Febrile Neutropenia

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.2.2009 • European Society for Medical Oncology. Management of Febrile Neutropenia: ESMO Clinical Practice Guidelines 2010 • Infectious Disease Society of America. 2010 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.

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 • Type • Advanced/refractory • Obstructive • Surgical risk • Grade of neutropenia • Disruption of mucosal barriers • Corticosteroid use

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

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

11. 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 Detailed H&P

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

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

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

17. 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, adult patients 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 Low Risk Treatment

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)

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

23. IV Combination Therapy • Aminoglycoside + (meropenem, imipenem-cilastin or piperacillin-tazobactam) • Aminoglycoside + (cefepime or ceftazidime) • Ciprofloxacin + (meropenem, imipenem-cilastin or piperacillin-tazobactam)

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 • Use for intra-abdominal source • 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

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 24-48 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: • 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 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: 10-21 days • Bacterial pneumonia: 10-21 days

38. Duration of Therapy for Documented Infection • Uncomplicated bacteremia: • Gram negative: 10-14 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. Additional Tests: 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 Pneumonia

43. 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 Gastrointestinal Symptoms

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

45. 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 CNS Symptoms