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 > 38.3oC (101oF) OR

– Repeated oral temps > 38.0oC (100.4oF) for one hour

– AND

– ANC < 500/mm3 or < 1000/mm3 and < 500/mm3 expected

00.5

11.5

22.5

33.5

44.5

5

0 100 500 1000

All Infxns Severe Infxns Bacteremia

Ann Int Med,1966;64:329Clin 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 YesCatheter-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*

71

29

59

41 37

63

31

69

0

10

20

30

40

50

60

70

80

73-76 80-83 86-88 93-94

Gm (-) Gm (+)

% of Isolates

Year of StudySummarized from Jones, Clin Inf Dis,1999;29:495

Changing Etiology of Infection in Cancer Patients*

12

31

37

46

05

101520253035404550

73-76 80-83 86-88 88-91

Streptococcal Isolates

% of Isolates

Year of StudySummarized from Jones, Clin Inf Dis,1999;29:495

Resistance (%) in viridans Streptococci

Agent Carratla, et al. Marron et al.

PCN 56 40

CTZ 74 56

Cefepime ---- 22

Imipenem 30 7

Vanc 0 0

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

Response Rates in Trials of Vanco vs. No Vanco Up Front*

62

85

63

76

56 61

4645

010

203040

506070

8090

Tic/Amik Ceftaz Ceftaz Ceftaz

Std Std + Vanc

% Response

Type of Standard TherapySummarized 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)

0

20

40

60

80

100

CTZCip

ro

PTAZM

ero

Cefep

ime

Gen

t

Overall (n=714) Oncology (n=21)

Susceptibility Data for Staphylococcus aureus at WFUBMC (2002)

0

20

40

60

80

100

Oxa

cillin

Cipro

Vanc

Clinda

Overall (n=1466) Oncology (n=65)

Susceptibility Data for Enterococcus spp. at WFUBMC (2002)

0

20

40

60

80

100

PCNCip

roVan

c

Hi G

ent

Hi S

trep

Overall (n=1199) Oncology (n=83)

Hemodynamically unstable &/or new organ dysfunction?

No YesCatheter-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

0102030405060708090

100

0 2 4 6 8 10 12 14 16 18

Pip + Cipro Pip + Tobra

Days

% febrile

p=0.0052

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*

40

510

55

10

25 Fungi-SFungi-RBact (R or cryptic)Atypical BactViralGVHD (HSCT only)Undefined

*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/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

01020304050607080

Ampho B Placebo

* *

% R

espo

nded

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

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%

0

20

40

60

80

100

Amibsome Ampho B

*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

0102030405060708090

IV Itra Ampho B

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

0

200

400

600

800

1000

1200

1400

Day 3 Day 8 Day15

Day22

IV Itra PO Itra

Effective level 250 mg/mL

Glucan Synthase InhbitorsActivity Against Common and Uncommon Fungi

Active Mod Activity Poor ActivityCandida 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

CaspofunginCancidas®

• 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

020406080

100

Caspofungin Liposomal Ampho B

*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 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.)

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

0

5

10

15

20

25

Vori L-AmB

*Walsh, et al. NEJM, 2002;346:225-34

* *

**

VoriconazoleEmpiric 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?

0

2

4

6

8

10

HighRisk

ModRisk

AFProphy

No AFProphy

Vori L-Ampho

*Walsh, et al. NEJM, 2002;346:225-34

Breakthrough rate (%) stratified by risk and prior prophylaxis

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

01020304050607080

Ampo B Vori

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;)

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

0.1 1 10

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

0.1 1 10

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 AlloDuration 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) XNo/Mild Sxs 5Mod Sxs 3

No hypotension 5No COPD 4Solid tumor OR No fungi 4No dehydration 3Onset of fever as OP 3Age < 60 yrs 2Total > 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)

010203040506070

Succes

s

Failure

% m

odifi

ed

Into

leran

ce

IV PO

*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

0

10

20

30

40

50

60

70

80

Succes

s

Failure

% m

odifi

ed

Death

IV PO

*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

0

20

40

60

80

100

ASC-II ASC-I

IV PO

*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