Download C. neoformans

1. Candida의 항진균제 감수성과 항진균제 간의 교차내성
2. Disseminated candidiasis의 치료 약제 선택
3. Refractory case에서의 치료 약제 선택
1. Candida의 항진균제 감수성과 항진균제 간의 교차내성
2. Disseminated candidiasis의 치료 약제 선택
3. Refractory case에서의 치료 약제 선택
항진균제 내성 검사
필요성
1. 진균에 의한 감염 증가
2. 다양한 항진균제의 개발 - 치료제 선택
3. 항진균제 내성 균주의 출현
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NCCLS (US National Committee for Clinical and
Laboratory Standards) 법: 검사표준화, 임상적 적용
새로운 검사법: NCCLS법의 단점 보안
NCCLS법의 최근 진전
Antifungal Susceptibility Testing Subcommittee
Candida & C. neoformans
1992년 M27-P (Proposed) - broth macrodilution
1995년 M27-T (Tentative) - broth microdilution
1997년 M27-A (Approved) - MIC breakpoints
2002년 M27-A2 - modifications
Filamentous fungi
2002년 M38-A (Approved)
NCCLS conditioning for antifungal susceptibility testing
Clin Microbiol Rev 2001;14:643-658
1. 항진균제 감수성 검사는 임상적 결과를 예측할 수 있는가?
1) Azole 항진균제
Flu: Orophargeal & invasive candidiasis
Itra: Orophargeal candidiasis only
NCCLS macrodilution & microdilution법 기준
C. krusei: 제외 (fluconazole 자연 내성)
Fluconazole
Oropharyngeal candidiasis (n=528) (Rex, 1997)
70
60
No Cure
50
Cure
40
30
20
10
0
<
0.25 0.5
1
2
4
8
16
32
>64
Rex JH, Clin Infect Dis, 1997; NCCLS M27-A
Interpretative MIC breakpoints:
orophayngeal candidiasis
Antifungals
MIC (ug/mL)
Interpretation
Cured
Fluconazole
<8
S
97%
16 – 32
S-DD
82%
> 64
R
60%
< 0.125
S
90%
0.25 - 0.5
S-DD
63%
> 1.0
R
53%
Itraconazole
Rex JH, Clin Infect Dis, 1997; NCCLS M27-A
In vitro and in vivo correlation for fluconazole
In severe Candida infections
Outcome
No. of cases
S
Clinical cure
DD-S
R
Total
19 (79%)
4
0
23
Clinical failure
5 (21%)
2
2
9
Total
24
6
2
32
Lee, Antimicrob Agents Chemother, 2000
2) Amphotericin B - No correlation
Rex (1995) – NCCLS M27, 146 cases
모든 균주의 MIC가 유사 (0.25 - 1 ug/mL)
NCCLS M27법: 내성검출에 문제, 수정이 필요
내성 균 - C. lusitaniae, C. glabrata, C. krusei
Antibiotic medium 3 / E test 시행 ??
Amphotericin B MICs (ug/mL) of Candida by M27
0.03
0.25
0.5
CA (11)
9
2
CP (18)
4
13
1
11
1
CT (13)
0.06
0.12
1
CG (1)
CK (2)
1
2 4 8 16
1
1
1
김 등, 임상병리학회지,1999
2. General patterns of susceptibility of Candida species
CID 2004;38:161-189
임상적 결과를 예측할 수 있는가?
Fluconazole: Yes
- Orophargeal & invasive candidiasis
Itraconazole: Yes
- Orophargeal candidiasis only
Amphotericin B: No
C. neoformans & molds: No
1. Candida의 항진균제 감수성과 항진균제 간의 교차내성
2. Disseminated candidiasis의 치료 약제 선택
3. Refractory case에서의 치료 약제 선택
Open label and observation studies
1. Fluconazole (6mg/kg/d): generally preferred
2. Amphotericin B deoxycholate (0.6-0.7 mg/kg/d)
Refracotry case
3. lipid-associated amphotericin B (3-5 mg/kg/d)
4. Capsofungin
1) until calcification or resolution of lesions
2) not life threatening but prolonged therpy
Sever candidal infection: Candidemia, Candiduria, Hepatosplenic
candidiasis, Candidal endophthalmitis, Candidal peritonitis
Neutropenia: ANC < 500/mm3
Stable patient: not hypotension, condition – improve or remaining same
Unstable patient: hypotension, undiagnosed problem, recovery - uncertain
CID 1997:25:43-59
CID 1997:25:43-59
CID 1997:25:43-59
Capsofungin
19/male, PBSCT d/t AML
A few day, Fever,abd pain : neutrophil < 100 cells/ug
→ imipenem, vancomycin, amikacin → persistent fever for 3 days
Added liposomal amphotericin B (5mg/kg/d)
: blood culture – DRPA, laparoscopy – diffuse adenomesenteritis
#40: fever develop, multiple sites-C.albicans, CT-Hepatosplenic abscess
Ketoconazole added – not improved
#100: drug stop and capsofungin 70 mg start → 50 mg/d
After 30 days, fever subsided, CT improved → adminstered for 60 days
CID 2002:35:1135-1136
Clin Microb Rev 1999;12:40-79
1. Candida의 항진균제 감수성과 항진균제 간의 교차내성
2. Disseminated candidiasis의 치료 약제 선택
3. Refractory case에서의 치료 약제 선택
Antifungal resistance
1. Primary (intrinsic)
2. Secondary (acquired)
3. Clinical resistance – AIDS, Neutropenia, infected
prosthetic materials (Central venous catheters),
suboptimal drug conc.
Ergosterol biosynthetic pathway
Clin Micro Rev 1998;11:382-402
1. mRNA overexpression of
CDR/MDR genes
2. Mutation or overexpression
of ERG11
Clin Micro Rev 1998;11:382-402
Systemic antifungal agents
Lancet 2002:309:1135-1144
Lancet 2002:309:1135-1144
Factors that may contribute to clinical antifungal drug resistance
Clin Micro Rev 1998;11:382-402
Potential molecular mechanisms of antifungal drug resistance
Clin Micro Rev 1998;11:382-402
1. Oropharyngeal candidiasis in
AIDS, Transplantation
2. Repeated or continuous exposure
to low dose fluconazole therapy
(50-200 mg/D)
CID 1997;25-908-910
Mechanisms of antifungal agents
Lancet 2002:309:1135-1144
Lancet 2002:309:1135-1144
Strategies to overcome antifungal resistance
1. Dose intensity
2. Combination therapy
3. Immunomodulators
4. New antifungals
Dose intensity
No clinical trials
1. Fluconazole – next page
2. Amphotericin B – confounded factors
1) lack of appropriate control group
2) presence of immune recovery in some pts
AUC/MIC : 25-50
400 mg/d (MIC < 8mg/d)
800 mg/d (MIC 16-32 mg/d)
Antimicrb Agents Chemother 1998:42:1105-1109
Combination therapy
No clinical studies
Combinations of amphotericin B and flucytosine can decrease
flucytosine resistance
CID 1992;15:1003-1018
2ndary antifungal resistance for bloodstream infection : rare
Scedosprorium, Fusoarium spp, Trichosporon beigelli, non-fumigatus
Aspergillus spp, or other resistant moulds – empirical therapy
Immunomodulators
Cytokines (GM-CSF, GCSF, IFN-gamma, immune
effector cells)
CID 1998:26:1270-1278
New antifungals
Clin Microb Rev 1999;12:40-79