Evaluation and Management of Fever in the Neutropenic Patient 2003

1
Evaluation and Management of Fever in the
Neutropenic Patient2003

• Kevin P. High, M.D., M.Sc.
• Associate Professor of Medicine
• Sections on Infectious Diseases and
  Hematology/Oncology

2
Definition and Risk of Infection as Absolute
Neutrophil Count Declines

• Defined as
• A single oral temp gt 38.3oC (101oF) OR
• Repeated oral temps gt 38.0oC (100.4oF) for one
  hour
• AND
• ANC lt 500/mm3 or lt 1000/mm3 and lt 500/mm3
  expected

Ann Int Med,196664329
Clin Inf Dis, 2002 34730-51
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/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 Onc199917796-805)
• wound cultures when appropriate

Clin Inf Dis, 2002 34730-51
4
Algorithm for Fever/Neutropenia
Hemodynamically unstable /or new organ
dysfunction?
Note, there are many other regimens AZM/Clinda,
Cipro/ Clinda or Vanc/AZM for severe PCN
allergy If other nephrotoxic meds, consider
meropenem or cefepime montherapy
No
Yes
Catheter-related erythema/induration, or chills
with CVC flushing?
Pip-tazo cipro vanco
No
Yes
ANC gt 100 clinically stable?
Cefepime vanco
Pip-tazo cipro
No
Yes
Quinolone prophylaxis?
Pip-tazo gent
Cefepime monotherapy
5
Justification for Empiric Antimicrobial Therapy
in Fever/Neutropenia

• Never been (and probably never will be) a
  randomized/controlled trial
• Retrospective Data (NEJM,19712841061) indicated
  that 50 of Pseudomonas bacteremias result in
  death w/in 72 hrs when ANC lt 1000
• Early trials aimed at Pseudomonas decreased
  mortality to 33 (Carb/Gent JID,197814714)
• Peak serumcidal levels of gt 116 correlated with
  success, ? Combinations w/synergy should be more
  potent (Am J Med,198476429)

6
Empiric Combinations

• Anti-Pseudomonal PCN or Cephalosporin
  aminoglycoside (NEJM,19933261323)
• 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,1991115849)
  CTZ/CPZ Pip
• equal efficacy, less nephrotoxic, high cost

7
Monotherapy Pro

• Ceftazidime (NEJM,1986315552)
• equivalent overall success rate to combination
  therapy entry criteria fever ANC lt 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,1991115849)
• overall efficacy of monotherapy (85)
• ? Increased risk of fungal infxn. Definite risk
  factor for S. maltophilia infection

8
Cefipime in Treatment of Fever/Neutropenia

• susceptible
• GP GN
• Cefipime 82 93
• Ceftazidime 74 91
• Piperacillin 61 93
• Gentamicin 76 100
• bacterial eradication in 97 for cefipime, 100
  for comparator

• 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.
9
Some Published Monotherapy Trials in Febrile
Neutropenic Patients

• Meropenem (58) vs. Imipenem (60)
  (Infection,199624480-4)
• Meropenem (56) vs. CTZ/Amikacin (52)
  (AAC,1996401108-15)
• Cefepime (74) vs. CTZ OR Pip/Gent (76) (Am J
  Med,199610083S-89S)
• Meropenem vs. CTZ/Amikacin (80) vs. (77)
  (Haematologica,199782668-75)

• Cefepime ( 79) vs. Imipenem (72) (J Antim
  Chemo,199842511-8)
• Cefepime (57) vs. CTZ (60) (Ann Pharmacother,
  200034989-95)
• Meropenem (54) vs. CTZ (44) (J Clin Oncol,2000
  183690-8)
• Meropenem (48) vs. CTZ (38) (Ann Hematol,2000
  79152-7)
• Clinafloxacin (32/95) vs. Imipenem (33/92)
  (Clin Inf Dis,200132381-90)

10
Monotherapy Con

• Ceftazidime 3d of Amikacin vs. CTZ 9d of
  Amikacin (NEJM,1986315552)
• entry criteria fever ANC lt 100
• modification of initial regimen counted as
  failure
• success rate in 3d group 48 vs. 81 in 9d
  group in patients with documented bacteremia
• Death rate 17 vs. 8

11
Meta-analysis of Monotherapy vs. Combination
Therapy

• 47 trials, 7807 patients
• Monotherapy RR
• All cause mortality 0.85 (0.72,1.02)
• Same b-lactam no difference, different b-lactams,
  difference became significant 0.87 (0.80,0.93)
• Superinfection 0.97 (0.82,1.14)
• Treatment Failure 0.92 (0.85,0.99)
• Any Adverse Event 0.85 (0.72,1.02)
• Nephrotoxicity 0.42 (0.32, 0.56)

Paul M, Soures-Weiser K, Leibovici L. Br Med J,
2003326111-1119
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,198810630
  NEJM,19883191053)
• VRE

13
Changing Etiology of Infection in Cancer Patients
of Isolates
Year of Study
Summarized from Jones, Clin Inf Dis,199929495
14
Changing Etiology of Infection in Cancer Patients
of Isolates
Year of Study
Summarized from Jones, Clin Inf Dis,199929495
15
Resistance () in viridans Streptococci
Summarized in Clin Inf Dis, 2002 341524-9
16
Response Rates in Trials of Vanco vs. No Vanco Up
Front
Response
Note no mortality difference in any study
!!!!!!!!
Type of Standard Therapy
Summarized from Feld, Clin Inf Dis,199929503
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,200234730-51. Recs are A-II
18
Susceptibility Data for Pseudomonas aeruginosa at
WFUBMC (2002)
19
Susceptibility Data for Staphylococcus aureus at
WFUBMC (2002)
20
Susceptibility Data for Enterococcus spp. at
WFUBMC (2002)
21
Algorithm for Fever/Neutropenia
Hemodynamically unstable /or new organ
dysfunction?
Note, there are many other regimens AZM/Clinda,
Cipro/ Clinda or Vanc/AZM for severe PCN
allergy If other nephrotoxic meds, consider
meropenem or cefepime montherapy
No
Yes
Catheter-related erythema/induration, or chills
with CVC flushing?
Pip-tazo cipro vanco
No
Yes
ANC gt 100 clinically stable?
Cefepime vanco
Pip-tazo cipro
No
Yes
Quinolone prophylaxis?
Pip-tazo gent
Cefepime monotherapy
22
Why do we use Pip-tazo Cipro for our
combination therapy standard?

• Largest enrolling center in a study recently
  published (Ann Int Med, 200213777-86)
• 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
p0.0052
Days
23
Can Antibiotics Be Discontinued in the Face of
Continued Neutropenia?
Etiology IDd
Afebrile in 3-5 days
Finish course of therapy
ANC lt 500
ANC gt 500
mucositis, ANC lt 100, unstable vital signs
? Clinically well
Discontinue Abxs after 48 hours of no fever
ANC gt 500
Yes
No
Stop Abxs after afebrile for 5-7 days change to
po Re-evaluate
Cont Abxs
Clin Inf Dis, 2002 34730-51
24
Persistent Fever After Initial Therapy
Febrile 3-5 days after starting Abxs?
ANC lt 500
ANC gt 500

• ? Change Abxs
• ? Add Vancomycin
• ? Add Ampho B

Stop Abxs after ANC gt 500 for 4-5 days
Re-evaluate
Clin Inf Dis, 200234730-51
25
Causes of Persistent Fever in Neutropenic
Patients
Editorial by Corey and Boeckh,
NEJM,2002346222-4.
26
Adding Amphotericin B

• In F/N patients still febrile 7d after Abxs
  addition of Amphotericin B appears to improve
  outcome (Am J Med,198272101)
• EORTC trial published in 1989 (Am J
  Med,198986668) 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,198986668-73)

• 132 Pts, ANC lt 500/mm3 and on Abxs for gt 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 gt 2.0 and not on dialysis
  (long-term)
• Creat ? gt 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 lt 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

or Days
Malik, et al. Am J Med,1998105478
30
Other Alternatives to Ampho B?

• 687 patients with ANC lt 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,1999340764.
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 lt 3 d

Boogaerts, et al. Ann Int Med, 2001135412-22
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 gt 500 x
  2d

Effective level 250 mg/mL
Boogaerts, et al. Ann Int Med, 2001135412-22
33
(No Transcript)
34
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-gt64 mg/mL

Data are from Merck, on file and J Antibiot,
2000531175-81
35
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

36
Caspofungin Empiric Therapy in Febrile
Neutropenia

• RCT
• Caspofungin 70/50 qd (n564)
• Liposomal Ampho B 3 mg/kg/d (n547)
• 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 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.)

38
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, 2002346225-34
39
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, 2002346225-34
40
Voriconazole Rx for AspergillosisHerbrecht, et
al. NEJM,2002347408-15.

• Only RCT of primary Rx of invasive aspergillosis
  (n277)
• 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 gt 50 radiologic and significant clinical
  improvement

p lt 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 gt Caspofungin gt L-Ampho
  B gt 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 gt 2.0
  at baseline
• A doubling of serum creatinine and gt 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 AgentsAWP per 2002
Medical Letter (4463-65)

• 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. 1988148129-35
Barton Schuster, Clin Inf Dis, 1996221064-8.
45
Quinolone Prophylaxis in Neutropenic Hosts
GN bact p lt 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 p0.4
Cruciani, et al. Clin Inf Dis,199623795-805
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 p0.8
Cruciani, et al. Clin Inf Dis,199623795-805
47
Growth Factors and Clinical Endpoints in
Chemotherapy Recipients
Bone Marrow Tx

• Endpoint ChemoRx Auto Allo
• Duration Neutropenia
• Neutropenic Fever /-
• Documented Infxns -- /- --
• Abx Use /- -- /-
• Length of stay /- /- --
• Cost /- /- NA
• Survival -- -- /-
• Infectious Deaths -- -- --

Adapted from Wingard Elfenbein, Inf Dis Clin
NA,199610345-64
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)
• lt 3 morbidity, no mortality

J Clin Onc,199210316-22.
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 (cant 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 2000183038-51))
• In children, monocyte count gt 100/mm3, no
  comorbidity and normal CXR indicate low risk (J
  Clin Onc 2000181012-9)

• 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 lt 60 yrs 2
• Total gt 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 lt 500 3.6 DAYS
• 8-16 unable to tolerate po meds at all (even
  placebo)

Freifeld, et al. NEJM,1999341305.
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 lt 1000 4 DAYS
• secondary infection and adverse events equivalent

Kern, et al. NEJM,1999341312.
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,19962223-37
54
Proposed Classification/Management for
Febrile/Neutropenic Patients

• High Risk Prolonged Neutropenia ( gt 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 lt 7d neutropenia, solid tumor, stable
• Outpatient IV or po therapy azole Rx ok for
  contd fever

Adapted from Rolston, Clin Inf Dis,199929515