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Febrile Neutropenia and Fungal Infections. Lin Chien-ting 林建廷 Dec 4, 2009. 40. 35. 30. 25. 20. 15. 10. 5. 0. Febrile Neutropenia (FN). 39. 60. 53. 50. 37. 40. 19. 發燒 (%). 30. 感染 (%). 22. 11. 20. 10. 11. 10. 3. 0. 0. 2. 0. 1. 3. > 4.
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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