Febrile Neutropenia

1. Febrile Neutropenia Dr. Marianne Taylor BC Cancer Agency – CSI November 29, 2003

2. Introduction • When? • What is it? • Why is it important? • How to treat? • What is in the future?

3. When Does Neutropenia Occur? • Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 days • But can see anytime from a few days after chemotherapy to up to 4-6 weeks later depending on the agents used

4. What Is Febrile Neutropenia? Definition – varies Infectious Disease Society of America 2002 • Temp of  38.5C assoc. With a ANC of  0.5 x 109/L or a temp of  38C for  1 hr. • Or ANC < 1.0 x 109/L with a predicted decrease to < 0.5 • If early neutropenia < 10-14 days

5. Significance of Febrile Neutropenia? • Infections in the neutropenic patient can be rapidly fatal if not managed properly • Mortality rate in the 1960’s was  50% • With proper management  5% today

6. Significance of Febrile Neutropenia • Most patients don’t have bacterial infection • 30-50% will have infection • Primary sites: • GI tract – • Skin • Risk increases with lower counts (< 0.5 vs. < 0.1) and duration of neutropenia

7. Significance of Febrile Neutropenia • But no reliable way of knowing or predicting who is infected • So all are treated with empiric antibiotics • Fevers may be due to other infections or to non-infectious causes

9. Assessment • Good history and physical exam • be aware that with  ANC may not have inflammation - so redness, swelling and infiltrates may not be seen • mouth, pharynx, lower esophagus, lung, skin, anus and perineum are often sites of infection • Blood work - CBC, creat, BUN, liver profile • Culture • blood cultures (include central line if present)

10. Assessment • Other cultures only indicated if symptoms • If diarrhea should do C. Difficile toxin • Urine if symptoms or catheter • CXR – if outpatient therapy or if symptomatic • Other – LP, lesion aspiration, wound cultures as indicated

11. What Bugs?? • Traditionally - gram negatives • Pseudomonas, E. Coli, Klebsiella • but more recently - gram positives (60-70%) • Staph epi, Staph aureus • reason for switch may be  central lines, prophylaxis with quinolones, or due to  mucositis • Rarely fungal – usually secondary

12. What Therapy? Low Risk • IV combination • IV Monotherapy • Oral either inpatient or ??outpatient • Short admission (24 hrs.) then D/C High Risk – must be hospitalized • IV combination or IV monotherapy • Consider G-CSF

13. Low Risk - Features

14. Combination IV Therapy • Combined therapy with at least one drug which covers pseudomonas • KGH - Cefotaxime & Gentamicin • Other options: Piperacillin/ aminoglycoside • Avoid aminoglycosides in those on Cisplatin or other renal toxic agents

15. Immediate Vancomycin? • Generally not recommended- add in on basis of cultures • Recommended for the these situations: • Suspected serious catheter infections • Known colonization with organisms resistant to other antibiotics • +ve blood cultures • hypotension

16. Monotherapy • RCT have shown equivalence: • Ceftazadime • Impenem/Cilastatin • Meropenem

17. Oral Therapy NEJM July 1999 • Two randomized trials looked at oral vs. IV inpatient therapy in low risk patients • N= 112 NCI N=356 European • Slightly different definitions of the low risk group

18. Oral Therapy • Both showed that oral therapy with Ciprofloxacin and amoxicillin-clavulanate was equivalent to IV therapy • Success rates -- oral vs. IV • 71 vs. 67% / 80 vs. 77% • No deaths NIH trial • No differences in the deaths European trial

20. Duration of Therapy • If ANC  0.5 for two days • Afebrile X 48 hrs. • No infection • If continued neutropenia continue to 5-7 days of afebrile then D/C • If on IV can be switched to oral medication as directed by cultures or Ciprofloxacin/Clavulin and potentially discharge if stable

21. Role of G-CSF • Studies of G-CSF used in febrile neutropenia show: •  Length of neutropenia but generally not hospitalization • No mortality advantage • Generally not recommended • Exception may be those in high risk group esp. if unstable

22. Outpatient Therapy • Can we translate this to the outpatient setting? • Possibly

23. Outpatient Therapy Malik et al. Amer. J. Medicine 1995 • 182 low risk episodes • randomized to Orafloxacin inpatient or outpatient • Success 78 vs. 77% • 21% readmission rate • 2% inpatient mortality vs. 4% outpatient (1 outpt. Death)

24. Outpatient Therapy Hidalgo et al. Cancer 1999 • 100 low risk episodes randomized to Orafloxacin vs. Ceftazadime/Amikacin • Success 91 vs. 89.5% (oral) • 8 patients had to be admitted on the outpatient arm • 3 positive blood cultures • 5 failure of oral regimen

25. Outpatient therapy • Not considered the standard but is often done • Must be reliable patient who doesn’t live alone, able to take oral antibiotics • Re-evaluate q 2days until ANC > 0.5 x 109/L and afebrile x 48hrs. • If complications or continued fever admit

26. Neutropenia without fever • If patient is ill and neutropenic, but doesn’t have fever still treat with same regimens • Beware in the elderly – might not mount a fever • afebrile pt. with neutropenia and severe diarrhea – Ciprofloxacin recommended

27. BCCA Guidelines • On our website: www.bccancer.bc.ca • Cancer management guidelines • Supportive care • Febrile Neutropenia

28. Summary of Recommendations • Do careful history and physical • Do CBC, creat, liver profile and blood cultures, other cultures as appropriate • CXR –if pulm. Symptoms or outpatient • Treat immediately with appropriate antibiotics • Continue antibiotics until ANC  0.5 or as appropriate for +ve cultures

29. Summary of Recommendations • Decide Low risk vs. high risk • High risk • Combination/ mono therapy • ? G-CSF • Low risk • In-patient vs. outpatient therapy • Oral vs. IV

30. Conclusions • Be vigilant for febrile neutropenia in chemotherapy patients • Be vigilant for infection even when no fever • Febrile Neutropenia is a serious complication of chemotherapy • Can be treated a number of ways