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

2. 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.

3. 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.

4. 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)

5. What is the Risk? Incidence of Febrile Neutropenia Induction-remission for AML70-90% Elderly patients receiving CHOP35-45% Patients with NHL10-20% Mortality Estimates from Febrile Neutropenia Solid tumours5% Hematological malignancyUp to 11% Gram-positive bacteremia5% Gram-negative bacteremia18%

6. 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 2 nd cycle Taxotere® q3wk on Sept 13  Receiving Neulasta® dose Day 1 post- Taxotere®  Plan for surgery in Nov.

7. Case Presentation  Presented on Sept 20 th with Temp=39.5  C and feeling “unwell”.  WBC = 2.2 (4-11), Neutrophil = 0.42 (2- 7.5)  Creat = 87 (50-100)  BP 170/60, RR 16  Ht = 178 cm, Wt = 90.7 kg

8. 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

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

10. 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

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

12. 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

13. Site-Specific H&P  Oropharynx  Respiratory system  GI tract  Skin  Genitourinary  CNS No mucositis Mild cough No N/V/D No skin lesions, CVAD Yeast Infection No CNS symptoms

14. Lab assessments  CBC with differential  BUN, SCr  Electrolytes  LFTs  Urinalysis WBC=2.2, ANC=0.42, Hgb=99, Plt=345 BUN=3, SCr=87 Na=139, K=3.6, Cl=104, HCO3=28 Tbili=16, ALT=117, AST=76, Alp=84 Normal

15. Microbiologic evaluations  Blood cultures x2  1 catheter + 1 peripheral  2 catheter  2 peripheral  Urine culture  if symptomatic  urinary catheter  or abnormal urinalysis Blood & urine cultures Negative

16. 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

17. Initial Therapy Organ Function Allergy Status Previous ABx Use Anti- Pseudomonal Broad Spectrum Bacteri- cidal Potential Organisms Local ABx Susceptibility Site of Infection Patient Assessment

18. Low RiskHigh Risk Outpatient at time of feverInpatient at time of fever No acute comorbid illnessesSignificant medical comorbidity Anticipated short duration of severe neutropenia Anticipated severe or prolonged neutropenia No renal insufficiencyCrCL <30 ml/min No hepatic insufficiencyTransaminases ≥5x ULN Good performance statusUncontrolled/progressive cancer, Mucositis grade 3-4 MASCC Risk Index score ≥21MASCC Risk Index score <21 Complex infection Risk Status Assessment LOW RISK

19. 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

20. 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

21. 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.

22. IV Monotherapy  Cefepime  Imipenem-cilastin  Meropenem**  Piperacillin-tazobactam** (NCCN)  Ceftazidime** (with concerns) **Formulary (all others Non-formulary at THC)

23. IV Combination Therapy  Advantages:  Synergistic effect against gram- negatives  Reduced emergence of resistance  Disadvantages:  Lack of activity against gram- positives?  Toxicity

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

25. 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

26. 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

27. 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

28. 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

29. THC protocol:  Ceftazidime 2g IV q8h  Gentamicin 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 kg  SCr=73, CrCl=92 ml/min  Gentamicin once daily dosing appropriate  Dose: Age 16-65: 6 mg/kg (DW)/dose = 460 mg IV  Frequency: CrCl >60 ml/min: Q24h

30. 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.

31. 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

32. 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

33. 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.

34. Case Presentation  Does she need antifungal coverage?  Symptomatic vaginal yeast infection, unsuccessfully treated  Fluconazole 200 mg PO x1 dose given.  Clotrimazole Vaginal ovule daily x3 days with prn use of cream.

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

36. 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)

37. Pneumonia 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

38. 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

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

40. 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

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

42. Assessment of Response Sept 21Sept 22Sept 23 WBC 3.6 ANC 0.9 WBC 4.0 ANC 1.4 WBC 5.4 ANC 3.7 SCr=75 CrCl 92 ml/min SCr=73 Temp=37Temp=37.4Temp=37.7 Urine C&S negative, CXR clear Gent trough 0.4 Decision to discharge in 24hr. Case Presentation

43. 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

44. 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

45. Duration of Therapy for Documented Infection  Skin/soft tissue: 7-14 days  Sinusitis: 10-21 days  Bacterial pneumonia: 10-21 days

46. Duration of Therapy f or 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

47. Duration of Therapy f or Documented Infection  mold (aspergillus etc): min 12 weeks  Viral:  HSV/VZV: 7-10 days  Influenza: ≥5 days.

48. 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

49. Questions??