Antifungals Drugs By Baasir Umair Khatak.pptx

Explore the intriguing world of antifungal medications with our extraordinary presentation, showcasing five distinct categories with a personal touch. Curated from an extensive range of scholarly sources, this PPT stands out with its unparalleled depth and insight. Delve into meticulously chosen content, including detailed pharmacokinetics, pharmacodynamics, indications, and dosage information, offering a comprehensive understanding that sets this presentation apart from the rest. Prepare to be amazed by the unique perspectives and thorough analysis presented.

1. Isovuconazole 130 hrs

2. Systemic Antifungal Drugs For Subcutaneous Systemic Infections

3. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 12 POLYENE ANTIBIOTICS Amphotericin B: Chemistry: Amphotericin B is an amphipathic or amphoteric polyene macrolide molecule with the broadest spectrum of activity of any of the currently available antifungal drugs. Polyene macrolide compounds share the characteristics of four to seven conjugated double bonds , an internal cyclic ester , poor aqueous solubility, substantial toxicity when administered systemically, and a common mechanism of antifungal action. Amphotericin B, a heptaene macrolide, contains seven conjugated trans-double bonds and a 3-amino-3,6-dideoxymannose ( mycosamine ) connected to the macrolide ring through a glycosidic bond. The amphoteric properties of the drug, from which it derives its name, are due to the presence of a carboxyl group on the main ring and a primary amino group on mycosamine ; these groups confer aqueous solubility at extremes of pH Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus . Amphotericin A is not in clinical use.

4. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 13 Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease . It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin B and sodium deoxycholate for intravenous injection . The intravenous injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 mcg/mL; The drug is more than 90% bound by serum proteins. Although it is mostly metabolized, ( 60% of AMB is metabolized some amphotericin B is in the liver) excreted slowly in the urine over a period of several days. The serum half-life is approximately 15 days. Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjustment is required. The drug is widely distributed in most tissues , but only 2–3% of the blood level is reached in cerebrospinal fluid , thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis. No dose adjustment is needed in patients with kidney or liver disease. Pharmacokinetics Goodman and Gillman

5. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 14 Despite poor penetration into CSF, amphotericin B ± flucytosine is the treatment of choice for certain CNS fungal infections, such as cryptococcal meningitis and Coccidioides meningoencephalitis. Goodman and Gillman

6. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 15 Antifungal Activity Amphotericin B has useful clinical activity against a broad spectrum of pathogenic fungi, including: Candida spp. Cryptococcus neoformans Blastomyces dermatitidis Histoplasma capsulatum Sporothrix schenckii Coccidioides spp. Paracoccidioides braziliensis Aspergillus spp. Penicillium marneffei ( Talaromyces marneffei ) Fusarium spp., Mucorales. Amphotericin B has limited activity against the protozoa Leishmania spp. and Naegleria fowleri . The drug has no antibacterial activity Fungal Resistance Isolates of Candida lusitaniae are frequently resistant to amphotericin B. Aspergillus terreus and Aspergillus nidulans likewise appear to be less susceptible to amphotericin B than other Aspergillus spp. (Steinbach et al., 2004). Mutants selected in vitro for resistance to nystatin (a related polyene antifungal used topically) or amphotericin B replace ergosterol with certain precursor sterols. Mutations in ergosterol biosynthesis genes ERG2, ERG3, ERG5, ERG6, and ERG11 reduce susceptibility to amphotericin B, likely the result of reduced ergosterol in the cell membrane Goodman and Gillman Goodman and Gillman

7. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 16 Candida auris is an exception; nearly one-third of clinical isolates are considered resistant to amphotericin B based on tentative breakpoints proposed by the CDC (U.S. Centers for Diseases Control and Prevention) (CDC, 2020). Goodman and Gillman Fungal Resistance Some fungal organisms such as Candida lusitaniae and Pseudallescheria boydii display intrinsic amphotericin B resistance . ( Basic and clinical Pharmacology, Bernard Ketzung ) Other sensitive strains (KD Tripathi ) Torulopsis Rhodotorula Dermatophytes are inhibited in vitro, but concentrations of AMB attained in infected skin are low and ineffective. It is fungicidal at high and static at low concentrations KD Tripathi

8. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 17 Mechanisms of Action Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B–associated pores in the cell membrane As suggested by its chemistry, amphotericin B combines avidly with lipids (ergosterol) along the double bond– rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.

9. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 18 MOA 1 The micropore is stabilized by membrane sterols which fill up the spaces between the AMB molecules on the lipophilic side—constituting the outer surface of the pore. Thus, cell permeability is markedly increased. Cholesterol, present in host cell membranes, closely resembles ergosterol; the polyenes bind to cholesterol as well, though with lesser affinity. Thus, the selectivity of action of polyenes is low, and AMB is one of the most toxic systemically used antibiotics, though it is the least toxic polyene. Bacteria do not have sterols and are unaffected by polyenes. It has been found that AMB enhances immunity in animals, and this action may aid immunocompromised individuals in handling fungal infection MOA 2: Mechanisms of Action Basic and clinical Pharmacology, Bernard Ketzung and KD Tripathi

10. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 19 MOA 2: I nduction of Immune Mediators : Amphotericin B can  induce the transcription  of immune mediators. These include proinflammatory cytokines such as  IL-1 ,  TNF , and  IFN- γ .   These cytokines play a crucial role in optimal antifungal host defense 1 . Activation of Macrophages : In macrophages, amphotericin B’s effects are dependent on  Toll-like receptor (TLR)2 ,  CD14 , and  MyD88 . These components are essential for innate pattern recognition signaling.   The drug can boost protective antifungal pathways, including  NADPH-dependent reactive oxygen species  production and enhancing the  Th1 response 1 2 Mechanisms of Action

11. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 20 Administration and dose: Amphotericin B can be administered orally (50–100 mg QID) for intestinal moniliasis; also topically for vaginitis, otomycosis. Conventional formulation of AMB (C-AMB) For systemic mycosis: C-AMB is available as dry powder along with deoxycholate (DOC) for extemporaneous dispersion before use It is first suspended in 10 ml water and then diluted to 500 ml with glucose solution (saline makes the suspension coarse, should be avoided). Initially 1 mg test dose is injected i.v. over 20 minutes. If no serious reaction follows, 0.3 mg/kg is infused over 4–8 hours. Daily dose may be gradually increased to 0.7 mg/kg depending on tolerance of the patient. The total dose of AMB for majority of cases is 3–4 g given over 2–3 months. Intrathecal injection of 0.5 mg twice weekly has been given in fungal meningitis.

12. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 21 L-AMB: Liposomal amphotericin B is a formulation in which amphotericin B is incorporated within a small, unilamellar liposomal vesicle formulation. The drug is supplied as a lyophilized powder and is reconstituted with sterile water for injection (Boswell et al., 1998). Blood levels following intravenous infusion are almost equivalent to those obtained with C-AMB, and because L-AMB can be given at higher doses, blood levels have been achieved that exceed those obtained with C-AMB. ABLC: Amphotericin B lipid complex is a complex of amphotericin B with two phospholipids (dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol ) (Slain, 1999). ABLC is given in a dose of 5 mg/kg in 5% dextrose in water, infused intravenously once daily over 2 hr. Blood levels of amphotericin B are much lower with ABLC than with the same dose of C-AMB. ABLC is effective in a variety of mycoses, with the possible exception of cryptococcal meningitis.

13. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 22 ABCD: Amphotericin B colloidal dispersion contains roughly equimolar amounts of amphotericin B and cholesteryl sulfate formulated for injection. Like C-AMB, ABCD forms a colloidal solution when reconstituted in aqueous solution. ABCD provides much lower blood levels than C-AMB in humans, requiring administration of larger volumes to achieve equal blood levels. In a study of patients with neutropenic fever that compared daily ABCD (4 mg/kg) with C-AMB (0.8 mg/kg), chills and hypoxia were significantly more common in patients who received ABCD as compared with C-AMB (White et al., 1998). Hypoxia was associated with severe febrile reactions. In a study that compared ABCD (6 mg/kg) to C-AMB (1–1.5 mg/kg) in patients with invasive aspergillosis, ABCD was less nephrotoxic than C-AMB (15% vs. 49%) but caused more fever (27% vs. 16%) and chills (53% vs. 30%) (Bowden et al., 2002). ABCD is currently not commercially available in the U.S Goodman and Gillman

14. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 23 Adverse effects The toxicity of AMB is high (a)Acute reaction: This occurs with each infusion and consists of chills, fever, aches and pain all over, nausea, vomiting and dyspnoea lasting for 2–5 hour, probably due to release of cytokines (IL, TNFα). When the reaction is severe—the dose should be increased gradually. Usually the intensity of reaction decreases with continued medication. Injection of hydrocortisone 0.6 mg/kg with the AMB infusion may reduce the intensity of reaction. Thrombophlebitis of the injected vein can occur. (b) Long-term toxicity : Nephrotoxicity is the most important . It occurs fairly uniformly and is dose-related. Manifestations are—azotemia, reduced g.f.r ., acidosis, hypokalaemia and inability to concentrate urine. Nephrotoxicity reverses slowly and often incompletely after stoppage of therapy (c) Anaemia : Most patients develop slowly progressing anaemia which is due to bone marrow depression . This is largely reversible. CNS toxicity: occurs only on intrathecal injection—headache, vomiting, nerve palsies, etc. KD Tripathi

15. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 24 Uses The toxicity of AMB is high Amphotericin B can be applied topically for oral, vaginal and cutaneous candidiasis, fungal corneal ulcer and otomycosis. It is the most effective drug for practically all types of systemic mycoses and is the gold standard of antifungal therapy. However, because of higher toxicity of AMB, the azole antifungals are now preferred in conditions where their efficacy approaches that of AMB. In serious fungal infections, especially in immunocompromised patients, initial induction therapy with AMB may be replaced by the alternative safer azole antifungal drug for continuation of therapy. Some properties of antifungal drugs used for systemic mycosis are compared. 4 . Febrile neutropenia: Empirical use of i.v. AMB is often made in neutropenic patients whose fever is not responding to i.v. bactericidal antibiotics. Leishmaniasis: AMB is the most effective drug for resistant cases of kala azar and mucocutaneous leishmaniasis KD Tripathi

16. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 25 KD Tripathi

17. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 26 FLUCYTOSINE Chemistry & Pharmacokinetics Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Though devoid of anti-cancer properties, it became apparent that it is a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent 5-fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. Flucytosine is currently available in North America only in an oral formulation. The dosage is 100 mg/kg/d in divided doses in patients with normal renal function. It is well absorbed (>90%), with serum concentrations peaking 1–2 hours after an oral dose. It is poorly protein-bound and penetrates well into all body fluid compartments, including the cerebrospinal fluid. It is eliminated by glomerular filtration with a half-life of 3–4 hours and is removed by hemodialysis. Toxicity is more likely to occur in AIDS patients and those with renal insufficiency. Basic and clinical Pharmacology, Bernard Ketzung

18. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 27 MOA All susceptible fungi are capable of deaminating flucytosine to 5- fluorouracil (5FU) (Figure 61–3), a potent antimetabolite that is used in cancer chemotherapy. Fluorouracil is metabolized first to 5-fluorouracilribose monophosphate (5FUMP) by the enzyme uracil phosphoribosyl transferase ( UPRTase ). 5FUMP is then either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5FdUMP), a potent inhibitor of thymidylate synthase, ultimately inhibiting DNA synthesis. Flucytosine Mechanism of Action DNA Goodman and Gillman: Antifungal:

19. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 28 5-FC is a narrow spectrum fungistatic Active against: Cryptococcus neoformans Torula Chromoblastomyces Few strains of Candida. Other fungi and bacteria are insensitive Antifungal Activity The mechanism for this resistance can be loss of the permease necessary for cytosine transport or decreased activity of either UPRTase or cytosine deaminase. In Candida albicans, substitution of thymidine for cytosine at nucleotide 301 in the gene encoding UPRTase ( FURl ) causes a cysteine to become an arginine, modestly increasing flucytosine resistance (Dodgson et al., 2004). Flucytosine resistance is further increased if both FURl alleles in the diploid fungus are mutated Fungal Resistance KD Tripathi Flucytosine is given orally, 50 to 150 mg/kg per day, in four divided doses at 6-h intervals. Dose Goodman and Gillman: Antifungal: Goodman and Gillman: Antifungal:

20. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 29 5-FC causes: Reversible neutropenia Thrombocytopenia Dose-related bone marrow depression. Reversible hepatic dysfunction with elevation of serum transaminases has been observed (5% of patients). Nausea, vomiting, and diarrhea are common Severe enterocolitis may occur. Adverse effects Toxicity may result from conversion of flucytosine to 5FU by the microbial flora in the intestinal tract of the host USES Flucytosine is not employed as the sole therapy. Rapid development of resistance limits its utility in deep mycosis. In cryptococcosis (both meningeal and nonmeningeal) its synergistic action with AMB is utilized to reduce the total dose of the more toxic latter drug. Therapy with 5-FC is generally limited to first 2 weeks of AMB regimen to avoid its bone marrow toxicity.

21. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 30 AZOLES Chemistry & Pharmacokinetics Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring, as indicated below The imidazoles consist of ketoconazole, Oxiconazole, miconazole, and clotrimazole The latter two drugs are now used only in topical therapy . The triazoles include itraconazole, fluconazole, voriconazole, isavuconazole , and posaconazole. Other triazoles are currently under investigation.

22. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 31 Triazole antifungals Mechanism of Action The major effect of imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase, a cytochrome P450 (CYP) and the product of the gene ERG11. Imidazoles and triazoles thus impair the biosynthesis of ergosterol, resulting in depletion of membrane ergosterol and accumulation of the toxic product 14α-methyl-3,6-diol, leading to growth arrest (Kanafani and Perfect, 2008), possibly by disrupting the close packing of acyl chains of phospholipids and impairing the functions of membrane-bound enzyme systems. Some azoles directly increase permeability of the fungal cytoplasmic membrane, but the concentrations required are likely only obtained with topical use.

23. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 32 Fluconazole It is a water-soluble triazole having a wider range of activity than KTZ. Spectra: Include: Cryptococcal meningitis Systemic and mucosal candidiasis in both normal and immunocompromised patients Coccidioidal meningitis And some tinea infections. Fluconazole displays no activity against Aspergillus or other filamentous fungi. Dosage forms and Dosage: Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–800 mg/d. Absorption: Fluconazole is 94% absorbed; oral bioavailability is not affected by food or gastric pH. Distribution: It is the preferred azole for fungal meningitis because of good penetration into brain and CSF. Dose reduction is needed in renal impairment. Excretion: It is primarily excreted unchanged in urine with a t½ of 25–30 hr. Fungicidal concentrations are achieved in nails, vagina and saliva . PK CP = 4-8 ug/ml

24. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 33 Adverse effects: The gastrointestinal tolerability of fluconazole is better than other azoles, but nausea, vomiting, abdominal pain, rash and headache are produced. Incidence and severity of these side effects increases with dose and duration of therapy. Selectivity for fungal cytochrome P450 is higher. unlike KTZ, it does not inhibit steroid synthesis in man: antiandrogenic and other endocrine side effects have not occurred. Elevation of hepatic transaminase has been noted in AIDS patients. Fluconazole is not recommended in pregnant and lactating women Reversible alopecia may occur with prolonged therapy at 400 mg daily. Fluconazole Interactions: While fluconazole affects hepatic drug metabolism to a lesser extent than KTZ, increased plasma levels of phenytoin, cyclosporine, warfarin, zidovudine and sulfonylureas have been observed. The drug interaction potential of fluconazole is the lowest among azole antifungals, but caution needs to be applied in coadministering other drugs. Proton pump inhibitors and H2 blockers do not affect its absorption.

25. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 34 Uses A single 150 mg oral dose can cure vaginal candidiasis with few relapses. oral fluconazole (100 mg/day for 2 weeks) is highly effective in oropharyngeal candidiasis, but is reserved for cases not responding to topical antifungals Fluconazole (100 mg/day) for 2–3 weeks is the first line treatment for candida esophagitis. Most tinea infections including pityriasis versicolor involving large area of skin and cutaneous candidiasis can be treated with 150 mg weekly fluconazole for 4 weeks For disseminated candidiasis, cryptococcal or coccidioidal meningitis and other systemic fungal infections the dose is 200–400 mg/ day for 4–12 weeks or longer In candidemia, therapy may be initiated with i.v. fluconazole and continued orally.

26. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 35 Uses Long-term oral fluconazole maintenance therapy after initial treatment with i.v. AMB is used in AIDS patients with fungal meningitis to prevent relapse An eye drop is useful in fungal keratitis Fluconazole is ineffective in aspergillosis and mucormycosis, and inferior to itraconazole for histoplasmosis, blastomycosis and sporotrichosis, as well as for tinea unguium . Fluconazole is used for prophylaxis against invasive fungal infections in recipients of bone marrow transplants. Resistance is a concern, however, with other species, including C. krusei and C. glabrata

27. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 36 Itraconazole Spectra: This orally active triazole antifungal has a broader spectrum of activity than KTZ or fluconazole; includes few moulds like Aspergillus as well. Some fluconazole resistant Candida are susceptible. It is fungistatic, but effective in immunocompromised patients. Steroid hormone synthesis inhibition is absent in itraconazole, and serious hepatotoxicity is rare. Dosage forms and Dosage: Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–400 mg/d. Newer formulations, including an oral liquid and an intravenous preparation, have utilized cyclodextrin as a carrier molecule to enhance solubility and bioavailability. Absorption: Drug absorption from capsules is increased by food and by low gastric pH. PPB . Itraconazole is highly protein bound, Distribution: has a large volume of distribution (10 L/Kg), accumulates in vaginal mucosa, skin and nails, but penetration into CSF is poor. PK

28. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 37 Itraconazole PK

29. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 38 Adverse effects: Dizziness Pruritus Headache Hypokalaemia are the other common side effects. Unsteadiness and impotence are infrequent. Plasma transaminase may rise and liver damage is reported. However, antiandrogenic and other hormonal adverse effects are not seen. Impaired left ventricular function has been worsened in some patients after prolonged treatment with itraconazole. Itraconazole DDI Drug interactions Oral absorption of itraconazole is reduced by antacids, H2 blockers and proton pump inhibitors. Rifampin, phenobarbitone, phenytoin and carbamazepine induce itraconazole metabolism and reduce its efficacy. On the other hand, clarithromycin and HIV protease inhibitors reduce the metabolism of itraconazole and raise its blood levels. Itraconazole inhibits CYP3A4, but the effect on metabolism of other drugs is less marked than that of KTZ. Nevertheless, phenytoin, digoxin, sulfonylureas, statins, dihydropyridines, protease inhibitors, warfarin and cyclosporine levels are increased by itraconazole.

30. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 39 Uses: Itraconazole is the preferred azole antifungal for most systemic mycosis that are not associated with meningitis. It is superior to fluconazole for histoplasmosis, blastomycosis, sporotrichosis and is the drug of choice for the rare fungal infections— paracoccidioidomycosis and chromomycosis . It also affords some relief in chronic aspergillosis, but voriconazole is superior. A dose of 200 mg OD/ BD with meals is used for 3 months or more. Vaginal candidiasis : 200 mg OD oral for 3 days is as effective as intravaginal clotrimazole. Dermatophytosis: 100–200 mg OD for 7–15 days. Itraconazole is more effective than griseofulvin, but systemic therapy is resorted to only when topical antifungals fail or in patients with extensive involvement or scalp infection. Onychomycosis: 200 mg/day for 3 months. An intermittent pulse regimen of 200 mg BD for 1 week each month for 3 months is equally effective. Relapses have occurred after itraconazole therapy, though it remains in the nail for few months after completion of the course. Pityriasis versicolor: Oral itraconazole is the drug of choice when systemic therapy is needed for involvement of extensive area of skin Itraconazole

31. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 40 Voriconazole Voriconazole is a second generation triazole with a structure similar to fluconazole but with increased activity in vitro, an expanded spectrum, and poor aqueous solubility. ADME: Dosage Form: Voriconazole is available as 50- or 200-mg tablets or a suspension of 40 mg/mL when hydrated. The tablets, but not the suspension, contain lactose. BA Because high-fat meals reduce voriconazole bioavailability , oral drug should be given either 1 h before or 1 h after meals. Oral bioavailability is 90-96% VD volume of distribution is high (4.6 L/kg), with extensive drug distribution in tissues. Metabolism: Metabolism occurs through CYPs 2C19 and 2C9; CYP3A4 plays a limited role. Voriconazole exhibits nonlinear metabolism so that higher doses may cause greater-than-linear increases in systemic drug exposure.

32. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 41 Half life Plasma elimination t 1/2 is 6 h. Genetic polymorphisms in CYP2C19 can cause up to 4-fold differences in drug exposure Exretion : Less than 2% of parent drug is recovered from urine; 80% of the inactive metabolites are excreted in the urine. The oral dose does not have to be adjusted for azotemia or hemodialysis. Patients with mild-to-moderate cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose The intravenous formulation of voriconazole contains sulfobutyl ether β-cyclodextrin (SBECD), which is excreted by the kidney. Significant accumulation of SBECD occurs with a creatinine clearance less than 50 mL/min; in that setting, oral voriconazole is preferred. Therapeutic drug monitoring is frequently used, with target serum concentrations between 1 and 5 mg/L thought to maximize efficacy and minimize adverse events. Voriconazole

33. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 42 Voriconazole is the drug of choice for invasive aspergillosis , disseminated infections caused by fluconazole resistant Candida, ( Candida Krusi ) Fusarium infections, and febrile neutropenia not responding to antibacterial therapy. some environmental molds ( Iatrogenic Fungal Meningitis ). It is also active against histoplasmosis and blastomycosis . Serious cases are first treated i.v. followed by oral voriconazole Spectra Therapeutic trough levels should be between 1 and 5 mcg/ mL. Rashes, photosensitivity, rise in liver enzymes and QTc prolongation can occur. Short lasting visual disturbances are common after i.v. injection, and an acute reaction is also possible. ADRS Dose: 200 mg oral BD taken 1 hour before or 1hour after meal. Begin i.v. infusion with 6 mg/kg 12 hourly infused over 2 hours twice followed by 3–4 mg/kg 12 hourly.

34. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 43 POSACONAZOLE Route and Dosage form Posaconazole was originally available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or four doses. An intravenous form of posaconazole and a sustained acting tablet form with higher bioavailability are now available. Absorption Absorption is improved when taken with meals high in fat. Distribution Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. ADME: Measurement of posaconazole levels is recommended in patients with serious invasive fungal infections (especially mold infections); steady-state posaconazole levels should be between 0.5 and 1.5 mcg/mL This recently introduced broad-spectrum triazole has potent antifungal activity and is the only azole which has shown efficacy in mucormycosis. Metabolism It is partly metabolized by CYP2C19 and glucuronidation Excretion Excreted mostly unchanged in faeces . Half life The t½ is > 24 hours.

35. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 44 Therapeutic Uses Posaconazole is approved for treatment of oropharyngeal candidiasis , although fluconazole is the preferred drug because of safety and cost . Posaconazole is also approved for prophylaxis against candidiasis and aspergillosis in patients more than 13 years of age who have prolonged neutropenia or severe graft-versus-host disease (Ullmann et al., 2007). It is approved in the E.U. as salvage therapy for aspergillosis and several other infections , as are itraconazole and voriconazole. A recent comparison trial of posaconazole and voriconazole supports the use of posaconazole as a first-line treatment for invasive Aspergillus ( Maertens et al., 2021). Posaconazole has increased activity against the molds that cause mucormycosis and is frequently used as an alternative to amphotericin B for intolerant patients ( Cornely et al., 2019) posaconazole is used in the treatment of invasive fungal infections caused by Scedosporium and Zygomycetes.

36. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 45 Dosage For prophylaxis of invasive Aspergillus and Candida infections, the adult intravenous dose is 300 mg twice on day 1 and 300 mg daily thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. The same dose is used for the delayed-release tablets. The dose for the oral suspension is 200 mg (5 mL) three times Adverse Effects Common adverse effects include nausea, vomiting, diarrhea, abdominal pain, and headache (Smith et al., 2009). Although adverse effects occur in at least a third of patients, the rate of discontinuation due to adverse effects in long-term studies has been only 8%. Drug Interactions: Posaconazole inhibits CYP3A4. Coadministration with rifabutin or phenytoin increases the plasma concentration of these drugs and decreases posaconazole exposure by 2-fold. Posaconazole increases the AUC of cyclosporine, tacrolimus (121%), sirolimus (790%), midazolam (83%), and other CYP3A4 substrates (Frampton and Scott, 2008; Krishna et al., 2009; Moton et al., 2009). Posaconazole can prolong the QTc interval and should not be coadministered with drugs that are CYP3A4 substrates that likewise prolong the QTc interval, such as methadone, haloperidol, pimozide, quinidine, risperidone, sunitinib, tacrolimus, and halofantrine.

37. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 46 Ketoconazole (KTZ) Ketoconazole was the first oral azole (imidazole antifungal) introduced into clinical use. It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes; that is, it is less selective for fungal P450 than are the newer azoles. As a result, systemic ketoconazole has fallen out of clinical use, topical forms are still in use. Useful in both dermatophytosis and deep mycosis. The oral absorption of KTZ is facilitated by gastric acidity. Hepatic metabolism is extensive Metabolites are excreted in urine and faeces with a variable t½ of 4–8 hours. The oral dose is 200 mg OD, but systemic use of KTZ is infrequent now. ADME: Adverse effects: nausea and vomiting loss of appetite, headache, paresthesia, rashes and hair loss. Gynaecomastia , loss of hair and libido, and oligozoospermia . Menstrual. A dose-dependent decrease in serum hydrocortisone due to synthesis inhibition has also been noted

38. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 47 Ketoconazole (KTZ) Interactions Ketoconazole (and most azoles) interact with several drugs. Due consideration must be given when azoles are co-prescribed with other drugs H2 blockers, proton pump inhibitors and antacids decrease oral absorption of KTZ by reducing gastric acidity. Rifampin, phenobarbitone, carbamazepine and phenytoin induce KTZ metabolism and reduce its efficacy. Ketoconazole inhibits CYP450 enzymes, especially CYP3A4, CYP2C9; CYP2C19 and raises the blood levels of several drugs including: Phenytoin Digoxin Carbamazepine Omeprazole Diazepam Cyclosporine Haloperidol Nifedipine and other DHPs Warfarin HIV protease inhibitors Sulfonylureas Statins

39. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 48 Uses Pityriasis versicolor involving limited area of skin can also be treated by topical application of the lotion/shampoo formulation. Though effective in monilial vaginitis, oral therapy (for 5–7 days) with KTZ is reserved for recurrent cases or those not responding to topical agents Used as a lotion or shampoo, KTZ is quite effective in seborrhoea of scalp and dandruff. Orally administered KTZ is effective in dermatophytosis because it is concentrated in the stratum corneum High-dose KTZ has been used in Cushing’s syndrome to decrease corticosteroid production. Oral KTZ is no longer used in systemic mycosis. KTZ

40. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 49 Isavuconazole is a triazole that is administered as the isavuconazonium prodrug. Isavuconazole ADME: Form Isavuconazole is available in both oral and cyclodextrin-free intravenous formulations. Administeration : Administration of oral isavuconazonium with food reduces AUC by about 20%. BA: It is highly bioavailable (98%) PPB: 99% protein bound in serum. Metabolism The parent form, isavuconazonium sulfate, is rapidly hydrolyzed to the active form, isavuconazole , which has a long plasma half-life (~130 h). Overall bioavailability of the active form is 98%. Therapeutic Uses: Isavuconazole exhibits a broad spectrum of activity against most yeast species, including Candida spp., Cryptococcus gattii and C. neoformans, and molds such as Aspergillus spp. and most Mucorales species complex. The drug is approved for the treatment of invasive aspergillosis and invasive mucormycosis

41. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 50 Isavuconazole Dosage: Isavuconazole is dosed as 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole ) every 8 h for six doses followed by 372 mg isavuconazonium sulfate by mouth or intravenously once daily starting 12 to 24 h after the last loading dose. Adverse Effects: Isavuconazole is generally well tolerated. GI disorders, pyrexia, hypokalemia, headache, constipation, and cough are the most frequently reported adverse effects Drug Interactions: Isavuconazole is both a substrate and an inhibitor of CYP3A4. Consequently, a 5-fold increase in isavuconazole AUC results when it is administered with strong CYP inhibitors such as ketoconazole. Substantial reductions in isavuconazole AUC also result from coadministration of isavuconazole with rifampin. Midazolam and sirolimus AUCs are increased by coadministration with isavuconazole . Isavuconazole causes a dose-related shortening of QTc and is contraindicated in patients with familial short QT syndrome.

42. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 51 Echinocandins Echinocandins are cyclic lipopeptides with a nucleus. Three echinocandins are approved for clinical use: caspofungin , anidulafungin, and micafungin. All act through the same mechanism but differ in pharmacological properties. Fungi that are susceptible to echinocandins include Candida and Aspergillus spp. (Bennett, 2006). General Pharmacological Characteristics Mechanism of Action: The echinocandins inhibit 1,3-β-D-glucan synthesis, which is an essential component of the fungal cell wall and is required for in cellular integrity

43. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 52 Antifungal Activity: Echinocandins exhibit fungicidal activity against Candida spp. In contrast, they are fungistatic against Aspergillus spp . and cause morphological changes to the filaments. Echinocandins do not appear to have clinically useful activity against dimorphic fungi such as H. capsulatum and do not have clinically useful activity against C. neoformans, Trichosporon spp., Fusarium spp., or agents of mucormycosis. Echinocandins Resistance: Echinocandin resistance has emerged as a clinical problem and results from mutations leading to amino acid substitutions in the Fks subunits of glucan synthase (Perlin, 2015). Multidrug transporters do not appear to play a role in echinocandin resistance. Mutations conferring resistance occur in two conserved “hot spot” regions of FKS1 in C. albicans and C. auris, and in FKS1 and FKS2 in C. glabrata. Candida parapsilosis complex and Candida guilliermondii display reduced in vitro echinocandin susceptibility as compared to other Candida spp. owing to inherently occurring polymorphisms in Fks hot spot regions. S pecies -specific clinical breakpoints for echinocandins have been recently described.

44. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 53 Echinocandins differ somewhat pharmacokinetically but all share extensive protein binding (>97%), inability to penetrate into CSF, lack of renal clearance, and only a slight-to-modest effect of hepatic insufficiency on plasma drug concentrations (Kim et al., 2007; Wagner et al., 2006). Currently available echinocandins also lack oral bioavailability and are available only for intravenous administration. Generally speaking, adverse effects are minimal and rarely lead to drug discontinuation (Kim et al., 2007). All three agents are well tolerated, with the exception of phlebitis at the infusion site. Histamine-like effects have been reported with rapid infusions. All three echinocandins are contraindicated in pregnancy Echinocandins General Pharmacological Characteristics

45. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 54 Caspofungin . Caspofungin acetate is a water-soluble, semisynthetic lipopeptide synthesized from the fermentation product of Glarea lozoyensis (Johnson and Perfect, 2003; Keating and Figgitt , 2003)

46. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 55 Absorption Caspofungin is not absorbed orally; has to be infused i.v. as freshly prepared aqueous solution. Distribution It is distributed into tissues, but does not enter CSF. Metabolism Metabolism is extensive and metabolites are excreted in urine as well as faces. Plasma t½ Plasma t½ of 10 hours. ADME: Caspofungin . Therapeutic Use: Caspofungin is approved for the treatment of invasive candidiasis. It is a first-line agent, along with other echinocandins, for the initial treatment of candidemia (Pappas et al., 2016). It is also approved as salvage therapy for patients with invasive aspergillosis who fail or are intolerant of approved drugs, such as amphotericin B formulations or voriconazole. Caspofungin is also approved for both esophageal and invasive candidiasis (Mora-Duarte et al., 2002; Villanueva et al., 2001) and for treatment of persistently febrile neutropenic patients with suspected fungal infections (Walsh et al., 2004).

47. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 56 Dosage Caspofungin is administered intravenously once daily over 1 h . For candidemia and salvage therapy of aspergillosis, the initial dose is 70 mg, followed by 50 mg daily. The dose should be increased to 70 mg daily in patients receiving rifampin as well as in those failing to respond to 50 mg. Esophageal candidiasis is treated with 50 mg daily. In moderate hepatic failure, the dose should be reduced to 35 mg daily . Caspofungin . Drug Interactions Caspofungin increases tacrolimus levels by 16%, which should be managed by standard monitoring. Cyclosporine slightly increases caspofungin levels . Rifampin and other drugs activating CYP3A4 can cause a slight reduction in caspofungin levels.

48. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 57 Micafungin Micafungin is a water-soluble semisynthetic echinocandin derived from the fungus Coleophoma empedri . ADME (Drug Interactions) Absorption Micafungin has linear pharmacokinetics over a large range of doses (1–3 mg/kg) and ages (premature infants to elderly). Metabolism Small amounts of drug are metabolized in the liver by arylsulfatase and catechol O-methyltransferase. Hydroxylation by CYP3A4 is barely detectable. Unlike caspofungin , reduction of the micafungin dose in moderate hepatic failure is not required. Clearance Micafungin shows age-dependent clearance in children, with rapid clearance in premature infants and intermediate clearance in children 2 to 8 years of age, compared to older children and adults (Downes et al., 2020). DDI In normal volunteers, micafungin appears to be a mild inhibitor of CYP3A4, increasing the AUC of nifedipine by 18% and sirolimus by 21%. Micafungin has no effect on tacrolimus clearance

49. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 58 Therapeutic Uses: Micafungin is approved for the treatment of invasive candidiasis (Fritz et al., 2008) and esophageal candidiasis and for prophylaxis in hematopoietic stem cell transplant recipients. Dosage: Micafungin is administered intravenously as a 100-mg daily dose over 1 h for adults, with 50 mg recommended for prophylaxis and 150 mg for esophageal candidiasis. No loading dose is required Micafungin

50. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 59 Anidulafungin Anidulafungin is a water-insoluble semisynthetic compound extracted from the fungus A. nidulans , from which the drug’s name derives. ADME; Drug Interactions: Anidulafungin is cleared from the body by slow chemical degradation (Vazquez and Sobel, 2006). No hepatic metabolism or renal excretion of active drug occurs; thus, no dose adjustment for hepatic or renal failure is needed. No clinically relevant drug-drug interactions have been observed with drugs likely to be coadministered with anidulafungin Therapeutic Use and Dosing Anidulafungin is approved for the treatment of candidemia and other forms of Candida infections ( Reboli et al., 2007), including intra-abdominal abscess, peritonitis, and esophageal candidiasis. For invasive candidiasis, anidulafungin is given daily as a loading dose of 200 mg followed by 100 mg daily. For esophageal candidiasis, a loading dose of 100 mg is followed by 50 mg daily. Anidulafungin is not approved for use in children; the other two currently available echinocandins are approved and frequently used in premature infants.

51. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 60 Drugs for Cutaneous Mycotic Infections Griseofulvin Terbinafine

52. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 61 Mold-like fungi that cause cutaneous infections are called dermatophytes or tinea. Tinea infections are classified by the affected site (for example, tinea pedis, which refers to an infection of the feet). Common dermatomycoses, such as tinea infections that appear as rings or round red patches with clear centers, are often referred to as “ringworm.” This is a misnomer because fungi rather than worms cause the disease. The three different fungi that cause the majority of cutaneous infections are Trichophyton, Microsporum , and Epidermophyton. Oral Systemic Antifungal Drugs For Mucocutaneous Infections

53. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 62 HETEROCYCLIC BENZOFURAN Griseofulvin It was one of the early antibiotics extracted from Penicillium griseofulvum . However, because of lack of antibacterial activity, little attention was paid to it: clinical utility in dermatophytosis was demonstrated only around 1960. Griseofulvin is an orally administered, fungistatic antifungal agent. It is practically insoluble in water Griseofulvin interferes with mitosis—multinucleated and stunted fungal hyphae are produced under its action. Metaphase arrest does not occur, but daughter nuclei fail to move apart or move only a short distance. It binds to polymerized microtubules and interferes with their function. MOA Griseofulvin is fungistatic in vitro for various species of the dermatophytes Microsporum , Epidermophyton, and Trichophyton. The drug has no effect on other fungi or on bacteria. Although failure of ringworm lesions to improve is not rare, isolates from these patients usually are still susceptible to griseofulvin in vitro. Antifungal Activity

54. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 63 ADME Blood levels after oral administration of griseofulvin are quite variable. Some studies have shown improved absorption when the drug is taken with a fatty meal. Because the rates of dissolution and disaggregation limit the bioavailability of griseofulvin, microsize and ultramicrosize powders are now used. Griseofulvin has a plasma t 1/2 of about 1 day ; about 50% of the oral dose can be detected in the urine within 5 days, mostly in the form of metabolites . The primary metabolite is methylgriseofulvin . Barbiturates decrease griseofulvin absorption from the GI tract. Griseofulvin is deposited in keratin precursor cells; when these cells differentiate, the drug is tightly bound to, and persists in, keratin, providing prolonged resistance to fungal invasion. For this reason, the new growth of hair or nails is the first to become free of disease. As the fungus ontaining keratin is shed, it is replaced by normal tissue. Griseofulvin is detectable in the stratum corneum of the skin within 4 to 8 h of oral administration. Sweat and transepidermal fluid loss play an important role in the transfer of the drug in the stratum corneum. Only a very small fraction of a dose of the drug is present in body fluids and tissues.

55. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 64 Uses Pityriasis versicolor involving limited area of skin can also be treated by topical application of the lotion/shampoo formulation. Treatment must be continued until infected tissue is replaced by normal hair, skin, or nails, which requires 1 month for scalp and hair ringworm, 6 to 9 months for fingernails, and at least a year for toenails. Itraconazole or terbinafine is much more effective for onychomycosis Mycotic disease of the skin, hair, and nails due to Microsporum , Trichophyton, or Epidermophyton responds to griseofulvin therapy. Griseofulvin is also effective for ringworm of the glabrous skin; tinea cruris and tinea corporis caused by M. canis , Trichophyton rubrum, T. verrucosum , and Epidermophyton floccosum ; and tinea of the hands (T. rubrum and Trichophyton mentagrophytes) and beard (Trichophyton spp.) For tinea capitis in children, griseofulvin remains the drug of choice for efficacy, safety, and availability as an oral suspens

56. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 65 Uses Griseofulvin also is highly effective in the treatment of tinea pedis, the vesicular form of which is most commonly due to T. mentagrophytes and the hyperkeratotic type to T. rubrum. Topical therapy is sufficient for most cases of tinea pedis. T. rubrum and T. mentagrophytes infections may require higher-than-conventional doses of griseofulvin.

57. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 66 Adverse Effects: The incidence of serious reactions due to griseofulvin is very low: headache (15% of patients), GI and nervous system manifestations, and augmentation of the effects of alcohol. Hepatotoxicity has been observed. Hematological effects include leukopenia, neutropenia, punctate basophilia, and monocytosis; these often disappear despite continued therapy. Blood studies should be carried out at least once a week during the first month of treatment or longer. Common renal effects include albuminuria and cylindruria without evidence of renal insufficiency. Reactions involving the skin are cold and warm urticaria, photosensitivity, lichen planus, erythema, erythema multiforme–like rashes, and vesicular and morbilliform eruption s. Serum sickness syndromes and severe angioedema develop rarely. Estrogen-like effects have been observed in children. A moderate but inconsistent increase of fecal protoporphyrins has been noted with chronic use.

58. 3/28/2024 巴西尔 · 乌迈尔 · 哈塔克 67 Squalene epoxidase inhibitors Terbinafine is a synthetic allylamine, structurally similar to the topical agent naftifine (see discussion that follows). It inhibits fungal squalene epoxidase and thereby reduces ergosterol biosynthesis. Terbinafine ADME Dosage form : Oral tab and topical cream Absorption: Terbinafine is well absorbed BA: bioavailability is about 40% due to first-pass metabolism in the liver. Distribution: The drug accumulates in skin, nails, and fat. Half life: The initial t 1/2 is about 12 h but extends to 200 to 400 h at steady state. Metabolism: Oral terbinafine is extensively metabolized by several CYP450 isoenzymes Excretion: Excreted mainly via the urine Contraindication: Terbinafine is not recommended in patients with marked azotemia or hepatic failure. DDI: Rifampin decreases and cimetidine increases plasma terbinafine concentrations. Terbinafine is an inhibitor of the CYP450 2D6 isoenzyme, and concomitant use with substrates of CYP450 2D6 may result in an increased risk of adverse effects with those agents

59. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 68 MOA It acts as a noncompetitive inhibitor of “squalene epoxidase”. These agents act by inhibiting squalene epoxidase, thereby blocking the biosynthesis of ergosterol, an essential component of the fungal cell membrane . Accumulation of toxic amounts of squalene results in increased membrane permeability and death of the fungal cell. Accumulation of squalene within the fungal cells appears to be responsible for the fungicidal action. The mammalian enzyme is inhibited only by 1000-fold higher concentration of terbinafine

60. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 69 Uses Duration of treatment varies with the site of infection but typically ranges between 6 and 12 weeks. Terbinafine, given as one 250-mg tablet daily for adults, is somewhat more effective than itraconazole for nail onychomycosis. The efficacy for the treatment of onychomycosis can be improved by the simultaneous use of amorolfine 5% nail lacquer (amorolfine is not approved for use in the U.S.) Terbinafine is also effective for the treatment of tinea capitis and has been used for the off-label treatment of ringworm elsewhere on the body.

61. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 70 Adverse Effects Systemic terbinafine therapy for onychomycosis should be postponed until after pregnancy is completed. Very rarely, fatal hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, or toxic epidermal necrolysis may occur. The drug is well tolerated, with a low incidence of GI distress, headache, or rash.

62. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 71 Agents Active Against Microsporidia and Pneumocystis Albendazole Fumagillin Pentamidine

63. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 72 Microsporidia are spore-forming unicellular eukaryotic organisms that were once thought to be parasites but are now classified as fungi (Field and Milner, 2015). They can cause several disease syndromes, including diarrhea in immunocompromised individuals. Microsporidia and Pneumocystis

64. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 73 Albendazole: Intestinal infections with most microsporidia are treated with albendazole, an inhibitor of α-tubulin polymerization Fumagillin Sources: Fumagillin is an acyclic polyene macrolide produced by the fungus A. fumigatus. Fumagillin and its synthetic analogue TNP-470 are toxic to microsporidia. Oral route Immunocompromised individuals with intestinal microsporidiosis due to Enterocytozoon bieneusi (which does not respond as well to albendazole) can be treated successfully with fumagillin (Didier et al., 2005; Rex and Stevens, 2014; Szumowski and Troemel , 2015). For the treatment of intestinal microsporidiosis caused by E. bieneusi , fumagillin is used at a dose of 20 mg orally three times daily for 2 weeks (Medical-Letter, 2013; Molina et al., 2002; Rex and Stevens, 2014). Topical Fumagillin is used topically to treat keratoconjunctivitis caused by Encephalitozoon hellem at a dose of 3 to 10 mg/mL in a balanced salt suspension. Adverse effects: may include abdominal cramps, nausea, vomiting, and diarrhea. Reversible thrombocytopenia and neutropenia also have been reported ( Anane and Attouchi , 2010). Fumagillin is not approved for use in humans in the U.S.

65. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 74 Pentamidine Pneumocystis jirovecii is another fungus that, until recently, was classified as a protozoan parasite. It is the causative agent of PJP (Pneumocystis jirovecii pneumonia), formerly known as PCP (Pneumocystis carinii pneumonia). Pentamidine is one of several drugs or drug combinations used to treat or prevent PJP, which is a major cause of mortality in immunocompromised individuals, including patients with AIDS. Note, however, that trimethoprim-sulfamethoxazole is the drug of choice for the treatment and prevention of PJP Therapy for PJP: Pentamidine as therapy for PJP is reserved for two indications As a 4 mg/kg single daily intravenous dose for 21 days to treat severe PJP in individuals who cannot tolerate trimethoprim-sulfamethoxazole and are not candidates for alternative agent As a “salvage” agent for individuals with PJP who fail to respond to trimethoprim-sulfamethoxazole (pentamidine may be less effective than the combination of clindamycin and primaquine or atovaquone for this indication) (Gilroy and Bennett, 2011; Rex and Stevens, 2014)

66. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 75 Prophylaxis: Pentamidine administered as an aerosol preparation is used to prevent PJP in at-risk individuals who cannot tolerate trimethoprim-sulfamethoxazole, such as patients with severe bone marrow suppression. For prophylaxis, pentamidine isethionate is given monthly as a 300-mg dose in a 5% to 10% nebulized solution over 30 to 45 min (Gilroy and Bennett, 2011). Aerosolized pentamidine has several disadvantages including: its failure to treat any extrapulmonary sites of Pneumocystis the lack of efficacy against any other potential opportunistic pathogens and a risk for pneumothorax (Rex and Stevens, 2014). Recently, an intravenous dose of pentamidine every 28 days has been successfully used as PJP prophylaxis ( Diri et al., 2016). Pentamidine

67. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 76 Adverse Effects: Reported adverse effects of inhaled pentamidine include bronchospasm (15%). For parenteral pentamidine, adverse effects (more likely with rapid injection) can include injection site irritation and pain, cardiac arrhythmias, severe hypotension, hypoglycemia, and acute pancreatitis. The FDA warns that administration of pentamidine should be limited to patients in whom Pneumocystis is identified and should proceed with careful monitoring for the development of adverse effe Pentamidine

68. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 78 Modes of Administration The preparations for cutaneous use are effective for tinea corporis, tinea pedis, tinea cruris, tinea versicolor, and cutaneous candidiasis. They should be applied twice a day for 3 to 6 weeks. Cutaneous formulations are not suitable for oral, vaginal, or ocular use. Cutaneous Application : Use of the oral troche of clotrimazole is properly considered as topical therapy. The only indication for this 10-mg troche is oropharyngeal candidiasis. Antifungal activity is due entirely to the local concentration of the drug; there is no systemic effect, Oral Use

69. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 79 Vaginal Application. Vaginal creams, suppositories, and tablets for vaginal candidiasis are all used once a day for 1 to 7 days, preferably at bedtime to facilitate retention. None is useful in trichomoniasis. Most vaginal creams are administered in 5-g amounts. Three vaginal formulations—clotrimazole tablets (no longer marketed in the U.S.), miconazole suppositories, and terconazole cream—come in both low- and high-dose preparations. A shorter duration of therapy is recommended for the higher dose of each. These preparations are administered for 3 to 7 days. Approximately 3% to 10% of the vaginal dose is absorbed. Although some imidazoles are teratogenic in rodents, no adverse effects on the human fetus have been attributed to the vaginal use of imidazoles or triazoles. The most common side effect is vaginal burning or itching. A male sexual partner may experience mild penile irritation .

70. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 80 Imidazole Clotrimazole : It is the most commonly used topical imidazole effective in the treatment of tinea infections like ringworm: 60–100% cure rates are reported with 2–4 weeks application on a twice daily schedule . Form: Cream, lotion, gel, oral troche, Powder, Tabs Absorption: Absorption of clotrimazole is less than 0.5% after application to the intact skin; Absorption from the vagina, it is 3% to 10%. Fungicidal concentrations remain in the vagina for as long as 3 days after application of the drug . Dose: In adults, an oral dose of 200 mg/day will give rise initially to plasma concentrations of 0.2 to 0.35 μg /mL, followed by a progressive decline. ADRS In a small fraction of patients, clotrimazole on the skin may cause skin irritation, stinging sensations, erythema, edema, vesication, desquamation, pruritus, or urticaria. When applied to the vagina, about 1.6% of patients experience a mild burning sensation. In rare instances, lower abdominal cramps, a slight increase in urinary frequency, or skin rash may occur. Occasionally, a patient’s sexual partner may experience penile or urethral irritation. Oral clotrimazole troches cause GI irritation in about 5% of patients

71. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 81 Clotrimazole Therapeutic Uses: Clotrimazole is available as a 1% cream, lotion, powder (no longer marketed in the U.S.), aerosol solution, and solution; 1% or 2% vaginal cream; vaginal tablets (no longer marketed in the U.S.) of 100, 200, or 500 mg; and 10-mg troches. On the skin, applications are made twice a day. For the vagina, the standard regimens are one 100-mg tablet once a day at bedtime for 7 days, one 200-mg tablet daily for 3 days, one 500-mg tablet inserted only once, or 5 g of cream once a day for 3 days (2% cream) or 7 days (1% cream). For oropharyngeal candidiasis, troches are to be dissolved slowly in the mouth five times a day for 14 days . Topical clotrimazole cures dermatophyte infections in 60% to 100% of cases. The cure rates in cutaneous candidiasis are 80% to 100%. In vulvovaginal candidiasis, the cure rate is usually greater than 80% when the 7-day regimen is used. A 3-day regimen of 200 mg once a day appears to be similarly effective, as does single-dose treatment (500 mg). Recurrences are common after all regimens. The cure rate with oral troches for oral and pharyngeal candidiasis may be as high as 100% in the immunocompetent host.

72. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 82 Econazole Econazole is the deschloro -derivative of miconazole. Econazole readily penetrates the stratum corneum and achieves effective concentrations at the level of the mid dermis. Approximately 3% of recipients experience local erythema, burning, stinging, or itching. Econazole nitrate is available as a water-miscible cream (1%) to be applied twice a day Miconazole Miconazole readily penetrates the stratum corneum of the skin and persists for more than 4 days after application. Adverse effects from topical application to the vagina include burning, itching, or irritation in about 7% of recipients, as well as infrequent pelvic cramps (0.2%), headache, hives, or skin rash. Irritation, burning, and maceration are rare after cutaneous application. Miconazole is considered safe for use during pregnancy, although some experts advocate avoiding vaginal use during the first trimester

73. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 83 Luliconazole Luliconazole is available as a 1% cream and is effective for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by susceptible organisms. It should be applied to the affected area once daily for 2 weeks Butoconazole: it is an imidazole that is pharmacologically comparable to clotrimazole. Butoconazole nitrate is available as a 2% vaginal cream; it is used at bedtime in nonpregnant females. Because of the slower response during pregnancy, a 6-day course is recommended (during the second and third trimesters). Tioconazole: Tioconazole is an imidazole marketed for treatment of Candida vulvovaginitis. A single 4.6-g dose of ointment (300 mg of drug) is given at bedtime Oxiconazole, Sulconazole , and Sertaconazole : The imidazole derivatives oxiconazole, sulconazole , and sertaconazole are used for the topical treatment of infections caused by the common pathogenic dermatophytes. Oxiconazole nitrate is available as a 1% cream and lotion; sulconazole nitrate is supplied as a 1% solution or cream. Sertaconazole is a 2% cream marketed for tinea pedis. Ketoconazole: The imidazole ketoconazole is available as a 0.5% cream, foam, gel, and shampoo

74. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 84 Efinaconazole : Efinaconazole is an azoleamine derivative with excellent in vitro activity against T. rubrum and T. mentagrophytes. It is available as a 10% topical solution for the treatment of onychomycosis Terconazole: Terconazole is a ketal triazole. The 80-mg vaginal suppository is inserted at bedtime for 3 days; the 0.4% vaginal cream is used for 7 days and the 0.8% cream for 3 days. Clinical efficacy and patient acceptance of both preparations are at least as good as for clotrimazole in patients with vaginal candidiasis. approved for the treatment of toenail onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes. Duration of treatment is 48 weeks. It has also shown activity against Candida albicans. Topical Triazole

75. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 85 Ciclopirox Olamine Spectrum It is fungicidal to C. albicans, E. floccosum , M. canis , T. mentagrophytes, and T. rubrum. It also inhibits the growth of Malassezia furfur . Ciclopirox olamine has broad-spectrum antifungal activity. MOA Ciclopirox appears to chelate trivalent metal cations and thereby inhibits metal-dependent enzymes required for degradation of peroxides within the fungal cell ( Subissi et al., 2010). Absorption After application to the skin, it penetrates the epidermis to reach the dermis, but even under occlusion, less than 1.5% is absorbed into the systemic circulation. Furthermore, because the t 1/2 is 1.7 h, no systemic accumulation occurs. The drug penetrates hair follicles and sebaceous glands. It can sometimes cause hypersensitivity. Dose and Uses It is available as a 0.77% cream, gel, suspension, and lotion for the treatment of cutaneous candidiasis and for tinea corporis, cruris, pedis, and versicolor. An 8% nail lacquer is available for onychomycosis. Cure rates in the dermatomycoses and candidal infections are 81% to 94%. No topical toxicity has been noted. Ciclopirox 0.77% gel and 1% shampoo are also used for the treatment of seborrheic dermatitis of the scalp. An 8% topical solution is an effective treatment of mild-to-moderate superficial white onychomycosis.

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77. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 87 Haloprogin Chemistry Haloprogin is a halogenated phenolic ether. Absorption Haloprogin is poorly absorbed through the skin Metabolism it is metabolized to trichlorophenol in the patient. Spectrum It is fungicidal to various species of Epidermophyton, Pityrosporum , Microsporum , Trichophyton, and Candida. ADRs During treatment with this drug, irritation, pruritus, burning sensations, vesiculation, increased maceration, and “sensitization” (or exacerbation of the lesion) occasionally occur, especially on the foot if occlusive footgear is worn. However, systemic toxicity from topical application appears to be low. Haloprogin cream or solution is applied twice a day for 2 to 4 weeks. Its principal use is against tinea pedis, for which the cure rate is about 80%; it is thus approximately equal in efficacy to tolnaftate. It also is used against tinea cruris, tinea corporis, tinea manuum , and tinea versicolor. Haloprogin is no longer available in the U.S.

78. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 88 Tolnaftate: Chemistry Tolnaftate is a thiocarbamate. Dosage form: Tolnaftate is available in a 1% concentration as a cream, gel, powder, aerosol powder, topical solution, or topical aerosol liquid. Spectrum It is effective in the treatment of most cutaneous mycoses caused by T. rubrum, T. mentagrophytes, Trichophyton tonsurans, E. floccosum , M. canis , M. audouinii , Microsporum gypseum , and M. furfur, but it is ineffective against Candida. Uses: In tinea pedis, the cure rate is about 80%, compared with about 95% for miconazole. The preparations are applied locally twice a day. Pruritus is usually relieved in 24 to 72 h. Involution of interdigital lesions caused by susceptible fungi is very often complete in 7 to 21 days. Toxic or allergic reactions to tolnaftate have not been reported. Thiocarbamate Antifungal Distorts the hyphae and stunts mycelial growth in susceptible fungi.

79. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 89 Naftifine : Chemistry Naftifine is a synthetic allylamine. Form: Naftifine hydrochloride is available as a 1% cream or gel. MOA Inhibits squalene-2,3-epoxidase, a key enzyme in the fungal biosynthesis of ergosterol. Spectrum The drug has broad-spectrum fungicidal activity in vitro. ADRS The drug is well tolerated, although local irritation in 3% of treated patients and allergic contact dermatitis have been reported. Uses Naftifine also may be efficacious for cutaneous candidiasis and tinea versicolor, although the drug is not approved for these uses. It is effective for the topical treatment of tinea cruris and tinea corporis; twice-daily application is recommended. Butenafine: Butenafine hydrochloride is a benzylamine derivative with a mechanism of action similar to that of terbinafine and naftifine . Its spectrum of antifungal activity and use also are similar to those of the allylamine Terbinafine: Like naftifine , terbinafine is an allylamine that targets ergosterol biosynthesis. Terbinafine 1% cream or spray, applied twice daily, is effective in tinea corporis, tinea cruris, and tinea pedis. Terbinafine is less active against Candida species and Malassezia furfur, but the cream also can be used in cutaneous candidiasis and tinea versicolor.

80. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 90 Chemistry Nystatin, a tetraene macrolide. Structurally similar to amphotericin B. Source: Produced by Streptomyces noursei . MOA Share the same mechanism like Amphotericin B . Nystatin Polyene Antibiotic/ Tetraene Macrolide Antifungal Dose, Dosage and Uses: The drug is not absorbed from the GI tract, skin, or vagina. Nystatin is useful only for candidiasis and is supplied in preparations intended for cutaneous, vaginal, or oral administration for this purpose. The vaginal preparations are no longer marketed in the U.S. Infections of the nails and hyperkeratinized or crusted skin lesions do not respond. Powders are preferred for moist lesions such as diaper rash and are applied two to three times daily. Creams or ointments are used twice daily. Combinations of nystatin with corticosteroids also are available. Dosage forms: Cream, ointment, Vaginal Tab, Oral Suspension Bitter taste Nausea It is ineffective in dermatophytosis . “Cutaneous and corneal candidiasis can be treated by nystatin ointment”.

81. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 91 Undecylenic Acid Chemistry Undecylenic acid is 10-undecenoic acid, an 11-carbon unsaturated compound. Spectrum It is primarily fungistatic, although fungicidal activity may be observed with long exposure to high concentrations of the agent. The drug is active against a variety of fungi, including those that cause ringworm. Dosage Form/ Combination Product Undecylenic acid is available in a cream, powder, spray powder, soap, and liquid. Zinc undecylenate is marketed in combination with other ingredients. The zinc provides an astringent action that aids in the suppression of inflammation. Compounded undecylenic acid ointment contains both undecylenic acid (~5%) and zinc undecylenate (~20%). Calcium undecylenate is available as a powder. Undecylenic acid preparations also are approved for use in the treatment of diaper rash, tinea cruris, tinea pedis and other minor dermatologic conditions. Uses

82. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 92 Benzoic and Salicylic Acids An ointment containing benzoic and salicylic acids in a ratio of 2:1 (usually 6% and 3%) is known as Whitfield ointment. It combines the fungistatic action of benzoate with the keratolytic action of salicylate and is used mainly in the treatment of tinea pedis. Because benzoic acid is only fungistatic, eradication of the infection occurs only after the infected stratum corneum is shed; thus, continuous medication is required for several weeks to months. The salicylic acid accelerates desquamation. The ointment also is sometimes used to treat tinea capitis. Mild irritation may occur at the site of application.

83. 3/29/2024 巴西尔 · 乌迈尔 · 哈塔克 93 Tavaborole: Tavaborole is an oxaborole antifungal indicated for the topical treatment of onchomycosis of the toenails. MOA The drug inhibits fungal leucyl-tRNA synthetase, thereby inhibiting protein synthesis and ultimately causing fungal cell death. Spectrum: Tavaborole is active against Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans. Uses A topical solution is approved for the treatment of toenail onychomycosis, requiring 48 weeks of treatment.

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