Febrile Neutropenia: A Review of the Guidelines September 29, 2010 Andrea Beaman, BScPhm, RPh PharmD...
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Transcript of Febrile Neutropenia: A Review of the Guidelines September 29, 2010 Andrea Beaman, BScPhm, RPh PharmD...
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??