin B) if

high risk

Gastrointestinal SymptomsAbdominal pain Abdominal CT is preferred ALP, transaminases, bilirubin, amylase, lipase Ensure anaerobic coverage + anti-pseudomonal coverage Anti-fungal prophylaxis as candida resides in colon.

Diarrhoea C.difficile assay, (rotavirus & norovirus?) Consider stool bacterial cultures +/- parasite exam if C.difficile suspected, oral metronidazole + nasogastric vancomycin

DOC Oral Fidaxomicin, US FDA approved, recommended as 2nd line.

Neutropenic Colitis is life threatening condition, preferably to be managed conservatively.

Vascular Access Device Chlorhexidine / Silver sulfadiazine and

minocycline/rifampicin coated devices are safe for long term access especially in hematologic malignancies.

Increased risk of candida

CDC recommended for access > 5 days.

Not needed to be removed for exit site infection.

DTP > 120 minutes highly sensitive for catheter induced bacteremia.

Adequate gram +ve

Linezolid not approved.

Mouth and esophageal Increased mucositis + endogenous flora

Anaerobic coverage must be provided

HSV reactivation is common, if vesicular lesions.

Candida thrush is common.

Tissue biopsy must be preferred for diagnosis in persistent immunocompromised patients.

Urinary tract symptoms Urine culture

Urinalysis

No additional therapy until pathogen identified

Invasive Fungal Infection

INVASIVE CANDIDIASIS

4th most common infection in cancer patients

Fluconazole/Echinocandin DOC in non-neutropenic pts.

Echinocandin / Capsofungin iv is drug of choice (IDSA update) in neutropenic patients.

Fluconazole , if species is sensitive.(C. albicans and parapsilosis)

Ampho B (NCCN) only in meningitis and endocarditis.

INVASIVE ASPERGILLOSIS

IV Voriconazole is drug of choice.

With oral Posaconazole prophylaxis, choose either iv voriconazole with or without capsofungin or switch to Ampho B.

ZYGOMYCOSIS

Ampho B along with surgical debridement must be considered.

Oral Posaconazole is an alternative.

VACCINATION Only IDSA guidelines

Live attenuated vaccines must not be given until 3 months of chemotherapy and radiotherapy.

Ideally any vaccines should be administered 2 weeks before start of therapy.

Inactivated influenza vaccine must be given annually.

Intranasal C/I.

Pneumococcal, meningococcal and Hib vaccine in patients of splenectomy, hypogammaglobulinemia and B cell malignancies.

TAKE HOME MESSAGE

Febrile neutropenia is a preventable entity and must be treated as oncology emergency.

Patient must be individualized and risk for FN must be calculated for all.

Every institution must have it’s own microbial sensitivity pattern registry and antibiotic policy.

Universal precautions must be strictly applied.

Discussion