Febrile Neutropenia: A Review of the Guidelines

September 29, 2010Andrea Beaman, BScPhm, RPh

PharmD Candidate

Learning Objectives

1. Identify predisposing factors and common pathogens that cause infections in febrile neutropenic patients.

2. Review initial investigations that will help direct therapy in febrile neutropenic patients.

Learning Objectives

3. Compare recommendations for empiric antibiotic selections for high risk and low risk febrile neutropenic patients.

4. Discuss assessment of response, treatment modifications and duration of therapy.

Recent Guidelines National Comprehensive Cancer Network

Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections v.2.2009

European Society for Medical Oncology. Management of Febrile Neutropenia: ESMO Clinical Practice Guidelines (2010)

Infectious Disease Society of America. 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer (Update expected Winter 2011)

What is the Risk?Incidence of Febrile Neutropenia

Induction-remission for AML 70-90%

Elderly patients receiving CHOP 35-45%

Patients with NHL 10-20%

Mortality Estimates from Febrile Neutropenia

Solid tumours 5%

Hematological malignancy Up to 11%

Gram-positive bacteremia 5%

Gram-negative bacteremia 18%

Case Presentation A 40 yr old woman diagnosed with locally

advanced breast Ca in Mar/2010 Plan of care:

Completed 3 cycles neoadjuvant FEC q3wk

Received 2nd cycle Taxotere® q3wk on Sept 13

Receiving Neulasta® dose Day 1 post-Taxotere®

Plan for surgery in Nov.

Case PresentationPresented on Sept 20th with

Temp=39.5C and feeling “unwell”.WBC = 2.2 (4-11), Neutrophil = 0.42

(2-7.5)Creat = 87 (50-100)BP 170/60, RR 16Ht = 178 cm, Wt = 90.7 kg

Definition of Febrile Neutropenia

Does this patient have febrile neutropenia? Fever: Single oral temperature ≥38.3°C or

persistent temperature ≥38.0 °C for >1 hour.

Temp 39.5 °C

Neutropenia: ANC <0.5, or ANC <1.0 and a predicted decline to <0.5 over next 48 hrs. (ANC= absolute neutrophil count)

ANC 0.42

Predisposing FactorsMalignancy

TypeAdvanced/refractoryObstructive

Surgical riskGrade of neutropenia Disruption of mucosal barriersCorticosteroid use

Microbiology Mainly gram-positive

organisms (~70%) Coagulase-negative

staphylococci S. aureus S.viridans Enterococci

Gram-negative organisms Coliforms (E.coli,

Klebsiella, Enterobacter) P.aeruginosa

Yeast Candida Aspergillus

Viruses Herpes simplex

(HSV) Influenza,

paranifluenza CMV

Initial Investigations History & physical examLab assessmentsDiagnostic imagingMicrobiologic evaluations

Detailed H&P Including Chemotherapy

regimen & last dose given

Presence of vascular devices

Prophylactic antibiotic

Steroid use Allergies

Major comorbid illnesses

Recent surgical procedures

Recent infections or positive cultures

Previous antibiotic-resistant organisms or bacteraemia

Recent exposures

Site-Specific H&P Oropharynx Respiratory

system GI tract Skin Genitourinary CNS

No mucositisMild coughNo N/V/DNo skin lesions, CVADYeast InfectionNo CNS symptoms

Lab assessments CBC with differential

BUN, SCr Electrolytes

LFTs

Urinalysis

WBC=2.2, ANC=0.42, Hgb=99, Plt=345BUN=3, SCr=87Na=139, K=3.6, Cl=104, HCO3=28Tbili=16, ALT=117, AST=76, Alp=84Normal

Microbiologic evaluationsBlood cultures x2

1 catheter + 1 peripheral2 catheter 2 peripheral

Urine culture if symptomaticurinary catheteror abnormal urinalysis

Blood & urinecultures Negative

Site-Specific Cultures Diarrhea: C.difficile assay, stool

microscopy and culture Sputum microscopy and culture Aspirate/swab/biopsy of any skin lesions or

CVAD-associated symptoms Viral cultures

Vesicular or ulcerated skin/mucosal lesions Throat or nasopharynx for respiratory

symptoms (esp. during outbreaks) LP if CNS symptoms

Fungal cultures

BroadSpectrum

Anti-Pseudomonal

LocalABx

Susceptibility

PotentialOrganisms

Bacteri-cidal

PreviousABxUse

AllergyStatus

OrganFunction

Site ofInfection

PatientAssessment

Initial Therapy

Low Risk High RiskOutpatient at time of fever Inpatient at time of fever

No acute comorbid illnesses Significant medical comorbidity

Anticipated short duration of severe neutropenia

Anticipated severe or prolonged neutropenia

No renal insufficiency CrCL <30 ml/min

No hepatic insufficiency Transaminases ≥5x ULN

Good performance status Uncontrolled/progressive cancer, Mucositis grade 3-4

MASCC Risk Index score ≥21 MASCC Risk Index score <21

Complex infection

Risk Status Assessment

LOW RISK

Klastersky J,J Clin Oncol 2000; 18:3038–51.

MASCC Index Multinational Association for Supportive Care in

Cancer Prospectively validated tool to rapidly assess risk

before access to neutrophil count. Scores 21 are at low risk of complications (max

score 26). MASCC scoring index:

Burden of illness: no or mild symptoms 5 Burden of illness: moderate symptoms 3 Burden of illness: severe symptoms 0 No hypotension (systolic BP >90 mmHg) 5 No chronic obstructive pulmonary disease 4 Solid tumour/lymphoma with no previous fungal infection 4 No dehydration 3 Outpatient status at onset of fever 3 Age <60 years (not valid in children <18 years) 2

MASCC Score=26

Low Risk Treatment Low risk, adult

patients No focus of infection,

hemodynamically stable No systemic symptoms

other than fever No organ failure,

pneumonia, soft tissue infection, CVAD

Recovering bone marrow

Reliable patient

Vigilant observation Access to medical care

24-7 Return to clinic if

Positive cultures Persistent/recurrent

fever @ 3-5 days Unable to tolerate PO

regimen

Cipro 500 mg PO Q8h + amoxicillin-clavulanate 500 mg PO Q8h

Principles of High Risk Treatment

Inpatient treatment with IV antibiotics

Coverage for MRSA or resistant Gram-negative bacteria may be required.

B-lactam antibiotic in combination with an aminoglycoside is preferable to monotherapy with antipseudomonal cephalosporins.

IV MonotherapyCefepime Imipenem-cilastin Meropenem** Piperacillin-tazobactam** (NCCN)Ceftazidime** (with concerns)

**Formulary (all others Non-formulary at THC)

IV Combination Therapy Advantages:

Synergistic effect against gram-negatives

Reduced emergence of resistance

Disadvantages:Lack of activity

against gram-positives?

Toxicity

IV Combination TherapyAminoglycoside + (meropenem,

imipenem-cilastin or piperacillin-tazobactam)

Aminoglycoside + (cefepime or ceftazidime)

Ciprofloxacin + (meropenem, imipenem-cilastin or piperacillin-tazobactam)

IV Therapy Options: 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

IV Therapy Options: Comparison

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

IV Treatment Options: Comparison

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

Vancomycin Vancomycin not routinely recommended for

empiric therapy Use should be limited to specific indications:

clinically suspected serious catheter-related infection known colonization with MRSA or pcn/ceph-resistant

pneumococci gram-positive bacteremia pending further C&S hypotension or other cardiovascular impairment soft-tissue infection risk factors for viridans strep bacteremia (severe

mucositis + prophylaxis with Septra or Cipro) Reassess Vancomycin after 24-48 hours

THC protocol:Ceftazidime 2g IV q8hGentamicin 120 mg IV q12h x2 doses,

then Pharmacist to dose Case Patient Gentamicin Dosing:

ABW=90.7 kg, Ht = 178 cm IBW=70.7 kg, DW=78.8 kgSCr=73, CrCl=92 ml/minGentamicin once daily dosing appropriateDose: Age 16-65: 6 mg/kg (DW)/dose = 460 mg IVFrequency: CrCl >60 ml/min: Q24h

Antifungals as Empiric Therapy?

Clinical suspicion: High risk patients with prolonged neutropenia and site-specific symptoms: Oral thrush: Mucositis mouthwash , Fluconazole Esophageal lesions: Fluconazole Sinus/nasal symptoms and suspicious CT/MRI:

Amphotericin B Pneumonia: voriconazole, amphotericin B

Empiric treatment required based on H&P as positive cultures can take several days.

Antifungals Added Later?IDSA recommends consider

antifungal if febrile after 3-5 days and remains neutropenicAmphotericin B is preferredFluconazole may be acceptable at

institutions with low rates of mold infections or drug-resistant Candida species

Antifungals Added Later?NCCN 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

Antifungals Added Later?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 Amphotericin B 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.

Case Presentation Does she need antifungal coverage?Symptomatic vaginal yeast infection,

unsuccessfully treatedFluconazole 200 mg PO x1 dose

given.Clotrimazole Vaginal ovule daily x3

days with prn use of cream.

When to Add Antiviral Therapy

Oral vesicular lesions: HSVEsophageal lesions: HSV, CMVSkin lesions: VZV Pneumonia: Influenza CNS symptoms: HSV

Antiviral Doses 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)

PneumoniaAdditional Tests:sputum culturesNasal wash for respiratory virusesLegionella urine antigen testConsider BAL

If high risk consider addingCT chest to define infiltrates ID Consult

Include coverage for: atypical bacteria with

azithromycin P.jirovecii with Septra MRSA with vancomycin or

linezolid adding antiviral therapy

(influenza outbreak) mold-active antifungal

(voriconazole or liposomal amphotericin B) if high risk

Gastrointestinal Symptoms

Abdominal pain Abdominal CT or

ultrasound ALP,

transaminases, bilirubin, amylase, lipase

Ensure anaerobic coverage

Diarrhea C.difficile assay,

(rotavirus & norovirus?)

Consider stool bacterial cultures +/- parasite exam

Metronidazole if C.difficile suspected

Urinary tract symptomsUrine cultureUrinalysisNo additional therapy until pathogen

identified

CNS Symptoms ID consult Neurology consult CT +/- MRI LP recommended

Empiric therapy: Anti-pseudomonal

penicillin that enters CSF (ceftazidime, meropenem)

Vancomycin Ampicillin unless using

meropenem For encephalitis add

high dose acyclovir

Assessment of Response

Daily assessment until afebrile and ANC 0.5:

FeverCBCRenal functionClinical Symptoms

Assessment of Response

Sept 21 Sept 22 Sept 23

WBC 3.6ANC 0.9

WBC 4.0ANC 1.4

WBC 5.4ANC 3.7

SCr=75CrCl 92 ml/min

SCr=73

Temp=37 Temp=37.4 Temp=37.7

Urine C&S negative, CXR clear

Gent trough 0.4

Decision to discharge in 24hr.

Case Presentation

IDSA 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer

Duration of Therapy Afebrile and ANC 0.5 x48 hrs:

Low risk patients, no source of infection identified: can discontinue abx

High risk patients or with documented infection: continue tailored therapy 7 days

Afebrile but ANC <0.5 after 5-7 days: low risk: can discontinue abx high risk: continue abx until ANC 0.5 or 14 days in pts

not expecting ANC recovery. Febrile:

Neutropenic: continue abx at least 14 days, reassess for non-response

Non-neutropenic: discontinue abx 4-5 days after ANC >0.5 if no source of infection identified

Follow up for Non-Responsive Patients

Febrile but otherwise stable If non-neutropenic consider d/c abx 4-5 days

after ANC >0.5 Consider antifungal therapy with activity against

mold if fever continuing ≥4-5 days. Febrile and clinically unstable

Broaden coverage to include anaerobes, resistant gram negative rods, resistant gram positive organisms

Ensure coverage of Candida Consider antifungal therapy with activity against

mold if fever continuing ≥4 days of therapy ID consult

Duration of Therapy for Documented Infection

Skin/soft tissue: 7-14 daysSinusitis: 10-21 daysBacterial pneumonia: 10-21 days

Duration of Therapy for Documented Infection

Uncomplicated bacteremia:Gram negative: 10-14 daysGram positive: 7-14 daysS.aureus: at least 2 weeks after first

negative blood culture and normal TEEYeast: ≥2 weeks after first negative

blood culture

Duration of Therapy for Documented Infection

mold (aspergillus etc): min 12 weeksViral:

HSV/VZV: 7-10 daysInfluenza: ≥5 days.

Where do we go from here?

The role of oral therapy and IV monotherapy?

Antibiotic lock solutions for CVADs The role of G-CSFs Updated IDSA Guidelines

Questions??