Febrile Neutropenia and Febrile Neutropenia and Fungal InfectionsFungal InfectionsLin Chien-ting 林建廷Dec 4, 2009

Febrile Neutropenia (FN)Febrile Neutropenia (FN)Neutropenia FeverANC <500/μL

or

ANC <1000/μL 且預期將在48 小時內降到≤ 500/μL

Oral BT >38.3°C ( 單次 )

or

>38.0°C ( 超過 1 小時 )

2

1110

22

37

53

0

10

20

30

40

50

60

<100 100-500

500-1000

1000-1500

>1500

ANC數目 (/μL)

感染

(%

)

03

11

19

39

0

5

10

15

20

25

30

35

40

0 1 3 >4

Severe Neutropenia天數 ( 日 )

發燒

(%

)

2

3

4

牙齦 , 口腔黏膜 , 鼻竇—HSV/ Candida/ mold

Abd/perianal:enterococci/ G(-)/ anaerobes

CVP, Port-A, PICC:G(+)/ G(-)/ fungus

肺部 :

bacteria, PJP, CMV, fungus

Diarrhea: C. difficile

即使很完整的評估 , 只有大約 50 ~70% 可以確定感染源

找出感染源找出感染源--esp. Hx of sinusitis and hemorrhoid

5

(%)

Chen CY et al. J Formos Med Assoc 2004;103:526-32.

57

32

7

3

Febrile Neutropenia-- Febrile Neutropenia-- EtiologyEtiologyNTUH, 1996-2001NTUH, 1996-2001

6

%

Chen CY et al. J Formos Med Assoc 2004;103:526-32.

MRSA, 67% of Stapylococcus

Febrile Neutropenia– EtiologyFebrile Neutropenia– Etiology1996-2001, NTUH1996-2001, NTUH

C, tropicalis. C. albicans

7

Oral IV

Ciprofloxacin+

Amoxicillin-clavulanate(adults only)

Reassess after 3-5 days

Monotherapy

Cefepime,Ceftazidime, orCarbapenem

Two Drugs

Aminoglycoside+

Antipseudomonal penicillin, CefCefepime,Ceftazidime, orcarbapenem

Vancomycin +

Vancomycin+

Cefepime, ceftazidime orCarbapenem

aminoglycoside

High risk

FN

Low risk

VancomycinNot needed

Vancomycinneeded

Hughes WT et al. Clin Infect Dis 2002;34:730-51.

IDSA 2002Initial Management of FNInitial Management of FN

8

Factors that favor a Factors that favor a Low RiskLow Risk for severe infections for severe infections during Neutropeniaduring Neutropenia

ANC > 100 cells/mm3 AMC >100 cells/mm3 Normal CXR Nearly normal RFT and LFT Duration of neutropenia < 10 days No CVC infection Malignancy in remission BT <39 °C No neurological or mental status changes No abd pain No appearance of illness No co-morbidity

Laboratory

Clinical

9

(%)

Resistant Gram (-) Blood Pathogens 1996-2001, NTUH

Chen CY et al. J Formos Med Assoc 2004;103:526-32. 10

Algorithm for Initial Management of FN

Oral IV

A fluoroquinolone a

+Amoxicillin-

clavulanate or Ampicillin-sulbactam

(adults)

Reassess after 3-5 days

Monotherapy (A)Cefepime,

Cefpirome, Piperacillin-tazobactam, A carbapeneme

Two Drugs (B)

An aminoglycosidec +

Ceftazidime, Piperacillin-tazobactam,Cefepime, Cefpirome orA carbapenemc

A glycopeptided

+A or B

High risk

FN

Low risk

Glycopeptided

Not neededGlycopeptide

needed

a Includes ciprofloxacin, levofloxacin, or moxifloxacinb Includes a first-, second-, or third-generation cephalosprinc Includes amikacin or isepamicin d Includes vancomycin or teicoplanine Includes imipenem or meropenem

A cephalosporinb

An

aminoglycoside

11

抗生素 及抗生素 及 G-CSF G-CSF 預防性使用預防性使用 對對發燒的影響發燒的影響

*Cycle 1.Cullen M, et al. N Engl J Med. 2005;353:988-998; Bucaneve G, et al. N Engl J Med. 2005;353:977-987; Vogel CL, et al. J Clin Oncol. 2005;23:1178-1184.

Placebo

發燒

(%)

Levofloxacin

Bucaneve, et al. 2005

P = .001

Cullen, et al. 2005

P = .01

0

10

20

30

40

50

60

70

80

90

Vogel, et al. 2005

Pegfilgrastim

Placebo

0

10

20

30

40

50

60

70

80

90

發燒

(%)

P <.001

12

何時要用預防性抗生素何時要用預防性抗生素 ?? 哪一種哪一種藥物好藥物好 ??何時要用預防性抗生素 ?

◦幹細胞移植時 (Conditioning chemotherapy)

◦預備收集幹細胞時

哪一種藥物好 ?◦Cover GPC + GNB◦Augmentin 1#bid + Ciproxin 2#bid?

13

14

15

16

G-CSF G-CSF 的預防性使用的預防性使用• Granocyte vs Filgrastim

• 在化療結束後 1-3 天開始給予

• 5 µg/kg/day 直到 ANC 恢復 (Max: 10 µg/kg/day )• WBC>4000, 可先減半• 仍然 WBC>4000, 可 DC

• AML induction? AML consolidation?• MDS?

17

Clinical Infectious Diseases 2006; 43:S3–14

~60% of all Invasive Aspergillosis !!

Underlying Dz in Invasive Underlying Dz in Invasive AspergillosisAspergillosis

18

nu

mb

er

of

cases

Asper

gillu

s

Zygo

myc

etes

Fusa

rium

Cand

ida

Cryp

toco

ccus

Tricho

spor

on0

100200

300400

Lethality of Invasive Fungal Lethality of Invasive Fungal InfectionsInfections

cases casualties

42%

61% 53%

33%

50% 29%

Pagano et al. Haematologica 2006; 91:1068-1075

19

20

(1)Host factors(1)Host factors 現在 :

Neutropenia > 10 daysFever > 96 hrs refractory to AbxGVHD, esp >Gr2 aGVHD or extensive cGVHD

過去 :Prolonged (> 3 weeks) steroids use in previous 60

days> 38C or < 36C, AND any of:

Prolonged neutropenia (>10 days) in previous 60 days Significant immunosuppressive agents in previous 30 days Proven/ probable IFI during previous episode of neutropenia

CID 2002 34: 7-14

(2)Clinical criteria/ Image (2)Clinical criteria/ Image criteriacriteria

CID 2002 34: 7-14

Neutropenic fever… 11 days later…

(3)Microbiological criteria(3)Microbiological criteria

CID 2002 34: 7-14

Galactomannan TestGalactomannan TestPositive:

◦Aspergillus◦Penicillium◦Paecilomyces◦Cryptococcus neoformans◦Penicillin-like Abx

Cut-point:◦0.5 is well accepted wordwide

29Medical mycology, 2006, 44, S179-S183

Medical Mycology:Medical Mycology:

0

2

4

6

8

10

12

14

1950 1960 1970 1980 1990 2000

Nys

tatin

Am

phot

eric

in B

(195

8)

Gris

eofu

lvin

5-FCMiconazole

KetoconazoleFluconazole

Itraconazole

L-AmB ABCD ABLC

Terbinafine

VoriconazolePosaconazole

Sordarins

Caspofungin

Micafungin

Ravuc

onaz

oleAnidulafungin

No of drugs

31

?Micafungin 50mg qd

IAI IC

Caspofungin 70/50Micafungin 100Ambisome 3-5Fluconazole 800/400Voriconazole

FDA Approved Indications, FDA Approved Indications, updated 2009updated 2009

Caspofungin

Micafungin Anidulafungin

Voriconazole

Posaconazole

IC V V V V

Aspergillosis (1 line)

V

Aspergillosis (2 line)

V

FN, empirical

V

FN, prophylaxis

V

SCT prophylaxis

V

32