Drugs Classification

Antimicrobials for systemic use

Systemic antimycotics

  1. Antifungals overview
  2. Polyenes or natural antimycotics
  3. Azole antifungals overview
  4. Azoles: Indications, Adverse reactions, Contraindications, Interactions
1. Antifungals overview

Antifungal drugs, or antimycotics, represent a large class of different chemical compounds, both natural and synthetic, which have specific activity against pathogenic fungi. Depending on the chemical structure, they are divided into several groups that differ in the specifics of the spectrum of activity, pharmacokinetics and clinical use in various fungal infections (mycosis).

Classification of systemic antimycotics

  • Polyenes (natural antimycotics): Nystatin, Levorin, Natamycin, Amphotericin B, Amphotericin B liposomal.
  • Azoles: Ketoconazole, Fluconazole, Itraconazole
  • Allylamines: Terbinafine
  • Others: Potassium iodide, Griseofulvin
2. Polyenes or natural antimycotics

Depending on the concentration, animycotics can express fungistatic or fungicidal action due to binding of the drug with ergosterol of fungal membranes, leading to violation of its integrity, loss of the cytoplasm contents and cell's death. Polyenes have the broadest spectrum of activity in vitro among the antimycotics. Active against Candida spp. (some C.lusitaniae strains can be resistant), Aspergillus spp. (A.terreus can be resistant), C.neoformans, mucormycosis pathogens (Mucor spp., Rhizopus spp. Etc.), S.schenckii, causative agents of endemic mycoses (B.dermatitidis, H.capsulatum, C.immitis, P. brasiliensis) and some other fungi. Also active against ome protozoa - Trichomonas vaginalis (natamycin), Leishmania and amoebae (amphotericin B). All polyenes are almost not absorbed in the GI tract, poor pass through BBB. Slowly excreted by the kidneys, 40% of the administered dose is excreted within 7 days. The half-life is 24 to 48 hours, but prolonged use can increase it up to 2 weeks due to accumulation in tissues.

Adverse reactions

Nystatin, levorin, natamycin

  • abdominal pain, nausea, vomiting, diarrhea
  • rash, itching, Stevens-Johnson syndrome (rare)

Amphotericin B

  • fever, chills, nausea, vomiting, headache, hypotension, bronchospasm
  • renal dysfunction, possible hepatotoxic effect
  • hypokalemia, hypomagnesemia
  • abdominal pain, anorexia, nausea, vomiting, diarrhea
  • dizziness, paresis, sensitivity disorder, tremors, convulsions

Indications

Nystatin, levorin: candidiasis of the skin, oral cavity, pharynx,and intestine, candidal vulvovaginitis

Natamycin: candidiasis of the skin, oral cavity, pharynx,and intestine, candidal vulvovaginitis, candidal balanoposthitis, trichomonal vulvovaginitis

Amphotericin B: severe form of systemic fungal infections (invasive candidiasis, cryptococcosis, aspergillosis, sporotrichosis, zygomycosis, trichosporonosis, endemic mycoses, leishmaniasis, primary amoebic meningoencephalitis caused by N. fowleri.

Amphotericin B liposomal: severe forms of systemic fungal infections (see amphotericin B) in patients with renal insufficiency, with the ineffectiveness of a standard drug and in its nephrotoxicity.

Contraindications (for all polyenes)

  • Allergic reactions to polyenes
  • In addition to amphotericin B: liver and / or renal dysfunction, diabetes
  • With caution: pregnancy, breastfeeding, elderly patients.

Interactions

Amphotericin B used with myelotoxic drugs (methotrexate, chloramphenicol, etc.) increases the risk of anemia and other blood formation disorders. Combination of amphotericin B with nephrotoxic drugs (aminoglycosides, cyclosporin, etc.) increases the risk of severe renal impairment. Combination of amphotericin B with thiazide and loop diuretics and glucocorticoids increases the risk of hypokalemia, hypomagnesemia. Amphotericin B, causing hypokalemia and hypomagnesaemia, may increase the toxicity of cardiac glycosides. Amphotericin B (standard and liposomal) is incompatible with 0.9% sodium chloride and other solutions containing electrolytes.

3. Azole antifungals overview

Azoles have predominantly fungistatic effect, which is associated with inhibition of cytochrome P-450-dependent 14-alpha-demethylase that catalyzes transformation of lanosterol to ergosterol, the main structural component of fungal membranes.

Azoles have a broad spectrum of antifungal activity. Itraconazole is active against major pathogens of candidiasis (S.albicans, C.parapsilosis, C.tropicalis, C.lusitaniae, etc.), Aspergillus spp., Fusarium spp., C.neoformans, dermatomitsety (Epidermophyton spp., Trichophyton spp., Microsporum spp.), S.schenckii, P.boydii, H.capsulatum, B.dermatitidis, C.immitis, P.brasiliensis and some other fungi. C.glabrata and C.krusei are usually resistant.

Ketoconazole has the spectrum of activity similar to itraconazole, but it has no effect on Aspergillus spp.

Fluconazole is most active against most pathogens of candidiasis (S.albicans, C.parapsilosis, C.tropicalis, C.lusitaniae, etc.), Cryptococcus, coccidioides, dermatomycetes. Is not effective against Aspergillus.

Ketoconazole, fluconazole and itraconazole are well absorbed in the gastrointestinal tract. Peak blood concentrations of fluconazole are achieved in 1-2 h, ketoconazole and itraconazole in 2-4 hours. Fluconazole is characterized by low degree of binding to plasma proteins (11%), whereas ketoconazole and itraconazole bind with proteins almost on 99%.

Fluconazole and ketoconazole are relatively evenly distributed in the body, creating high concentrations in various organs, tissues and secretions. Fluconazole passes through the BBB and the blood aqueous barrier. Itraconazole, being highly lipophilic, is distributed mainly in the organs and tissues with high fat content: liver, kidney, caul. Can accumulate in tissues that are particularly susceptible to the fungus, such as skin (including epidermis), nail plate, lung tissue, the genitals, where its concentration is almost 7 times higher than in plasma.

Ketoconazole and itraconazole are metabolized in the liver and excreted mainly by gastrointestinal tract. Itraconazole is partially excreted with the secretion of sebaceous and sweat glands of the skin. Fluconazole is only partially metabolized, excreted by the kidneys mainly unchanged. The half-life of ketoconazole is 6-10 h, itraconazole - 20-45 h, with renal failure does not change. The half-life of fluconazole - 30 h, with renal insufficiency may increase up to 3-4 days.

4. Azoles: Indications, Adverse reactions, Contraindications, Interactions

Indications

Itraconazole

  • Dermatomycoses: epidermophytia, trichophytosis, microsporia
  • Chromophytosis, cryptococcosis
  • Candidiasis of esophagus, skin and mucous membranes, nails, candidal paronychia, vulvovaginitis
  • Aspergillosis (with resistance or poor tolerability of amphotericin B)
  • Pseudallescheriosis, phaeohyphomycosis, chromomycosis, sporotrichosis
  • Endemic mycoses
  • Prevention of fungal infections in AIDS

Fluconazole

  • Invasive candidiasis
  • Candidiasis of the skin, mucous membranes, esophagus, candidal paronychia, onychomycosis, vulvovaginitis
  • Cryptococcosis
  • Dermatomycoses: epidermophytia, trichophytosis, microsporia
  • Chromophytosis, sporotrichosis, pseudallescheriosis, trichosporosis, some endemic mycoses

Ketoconazole

  • Candidiasis of the skin, esophagus, candidal paronychia, vulvovaginitis
  • Chromophytosis, paracoccidioidosis

Adverse reactions

Common to all systemic azoles

  • GI tract: abdominal pain, appetite disorders, nausea, vomiting, diarrhea, constipation
  • CNS: headache, dizziness, drowsiness, visual disturbances, paresthesia, tremors, convulsions
  • Allergic reactions: rash, itch, exfoliative dermatitis, Stevens-Johnson syndrome
  • Hematologic reactions: thrombocytopenia, agranulocytosis
  • Liver: increase of transaminases' activity, cholestatic jaundice

Contraindications

  • Allergic reactions to azoles
  • Pregnancy, breastfeeding
  • Severe hepatic dysfunction
  • Pediatric and adolescent patients

Interactions

Antacids, sucralfate, cholinoblockers, H2 blockers and proton pump inhibitors reduce the bioavailability of ketoconazole and itraconazole as they reduce the acidity in the stomach and violate the transformation of azoles in soluble form. Didanosine reduces the bioavailability of ketoconazole and itraconazole.

Ketoconazole, itraconazole, and to a lesser extent, fluconazole are inhibitors of cytochrome P-450, and therefore may violate the metabolism of the following drugs in the liver:

  • oral antidiabetics (chlorpropamide, glipizide, etc.), the result could be hypoglycemia. Requires strict control of blood glucose with a possible correction of the antidiabetic drugs dosage;
  • indirect coumarin anticoagulants (warfarin, etc.) that may be accompanied by hypocoagulation and bleeding. Requires laboratory control of hemostasis indicators;
  • cyclosporine, digoxin (ketoconazole and itraconazole), theophylline (fluconazole), which can lead to an increase in their concentration in the blood and toxic effects. Requires clinical monitoring, monitoring of drugs concentrations with a possible correction of their dosage;
  • terfenadine, astemizole, cisapride, quinidine, pimozide. The growth of their concentration in the blood may be accompanied by lengthening of the QT interval on the ECG with the development of severe, potentially fatal ventricular arrhythmias. Therefore, a combination of azoles with these drugs is not recommended.

The combination of itraconazole with lovastatin or simvastatin is accompanied by increase in their concentration in the blood and the development of rhabdomyolysis. During treatment with itraconazole statins should be discontinued.

Rifampicin and isoniazid increase the metabolism of azoles in the liver and reduce their concentration in plasma, which can lead to failures in treatment. Thus, azoles are not recommended to be used in combination with rifampicin or isoniazid.

Carbamazepine reduces the concentration of itraconazole in blood that can cause failure of the latter.

Inhibitors of cytochrome P-450 (cimetidine, erythromycin, clarithromycin, and others) can block the metabolism of ketoconazole and itraconazole and increase their concentration in the blood. Concomitant use of erythromycin and itraconazole is not recommended due to the possible development of cardiotoxicity of the latter.

Ketoconazole violates the metabolism of alcohol and may cause disulfiram-like reactions.

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