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Evaluation and Management of Fever in the Neutropenic Patient 2003

Evaluation and Management of Fever in the Neutropenic Patient 2003. Kevin P. High, M.D., M.Sc. Associate Professor of Medicine Sections on Infectious Diseases and Hematology/Oncology. Definition and Risk of Infection as Absolute Neutrophil Count Declines. Defined as:

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Evaluation and Management of Fever in the Neutropenic Patient 2003

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  1. Evaluation and Management of Fever in the Neutropenic Patient2003 Kevin P. High, M.D., M.Sc. Associate Professor of Medicine Sections on Infectious Diseases and Hematology/Oncology

  2. Definition and Risk of Infection as Absolute Neutrophil Count Declines • Defined as: • A single oral temp > 38.3oC (101oF) OR • Repeated oral temps > 38.0oC (100.4oF) for one hour • AND • ANC < 500/mm3 or < 1000/mm3 and < 500/mm3 expected Ann Int Med,1966;64:329 Clin Inf Dis, 2002; 34:730-51

  3. Initial Evaluation in Fever/Neutropenia • Hx/PEx • focus on lungs, perirectal region (no rectal exam), catheter sites, oropharynx, sinuses, skin (& nail beds) • CBC, SMAC (w/LFT’s) • U/A?, Urine Cx • 2 blood cultures (1 peripheral, 1 central preferred; if not, at least two centrally; volume is the key ~10mL) • CXR if SSx’s or OP Rx contemplated; High Res CT (+) in 50% w/NL CXR (J Clin Onc1999;17:796-805) • wound cultures when appropriate Clin Inf Dis, 2002; 34:730-51

  4. Algorithm for Fever/Neutropenia Hemodynamically unstable &/or new organ dysfunction? *Note, there are many other regimens; AZM/Clinda, Cipro/ Clinda or Vanc/AZM for severe PCN allergy **If other nephrotoxic meds, consider meropenem or cefepime montherapy No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco Yes No ANC > 100 & clinically stable? Cefepime* + vanco Pip-tazo* + cipro No Yes Quinolone prophylaxis? Pip-tazo* + gent** Cefepime* monotherapy

  5. Justification for Empiric Antimicrobial Therapy in Fever/Neutropenia • Never been (and probably never will be) a randomized/controlled trial • Retrospective Data (NEJM,1971;284:1061) indicated that ~50% of Pseudomonas bacteremias result in death w/in 72 hrs when ANC < 1000 • Early trials aimed at Pseudomonas decreased mortality to 33% (Carb/Gent; JID,1978;147:14) • Peak serumcidal levels of > 1:16 correlated with success, ? Combinations w/synergy should be more potent (Am J Med,1984;76:429)

  6. Empiric Combinations • Anti-Pseudomonal PCN or Cephalosporin + aminoglycoside (NEJM,1993;326:1323) • response rates all around 70%, no advantage of one b-lactam over another, ? Tobra vs. Gent • Advantages; synergy vs. some GNRs, ?  resistance • Disadvantage; nephrotoxicity • Double b-lactam(Ann Int Med,1991;115:849) ; CTZ/CPZ + Pip • equal efficacy, less nephrotoxic, high cost

  7. Monotherapy: Pro • Ceftazidime (NEJM,1986;315:552) • equivalent overall ‘success’ rate to combination therapy; entry criteria = fever + ANC < 500 • addition of Vancomycin or aminoglycoside only required in 15% overall • when infection defined, 60% of patients modified (usually vanc added) • Imipenem (Ann Int Med,1991;115:849) • overall efficacy of monotherapy (85%) • ? Increased risk of fungal infxn. Definite risk factor for S. maltophilia infection

  8. Cefipime compared to Ceftazidime or Pip/Gent (~ 100 patients per group) dosed 2 gms q 8 hrs Vanc required in 40-45% & antifungals in 35% in both groups. efficacy, survival not different % susceptible GPGN Cefipime 82 93 Ceftazidime 74 91 Piperacillin 61 93 Gentamicin 76 100 bacterial eradication in 97% for cefipime, 100% for comparator Cefipime in Treatment of Fever/Neutropenia* *Ramphal, AM J Med,1996.

  9. Meropenem (58%) vs. Imipenem (60%) (Infection,1996;24:480-4) Meropenem (56%) vs. CTZ/Amikacin (52%) (AAC,1996;40:1108-15) Cefepime (74%) vs. CTZ OR Pip/Gent (76%) (Am J Med,1996;100:83S-89S) Meropenem vs. CTZ/Amikacin (80%) vs. (77%) (Haematologica,1997;82:668-75) Cefepime ( 79%) vs. Imipenem (72%) (J Antim Chemo,1998;42:511-8) Cefepime (57%) vs. CTZ (60%) (Ann Pharmacother, 2000;34:989-95) Meropenem (54%) vs. CTZ (44%) (J Clin Oncol,2000; 18:3690-8) Meropenem (48%) vs. CTZ (38%) (Ann Hematol,2000; 79:152-7) Clinafloxacin (32/95%) vs. Imipenem (33/92%) (Clin Inf Dis,2001;32:381-90) Some Published Monotherapy Trials in Febrile Neutropenic Patients

  10. Monotherapy: Con • Ceftazidime + 3d of Amikacin vs. CTZ + 9d of Amikacin (NEJM,1986;315:552) • entry criteria; fever + ANC < 100 • modification of initial regimen counted as ‘failure’ • ‘success’ rate in 3d group = 48% vs. 81% in 9d group in patients with documented bacteremia • Death rate 17% vs. 8%

  11. Meta-analysis of Monotherapy vs. Combination Therapy* • 47 trials, 7807 patients • Monotherapy RR • All cause mortality 0.85 (0.72,1.02) • Same b-lactam no difference, different b-lactams, difference became significant 0.87 (0.80,0.93) • Superinfection 0.97 (0.82,1.14) • Treatment Failure 0.92 (0.85,0.99) • Any Adverse Event 0.85 (0.72,1.02) • Nephrotoxicity 0.42 (0.32, 0.56) *Paul M, Soures-Weiser K, Leibovici L. Br Med J, 2003;326:111-1119

  12. PRO change in most common isolates in F/N ? Less febrile days overall, and perhaps less ampho B use viridans streptococci may be fatal and PCN I or R; particular problem with quinolone prophylaxis and regimens that induce severe mucositis CON overall mortality from documented gm(+) bacteremia only 5% vast majority of patients with gm(+) survive and respond to addition of Vanco (AIM,1988;106:30 & NEJM,1988;319:1053) VRE Vancomycin Up Front?

  13. Changing Etiology of Infection in Cancer Patients* % of Isolates Summarized from Jones, Clin Inf Dis,1999;29:495 Year of Study

  14. Changing Etiology of Infection in Cancer Patients* % of Isolates Summarized from Jones, Clin Inf Dis,1999;29:495 Year of Study

  15. Resistance (%) in viridans Streptococci Summarized in Clin Inf Dis, 2002; 34:1524-9

  16. Response Rates in Trials of Vanco vs. No Vanco Up Front* % Response Note: no mortality difference in any study !!!!!!!! Summarized from Feld, Clin Inf Dis,1999;29:503 Type of Standard Therapy

  17. Criteria for Adding Vancomycin Up Front* • Clinically obvious catheter infection • CRx w/severe mucositis (high dose Ara-C) • quinolone prophylaxis (?? and PCN allergic) • known colonization of MRSA • (+) blood culture for Gm (+) • hypotension or other evidence of hemodynamic instability/sepsis *Clin Inf Dis,2002;34:730-51. Recs are A-II

  18. Susceptibility Data for Pseudomonas aeruginosa at WFUBMC (2002)

  19. Susceptibility Data for Staphylococcus aureus at WFUBMC (2002)

  20. Susceptibility Data for Enterococcus spp. at WFUBMC (2002)

  21. Algorithm for Fever/Neutropenia Hemodynamically unstable &/or new organ dysfunction? *Note, there are many other regimens; AZM/Clinda, Cipro/ Clinda or Vanc/AZM for severe PCN allergy **If other nephrotoxic meds, consider meropenem or cefepime montherapy No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco Yes No ANC > 100 & clinically stable? Cefepime* + vanco Pip-tazo* + cipro No Yes Quinolone prophylaxis? Pip-tazo* + gent** Cefepime* monotherapy

  22. Why do we use Pip-tazo + Cipro for our combination therapy standard? • Largest enrolling center in a study recently published (Ann Int Med, 2002;137:77-86) • Q 4 h pip + either cipro OR tobra q 8 h • No diff in efficacy • Less renal failure with cipro if on no other nephrotoxic meds % febrile p=0.0052 Days

  23. Persistent Fever After Initial Therapy* Febrile 3-5 days after starting Abxs? ANC < 500 ANC > 500 • ? Change Abxs • ? Add Vancomycin • ? Add Ampho B Stop Abxs after ANC > 500 for 4-5 days; Re-evaluate *Clin Inf Dis, 2002;34:730-51

  24. Causes of Persistent Fever in Neutropenic Patients* *Editorial by Corey and Boeckh, NEJM,2002;346:222-4.

  25. Adding Amphotericin B • In F/N patients still febrile 7d after Abx’s; addition of Amphotericin B appears to improve outcome (Am J Med,1982;72:101) • EORTC trial published in 1989 (Am J Med,1989;86:668) the largest randomized controlled trial of empiric antifungal therapy vs. placebo in neutropenic patients with continued or recurrent fever after 4 days of antibacterial therapy

  26. EORTC Trial of Empiric Ampho B(Am J Med,1989;86:668-73) • 132 Pts, ANC < 500/mm3 and on Abx’s for > 4 d • 6 documented fungal infections (4 severe) in placebo group vs. one in Rx group (p= 0.1) • 4 fungal deaths vs. none (p= 0.05) • BUT no overall survival difference * * % Responded

  27. Other Considerations When Adding Antifungal Therapy • Image sinuses, chest (w/CT in continued fever) • Specific criteria for liposomal Ampho B • Intitial Creat > 2.0 and not on dialysis (long-term) • Creat  > 2.0 (x 2 measures at least 24 hrs apart) & no improvement after 24 h of IVFs & need to continued nephrotoxic agents (CsA, AGs) • refractory illness after 500 mg conventional Ampho B

  28. Other Alternatives to Ampho B?* • 687 patients with ANC < 500 and persistent fever after 5 days of antibacterials • Ambisome 3 mg/kg/d vs. Ampho B 0.6 mg/kg/d IV • Much higher toxicity with Ampho B (chills and nephrotoxicity) • Proven breakthrough fungal infxn less in Ambisome group 3.2% vs.7.8% % * *Walsh, et al. NEJM,1999:340:764.

  29. Itraconazole for Empiric Coverage in Fever/Neutropenia • 384 patients enrolled and compared to Ampho B • “Success” = alive, resolved fever/ neutropenia w/in 28 days, no emergent fungal infxn, no discontinuation due to toxicity • “Unevaluable” = Rx < 3 d * * * Boogaerts, et al. Ann Int Med, 2001;135:412-22

  30. Itraconazole for Empiric Therapy in Febrile Neutropenia • Important considerations in this study • Ampho B dose was 0.7-1.0 mg/kg/d • oral itraconazole could be substituted for IV as early as 7 days, but typically on d 15 (levels OK) • Rx continued until defervescence AND ANC > 500 x 2d Effective level 250 mg/mL Boogaerts, et al. Ann Int Med, 2001;135:412-22

  31. Glucan Synthase InhbitorsActivity Against Common and Uncommon Fungi Active Mod Activity Poor Activity Candida spp. H. capsulatum C. neoformans Aspergillus spp. C. imitis Fusarium spp. P. carinii B. dermatidis P. boydii S. schenckii Rhizopus spp. Alternaria spp. MICs 0.03-2.0 mg/mL 0.06-16 mg/mL 16->64 mg/mL Data are from Merck, on file and J Antibiot, 2000;53:1175-81

  32. CaspofunginCancidas® • IV infusion (over 1 hour); 70 mg load then 50 mg/d • Half-life of 9-11 hours (second g-phase of 40-50 hours) • Metabolized by slow hydrolysis and acetylation, and via spontaneous degradation • excreted in in urine and feces • No dose adjustment for renal failure • Dose adjust for moderate hepatic failure, no experience in severe liver disease

  33. Caspofungin Empiric Therapy in Febrile Neutropenia* • RCT • Caspofungin 70/50 qd (n=564) • Liposomal Ampho B 3 mg/kg/d (n=547) • Five criteria of ‘success’ • Successful Rx of baseline fungal infxn • Absence of breakthrough fungal infxn • Survival for at least 7 d after completion of drug • Absence of w/d due to study drug-related toxicity • Resolution of fever during neutropenia *Walsh, et al. ICAAC, Chicago, 2003

  34. Voriconazole • New triazole • Structure much more like fluconazole than ketoconazole or itraconazole, thus, very bioavailable orally, but hepatic metabolism (CYP2C9 and CYP3A4) and much higher protein binding, shorter T1/2 (6 h) • Fungistatic • Activity against Candida (including C. kruseii and C. glabrata) and Aspergillus spp., but also against Crypto, Histo, Cocci, Blasto, and some ‘oddball’ fungi (P. boydii, some Fusarium spp.)

  35. VoriconazoleEmpiric Therapy in Febrile/Neutropenia* • 837 Pts 73 centers; vs. lipo AmphoB (Ambisome®) • No difference in success (26% v. 31%), mortality (8% v. 6%), w/d due to toxicity (13% v. 10%) • Less breakthrough fungal infections (1.9% v. 5.0%) • BUT, failed to meet ‘non-inferiority’ criteria for a priori defined endpoint (defervescence during the period of neutropenia), thus did NOT get an FDA indication for F/N * * * * *Walsh, et al. NEJM, 2002;346:225-34

  36. VoriconazoleEmpiric Therapy in Febrile/Neutropenia* Breakthrough rate (%) stratified by risk and prior prophylaxis • A closer look • A little more than ½ in each group on antifungal prophylaxis • More infections present at randomization in V than in L-A group (13 vs. 6) • Response rate 46% for V vs. 67% for L-A • Almost all Candida • ? Something different about Candida that evolve through fluconazole and is that the reason for concern? *Walsh, et al. NEJM, 2002;346:225-34

  37. Voriconazole Rx for AspergillosisHerbrecht, et al. NEJM,2002;347:408-15. • Only RCT of primary Rx of invasive aspergillosis (n=277) • Ampo B 1 mg/kg/d vs. Vori 6 mg/kg X 2 doses, then 4 mg/kg • Response definitions • CR: resolution of clinical and radiologic • PR: > 50% radiologic and significant clinical improvement p < 0.05 for all three outcomes

  38. Bottom Line, Empiric Therapy • IV lipo-amphotericin and itraconazole FDA approved, Ampho-B is a standard of care and has most clinical experience • Caspofungin likely to be approved in near future • Data suggest adding ONLY after 96 hours of antibacterials AND either persistent or recurrent fever at that time • I would recommend Ampho B > Caspofungin > L-Ampho B > Itraconazole as empiric Rx in patients previously receiving fluconazole prophylaxis • Voriconazole may have a role in high risk, long-term prophylaxis (e.g. Allo BMT with GvHD), or as empiric therapy in high aspergillus risk patient after initial blood Cxs (-), but not drug of choice for empiric Rx of Fever/Neutropenia

  39. Recommended Use of Lipid Ampho B Preparations in H/O Patients • Non-HD patient requiring Ampho B and creat > 2.0 at baseline • A doubling of serum creatinine and > 2.0 mg/dL • severe or persistent infusional AE to AmphoB • refractory disease after 10 days (or 500 mg) of AmphoB • High risk patients (i.e. on CsA, tacrolimus, aminoglycosides, foscarnet, cis-platinum, ifosfamide;)

  40. U of P, 1983-6* 26/168 patients (15.5%) etiology documented in 23/26 (88%) 9 fungal infections 4 intra-abdominal 2 catheter infections 2 perirectal abscesses 2 viral infxns (HSV & NANB hepatitis) U of P, 1992-4** 29/145 patients (20%) etiology documented in 17/29 (59%) 6 fungal infections 6 non-infectious (3 drug fever, 2 clot, 1 relapsed disease) 5 bacterial (catheter & pneumonia) Fever After Resolution of Neutropenia *Talbot, et al. Arch Int Med. 1988;148:129-35 **Barton & Schuster, Clin Inf Dis, 1996;22:1064-8.

  41. Quinolone Prophylaxis in Neutropenic Hosts* GN bact p < 0.001 • Quinolone prophylaxis without additional gram positive coverage decreases gram-negative bacteremia, but has modest effects on fever and mortality GP bact p = 0.7 Fever p = 0.09 Mortality p=0.4 *Cruciani, et al. Clin Inf Dis,1996;23:795-805

  42. Quinolone + Gram Positive Prophylaxis in Neutropenic Hosts* • Quinolone prophylaxis with additional gram positive coverage decreases gram-positive bacteremia, but has no additional benefit on fever or mortality GN bact p = 0.29 GP bact p = 0.005 Fever p = 0.25 Mortality p=0.8 *Cruciani, et al. Clin Inf Dis,1996;23:795-805

  43. Growth Factors and Clinical Endpoints in Chemotherapy Recipients* Bone Marrow Tx EndpointChemoRxAutoAllo Duration Neutropenia ++++ ++++ +++ Neutropenic Fever +++ ++ +/- Documented Infxns -- +/- -- Abx Use +/- -- +/- Length of stay +/- +/- -- Cost +/- +/- NA Survival -- -- +/- Infectious Deaths -- -- -- *Adapted from Wingard & Elfenbein, Inf Dis Clin NA,1996;10:345-64

  44. ? Outpatient Therapy: Risk Assessment of Febrile/Neutropenic Patients* • Hospitalized w/BM malignancy or BMT (I) • Morbidity 35%, mortality 13% • OP w/ comorbidity (low BP, bleeding, etc)(II) • morbidity 40% , mortality 12% • OP w/no comorbidity, but progressive CA (III) • 25% morbidity, 18% mortality • OP w/no comorbidity and responsive CA (IV) • < 3% morbidity, no mortality *J Clin Onc,1992;10:316-22.

  45. Candidates for Outpatient Therapy of Fever/Neutropenia • Appears stable • No source identified • Responsive tumor (??) • No comorbidity • bleeding,  BP,  CA++, respiratory failure, altered MS • Suspected duration of neutropenia is not a determining factor (can’t predict at time of febrile presentation)

  46. Risk assessment based on Sxs, tumor type, co-morbidity, age, clinical status (for adults(J Clin Onc 2000;18:3038-51)) In children, monocyte count > 100/mm3, no comorbidity and normal CXR indicate low risk (J Clin Onc 2000;18:1012-9) Illness (choose one) X No/Mild Sxs 5 Mod Sxs 3 No hypotension 5 No COPD 4 Solid tumor OR No fungi 4 No dehydration 3 Onset of fever as OP 3 Age < 60 yrs 2 Total > 21 = low risk for complications Scoring Systems to Assess Risk

  47. Oral vs. IV Therapy in Inpatients with Fever/Neutropenia* • 116 episodes in each group (84 v 79 pts) • Talcott group IV • IV CTZ vs. PO Cipro/Amox-clav • 35% documented infxn • MEAN DURATION OF ANC < 500 = 3.6 DAYS • 8-16% unable to tolerate po meds at all (even placebo) * * *Freifeld, et al. NEJM,1999;341:305.

  48. Oral vs. IV Therapy in Inpatients with Fever/Neutropenia* • 312 evaluable patients of 353 enrolled • Talcott group IV • IV CTRX/AMIK vs. Cipro/ Amox-clav • 37% documented infxn • MEDIAN DURATION OF ANC < 1000 = 4 DAYS • secondary infection and adverse events equivalent *Kern, et al. NEJM,1999;341:312.

  49. ASCORP Trials of Outpatient Treatment of Fever/Neutropenia* • PO regimens were Cipro/Clinda or Cipro/ Amox-clav in ASCORP-I and -II, respectively. • IV Rx was AZM/Clinda in both • 6-8 hr observation and thorough w/u at start • w/in 30 miles, phone, etc *Summarized from Rolston, et al. Inf Dis Clin NA,1996;2:223-37

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