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Fever In The Neutropenic Patient

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This document summarizes guidelines for the evaluation and management of fever in neutropenic patients. It discusses the initial evaluation, appropriate antimicrobial therapy including both combination regimens and monotherapy options. It also addresses criteria for adding antifungal therapy if fever persists after initial treatment and antibiotics.

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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: A single oral temp > 38.3 o C (101 o F) OR Repeated oral temps > 38.0 o C (100.4 o F) for one hour AND ANC < 500/mm 3 or < 1000/mm 3 and < 500/mm 3 expected Ann Int Med,1966;64:329 Clin Inf Dis, 2002; 34:730-51
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
Hemodynamically unstable &/or new organ dysfunction? No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco ANC > 100 & clinically stable? Quinolone prophylaxis? No Yes No Yes Cefepime* monotherapy Algorithm for Fever/Neutropenia *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 Cefepime* + vanco Pip-tazo* + cipro Pip-tazo* + gent**
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)
Empiric Combinations Anti-Pseudomonal PCN or Cephalosporin + aminoglycoside (NEJM,1993;326:1323) response rates all around 70%, no advantage of one  -lactam over another, ? Tobra vs. Gent Advantages; synergy vs. some GNRs, ?  resistance Disadvantage; nephrotoxicity Double  -lactam( Ann Int Med,1991;115:849 ) ; CTZ/CPZ + Pip equal efficacy, less nephrotoxic, high cost
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
Cefipime in Treatment of Fever/Neutropenia* 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 GP GN Cefipime 82 93 Ceftazidime 74 91 Piperacillin 61 93 Gentamicin 76 100 bacterial eradication in 97% for cefipime, 100% for comparator *Ramphal, AM J Med,1996.
Some Published Monotherapy Trials in Febrile Neutropenic Patients 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)
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%
Meta-analysis of Monotherapy vs. Combination Therapy* 47 trials, 7807 patients Monotherapy RR All cause mortality 0.85 (0.72,1.02) Same  -lactam no difference, different  -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
Vancomycin Up Front? 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
Changing Etiology of Infection in Cancer Patients* % of Isolates Year of Study Summarized from Jones, Clin Inf Dis,1999;29:495
Changing Etiology of Infection in Cancer Patients* % of Isolates Year of Study Summarized from Jones, Clin Inf Dis,1999;29:495
Resistance (%) in viridans Streptococci Summarized in Clin Inf Dis, 2002; 34:1524-9 0 0 Vanc 7 30 Imipenem 22 ---- Cefepime 56 74 CTZ 40 56 PCN Marron et al. Carratla, et al. Agent
Response Rates in Trials of Vanco vs. No Vanco Up Front* % Response Type of Standard Therapy Summarized from Feld, Clin Inf Dis,1999;29:503 Note: no mortality difference in any study !!!!!!!!
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
Susceptibility Data for Pseudomonas aeruginosa at WFUBMC (2002)
Susceptibility Data for Staphylococcus aureus at WFUBMC (20 02 )
Susceptibility Data for Enterococcus spp. at WFUBMC ( 2002 )
Hemodynamically unstable &/or new organ dysfunction? No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco ANC > 100 & clinically stable? Quinolone prophylaxis? No Yes No Yes Cefepime* monotherapy Algorithm for Fever/Neutropenia *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 Cefepime* + vanco Pip-tazo* + cipro Pip-tazo* + gent**
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 Days % febrile p=0.0052
Can Antibiotics Be Discontinued in the Face of Continued Neutropenia?* Afebrile in 3-5 days Etiology ID’d Finish course of therapy ANC < 500 ? Clinically well Stop Abxs after afebrile for 5-7 days; change to po; Re-evaluate Yes Cont’ Abxs No mucositis, ANC < 100, unstable vital signs *Clin Inf Dis, 2002; 34:730-51 ANC > 500 Discontinue Abx’s after 48 hours of no fever + ANC > 500
Persistent Fever After Initial Therapy* Febrile 3-5 days after starting Abxs? ANC > 500 Stop Abxs after ANC > 500 for 4-5 days; Re-evaluate ANC < 500 *Clin Inf Dis, 2002;34:730-51 ? Change Abxs ? Add Vancomycin ? Add Ampho B
Causes of Persistent Fever in Neutropenic Patients* *Editorial by Corey and Boeckh, NEJM,2002;346:222-4.
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
EORTC Trial of Empiric Ampho B (Am J Med,1989;86:668-73) 132 Pts, ANC < 500/mm 3 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
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
Can Fluconazole Be Used As An Ampho B Substitute?* 106 patients with ANC < 500 and persistent fever after 7 days of antibacterials Flu 400 mg/d po vs. Ampho B 0.5 mg/kg/d IV Fever persisted in almost all until ANC recovered (7-8 days later) Much higher toxicity with Ampho B Malik, et al. Am J Med,1998;105:478 % or Days
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. % *
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 * * *
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 Boogaerts, et al. Ann Int Med, 2001;135:412-22 Effective level 250 mg/mL
 
Glucan Synthase Inhbitors Activity 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  g/mL 0.06-16  g/mL 16->64  g/mL Data are from Merck, on file and J Antibiot, 2000;53:1175-81
Caspofungin Cancidas ® IV infusion (over 1 hour); 70 mg load then 50 mg/d Half-life of 9-11 hours (second  -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
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
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 T 1/2 (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 .)
Voriconazole Empiric 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 * * * *
Voriconazole Empiric Therapy in Febrile/Neutropenia* 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 Breakthrough rate (%) stratified by risk and prior prophylaxis
Voriconazole Rx for Aspergillosis Herbrecht, 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
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
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;)
Cost of Systemic Antifungal Agents AWP per 2002 Medical Letter (44:63-65) Amphotericin preparations (cost/day at max dose; excludes loading dose) Ampho B; dose 0.3 – 1.5 mg/kg $ 37 ABLC ( Abelcet ); dose 3-5 mg/kg $ 480 Liposomal Ampho B ( Ambisome ) $ 1319 Others Fluconazole ( Diflucan ) IV $ 125 PO $ 24 Itraconazole ( Sporanox ) IV $ 185 PO $ 33 Voriconazole ( Vfend ) IV $ 255 PO $ 50 Caspofungin ( Cancidas ) IV $ 360
Fever After Resolution of Neutropenia 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) *Talbot, et al. Arch Int Med. 1988;148:129-35 **Barton & Schuster, Clin Inf Dis , 1996;22:1064-8.
Quinolone Prophylaxis in Neutropenic Hosts* Quinolone prophylaxis without additional gram positive coverage decreases gram-negative bacteremia, but has modest effects on fever and mortality GN bact p < 0.001 GP bact p = 0.7 Fever p = 0.09 Mortality p=0.4 *Cruciani, et al. Clin Inf Dis,1996;23:795-805
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
Growth Factors and Clinical Endpoints in Chemotherapy Recipients* Endpoint ChemoRx Auto Allo Duration Neutropenia ++++ ++++ +++ Neutropenic Fever +++ ++ +/- Documented Infxns -- +/- -- Abx Use +/- -- +/- Length of stay +/- +/- -- Cost +/- +/- NA Survival -- -- +/- Infectious Deaths -- -- -- Bone Marrow Tx *Adapted from Wingard & Elfenbein, Inf Dis Clin NA,1996;10:345-64
? 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.
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)
Scoring Systems to Assess Risk 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
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. * *
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.
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
Proposed Classification/Management for Febrile/Neutropenic Patients High Risk : Prolonged Neutropenia ( > 14 d), Heme CA or allo BMT, substantial comorbidity, unstable Admit, IV therapy (usually combination Rx) for duration of neutropenia; Ampho B empiric Rx for continued fever Moderate Risk : Neutropenia 7-14 d, auto BMT, stable, minimal comorbidity Initial IV Rx (monotherapy OK), early discharge with po if response; Ampho B for cont’d fever (especially if azole prophy) Low Risk : < 7d neutropenia, solid tumor, stable Outpatient IV or po therapy; azole Rx ok for cont’d fever Adapted from Rolston, Clin Inf Dis,1999;29:515

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Fever In The Neutropenic Patient

  • 1. 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
  • 2. Definition and Risk of Infection as Absolute Neutrophil Count Declines Defined as: A single oral temp > 38.3 o C (101 o F) OR Repeated oral temps > 38.0 o C (100.4 o F) for one hour AND ANC < 500/mm 3 or < 1000/mm 3 and < 500/mm 3 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. Hemodynamically unstable &/or new organ dysfunction? No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco ANC > 100 & clinically stable? Quinolone prophylaxis? No Yes No Yes Cefepime* monotherapy Algorithm for Fever/Neutropenia *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 Cefepime* + vanco Pip-tazo* + cipro Pip-tazo* + gent**
  • 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  -lactam over another, ? Tobra vs. Gent Advantages; synergy vs. some GNRs, ?  resistance Disadvantage; nephrotoxicity Double  -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 in Treatment of Fever/Neutropenia* 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 GP GN Cefipime 82 93 Ceftazidime 74 91 Piperacillin 61 93 Gentamicin 76 100 bacterial eradication in 97% for cefipime, 100% for comparator *Ramphal, AM J Med,1996.
  • 9. Some Published Monotherapy Trials in Febrile Neutropenic Patients 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)
  • 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  -lactam no difference, different  -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. Vancomycin Up Front? 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
  • 13. Changing Etiology of Infection in Cancer Patients* % of Isolates Year of Study Summarized from Jones, Clin Inf Dis,1999;29:495
  • 14. Changing Etiology of Infection in Cancer Patients* % of Isolates Year of Study Summarized from Jones, Clin Inf Dis,1999;29:495
  • 15. Resistance (%) in viridans Streptococci Summarized in Clin Inf Dis, 2002; 34:1524-9 0 0 Vanc 7 30 Imipenem 22 ---- Cefepime 56 74 CTZ 40 56 PCN Marron et al. Carratla, et al. Agent
  • 16. Response Rates in Trials of Vanco vs. No Vanco Up Front* % Response Type of Standard Therapy Summarized from Feld, Clin Inf Dis,1999;29:503 Note: no mortality difference in any study !!!!!!!!
  • 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 (20 02 )
  • 20. Susceptibility Data for Enterococcus spp. at WFUBMC ( 2002 )
  • 21. Hemodynamically unstable &/or new organ dysfunction? No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco ANC > 100 & clinically stable? Quinolone prophylaxis? No Yes No Yes Cefepime* monotherapy Algorithm for Fever/Neutropenia *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 Cefepime* + vanco Pip-tazo* + cipro Pip-tazo* + gent**
  • 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 Days % febrile p=0.0052
  • 23. Can Antibiotics Be Discontinued in the Face of Continued Neutropenia?* Afebrile in 3-5 days Etiology ID’d Finish course of therapy ANC < 500 ? Clinically well Stop Abxs after afebrile for 5-7 days; change to po; Re-evaluate Yes Cont’ Abxs No mucositis, ANC < 100, unstable vital signs *Clin Inf Dis, 2002; 34:730-51 ANC > 500 Discontinue Abx’s after 48 hours of no fever + ANC > 500
  • 24. Persistent Fever After Initial Therapy* Febrile 3-5 days after starting Abxs? ANC > 500 Stop Abxs after ANC > 500 for 4-5 days; Re-evaluate ANC < 500 *Clin Inf Dis, 2002;34:730-51 ? Change Abxs ? Add Vancomycin ? Add Ampho B
  • 25. Causes of Persistent Fever in Neutropenic Patients* *Editorial by Corey and Boeckh, NEJM,2002;346:222-4.
  • 26. 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
  • 27. EORTC Trial of Empiric Ampho B (Am J Med,1989;86:668-73) 132 Pts, ANC < 500/mm 3 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
  • 28. 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
  • 29. Can Fluconazole Be Used As An Ampho B Substitute?* 106 patients with ANC < 500 and persistent fever after 7 days of antibacterials Flu 400 mg/d po vs. Ampho B 0.5 mg/kg/d IV Fever persisted in almost all until ANC recovered (7-8 days later) Much higher toxicity with Ampho B Malik, et al. Am J Med,1998;105:478 % or Days
  • 30. 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. % *
  • 31. 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 * * *
  • 32. 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 Boogaerts, et al. Ann Int Med, 2001;135:412-22 Effective level 250 mg/mL
  • 33.  
  • 34. Glucan Synthase Inhbitors Activity 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  g/mL 0.06-16  g/mL 16->64  g/mL Data are from Merck, on file and J Antibiot, 2000;53:1175-81
  • 35. Caspofungin Cancidas ® IV infusion (over 1 hour); 70 mg load then 50 mg/d Half-life of 9-11 hours (second  -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
  • 36. 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
  • 37. 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 T 1/2 (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 .)
  • 38. Voriconazole Empiric 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 * * * *
  • 39. Voriconazole Empiric Therapy in Febrile/Neutropenia* 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 Breakthrough rate (%) stratified by risk and prior prophylaxis
  • 40. Voriconazole Rx for Aspergillosis Herbrecht, 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
  • 41. 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
  • 42. 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;)
  • 43. Cost of Systemic Antifungal Agents AWP per 2002 Medical Letter (44:63-65) Amphotericin preparations (cost/day at max dose; excludes loading dose) Ampho B; dose 0.3 – 1.5 mg/kg $ 37 ABLC ( Abelcet ); dose 3-5 mg/kg $ 480 Liposomal Ampho B ( Ambisome ) $ 1319 Others Fluconazole ( Diflucan ) IV $ 125 PO $ 24 Itraconazole ( Sporanox ) IV $ 185 PO $ 33 Voriconazole ( Vfend ) IV $ 255 PO $ 50 Caspofungin ( Cancidas ) IV $ 360
  • 44. Fever After Resolution of Neutropenia 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) *Talbot, et al. Arch Int Med. 1988;148:129-35 **Barton & Schuster, Clin Inf Dis , 1996;22:1064-8.
  • 45. Quinolone Prophylaxis in Neutropenic Hosts* Quinolone prophylaxis without additional gram positive coverage decreases gram-negative bacteremia, but has modest effects on fever and mortality GN bact p < 0.001 GP bact p = 0.7 Fever p = 0.09 Mortality p=0.4 *Cruciani, et al. Clin Inf Dis,1996;23:795-805
  • 46. 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
  • 47. Growth Factors and Clinical Endpoints in Chemotherapy Recipients* Endpoint ChemoRx Auto Allo Duration Neutropenia ++++ ++++ +++ Neutropenic Fever +++ ++ +/- Documented Infxns -- +/- -- Abx Use +/- -- +/- Length of stay +/- +/- -- Cost +/- +/- NA Survival -- -- +/- Infectious Deaths -- -- -- Bone Marrow Tx *Adapted from Wingard & Elfenbein, Inf Dis Clin NA,1996;10:345-64
  • 48. ? 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.
  • 49. 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)
  • 50. Scoring Systems to Assess Risk 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
  • 51. 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. * *
  • 52. 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.
  • 53. 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
  • 54. Proposed Classification/Management for Febrile/Neutropenic Patients High Risk : Prolonged Neutropenia ( > 14 d), Heme CA or allo BMT, substantial comorbidity, unstable Admit, IV therapy (usually combination Rx) for duration of neutropenia; Ampho B empiric Rx for continued fever Moderate Risk : Neutropenia 7-14 d, auto BMT, stable, minimal comorbidity Initial IV Rx (monotherapy OK), early discharge with po if response; Ampho B for cont’d fever (especially if azole prophy) Low Risk : < 7d neutropenia, solid tumor, stable Outpatient IV or po therapy; azole Rx ok for cont’d fever Adapted from Rolston, Clin Inf Dis,1999;29:515