Fungi may cause benign but unsightly infection of the skin, nail, or hair (dermatophytosis), relatively trivial infection of mucous membranes (thrush), or systemic infection causing progressive, often fatal disease. The taxonomy of fungi is highly complex, but for medical purposes they are commonly considered in four morphological groups:
In addition, Pneumocystis carinii, an important opportunist pathogen, especially of patients with AIDS, is now regarded as a fungus. The nomenclature is in dispute and the organism is sometimes referred to as Pneumocystis jiroveci.
Fungi are eukaryotic organisms and antibacterial agents are generally ineffective against them. Specialized antifungal agents must therefore be used, and some are quite toxic. In order to minimize problems of toxicity, superficial lesions are usually treated by topical application, but deep mycoses, which are serious life-threatening infections, need vigorous systemic therapy. Unfortunately, therapeutic resources for the treatment of systemic mycoses are slender. The polyene amphotericin B is the mainstay; otherwise choice is limited to flucytosine, a handful of azole derivatives (mainly triazoles), and a new group of semisynthetic antibiotics, the echinocandins. P. carinii is insusceptible to conventional antifungal agents, and alternative treatment regimens have been devised.
The differential activity of the main antifungal agents in common use is summarized in Table 4.1. Precise assessment of the activity of antifungal agents in vitro is beset with methodological difficulties and susceptibility tests are not generally available, except in reference centres.
Table 4.1 Summary of the differential activity of antifungal agents against the more common pathogenic fungi
The polyenes are naturally occurring compounds exhibiting a complex macrocyclic structure. All act by binding to sterols in the fungal cell membrane, thereby interfering with membrane integrity and causing leakage of essential metabolites. The only one that can be administered parenterally is amphotericin B (Fig. 4.1). Among related polyenes available for topical treatment in some countries are nystatin, natamycin (pimaricin), and trichomycin (hachimycin).
The activity of the polyenes embraces a variety of pathogenic fungi, and yeasts are particularly susceptible. Nystatin has been extensively used for treating Candida infections of the mucous membranes, but has largely been replaced by imidazoles (see below). Natamycin and trichomycin display some activity against the protozoon Trichomonas vaginalis; in countries in which they are available they are used for treating vaginitis in which either C. albicans or T. vaginalis may be involved.
Most polyenes are restricted to topical use, but intravenous amphotericin B remains the most important weapon in the antifungal armamentarium for the treatment of systemic fungal infections, including disseminated candidiasis, cryptococcosis, aspergillosis, and deep mycoses caused by dimorphic fungi. Amphotericin B can also be administered orally for the treatment of oral, oesophageal, and intestinal candidiasis, but azole derivatives are often preferred in these cases.
Toxicity is a major problem in systemic therapy with amphotericin B and it needs to be used with care. The drug is highly insoluble and for parenteral use it is normally formulated in a surfactant vehicle from which it readily precipitates; for this reason, other drugs should not be added to intravenous infusions of amphotericin B.
Fig. 4.1 Structure of amphotericin B.
Various ways have been tried to minimize toxicity problems. Lipidcomplexed colloidal formulations exhibit improved safety. Alternatively, phospholipid vesicles (liposomes) are used as carriers of the drug. Packaged in this way, the drug is delivered to the site of infection and this allows the use of higher doses without compromising safety. Another approach, at least in systemic candidiasis, is to administer amphotericin B in reduced dosage in combination with flucytosine (see below).
Many imidazole and triazole derivatives display antifungal activity and, in fact, these compounds offer the nearest approximation we have to broad-spectrum antifungal agents. They act selectively against fungi (and some protozoa) by interfering with the demethylation of lanosterol during the synthesis of ergosterol, which is the principal sterol in the fungal cell membrane.
Imidazoles: Topical use only
Antifungal imidazoles are most widely used for topical application in superficial fungal infections and vaginal candidiasis. Indeed, these are virtually the only useful roles for bifonazole, clotrimazole, econazole, fenticonazole, isoconazole, miconazole, sulconazole, and terconazole, all of which have very similar properties and indications. One antifungal imidazole, tioconazole, is also available in a formulation that is painted on infected nails, but is unlikely to be effective alone in severe nail infections, for which better treatment is available.
The only imidazole to be used in the oral therapy of systemic fungal infections is ketoconazole. This derivative achieves therapeutic concentrations for several hours after oral administration. However, early enthusiasm for ketoconazole waned when it was realized that it was occasionally implicated in fatal hepatotoxic reactions. It has been largely replaced by triazoles for the treatment of systemic mycoses. It should not be used for trivial dermatophyte infections.
Triazoles: For serious systemic mycoses
The triazoles, fluconazole (Fig. 4.2), itraconazole and voriconazole are well absorbed after oral administration. They have many properties in common, but also display some distinctive features:
Fig. 4.2 Structure of fluconazole.
Triazoles are used in many forms of systemic mycosis. Fluconazole is presently the drug of choice for the treatment of systemic Candidainfections and, because of its ability to penetrate into cerebrospinal fluid, cryptococcal meningitis. It is also widely used in chemoprophylactic regimens in patients vulnerable to systemic mycoses. Itraconazole and voriconazole are preferred in infections withAspergillus spp. or yeasts resistant to fluconazole.
Fluconazole and itraconazole can be used to treat superficial Candida infections if oral therapy is thought to be necessary or more acceptable than, for example, vaginal pessaries. Oral itraconazole is also effective in dermatophyte infections, including those involving nail.
Resistance to triazoles is increasing, and extensive use of these compounds could compromise their value in the long term.
Flucytosine (5-fluorocytosine): Severe yeast infections only
Flucytosine is a pyrimidine analogue originally developed as an anticancer drug, but found to have considerable activity against yeasts; it has no useful activity against filamentous fungi. The activity depends on its being converted intracellularly to 5-fluorouracil, which is incorporated into fungal RNA. The drug can be given orally or parenterally, but resistance develops readily and sometimes emerges during treatment. For this reason flucytosine is normally
administered together with amphotericin B, an arrangement that has the additional advantage of allowing a lower dose of amphotericin B to be used. Amphotericin B, by interfering with the permeability of the fungal membrane, may also facilitate entry of flucytosine into the fungal cell.
Flucytosine is usually well tolerated, but marrow toxicity can occur, particularly if the drug is allowed to accumulate in patients with impaired renal function. Adjustment of dosage according to the results of drug assays is therefore indicated.
Griseofulvin: Dermatophyte infections only
Griseofulvin was the first antifungal antibiotic to be described. It is well absorbed when administered orally, particularly if a fine-particle formulation is used, and serious side effects are uncommon. The mode of action has not been definitively established, but activity appears to be directed against the process of mitosis, perhaps by interfering with the microtubules of the mitotic spindle.
Use of griseofulvin is confined to the treatment of dermatophyte infections of the skin, nail, or hair. In the case of nail infections treatment is prolonged—sometimes for a year or more for toenail infections—to allow time for the infected nail to grow out, but even so only about one-third of toenail infections respond completely. For this reason alternative drugs, especially terbinafine (see below) are usually preferred.
Allylamines: Dermatophyte infections only
Allylamines, like the antifungal azoles, interfere with ergosterol synthesis, but act at an earlier stage by inhibiting the formation of squalene epoxide, a precursor of lanosterol. The most important compound of this type, terbinafine (Fig. 4.3) exhibits broad-spectrum antifungal activity and is almost completely absorbed when given orally. Despite being almost entirely protein bound and extensively metabolized in the body, it accumulates in keratin, where it persists after treatment is stopped. This is particularly important in dermatophyte infections of the toenails, which are notoriously refractory even to prolonged therapy with griseofulvin or azole derivatives, whereas relatively short courses of treatment (6 weeks-6 months) with terbinafine may be curative.
Fig. 4.3 Structure of terbinafine.
The broad spectrum of activity of terbinafine includes Aspergillus spp. and dimorphic fungi, but it does not appear to offer a useful alternative to older antifungal agents in these conditions. C. albicans is more susceptible in the mycelial phase than in the yeast form and, whereas the drug is generally fungicidal, the action against Candida is fungistatic. Pityriasis versicolor, a mild but chronic infection of skin does not respond to oral terbinafine, but this condition is usually treated topically.
Terbinafine is now the drug of choice for fungal infections of the toenail, and offers an alternative to griseofulvin and azoles for the treatment of other dermatophyte infections if systemic therapy is indicated. Any wider role remains to be defined. An earlier allylamine, naftifine, is insufficiently active to be useful systemically, but is marketed in some countries for topical use.
Echinocandins: Severe systemic mycoses only
In 2001, caspofungin, the first of new class of antifungal drugs—the echinocandins—appeared on the market. It was soon followed in some countries by a related compound, micafungin; a third, anidulafungin is expected to follow. The echinocandins are semisynthetic lipopeptide antibiotics that interfere with the formation of glucans in the fungal cell wall. They were originally called pneumocandins, reflecting the hope that they might be useful against Pneumocystis and Candida, but in the event the most notable attribute of caspofungin turned out to its activity against Aspergillus.
Clinical experience with echinocandins is limited and these agents have so far received limited approval from regulatory bodies: caspofungin for the salvage treatment of invasive aspergillosis; micafungin for serious systemic infection with Candida. Much more information is needed before they can be confidently recommended.
Pneumocystis carinii (P. jiroveci)
Originally encountered as a rare cause of interstitial pneumonia in infants, P. carinii was later recognized as an infection of severely immunocompromised individuals, in whom it can cause a life-threatening pneumonia. The organism came into particular prominence in the 1980s as a respiratory pathogen of individuals with AIDS, but the development of pneumocystis pneumonia has declined among patients treated with antiretroviral drug combinations (see p. 391). Prophylaxis, usually with the antibacterial agent, co-trimoxazole (p. 55) has also been successful in reducing the incidence of this disease.
Co-trimoxazole is the drug of choice for treatment of established pneumocystis infection, but patients suffering from AIDS are often intolerant of the high doses used. Other combinations that have found favour in some units are trimethoprim with the antileprosy drug dapsone (p. 65) or clindamycin (p. 49) with the antimalarial agent primaquine (p. 82). The diamidine derivative, pentamidine isethionate (p. 80) is also active against P. carinii, but the intravenous infusion carries problems of toxicity, which may be severe, and the drug is sometimes (at least in prophylactic use) administered directly into the lungs by nebulizer in an effort to reduce systemic toxicity. Atovaquone (p. 82), appears to be a safe alternative to co-trimoxazole and pentamidine, and is sometimes used in patients intolerant of the older drugs. Alternatively, trimetrexate glucuronate, a dihydrofolate reductase inhibitor (see p. 55-6), is used. Although it is non-specific in its action, it penetrates well into pneumocystis cells and serious toxicity can be avoided by concurrent administration of folinic acid, which is not taken up by the fungus.
Use of these agents in treatment and prophylaxis of pneumocystis infection is discussed in Chapter 28.
Topical antifungal agents
Apart from the azole, polyene, and allylamine derivatives that are available for topical use, a range of other agents is available in some countries for the treatment of ringworm and other superficial fungal infections. These include tolnaftate, haloprogin, and ciclopirox olamine. None of these agents exhibits useful activity against Candida spp. A variety of ointments containing benzoic acid (e.g. Whitfield's ointment: benzoic acid, and salicylic acid in an emulsifying base) have been used traditionally for treating dermatophyte infections of the skin. Though old-fashioned and a little messy, they are cheap and effective, and still have a place in treatment. The monounsaturated fatty acid, undecylenic (undecenoic) acid is also widely used in proprietary preparations for conditions such as ‘athlete's foot’.
A morpholine derivative, amorolfine, which is active against Candida and the dermatophytes, is marketed for the topical treatment of fungal infections of the skin and, in the form of a lacquer, for application to infected nails. Its action is said to persist so that it needs to be applied to infected nails only once or twice a week.
Antifungal agents: prescriber's survival kit