by Dr. David Denning

The incidence of invasive fungal infections has risen dramatically in the last twenty years. Response rates with currently available drugs are far from satisfactory, partially because late diagnosis often impedes successful treatment. This paper looks at the current situation regarding fungal infections and antifungal drugs, and discusses future trends and needs.

Fungi are ubiquitous in the environment and unavoidable. The yeast Candida lives in the human gut. Foods, cellars, bed clothes, potted plants and pillows are all sources of fungal spores. There are about 20 fungi that cause>99% of human fungal infections although about 600 different fungi have been reported as a cause of infection in man.

Fungal infections are classified broadly into four groups. These are invasive, life-threatening infections (e.g. aspergillosis and candidiasis), mucosal infections (e.g. oral and vaginal thrush), skin infections (e.g. athlete’s foot, ringworm and fungal nail infections) and allergic infections (e.g. asthma and chronic sinusitis).

Invasive fungal infections
The number of life-threatening, invasive fungal infections has risen dramatically over the last 20 years. Data collected over the 12 years up to 1992 show that the frequency of invasive fungal infections as judged after death by unselected autopsies had risen approximately 14 fold. Invasive aspergillosis has now overtaken candidiasis as the most frequent invasive fungal infection found after death in Europe and the USA [1, 2].

Today, 4% of all patients dying in modern tertiary care hospitals have invasive aspergillosis caused by the fungal pathogen, Aspergillus, while 2% of these patients have invasive candidiasis caused by Candida.

Patients at risk of aspergillosis include those with damaged immune systems, including transplant recipients, patients with leukaemia and patients with AIDS. Additionally, patients in intensive care units are at particular risk of candidiasis. The crude mortality from invasive aspergillosis is around 85% and for Candida bloodstream infections is 40%. Response rates following treatment with the currently available drugs however are far from satisfactory as shown below. It is very clear therefore that there is a major clinical need for new drugs.

Most patients with invasive fungal infections are complex patients with complex problems. The clinical features of fungal infections are often subtle; for example one third of patients with invasive aspergillosis have no fever. This means that diagnoses are often made late or not at all. When the diagnosis is made late, treatment is not as effective and the mortality is high. Most Aspergillus infections are in the lung, but if the infections spread to the brain as they do in 40% of bone marrow transplant patients, none of the current drugs are effective and the outcome is usually fatal. Aspergillus grows very rapidly and if the immune defences are poor, then it can very quickly invade the lungs causing enormous destruction.

Present diagnostic testing systems are not perfect; however numerous advances in diagnosis are on the horizon. Direct tests for Aspergillus antigens are now routine in leukaemia patients in many European centres, and have been recently licensed for use in the US. This speeds up diagnosis by about 6 days in these patients, but is untested in other types of patients. In-house PCR tests for Candida and Aspergillus are under evaluation in many labs, but are not available commercially. These tests will probably aid early diagnosis, improve patient outcomes but also increase sales of antifungal drugs because the patients will live longer on treatment.

There is a strong medical need for a better treatment for invasive aspergillosis which will improve survival from this disease (and increase the population of patients requiring long term therapy to ensure eradication). The prognosis in invasive candidiasis is better and whilst improved clinical outcomes will always be welcomed the need is less urgent than with aspergillosis.

Mucosal fungal infection
Vaginal thrush occurs in about 70% of women at some time in life, most commonly during pregnancy or after treatment with antibiotics. About 30% of women of childbearing age get recurrent episodes and approximately 1% are almost continuously troubled by it. Oral thrush, which is also caused by Candida, is common, especially in AIDS and cancer patients. Oesophageal thrush is common in AIDS and has been an important clinical entry point for clinical trials of new drugs. These indications are largely satisfied with the currently available therapies and have maintained the substantial sales figures of the oral prescription azoles fluconazole, itraconazole and ketoconazole, as well as numerous topical preparations.

Cutaneous fungal infection
Onychomycosis is common in the general adult population. According to recent surveys, the rate of infection is 3-10% depending on age. Many people with discoloured or distorted toenails have other problems, but are nevertheless empirically treated with antifungal therapy. Recurrent infection is well documented. Sales of terbinafine for this indication are close to $1billion annually, and a substantial proportion of the $600M sales of itraconazole are for this indication.

Scalp ringworm infection due to Trichophyton tonsurans is increasingly common in children, and readily passes amongst primary school children. There are studies that suggest a 10% carriage rate in some London schools. The infection is particularly common in children of Afro-Caribbean origin. Similar figures have been seen in other countries.

Athlete’s foot is common, affecting perhaps 20% of the population, sometimes recurrently. It can be difficult to treat, and if untreated, may lead to bacterial infection of the skin of the lower leg (cellulitis), accounting for 3% of general medical admissions to hospital.

Although there are specific needs for improved therapies, e.g. reducing the relapse rate in onychomycosis, the needs of this sector are satisfied by current therapies.

Allergic fungal infection
Allergy to fungi is quite common, as judged by skin testing. However antifungal therapy has not been used in this context, with two exceptions - allergic bronchopulmonary aspergillosis (ABPA) and allergic fungal sinusitis. ABPA is a long term condition of some asthmatic patients and approximately 25 % of patients suffering from cystic fibrosis. The infections lead to to deterioration in lung function and the need for higher steroid doses. Itraconazole yielded about a 50% response in a recent randomised study [3]. Local amphotericin B was helpful to 75% of patients [4]. While allergic fungal infection is probably more common than generally realised (chronic sinusitis, etc.), estimates of caseload are unreliable. Diagnostic tests are poorly developed, and the response to antifungal therapy is uncertain. Considerable evidence is emerging of the role of fungal allergy as a driver for asthma, especially in severe cases. Some data suggest antifungal treatment could reduce the dependence on steroids and other medication, as well as improving symptomatology but none of the currently available antifungal drugs have a safety/efficacy profile that would be suitable for such a primary care indication. Asthma and sinusitis are two of the commonest reasons for US patients to visit a doctor.

The antifungals market: current situation
There are only 4 classes of established antifungal drugs on the market - polyenes (e.g. amphotericin B), azoles (e.g. fluconazole and itraconazole), allylamines (e.g. terbinafine) and the newly introduced echinocandins (e.g. caspofungin). Of these classes, only three are used to treat systemic fungal infections.

Today’s market for systemic antifungal drugs that can used to treat invasive fungal infections is estimated to be about $5 billion worldwide. It is dominated by the azoles, the most successful of which is Pfizer’s Diflucan (fluconazole), which was first launched in the mid-1980s and now enjoys sales of over $1billion per year. Fluconazole succeeded in displacing amphotericin for the treatment of invasive Candida infections; J&J’s Sporanox (itraconazole) suffered from lack of an iv formulation for years. The toxicity problems of amphotericin have been ameliorated to some extent by the development of liposome formulations, the most successful of which is Gilead’s Ambisome, though these formulations are very costly. At the same time new azoles with improved spectrum and activity have appeared. Pfizer’s Vfend (voriconazole) is soon to be launched. Schering’s posaconazole will make further inroads into the amphotericin market.

A new class of antifungal drug, the echinocandins, has recently appeared on the market. The first representative, Merck’s Candidas (caspofungin), was launched early in 2002 for salvage therapy for invasive aspergillosis, for which it showed superiority over amphotericin, but the drug’s distinguishing feature is its fungicidal activity against the more common Candida species. The second echinocandin, Fujusawa’s Funguard (micafungin) was launched in 2002 (Japan only) and closely resembles Merck’s product.

Formulation remains a problem. The echinocandins and the various amphotericin formulations are all administered by intravenous infusion and there seems little prospect of developing oral formulations. Only the azoles and terbinafine have oral forms. The current iv formulation of the azoles useful for aspergillosis cannot be given to patients with poor renal function, limiting their use. Both routes of administration are important for the ideal treatment of invasive fungal infections, particularly for aspergillosis. The iv route is used for the acute phase (14 to 28 days) and is followed by prolonged oral therapy (months or years) to suppress disease. Long-term oral prophylaxis with an azole in at-risk patients is commonplace.

Drug interaction issues are a major impediment to the use of the azoles voriconazole, itraconazole and posaconazole. The interactions with cancer chemotherapy agents and immunosuppressants are particularly difficult to handle clinically.

The problem of drug resistance is less serious than that seen with antibacterials. Resistance does occur but because it is not transferable it is more manageable. On the other hand each year new pathogenic, mainly filamentous, fungi are identified, highlighting the need for broad spectrum coverage.

Despite the commercial success of the azoles and the introduction of the echinocandins mortality of invasive fungal infections remains high, particularly in those caused by filamentous fungi. It is too early to know if the echinocandins will reduce the mortality of invasive Candida infections to the levels comparable with those for bacterial disease. The high mortality associated with invasive aspergillosis is probably a consequence of the compromised immune function of most of the patients and the fact that none of the currently available drugs are sufficiently cidal.

Future trends
Over the next few years echinocandins can be expected to displace amphotericin, including the liposome formulations, in the majority of current iv indications, except for invasive aspergillosis where voriconazole will dominate. The competition between the new azoles and the echinocandins will be mainly limited to the hospital unless an oral echinocandin is developed or safety concerns with the new azoles become more manageable with experience. The use of combinations of currently used antifun¬gal drugs will be extensively debated and used for short periods as none alone matches the ideal. Generic fluconazole and itraconazole, introduced from 2004, will be widely used in prophylaxis and treatment. Antagonism of the effect amphotericin by azole pre-treatment will limit some prophylaxis and drive more usage of the echinocandins.

Developments of better diagnostics can be expected in a 5 to 10 year timescale. This will increase the available market by identifying patients who would otherwise remain undiagnosed in today’s setting. In addition, better diagnostics will allow earlier diagnosis of patients, leading to better survival and longer courses of (oral) antifungal therapy. There remains a need for antifungal drugs which are cidal and could treat infections caused by filamentous fungi more effectively, either as broad spectrum agents or as filamentous-only drugs.

References
1. Groll AH, Shah PM, Mentzel C, SchneiderM, Just-Neubling G, Heubling G, Huebner K. Trends in postmortem epidemiology of invasive fungal infections at a uni¬versity hospital. J Infect 1996; 33:23-32.

2. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, Warnock DW. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 2001;33:641-7.

3. Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Cantanzaro A, Bamberger DM, Weinman AJ, Tiazpm CU, Judson MA, Platts-Mills TAE, DeGraff AC. A randomised trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000; 11: 756-762.

4. Ponikau JU, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002;110:862-6.

The author
David W. Denning, MB BS FRCP FRCPath DCH,

University of Manchester and Wythenshawe Hospital,

Manchester,

UK

ddenning@man.ac.uk

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