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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:

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evaluation and management of fever in the neutropenic patient 2003

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

definition and risk of infection as absolute neutrophil count declines
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

initial evaluation in fever neutropenia
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

slide4

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

justification for empiric antimicrobial therapy in fever neutropenia
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
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
monotherapy pro
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

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.

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)

Some Published Monotherapy Trials in Febrile Neutropenic Patients
monotherapy con
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
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

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

Vancomycin Up Front?
changing etiology of infection in cancer patients
Changing Etiology of Infection in Cancer Patients*

% of Isolates

Summarized from Jones, Clin Inf Dis,1999;29:495

Year of Study

slide14

Changing Etiology of Infection in Cancer Patients*

% of Isolates

Summarized from Jones, Clin Inf Dis,1999;29:495

Year of Study

resistance in viridans streptococci
Resistance (%) in viridans Streptococci

Summarized in Clin Inf Dis, 2002; 34:1524-9

slide16

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

criteria for adding vancomycin up front
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

slide21

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

why do we use pip tazo cipro for our combination therapy standard
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

slide23

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

causes of persistent fever in neutropenic patients
Causes of Persistent Fever in Neutropenic Patients*

*Editorial by Corey and Boeckh, NEJM,2002;346:222-4.

adding amphotericin b
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
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

other considerations when adding antifungal therapy
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
slide28

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
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
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

glucan synthase inhbitors activity against common and uncommon fungi
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

caspofungin cancidas
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
caspofungin empiric therapy in febrile neutropenia
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
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.)
voriconazole empiric therapy in febrile neutropenia
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

voriconazole empiric therapy in febrile neutropenia37
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

voriconazole rx for aspergillosis herbrecht et al nejm 2002 347 408 15
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

bottom line empiric therapy
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
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;)
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)

Fever After Resolution of Neutropenia

*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 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

slide43

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
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

outpatient therapy risk assessment of febrile neutropenic patients
? 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
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

Scoring Systems to Assess Risk
oral vs iv therapy in inpatients with fever neutropenia
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.

slide49

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
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
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