1. Febrile Neutropenia
Prof. Arcangelo Liso

2. Recent Guidelines
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections v
European Society for Medical Oncology. Management of Febrile Neutropenia: ESMO Clinical Practice Guidelines 2010
Infectious Disease Society of America Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer

3. Too many guidelines ?

4. Objectives
Identify predisposing factors and common pathogens that cause infections
Review initial investigations that will help direct therapy

5. Objectives II
Compare recommendations for empiric antibiotic selections for high risk and low risk patients.
Discuss assessment of response, treatment modifications and duration of therapy.

6. Incidence of Febrile Neutropenia Induction-remission for AML 70-90%
Elderly patients receiving CHOP
35-45%
Mortality Estimates from Febrile Neutropenia
Hematological malignancies
Up to 11%
Gram-positive bacteremia 5%
Gram-negative bacteremia
18%

7. Definition of Febrile Neutropenia
Fever: Single oral temperature ≥38.3°C or persistent temperature ≥38.0 °C for >1 hour.
Neutropenia: ANC <0.5, or ANC <1.0 and a predicted decline to <0.5 over next 48 hrs. (ANC= absolute neutrophil count)

8. Predisposing Factors Malignancy Surgical risk Grade of neutropenia
Type
Advanced/refractory
Obstructive
Surgical risk
Grade of neutropenia
Disruption of mucosal barriers
Corticosteroid use

9. Microbiology Gram-positive Coagulase-negative staphylococci Yeast
S. aureus
S.viridans
Enterococci
Gram-negative
Coliforms (E.coli, Klebsiella, Enterobacter)
P.aeruginosa
Yeast
Candida
Aspergillus
Viruses
Herpes simplex (HSV)
Influenza, paranifluenza
CMV

10. Initial Investigations
History & physical exam
Lab assessments
Diagnostic imaging
Microbiologic evaluations

11. Detailed H&P Chemotherapy regimen & last dose given Vascular devices
Prophylactic antibiotic
Steroid use
Allergies
Major comorbid illnesses
Recent surgical procedures
Recent infections or positive cultures
Previous antibiotic-resistant organisms
Recent exposures

12. Site-Specific H&P Oropharynx Respiratory system Skin Genitourinary CNS
No mucositis
Cough
Skin lesions
Yeast Infection
CNS symptoms

13. Lab assessments CBC with differential BUN, SCr, LFTs Electrolytes
Urinalysis

14. Microbiologic evaluations
Blood cultures x2
1 catheter + 1 peripheral
Urine culture
if symptomatic
urinary catheter
or abnormal urinalysis

15. Site-Specific Cultures
Diarrhea: C.difficile assay, stool microscopy and culture
Sputum microscopy and culture
Aspirate/swab/biopsy of any skin lesions
Viral tests
Vesicular or ulcerated skin/mucosal lesions
Throat or nasopharynx for respiratory symptoms (esp. during outbreaks)
LP if CNS symptoms
Fungal cultures

16. Risk Status Assessment
Low Risk
High Risk
Outpatient 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

17. 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
Klastersky J,J Clin Oncol 2000; 18:3038–51.

18. Low Risk Treatment Low risk, adult patients Vigilant observation
No focus of infection, hemodynamically stable
No systemic symptoms other than fever
No organ failure, pneumonia, soft tissue infection
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

19. Principles of High Risk Treatment
Inpatient treatment with IV antibiotics (60 min)
Coverage for MRSA or resistant Gram-negative bacteria may be required.
Monotherapy is equivalent to combinations (with few exceptions)

21. IV Monotherapy Cefepime Imipenem-cilastin Meropenem**
Piperacillin-tazobactam** (NCCN)
Ceftazidime** (with concerns)
**Formulary (all others Non-formulary at THC)
The options for IV monotherapy are consistent between guidelines and are listed here in alphabetical order except that ceftazidime is not preferred due to reduced efficacy against gram-positive and ESBL organisms.
Quinolones have been evaluated as monotherapy but have shown equivocal results in clinical trials (some positive and some negative) and are not recommended in the current versions of any of the guidelines.

22. IV Combination Therapy
Advantages:
Synergistic effect against gram-neg
Reduced emergence of resistance
Disadvantages:
Lack of activity against gram-pos?
Toxicity

23. IV Combination Therapy
Aminoglycoside + (meropenem, imipenem-cilastin or piperacillin-tazobactam)
Aminoglycoside + (cefepime or ceftazidime)
Ciprofloxacin + (meropenem, imipenem-cilastin or piperacillin-tazobactam)
Although meta-analysis found equivalent efficacy, bactericidal activity and synergistic effect of a b-lactam antibiotic in combination with an aminoglycoside is preferable to monotherapy with antipseudomonal cephalosporins in high risk patients.
Although there have been many comparative trials, results have proven similar in meta-analysis when study design variations are taken into consideration.

24. 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
Risk of seizures in CNS malignancy or renal impairment

25. 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

26. 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
Levofloxacin: better gram (+) coverage but limited studies available for use as empiric therapy.

27. Vancomycin Vancomycin not routinely recommended
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
hypotension
soft-tissue infection
severe mucositis
Reassess Vancomycin after hours

28. Antifungals as Empiric Therapy?
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.

29. Antifungals Added Later?
IDSA recommends consider antifungal if febrile after 3-5 days and remains neutropenic
Amphotericin B is preferred
Fluconazole may be acceptable at institutions with low rates of mold infections or drug-resistant Candida species

30. 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

31. 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.

32. When to Add Antiviral Therapy
Oral vesicular lesions: HSV
Esophageal lesions: HSV, CMV
Skin lesions: VZV
Pneumonia: Influenza
CNS symptoms: HSV

33. Antiviral Doses Acyclovir: Valacyclovir: Ganciclovir: Foscarnet:
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)

34. Assessment of Response
Daily assessment until afebrile and ANC 0.5:
Fever
CBC
Renal function
Clinical Symptoms

35. 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
IDSA: Time to devervescence: 2-7 days, Median time to clinical response: 5-7 days
IDSA 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer

36. Follow up for Non-Responsive Patients
Febrile but otherwise stable
If non-neutropenic consider stop 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, resistant gram positive organisms
Ensure coverage of Candida
Consider antifungal therapy with activity against mold if fever continuing ≥4 days of therapy
ID consult

37. Duration of Therapy for Documented Infection
Skin/soft tissue: 7-14 days
Sinusitis: days
Bacterial pneumonia: days

38. Duration of Therapy for Documented Infection
Uncomplicated bacteremia:
Gram negative: days
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

39. Duration of Therapy for Documented Infection
Aspergillus min 12 weeks
Viral:
HSV/VZV: 7-10 days
Influenza: ≥5 days.

40. Future directions Compare the role of oral therapy and IV monotherapy
Antibiotic lock solutions for CVADs
New role for new CSFs ?

42. Pneumonia Additional Tests: If high risk consider adding
sputum cultures
Nasal wash for respiratory viruses
Legionella urine antigen test
Consider BAL
If high risk consider adding
CT 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

43. 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

44. Urinary tract symptoms
Urine culture
Urinalysis
No additional therapy until pathogen identified

45. 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