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

Clin Inf Dis, 2002; 34:730-51

Ann Int Med,1966;64:329

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/LFTs)

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 SSxs 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

Algorithm for Fever/Neutropenia

Hemodynamically
unstable &/or new organ
dysfunction?
No
Catheter-related
erythema/induration,
or chills with CVC
flushing?

Yes
Pip-tazo +
cipro + vanco

Yes

No

ANC > 100 &

clinically stable?

Cefepime* +
vanco
No

*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

Pip-tazo*
+ cipro

Yes
Quinolone prophylaxis?
Cefepime*
monotherapy

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

*Ramphal, AM J Med,1996.

% susceptible
GP GN
Cefipime 82
93
Ceftazidime
74
Piperacillin
61
Gentamicin
76

91
93
100

bacterial eradication in 97% for

cefipime, 100% for comparator

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
Treatment Failure
Any Adverse Event
Nephrotoxicity

0.97 (0.82,1.14)
0.92 (0.85,0.99)
0.85 (0.72,1.02)
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*
Gm (-)

% of
Isolates

80

Gm (+)

71

69

70

63

59

60
50

41

40

37
31

29

30
20
10
0

73-76

Summarized from Jones, Clin

Inf Dis,1999;29:495

80-83

Year of Study

86-88

93-94

Changing Etiology of Infection in

Cancer Patients*
Streptococcal Isolates

% of
Isolates

50
45
40
35
30
25
20
15
10
5
0

46
37
31

12

73-76

Summarized from Jones, Clin

Inf Dis,1999;29:495

80-83

Year of Study

86-88

88-91

Resistance (%) in viridans

Streptococci
Agent

Carratla, et al.

Marron et al.

PCN

56

40

CTZ

74

56

Cefepime

----

22

Imipenem

30

Vanc

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

Response Rates in Trials of Vanco

vs. No Vanco Up Front*
Std

%
Response

90
80
70
60
50
40
30
20
10
0

85
62

Std + Vanc
76

63

56

61
46

Tic/Amik

Summarized from Feld, Clin Inf

Dis,1999;29:503

Ceftaz

Ceftaz

45

Ceftaz

Type of Standard Therapy

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 (2002)

Susceptibility Data for Enterococcus spp. at

WFUBMC (2002)

Algorithm for Fever/Neutropenia

Hemodynamically
unstable &/or new organ
dysfunction?
No
Catheter-related
erythema/induration,
or chills with CVC
flushing?

Yes
Pip-tazo +
cipro + vanco

Yes

No

ANC > 100 &

clinically stable?

Cefepime* +
vanco
No

*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

Pip-tazo*
+ cipro

Yes
Quinolone prophylaxis?
Cefepime*
monotherapy

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

%
febrile

p=0.0052

Days

Persistent Fever After Initial Therapy*

ANC < 500

Febrile 3-5 days

after starting Abxs?
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*

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

Adding Amphotericin B
In F/N patients still febrile 7d after Abxs; 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 Abxs for > 4 d
% Responded

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

Ampho B
80
70
60
50
40
30
20
10
0

Placebo

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%

Amibsome

Ampho B

100
80
%
60
40
20
0

*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 drugrelated 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 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*
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 noninferiority 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 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 > LAmpho 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)

*Talbot, et al. Arch Int Med.

1988;148:129-35

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)

**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
0.1

*Cruciani, et al. Clin Inf Dis,1996;23:795-805

10

Quinolone + Gram Positive

Prophylaxis in Neutropenic Hosts*
Quinolone prophylaxis
with additional gram
positive coverage
decreases grampositive 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
0.1

*Cruciani, et al. Clin Inf Dis,1996;23:795-805

10

Growth Factors and Clinical Endpoints in

Chemotherapy Recipients*
Endpoint ChemoRx Auto Allo

Bone Marrow Tx

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*
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 (cant predict at time of febrile presentation)

Scoring Systems to Assess Risk

Risk assessment based on
Sxs, tumor type, comorbidity, 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)

No/Mild Sxs
5
Mod Sxs
3
No hypotension
No COPD
Solid tumor OR No fungi
No dehydration
Onset of fever as OP
Age < 60 yrs
Total > 21 = low risk for
complications

5
4
4
3
3
2

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)

IV
70
60
50
40
30
20
10
0

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/ Amoxclav
37% documented infxn
MEDIAN DURATION OF ANC <
1000 = 4 DAYS
secondary infection and adverse
events equivalent

IV

PO

80
70
60
50
40
30
20
10
0

*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

IV

PO

100
80
60
40
20
0
ASC-II

*Summarized from Rolston, et al. Inf Dis Clin NA,1996;2:223-37

ASC-I

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 contd fever (especially if azole prophy)

Low Risk: < 7d neutropenia, solid tumor, stable

Outpatient IV or po therapy; azole Rx ok for contd fever

Adapted from Rolston, Clin Inf Dis,1999;29:515