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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