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 classified in four morphological groups:
DNA sequence studies have shown that Pneumocystis carinii, long regarded as a protozoon, is, in fact, a fungus. Species infecting man are genetically distinct and are now usually decribed as P. carinii formae specialis hominis. This organism is an important opportunist pathogen, especially of patients with AIDS, and is included here in recognition of its new status.
Fungi are eukaryotic organisms and antibacterial agents have no effect on 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 systemic treatment are slender. The polyene amphotericin B is the mainstay; otherwise choice is limited to flucytosine, a handful of azole derivatives, and the allylamine, terbinafine. 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 macrocyclic lactone structure with an extensive conjugated system of double bonds. All act by binding to sterols in the fungal cell membrane, thereby interfering with membrane integrity and causing leakage of essential metabolites. The most commonly used members of the group are nystatin and amphotericin B (Fig. 4.1). Among related polyenes available for topical treatment in some countries are candicidin, natamycin (pimaricin), and trichomycin (hachimycin).
Fig. 4.1 Structure of amphotericin B.
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. Natamycin and trichomycin display some activity against the protozoonTrichomonas vaginalis, and have been used for treating vaginitis in which either C. albicans or T. vaginalis may be involved.
Most polyenes are restricted to topical use, but 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 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.
Various ways have been tried to minimize toxicity problems. Lipid-complexed 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 candidi-asis, 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. The structure of clotrimazole, which was the first imidazole to be introduced into clinical medicine, is shown in Fig. 4.2.
Fig. 4.2 Structure of clotrimazole.
Antifungal imidazoles are most widely used for topical application in superfi-cial fungal infections and as pessaries for use in vaginal candidiasis. Indeed, these are virtually the only useful roles for bifonazole, clotrimazole, econazole, fenticonazole, isoconazole, miconazole, and sulconazole, all of which have very similar properties and indications. One antifungal imidazole, tioconazole, is available in a formulation that is painted on infected nails. It is unlikely to be effective alone in severe nail infections, but may have a place as an adjunct to oral therapy with griseofulvin (see below).
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.
The triazoles, fluconazole and itraconazole, are associated with fewer side-effects. They are well absorbed after oral administration and have long plasma half-lives (20–30 h), properties that make them suitable for once-daily administration. Fluconazole appears to have several advantages over itraconazole: it achieves higher plasma concentrations, it is less extensively metabolized and protein bound, and it penetrates into cerebrospinal fluid (CSF) in therapeutically useful concentrations. Itraconazole is also more liable to give rise to hepatic injury. On the credit side, itraconazole exhibits better activity against Aspergillus spp. and against C. krusei and C. (Torulopsis) glabrata, yeasts that are seen with increasing frequency in immunocompromised patients and are often resistant to flucona-zole. A new triazole, voriconazole, appears to share the improved spectrum of itraconazole.
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. More importantly, they appear effective in many forms of systemic mycosis, including in the case of fluconazole, cryptococcosis and, in the case of itraconazole, aspergillosis. They are also used in chemoprophylactic regimens for profoundly neutropenic patients. Resistance is increasing, and extensive use of these compounds could compromise their value in the long term.
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 intracel-lularly 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. It has also been suggested that amphotericin B, by interfering with the permeability of the fungal membrane, may facilitate entry of flucytosine into the fungal cell.
Flucytosine is usually well tolerated, but marrow toxicity may 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 was the first antifungal antibiotic to be described. Use of the drug is confined to the treatment of dermatophyte infections of the skin, nail, or hair. In the case of nail infections treatment is prolonged to allow time for the infected nail to grow out, but even so only about one-third of toenail infections respond completely. The compound is well absorbed when administered orally, particularly if a fine-particle formulation is used, and serious side-effects are uncommon.
The mode of action of griseofulvin has not been definitively established, but its activity appears to be directed against the process of mitosis, perhaps by interfering with the microtubules of the mitotic spindle.
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 griseo-fulvin or azole derivatives, whereas relatively short courses of treatment (3–6 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 anti-fungal agents in these conditions. C. albicans seems to be more susceptible in the mycelial phase than in the yeast form and, whereas the drug is generally fungicidal, the action against Candida is fungistatic.
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 dermato-phyte 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.
Originally encountered as a rare cause of interstitial pneumonia in infants, P. carinii came into prominence in the 1980s as a respiratory pathogen of individuals with AIDS, in whom it often causes a life-threatening pneumonia. Prophylaxis with the antibacterial agent, co-trimoxazole (p. 48) has been successful in reducing the incidence of this complication.
Co-trimoxazole is also used for treatment, but patients suffering from AIDS are often intolerant of the high doses used. The diamidine derivative, pentami-dine isethionate (p. 68) is also active against P. carinii, but the intravenous infusion carries problems of toxicity, which may be severe, and the drug is sometimes administered directly into the lungs by nebulizer in an effort to reduce systemic toxicity. Atovaquone (p. 70), 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. 48), 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.
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 pityriasis versicolor, a mild but chronic infection of skin. 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. Undecanoic acids are also widely used in proprietary preparations for conditions such as ‘athlete's foot’.
A morpholine derivative, amorolfine, that 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.