[항진균제 각론] 항진규제에 분류와 각각의 기능

항진균제의 분류

 

Polyene 계 : Amphotericin B, nystatin

Pyrimidine 계 :  Flucytosine

Azole 계  

  - Imidazole :  miconazole,  ketoconazole

  - Triazole : fluconazole,  itraconazole, voriconazole

Echinocandin 계 : Caspofungin

 

Cell Membrane Active Antifungals

 

  Polyene antibiotics

    - Amphotericin B

    - Nystatin (topical)

  Azole antifungals

    - Ketoconazole

    - Itraconazole

    - Fluconazole

    - Voriconazole   

 

 

Amphotericin B deoxycholate

 

“Gold standard” of antifungal therapeutics

Acts by binding to ergosterols in the fungal cell membrane

  -> 세포막의 세공 형성

  -> 세포내 물질의 외부 유출(살균 작용)

임상 적응증

  - Candidiasis - blastomycosis

  - Cryptococcosis   - histoplasmosis

  - Aspergillosis   - paracoccidioidomy

  - Mucormycosis

 

Amphotericin B의 부작용

 

Administration related A/E

  : 주입 30-45분후에 PGE2유도

   à fever, chills, myalgias, arthalgias, HA, hypotensin

   à 비스테로이드성 진통소염제, hydrocortisone

        처음 투여 시 1mg, 30-60분, 1시간 관찰

 

Mechanism related A/E

  1. Nephrotoxicity (80%)

  -신세동맥의 혈관수축작용으로 신혈류 및 신배설기능 감소

  - 용량의존성, 대부분 가역적

  - 다른 신독성 유발 약제와 병용 시 신독성 증가

  2. Thrombophlebitis; hypo K, hypo Mg;

    anemia, thrombocytopenia, leukopenia

 

Liposomal Amphotericin B

 

Encapsulate Ampho B into a phospholipid bilayer membrane

  1. Amphotericin B lipid complex

  2. Amphotericin B colloidal dispersion

  3. Liposomal amphotericin B

 

Eliminated by the RES and taken up by macrophages and monocytes

    : 신부전 환자나 신독성 견딜 수 없는 경우로 제한

 

Characteristics of Amphotericin B and Lipid Formulations

 

	Ampho B	Ampho B Lipid Complex	Ampho B Colloidal Dispersion	Liposomal Ampho B
Trade name	Fungizone	Abelcet	Amphotec	AmBisome
Dose(mg/kg)	0.5-1.5	5	3-4	1-15
Duration of infusion (hr)	1-6	1-2	2-4	1
Compatible fluid	D5W	D5W	D5W	D5W
Nephrotoxicity	++++	++	++	+
Infusion-related toxicity	++++	+++	++++	+

 

Fluconazole

 

Increased water solubility and low protein binding

  - 경구 흡수율이 좋다(> 90%)

  - BBB 투과성이 우수 (50-90%)

항균 범위

  - Active against Candida, Cryptococcus

  - Not active against C. glabrata, C. krusei ;

                                   Aspergillus, Mucor spp.

임상 적응증

  - Candidiasis

  - Cryptococcosis

  - 동종 골수이식 환자에서 항진균 예방 요법

 

Itraconazole

 

경구 흡수율 좋지만 fluconazole보다 낮다(70%)

신장, 뇌, 피부 표피층과 같은 지용성이 강한

  조직에 혈장 농도의 2-5배의 높은 농도로 분포

뇌척수액과 소변내의 농도는 낮다

항진균 범위

  - Fluconazole과 유사, Aspergillus에는 더 좋다

  - C. neoformans, C. albicans, C. immitis

       H. capsulatum, B. dermatitidis, S. schenckii

  - 칸디다증, Tinea---, Onychomycosis

1일 200mg, 300-400mg, 중증 부하(600mg, 3d)

 

Voriconazole

 

• 2nd generation triazole, IV & PO

• Active against Candida , Aspergillus, & Cryptococcus spp.; Coccidioides,   Histoplasma, and Fusarium spp.

• Not active against Mucor spp.

• Against Candida spp;   4-16 times than fluconazole,

                                2-8 times than itraconazole

• Against Aspergillus spp:   >  itraconazole

 

active following both oral and intravenous

    administrations(bioavailability 90%)

Dose

:  loading dose 6mg/kg iv q12h for 2 doses, followed by

  maintenance dose 4mg/kg iv q12h or 200mg po bid

Side effects : 시각장애 (25-45%), 발진 (<10%),  간기능 이상 (10-20%), 환시 (<10%)

 

 

Characteristics of Triazole Antifungals

 

	Fluconazole	Itraconazole	Voriconazole
Spectrum  against Candida , Aspergillus	C. albicans, C. tropicalis C. glabrata Not Aspergillus	Similar Candida coverage as fluconazole, Aspergillus	Most Candida spp., Aspergillus, Fusarium sp. Not Zygomycoses
Oral formulation (% bioavailibility)	Tablet (>90%)	Capsule (6-25%) Solution (20-60%)	Tablet (>90%)
Intravenous formulation	Available, no solubilizer	Available, cyclodextrin	Available, cyclodextrin
Clearance	Renal (80%)	Hepatic 3A4	Hepatic 2C19, 3A4
Serum half life (hr)	24	24-30	6-24
CSF penetration	Excellent	Poor	Excellent
Adverse effects	N&V, hepatic	N&V, diarrhea (solution), hepatic, CHF	N&V, visual disturbances, hepatic, rash

 

DNA synthesis inhibiting Antifungals

 

DNA/RNA synthesis

 • Pyrimidine analogues

  - Flucytosine

 

Flucytosine

 

진균세포에서 RNA와 DNA의 기능을 억제

단독으로는 항진균 효과가 약하다.

Amphotericin B와 병용

Cryptococcus뇌막염 등에 사용된다.

  칸디다 감염증, chromoblastomycosis

경구로만 투여가능(경구 흡수율 90% 이상)

12.5-37.5 mg/kg씩 6시간마다 투여

혈청농도 100ug/ml 이상인 경우 부작용 흔함

 

Cell wall active Antifungals

 

Cell wall

  • Echinocandins

   -Caspofungin acetate

 

Caspofungin

 

1st licenced echinocandin product,

   synthetically modified lipopeptides

low toxicity, rapid fungicidal activity

  once daily dosing

active against Candida, Aspergillus spp., P. carinii;

  Not active against C. neoformans, Fusarum spp., Rhizopus

Poor substrate for cytochrome P450 enzyme

 

Indication

  - esophageal candidiasis

   - candidiasis / candidemia

   - neutropenic fever (empirical)

  - invasive aspergillosis (refractory to or intolerant of other Tx.)

Only given IV (LD 70 mg followed by 50 mg IV daily)

Dosage adjustments:

- Renal insufficiency : no adjustment

- Hepatic insufficiency : moderate insufficiency reduce dose to 35 mg IV daily after 70 mg LD