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Anti-TB & Antifungal Agents PDF

18 Pages·2004·0.3 MB·English
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Christine Kubin Antifungals and Anti-tuberculosis (TB) Agents FFuunnggii Yeasts Moulds Mucormycosis Aspergillussp. (rarely septate) Pneumocystis Candidasp. jirovecii Dimorphic (septate) Rhizopus Rhizomucor Histoplasmosis Mucor Cryptococcus Blastomycosis Absidia neoformans Coccidioidomycosis [Zygomycetes] Paracoccidioidomycosis Sporotrichosis Chromoblastomycosis Dermatophytes Trichophyton Microsporum Miscellaneous Epidermophyton Pseudoallerscheria boydii (Scedosporium apiospermum) Scedosporium prolificans Penicillium marneffei Fusariumsp. Phaeohyphomycosis (dark walled fungi) 1 Antifungals Voriconazole N N N OH CH3 F F N N F Caspofungin POLYENES (amphotericin B, nystatin) AMPHOTERICIN B A. Amphotericin B is produced by Streptomyces nodosus (aerobic actinomycete). B. Mechanism of action a. The mechanism of action focuses on the fungal cytoplasmic membrane and binding to sterols, specifically ergosterol. Amphotericin B increases cell membrane permeability via pore and channel formation resulting in fungal cell death from loss of intracellular molecules. C. Resistance a. Resistance to amphotericin is rare. Resistant strains appear to show slower growth rates and less virulence in vitro. Two mechanisms are possible. i. Resistant mutants replace ergosterol with other precursor sterols. ii. Failure of amphotericin to penetrate the fungal cell wall. 2 D. Spectrum a. Amphotericin is the most broad spectrum antifungal and is considered the “gold standard” for the treatment of a variety of fungal infections. Amphotericin has useful clinical activity against Candida sp. (although C. lusitaniae is relatively resistant to amphotericin B), Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenkii, coccidiodomycosis, paracoccidiodes, Aspergillus sp., Penicillium, mucormycosis. [G&G p. 1298] E. Pharmacokinetics a. Amphotericin is available only as an injection for intravenous (IV) use. An oral suspension may be compounded for treatment of oropharyngeal and esophageal candidal infections. When given orally it has negligible gastrointestinal absorption and is not reliable for the treatment of systemic infections. b. After IV administration, most of the drug leaves the circulation quickly and is stored in the liver and other organs and reenters the circulation slowly. It is extensively bound to tissues. As a result, the half-life of amphotericin is prolonged (~15 days) and it can be detected in the body up to 7 weeks after discontinuing therapy. About 2-5% of each dose is excreted unchanged in the urine. Most of the drug is degraded in the body. Accordingly, no dose adjustment is necessary in patients with renal and/or hepatic dysfunction. c. Amphotericin achieves its highest concentrations in the liver and spleen with less in the kidneys and lungs. It does not appear to penetrate cerebrospinal fluid, brain, pancreas, muscles, bone, vitreous humor, normal amniotic fluid, and bronchial secretions well. Concentrations are increased with inflammation where levels may approach 67% of serum levels in areas like the pleura, peritoneum, and joints. F. Formulations a. Amphotericin B deoxycholate: i. Amphotericin is insoluble in water and is formulated as a complex with the bile salt deoxycholate. This is “conventional” amphotericin B. b. Lipid formulations of amphotericin Lipid formulations of amphotericin are advantageous with respect to toxicities. While they are still nephrotoxic, they cause less nephrotoxicity compared to conventional amphotericin. In addition, Ambisome® appears to be associated with less infusion related reactions compared to the other lipid products. Their use, historically, however, is limited by cost as they are often 30-50 times more expensive than conventional amphotericin. No difference in efficacy has been shown between the lipid products and conventional amphotericin. i. Amphotericin B colloidal dispersion (ABCD, Amphotec®) is a colloidal dispersion containing equal amounts of amphotericin B and cholesteryl sulfate. ABCD particles are disk shaped. ii. Amphotericin B lipid complex (ABLC, Abelcet®) contains dimyristoylphosphatidylcholine and dimyristoyl phosphatidylglycert in a 7:3 mixture with ~35 mol% amphotericin in a ribbon-like sheet structure. iii. Liposomal amphotericin B (Ambisome®) is a unilamellar liposome (one molecule ampho B per 9 molecules lipid). The lipid contains phosphatidylcholine, cholesterol, and distearoylphosphatidylglycerol in a 10:5:4 molar ratio. 3 Amphotericin B Amphotericin B lipid Amphotericin B colloidal Liposomal amphotericin B Factor complex deoxycholate dispersion (ABCD, (Ambisome) (ABLC, Abelcet®) Amphotec®) Liposomes, small unilamellar Particle Micelle Lipid disks Ribbons, sheets vesicles Size (nm) <25 100 500-5000 90 dimyristoylphosphatidyl phosphatidylcholine, Carrier deoxycholate cholesteryl sulfate choline and dimyristoyl cholesterol, and phosphatidylglycert distearoylphosphatidylglycerol Infusion related toxicity High High Moderate Mild Nephrotoxicity ++++ ± ± ± Serum concentrations compared to conventional ↓ ↓ ↑ amphotericin Tissue concentrations Liver: ↑ Liver: ↑ Liver: ↑ compared to conventional Lungs: ↔ Lungs: ↑ Lungs: ↔ amphotericin Kidney: ↔ Kidney: ↔ Kidney: ↔ Dosage 0.5-1.5 3-4 mg/kg/day 5 mg/kg/day 3-5 mg/kg/day mg/kg/day Estimated cost/day $37 $480 $820 $1300 (Red Book 2002) G. Toxicities a. Nephrotoxicity i. All amphotericin products cause some degree of nephrotoxicity. This manifests as a dose-dependent decrease in glomerular filtration rate via a direct vasoconstrictive effect on afferent renal arterioles. Other effects include potassium, magnesium, and bicarbonate wasting, and a decrease in epoetin production. Permanent renal failure is related to the total dose and is due to destruction of renal tubular cells, disruption of tubular basement membrane, and loss of functioning nephron units. ii. Risk factors for nephrotoxicity include concomitant nephrotoxic drugs (e.g. cyclosporine, aminoglycosides), hypotension, intravascular volume depletion, renal transplant, and other pre-existing renal conditions. iii. Nephrotoxicity may be reduced through saline loading (500 mL to 1 L) with each dose. This prehydration depends on the ability of patients to tolerate fluids (may not be possible with heart failure, renal failure, and other fluid overload states). Lipid products are less nephrotoxic, but can still themselves cause nephrotoxicity. b. Electrolyte abnormalities i. Renal tubular acidosis and renal wasting of potassium, magnesium, and phosphate is commonly seen during treatment with amphotericin and for 4 several weeks after treatment is discontinued. Close monitoring (daily) and electrolyte supplementation are necessary. c. Infusion related reactions (IRRs) i. Infusion related reactions are common early in the course of amphotericin. Reactions are most severe with the first 3-5 doses and usually subside with continued use and premedications. Chills, fever, and tachypnea may occur during the infusion. Premedicating with diphenhydramine and acetaminophen for all doses can diminish reactions and is recommended. If severe shaking shills (rigors) occur, infusions are temporarily discontinued and meperidine administered to shorten the rigor. These reactions are expected and should not be mistaken for anaphylaxis. Allergic reactions can occur, but are extremely rare. More continued severe reactions may require premedication with hydrocortisone. IRRs appear less commonly with the Ambisome formulation. d. Other i. Nausea and vomiting are common. Thrombophlebitis may occur with peripheral administration. A normocytic normochromic anemia may occur and is associated with decreased epoetin levels. H. Clinical Uses a. Candidiasis (azole resistant strains too), cryptococcal meningitis, mucormycosis, invasive aspergillosis b. Empiric therapy in patients with febrile neutropenia c. Intrathecally for coccidiodal meningitis d. Intraocular injections for fungal endophthalmitis e. Bladder irrigation for fungal cystitis f. Oral suspension for oropharyngeal and esophageal candidiasis FLUCYTOSINE A. Flucytosine is a fluorinated pyrimidine related to fluorouracil. It is 5-FC (5- fluorocytosine). B. Mechanism of action a. Flucytosine is deaminated to 5-FC. It is then converted to 5-fluorodeoxyuridylic acid monophosphate which is a noncompetitive inhibitor of thymidylate synthetase and interferes with DNA synthesis. b. Mammalian cells do not convert flucytosine to fluorouracil, so flucytosine is selective for fungi. C. Mechanisms of resistance a. Drug resistance arises during therapy, especially monotherapy. The mechanism can be loss of the permease necessary for cytosine transport or decreased activity of UMP pyrophosphorylase or cytosine deaminase. D. Spectrum a. Flucytosine has useful activity against Cryptococcus neoformans, Candida sp., and chromomycoses. E. Pharmacokinetics a. Flucytosine is available for oral administration only. Absorption from the GI tract is rapid and complete. It is excreted renally with ~90% excreted unchanged in the urine and thus, requires dose adjustment in patients with renal disease. 5 b. Flucytosine penetrates well into the CSF (~75% of serum levels) and penetrates well into aqueous humor, joints, bronchial secretions, peritoneal fluid, brain, bile, and bone. c. The usual half-life is ~3-6 hours, but may be increased to ~200 hours in patients with renal failure. d. Serum concentration monitoring is recommended, if feasible. F. Toxicities a. Bone marrow suppression i. Bone marrow suppression is the most common and severe toxicity associated with flucytosine. It appears to be dose-related and associated with concentrations >100-125 mcg/mL. Leukopenia and thrombocytopenia are the usual manifestations. Risk factors include underlying hematologic disorders and concomitant bone marrow suppressive drugs. b. GI disturbances i. Nausea, vomiting, and diarrhea are also common. G. Clinical Uses a. Flucytosine may be clinically useful in cryptococal, candidal, and chromomycoses, but it is not a drug of choice. It is not as efficacious as other agents and is associated with the development of resistance. It is usually only used in combination with other agents, most commonly amphotericin. AZOLES Many older azole antifungals (clotrimazole, miconazole) are available in over the counter (OTC) topical preparations for the treatment of fungal infections such as athlete’s foot, vaginal candidiasis, etc. The systemic antifungals more commonly used will be discussed here. These are ketoconazole, fluconazole, itraconazole, and voriconazole. These azole antifungals are separated into two classes, imidazoles (ketoconazole) and triazoles (itraconazole, fluconazole, voriconazole). Both classes have the same mechanism of action, but triazoles appear to have less of an effect on human sterol synthesis than the imidazoles (improved adverse effect profile). The azoles inhibit C-14α demethylation of lanosterol in fungi by binding to one of the cytochrome P- 450 enzymes, which leads to the accumulation of C-14α methylsterols and reduced concentrations of ergosterol, a sterol necessary for the fungal cell membrane. Azole resistance has emerged gradually during prolonged therapy and has been associated with treatment failures. There is some degree of cross resistance among the azoles. There are three possible mechanisms of resistance: a. Accumulation of mutations in ERG11, the gene encoding for the C14α-sterol demethylase (primary mechanism) b. Increased azole efflux by both ATP binding cassette (ABC) and major facilitator superfamily (MFS) transporters c. Increased production of C14α-sterol demethylase. It is important to understand the drug’s activity against specific fungal organisms, especially among Candida species. The azoles differ in their activity against the different Candida species. 6 In vitro Susceptibility Testing of Candida sp. (NCCLS) (mcg/mL) Susceptible Dose- Susceptible Resistant Drug Dependent (S) (R) (S-DD) Fluconazole ≤ 8 16-32 ≥ 64 Itraconazole ≤ 0.125 0.25-0.5 ≥ 1 Flucytosine ≤ 4 8-16 (I) ≥ 32 Susceptibility of Candida sp. to Antifungal Agents Voriconazole Caspofungin Candida species Fluconazole Itraconazole Flucytosine Amphotericin (not standardized) (not standardized) C. albicans S S S S S S C. tropicalis S S S S S S C. parapsilosis S S S S S S to R C. glabrata S-DD to R S-DD to R S S S-I S C. krusei R S-DD to R S I-R S-I S C. lusitaniae S S S S S to R S KETOCONAZOLE (Nizoral®) A. Ketoconazole is a synthetic imidazole antifungal. With the introduction of more broad spectrum and less toxic azole antifungals, it is rarely used. B. Spectrum a. The drug has been used to treat mucocutaneous candidiasis, coccidiodomycosis, histoplasmosis, paracoccidiodomycosis, and blastomycosis in nonimmunosuppressed patients. It is not effective for aspergillosis and mucormycosis. C. Pharmacokinetics a. Ketoconazole is only available for oral administration and absorption varies between individuals. An acidic environment is required for absorption (affected by antacids and H -histamine antagonists). 2 b. Ketoconazole is liver metabolized and is excreted as inactive drug in bile, and to a small extent, in urine. The usual half-life is ~8 hours. Moderate hepatic dysfunction has no effect on ketoconazole blood levels. Ketoconazole is an inhibitor of CYP3A4 and its own metabolism is affected by inducers of the cytochrome P450 enzyme system. c. Ketoconazole levels in the CSF are minimal (<1%) compared to plasma. D. Toxicities a. GI disturbances i. Dose dependent nausea, vomiting, and anorexia are the most common adverse effects. b. Endocrinopathies 7 i. Ketoconazole inhibits steroid biosynthesis in humans as it does in fungi and as a result, endocrinopathies may develop. Specifically, it causes a dose-dependent decrease in testosterone synthesis and can suppress androgen production. Gynecomastia and oligospermia in men and menstrual irregularities in women have been seen. c. Hepatotoxicity i. Hepatotoxicity may also occur but is less common. The majority of cases occur in the first three months of therapy. E. Clinical Uses a. Ketoconazole use is very limited for fungal infections and has largely been replaced with itraconazole. Topical ketoconazole shampoo is the most commonly used formulation of ketoconazole. ITRACONAZOLE (Sporanox®) A. Itraconazole is a triazole antifungal with a broader spectrum of activity, a more desirable pharmacokinetic profile, and less toxicity than ketoconazole. It is, however, still limited by its pharmacokinetics, drug interactions, and toxicities. B. Spectrum a. blastomycosis, histoplasmosis, coccidiodomycosis, paracoccidiodomycosis, sporotrichosis, ringworm (including onychomycosis), tinea versicolor, and aspergillosis C. Pharmacokinetics a. Until recently, itraconazole was only available in an oral formulation associated with pharmacokinetic problems. Due to variability in concentrations achieved following oral dosing and association with treatment failures, the use of this agent has been limited. b. Itraconazole is water insoluble. It is available in oral capsules and an oral solution. The oral solution is coformulated with cyclodextrin to improve solubility and absorption (30% greater than capsules). Oral absorption of the capsules is improved with food while the solution is best absorbed on an empty stomach. c. Tissue, pus, and bronchial secretion concentrations are generally higher than plasma levels. CSF and ocular levels are low. d. Itraconazole is primarily metabolized in the liver by CYP3A4 and also inhibits this enzyme system. As a result, it is subject to drug interactions and these should always be evaluated before initiating therapy. The half-life is ~30-40 hours and will be prolonged in patients with severe liver disease. e. The intravenous formulation of itraconazole is coformulated with hydroxypropyl- β-cyclodextrin to improve solubility. This cyclodextrin is excreted renally, unlike itraconazole, and accumulates in patients with renal dysfunction. Intravenous use is not recommended in patients with CrCL <30 ml/min without evaluation of risk/benefit. D. Toxicities a. GI disturbances i. Dose-related nausea, diarrhea, and abdominal discomfort are the most common. b. Hepatotoxicity c. Thrombophlebitis i. Significant thrombophlebitis is associated with the intravenous formulation when administered peripherally. Increased fluid dilution volume is often necessary. 8 d. Negative inotrope i. Intravenous administration in dogs and humans has resulted in negative inotropic effects. Itraconazole should not be administered to patients with congestive heart failure or patients with ventricular dysfunction for the treatment of onychomycosis. E. Clinical Uses a. Treatment of pulmonary and extrapulmonary blastomycosis b. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis c. Pulmonary and extrapulmonary aspergillosis, usually in patients refractory of or who are intolerant to amphotericin d. Empiric fungal therapy in patients with neutropenic fever FLUCONAZOLE (Diflucan®) A. Fluconazole is the best tolerated and most widely used triazole antifungal. B. Spectrum a. candidiasis, Cryptococcus neoformans, coccidiodomycosis b. some activity against sporotrichosis, ringworm, histoplasmosis, and blastomycosis, but not as efficacious as itraconazole c. no activity against Aspergillus sp or mucormycosis C. Pharmacokinetics a. Fluconazole is available in both oral and intravenous forms. The oral formulation is very well absorbed from the GI tract and bioavailability is >80%. Oral absorption is not affected by pH. b. Fluconazole is mainly excreted renally with 60-75% of the drug appearing unchanged in the urine. Dose adjustment is necessary in patients with renal disease. c. Fluconazole penetrates well into saliva, sputum, urine and other body fluids including the CSF (~70% of plasma levels) and brain. d. Fluconazole is subject to a limited number of drug interactions including interactions with phenytoin, cyclosporine, warfarin, rifampin, rifabutin, sulfonylureas, tacrolimus, and warfarin. D. Toxicities a. Adverse effects are uncommon b. Nausea, vomiting, and anorexia may occur with higher doses c. Rare hepatotoxicity has occurred (usually with high, prolonged doses) E. Clinical Uses a. Commonly used for infections caused by susceptible Candida sp. (systemic, cutaneous, oropharyngeal, esophageal, intra-abdominal, vaginal, etc.) b. Has been used as initial treatment and maintenance of cryptococcal meningitis in HIV patients c. Fungal prophylaxis in neutropenic patients d. Coccidiodomycosis (meningitis and disseminated) VORICONAZOLE (Vfend®) A. Voriconazole is the newest triazole antifungal. It is structurally related to fluconazole but expands on fluconazole’s clinical activity to include fluconazole-resistant Candida sp., Aspergillus sp., and rare molds (Scedosporium sp., Fusarium sp.). Like the other azoles, it appears fungistatic against yeast, but fungicidal against molds. Voriconazole is available orally with good bioavailability and has become an attractive option for long 9 term maintenance therapy for mold infections in immunosuppressed patients. The pharmacokinetic profile of voriconazole is greatly improved over itraconazole, but drug interactions and toxicity may still be problematic. B. Spectrum a. Candida sp. (including most fluconazole-resistant strains), Aspergillus sp., Blastomyces dermatitidis, Coccidiodes immitis, Histoplasma capsulatum b. Some strains of Pseudoallescheria boydii, Scedosporium apiospermum, Fusarium sp., Paecilomyces sp., Bipolaris sp., and Alternaria sp. c. Voriconazole is less active against Sporothrix schenkii C. Pharmacokinetics a. Voriconazole is available in both IV and oral formulations. The oral formulation is best absorbed on an empty stomach with >90% bioavailability. b. Voriconazole exhibits nonlinear pharmacokinetics in adults due to saturation of metabolism. A significant degree of interpatient variability in serum concentrations has been observed. In children, elimination is linear and higher doses are required to attain similar concentrations as in adults. c. Voriconazole has a large volume of distribution and distributes well into the CSF (~50% of plasma concentrations). d. Voriconazole is metabolized in the liver via the CYP450 system, specifically CYP2C9, CYP3A4, and CYP2C19. Drug interactions are of major importance in the safe use of this agent and should be carefully evaluated. The usual half-life is ~6 hours. Dosage adjustment is necessary in patients with liver dysfunction. 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The intravenous formulation is formulated with sulfobutyl ether β-cyclodextrin sodium (SBECD) to increase the solubility of voriconazole. SBECD, unlike voriconazole, is eliminated via the kidneys and as a result accumulates in patients with renal disease. Use is not currently recommended in patients with CrCL <50 ml/min without evaluation of the risk/benefit. D. Toxicities a. Visual disturbances i. Visual disturbances have been reported to occur in about ~30% of patients but rarely results in discontinuation of therapy. Symptoms occur early in therapy with the first few doses, usually begin within 30 minutes of a dose, and last for about 30 minutes. Visual effects include altered color discrimination, blurred vision, appearance of bright spots, and 10

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standard” for the treatment of a variety of fungal infections. absorption and is not reliable for the treatment of systemic infections. b. After IV
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