Antifungal Antibiotics

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Chapter: Pharmaceutical Microbiology : Antibiotics And Synthetic Antimicrobial Agents: Their Properties And Uses

There has been a significant increase in the number of both systemically and topically acting antifungal agents in recent years; this has been prompted in part by the increase in patients with impaired immunity who are particularly vulnerable to such infections. For much of the second half of the 20th century nystatin, amphotericin and griseofulvin were the principal antifungal antibiotics available.



There has been a significant increase in the number of both systemically and topically acting antifungal agents in recent years; this has been prompted in part by the increase in patients with impaired immunity who are particularly vulnerable to such infections. For much of the second half of the 20th century nystatin, amphotericin and griseofulvin were the principal antifungal antibiotics available, and these were supplemented with a range of synthetic imidazoles which were used primarily for superficial rather than systemic fungal infections. The introduction of the triazole antifungals in the 1980s was a major advance and, more recently, the echinocandins have further increased the range of drugs available for severe infections.


Lack of toxicity is, as always, of paramount importance, but the differences between bacterial and fungal cells in both structure and biosynthetic processes mean that the low-toxicity antibacterial antibiotics are usually inactive against fungi. This limitation is further complicated by the fact that both fungal and human cells are eukaryotic in structure, which means that there are few differences that can be exploited in order to achieve selective toxicity towards fungi whilst leaving the human cells unharmed. Fungal infections are normally less virulent in nature than are bacterial or viral ones but may, nevertheless, pose major treatment problems in individuals with a depressed immune system, particularly in the case of systemic infection.




The azoles may be considered as two subgroups: the older imidazole drugs, the majority of which were introduced as topical products or pessaries for the treatment of superficial infections by dermatophytes (skin pathogens), Pityriasis species (causing flaky skin and dandruff) and C. albicans, and the more recently developed, more versatile and, in some cases, much more expensive, triazoles.


a)    Imidazoles


The imidazoles are a large and diverse group of compounds with activity against bacteria and protozoa (metronidazole and tinidazole), helminths (mebendazole) and fungi (clotrimazole, miconazole, ketoconazole, econazole, sulconazole and tioconazole). Table 11.8 lists infections for which the common antifungal drugs are employed; other imidazoles are available in various countries.



As Table 11.8 indicates, the imidazoles are available in a wide variety of dosage forms, but most of them have the same uses. They exhibit modest activity against some Gram-positive bacteria, but they are all essentially fungistatic drugs which might exert fungicidal action during prolonged exposure to high concentrations. Miconazole may be given orally for the treatment of intestinal fungal infections, and in this situation may show some absorption into the systemic circulation, although this may be more of a problem from the perspective of potential drug interactions than a benefit. Ketoconazole, however, achieves greater absorption from the gastrointestinal tract, but it has been largely superseded by newer and less toxic drugs so its use tends to be restricted to situations where resistance or patient intolerance to those drugs is a problem.


b)    Triazoles


Fluconazole (Figure 11.12A) and itraconazole were introduced in the 1980s and posaconazole and voriconazole much more recently. The two earlier drugs are more widely used, whilst the recent ones tend to be reserved for severe, possibly life-threatening infections, in which other antibiotics have failed or are inappropriate. All four of the triazole drugs are orally active and all but posaconazole are available in injection form.


Fluconazole is better absorbed from the gastrointestinal tract than itraconazole and, in addition to the treatment of dermatophytes, pityriasis and Candida infections, it is valuable in cases of cryptococcosis which, although uncommon, is very dangerous in immunocompromised patients. Itraconazole is used for similar infections to fluconazole but, in addition, it is more commonly selected as an alternative to amphotericin (see below) in cases of systemic Aspergillus infection (again, more common in the immunocompromised) and other rare systemic mycoses. It is more frequently associated with liver toxicity than fluconazole.


B)                POLYENES


Polyene antibiotics are characterized by possessing a large ring containing a lactone group and a hydrophobic region consisting of a sequence of four to seven conjugated double bonds. The only important polyenes are amphotericin B and nystatin.


Amphotericin B (Figure 11.12C) is active against most fungal pathogens and is used for systemic mycoses as a potentially more toxic, but possibly more effective, alternative to itraconazole. It is poorly absorbed from the gastrointestinal tract and is thus usually administered by intravenous injection under strict medical supervision. Lipid-based and liposomal formulations of amphotericin are available which exhibit lower toxicity than conventional aqueous formulations; they may therefore be given in higher doses. Nystatin is administered orally in the treatment of C. albicans infections in the intestine or the mouth (often referred to as thrush), and by cream or pessary for skin or vaginal infections by that organism. It is rarely used for the treatment of other infections and is too toxic to be given by injection.





The echinocandins are a new class of semisynthetic lipopeptide antibiotics that are fungicidal towards Aspergillus spp., Candida spp. and Pneumocystis jirovecii (previously known as P. carinii). Caspofungin, the first member of the class, is given as an intravenous infusion recommended for invasive aspergillosis or candidiasis that is unresponsive to treatment with amphotericin or itraconazole. Anidulafungin and micafungin are similarly injectable products licensed for the treatment of invasive candidiasis, and they, like caspofungin, tend to be used as reserve drugs, both to minimize the risk of resistance development and due to cost considerations.


D)                                                             OTHER ANTIFUNGAL AGENTS


Flucytosine (5-fluorocytosine, Figure 11.12B) is a narrow-spectrum antifungal agent with greatest activity against yeasts such as Candida, Cryptococcus and Torulopsis. It is normally used in combination with fluconazole or as a synergistic combination with amphotericin which permits amphotericin dose reduction and a lower risk of toxicity. Terbinafine (Figure 11.12D), a member of the allylamine class of antimycotics, is orally active, fungicidal, effective against a broad range of dermatophytes and yeasts and is the drug of choice for fungal nail infections. Griseofulvin too is employed for the treatment of dermatophyte infections of hair, skin and nails, but usually only when topical therapy has failed, and with the exception of Trichophyton infections in children, it is no longer regarded as a drug of choice. It is orally active, although the particle size of the powder used to manufacture the tablets has a significant effect on bioavailability. Tolnaftate (Figure 11.12E) is a synthetic thiocarbamate which is used topically in the treatment or prophylaxis of tinea (commonly referred to as ringworm, although not due to worms at all) and amorolfine is used as a cream or nail lacquer for the same purpose.

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