1. Candida 의 항진균제 감수성과 항진균제 간의 교차내성 2. Disseminated candidiasis 의 치료 약제 선택 3. Refractory case 에서의 치료 약제 선택

1. Candida 의 항진균제 감수성과 항진균제 간의 교차내성 2. Disseminated candidiasis 의 치료 약제 선택 3. Refractory case 에서의 치료 약제 선택

항진균제 내성 검사 필요성 1. 진균에 의한 감염 증가 2. 다양한 항진균제의 개발 - 치료제 선택 3. 항진균제 내성 균주의 출현  NCCLS (US National Committee for Clinical and Laboratory Standards) 법 : 검사표준화, 임상적 적용  새로운 검사법 : NCCLS 법의 단점 보안

NCCLS 법의 최근 진전 Antifungal Susceptibility Testing Subcommittee Candida & C. neoformans 1992 년 M27-P (Proposed) - broth macrodilution 1995 년 M27-T (Tentative) - broth microdilution 1997 년 M27-A (Approved) - MIC breakpoints 2002 년 M27-A2 - modifications Filamentous fungi 2002 년 M38-A (Approved)

NCCLS conditioning for antifungal susceptibility testing Clin Microbiol Rev 2001;14:

1. 항진균제 감수성 검사는 임상적 결과를 예측할 수 있는가 ? 1) Azole 항진균제 Flu: Orophargeal & invasive candidiasis Itra: Orophargeal candidiasis only NCCLS macrodilution & microdilution 법 기준 C. krusei: 제외 (fluconazole 자연 내성 )

Fluconazole Oropharyngeal candidiasis (n=528) (Rex, 1997) Rex JH, Clin Infect Dis, 1997; NCCLS M27-A

Interpretative MIC breakpoints: orophayngeal candidiasis AntifungalsMIC (ug/mL)InterpretationCured Fluconazole< 8S97% 16 – 32S-DD82% > 64R60% Itraconazole< 0.125S90% S-DD63% > 1.0R53% 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 DD-S RTotal Clinical cure 19 (79%) Clinical failure 5 (21%) Total Lee, Antimicrob Agents Chemother, 2000

2) Amphotericin B - No correlation Rex (1995) – NCCLS M27, 146 cases 모든 균주의 MIC 가 유사 ( ug/mL) NCCLS M27 법 : 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 M CA (11)92 CP (18)4131 CT (13)1111 CG (1)1 CK (2)11 김 등, 임상병리학회지,1999

2. General patterns of susceptibility of Candida species CID 2004;38:

임상적 결과를 예측할 수 있는가 ? Fluconazole: Yes - Orophargeal & invasive candidiasis Itraconazole: Yes - Orophargeal candidiasis only Amphotericin B: No C. neoformans & molds: No

1. Candida 의 항진균제 감수성과 항진균제 간의 교차내성 2. Disseminated candidiasis 의 치료 약제 선택 3. Refractory case 에서의 치료 약제 선택

Open label and observation studies 1. Fluconazole (6mg/kg/d): generally preferred 2. Amphotericin B deoxycholate ( mg/kg/d) 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 Refracotry case

Sever candidal infection: Candidemia, Candiduria, Hepatosplenic candidiasis, Candidal endophthalmitis, Candidal peritonitis Neutropenia: ANC < 500/mm 3 Stable patient: not hypotension, condition – improve or remaining same Unstable patient: hypotension, undiagnosed problem, recovery - uncertain 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:

Clin Microb Rev 1999;12:40-79

1. Candida 의 항진균제 감수성과 항진균제 간의 교차내성 2. Disseminated candidiasis 의 치료 약제 선택 3. Refractory case 에서의 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:

1.mRNA overexpression of CDR/MDR genes 2. Mutation or overexpression of ERG11 Clin Micro Rev 1998;11:

Lancet 2002:309: Systemic antifungal agents

Lancet 2002:309:

Factors that may contribute to clinical antifungal drug resistance Clin Micro Rev 1998;11:

Potential molecular mechanisms of antifungal drug resistance Clin Micro Rev 1998;11:

CID 1997; Oropharyngeal candidiasis in AIDS, Transplantation 2. Repeated or continuous exposure to low dose fluconazole therapy ( mg/D)

Lancet 2002:309: Mechanisms of antifungal agents

Lancet 2002:309:

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

Antimicrb Agents Chemother 1998:42: AUC/MIC : mg/d (MIC < 8mg/d) 800 mg/d (MIC mg/d)

Combination therapy No clinical studies Combinations of amphotericin B and flucytosine can decrease flucytosine resistance CID 1992;15: ndary 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:

New antifungals

Clin Microb Rev 1999;12:40-79