Therapeutic potential of terbina®ne in subcutaneous andsystemic mycoses

R.J.HAY

St. John's Institute of Dermatology, The Guy's, King's and St. Thomas' School of Medicine (KCL), St. Thomas' Hospital,

London, SE1 9RT, UK.E-mail: r.hay@umds.ac.uk

Summary Mycoses vary widely in severity, and may present as super®cial, subcutaneous and/or systemic

infection. Effective treatments for most super®cial mycoses now exist, but new agents withconvenient dosing regimens and a low level of adverse events are still needed to reduce morbidity

and mortality from serious subcutaneous and systemic fungal infections. In vitro, terbina®ne exhibits

a broad spectrum of activity against the pathogenic fungi responsible for deep mycoses. Clinical data,while not abundant, suggest that this in vitro activity of terbina®ne is re¯ected in its in vivo ef®cacy.

The limited data show that terbina®ne is a useful ®rst-line treatment in chromoblastomycosis

patients and has ef®cacy in pulmonary aspergillosis. There are also data to suggest that terbina®nemay be effective in treating histoplasmosis, Pneumocystis carinii infection, fungal mycetoma, and

cutaneous leishmaniasis. Moreover, there is some evidence of terbina®ne having synergistic activity

with amphotericin B, itraconazole, and ¯uconazole against clinical isolates of Candida species. Thus,the therapeutic potential of terbina®ne extends well beyond its current use in acute and chronic

dermatophytoses to include a wide range of subcutaneous and systemic mycoses. Studies are neededto determine the optimum dose in each disease, and whether combination therapy would have

advantages in certain circumstances.

Mycoses come in many forms and appearances, arecaused by numerous organisms and vary widely in

severity ± from the relatively trivial to those that are

dis®guring or life-threatening. There is a popular per-ception, to some extent justi®ed, that effective treat-

ments for super®cial mycoses are now available.

Unfortunately, many fungal infections are subcuta-neous and/or systemic, with high mortality even

when treated, and have the ability to cause permanent

visible damage. More effective drug treatments, withconvenient dosing regimens and a low level of adverse

events, are still needed to reduce morbidity and

mortality from these serious conditions.Terbina®ne is currently indicated for the treatment of

super®cial dermatophyte and yeast infections. However,

early in vitro studies1 have suggested that terbina®nealso exhibits a broad spectrum of activity against patho-

genic fungi responsible for deep mycoses, as measured

by minimum inhibitory concentration (MIC) levels(Table 1). Note that all MICs shown are <1´0 mg/mL,

indicating signi®cant in vitro activity. Excellent in vitroactivity is also displayed against many other

pathogens, as recently reviewed,2 including Fusarium;

dematiaceous fungi such as Madurella, Cladosporium andFonsecaea species and certain pathogenic protozoa.

Clinical data, while not abundant, suggest that the in

vitro activity of terbina®ne against many of these patho-gens is re¯ected in its in vivo ef®cacy, as discussed below.

Terbina®ne in chromoblastomycosis

Chromoblastomycosis is a tropical fungal disease char-

acterized by dense dermal ®brosis associated with ahighly organized granulomatous reaction. Lesions,

often with superimposed bacterial infection, can be

grossly dis®guring, and pursue a chronic course over10±20 years. In Madagascar, where the disease is ende-

mic, two species of dematiaceous fungi are responsible for

infection: Fonsecaea pedrosoi in the northern tropical forestregion and Cladophialophora (Cladosporium) carrionii in the

southern drier thicket region.

In an open study,3 42 Malagasy patients withchromoblastomycosis received terbina®ne 500 mg/day

for up to 12 months, with a 6-month follow up period.All of them were evaluable for safety and 35 for ef®cacy.

Patients infected with F. pedrosoi (n�30 evaluable)

British Journal of Dermatology 1999; 141 (Suppl. 56): 36±40.

36 q 1999 British Association of Dermatologists

showed disappearance of bacterial superinfection and

associated elephantiasis within 4 months, and 85%mycological cure at 12 months. Clinical cure (as de®ned

in the study) was more than 74% at 12 months. In the

smaller group of patients infected with C. carrionii (n�5evaluable), the ef®cacy of terbina®ne was judged to be

even greater, with a 90% decrease in mean number of

fungal cells in skin scrapings after 4 months; at12 months, four patients showed complete healing,

while one showed good clinical improvement associated

with mycological cure. When the data from the twogroups were combined, 74´3% showed clinical and

85´7% mycological cure at 12 months. Given that

total cure is generally achieved, even in the chronicform of this disease, with only minor adverse events,

terbina®ne should be considered as a ®rst-line treatmentfor chromoblastomycosis.

Terbina®ne in sporotrichosis

Cutaneous sporotrichosis is caused by traumatic

implantation into the skin by conidia from thedimorphic fungus Sporothrix schenckii. Infection may

remain con®ned to the inoculation site (®xed form),

but more often (70±80% of cases) spreads by lymphaticdrainage to form a series of proximal nodules (lymphan-

gitic form). Systemic sporotrichosis is usually seen only

in immunocompromised patients, including those withHIV infection.

In an open study,4 ®ve patients with cutaneous

sporotrichosis received terbina®ne 250 mg twice dailyfor an average of 18 weeks (range 4±37): treatment

continued until complete clinical cure had been

obtained in all cases. The average time to negativeculture was 12 weeks (range 4±32). A total of 13

other patients received terbina®ne for cutaneous

sporotrichosis. All were successfully treated, withdoses between 125 and 500 mg/day (W. Shaoxi,

personal communication).5±7 No serious adverse

events were recorded. These data suggest that terbina-®ne may well be a highly effective treatment for this

condition, although the optimum duration of the

therapy has not been de®ned precisely.

Terbina®ne in fungal mycetoma

Mycetomas can be caused by at least 16 differentorganisms. They are a signi®cant challenge to anti-

fungal agents, due to the greatly increased thickness

of the individual cell walls of fungi in clinical lesions.However, some encouraging results are emerging, with

high doses of terbina®ne (up to 1000 mg/day) able to

achieve remission in some cases.

Terbina®ne in aspergillosis

Pulmonary aspergillosis is becoming increasingly

common, due to the extensive therapeutic use of corti-costeroid and immunosuppressive agents. In a number

of in vitro studies,2 terbina®ne has shown activity

against Aspergillus species equivalent to amphotericinB or itraconazole, with a fungicidal action.

Terbina®ne, alone or in combination with other anti-

fungal agents, has been used to treat patients sufferingfrom Aspergillus infections. Terbina®ne at doses between 5

and 15 mg/kg/day for 84±264 days has been used to

treat 14 non-immunocompromised patients affected withlower respiratory tract Aspergillus infections,8 mainly

chronic necrotizing pulmonary aspergillosis. Terbina®ne

showed ef®cacy in all 14 patients; all were consideredmicrobiologically cured, eight were also clinically cured

and six improved. One patient also infected by Scedospor-

ium apiospermum, multiresistant to all previous treat-ments, was successfully treated.

In four lung transplant patients with relapses of

aspergillar bronchitis, terbina®ne (250±500 mg/day)was effective in treating and preventing new episodes

of Aspergillus infections.9 A relapsing aspergillus bron-chitis in a double lung transplant patient was treated

with liposomal amphotericin B and itraconazole. After

two relapses the patient received terbina®ne 250 mgtwice daily for 3 months. Cultures became negative

and were still negative 14 months after treatment

discontinuation.10

Two patients receiving chemotherapy for leukaemia

developed invasive pulmonary aspergillosis (J. Beytout,

TERBINAFINE IN SUBCUTANEOUS AND SYSTEMIC MYCOSES 37

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141: (Suppl. 56) 36±40

Table 1. Minimum inhibitory concentration (MIC) levels of terbina®nefor some of the pathogens responsible for deep mycotic infection. Data

from reference 1

Pathogen MIC (mg/mL)

Candida parapsilosis 0´44

Cryptococcus neoformans 0´73

Histoplasma capsulatum 0´06Sporothrix schenckii 0´11

Blastomyces dermatitidis 0´08

Aspergillus fumigatus 0´29

Aspergillus ¯avus 0´06Chromoblastomycosis agents 0´07

personal communication). One patient also developed aCNS abscess when he was under prophylaxis with

itraconazole. Terbina®ne 2000 mg/day was added to

the treatment, and as a monotherapy following neuro-surgical drainage of the abscess. Terbina®ne was given

for a total period of 13 months. The second patient was

treated successfully with amphotericin B plus terbina-®ne. Monotherapy with terbina®ne (1000 mg/day for

185 days) was continued after the patient became

intolerant of amphotericin B.

Terbina®ne in histoplasmosis

Terbina®ne has been rarely used in this indication. The

treatment of choice, for example in a person with AIDSbut in no immediate danger of death, would be itraco-

nazole. We have managed one female patient with AIDS

on terbina®ne 500 mg/day because of triazole intoler-ance. After 8 weeks she achieved clinical remission of

histoplasmosis, with negative antigen levels and resolu-

tion of oral ulceration. Unfortunately, her AIDS laterprogressed, and she defaulted from treatment. A case of

successful treatment of African histoplasmosis with

terbina®ne was recently reported.11

Terbina®ne in Pneumocystis carinii

This condition is a major life-threatening complication

of immunode®ciency diseases, especially AIDS.

Although it is now believed that Pneumocystis carinii isa fungus rather than a protozoan, the antimicrobial

susceptibility of this organism differs markedly from

that of most other pathogenic fungi. This is due, inall probability, to the lack of ergosterol in the cell

membrane.

Dif®culties in growing the organism in the laboratoryrequire that comparisons between different therapeutic

agents be carried out in animal models. This is not

problematical: the histological features of the disease inanimals are similar to those in humans, and agents

active in animals are usually active in humans.

In an animal study12 using immunosuppressedSprague-Dawley rats with experimentally induced

P. carinii pneumonia, terbina®ne at doses of 40 mg and

80 mg/kg bodyweight/day was compared to atova-quone 100 mg/kg/day, albendazole 600 mg/kg/day, tri-

methoprim-sulphamethoxazole 12´5 mg and 62´5 mg/

kg/day and control (rats treated only with cortisoneacetate 25 mg twice weekly subcutaneously). Treat-

ment duration was 5 weeks, with n�15 in each

group. The results (Table 2) show that terbina®ne isas effective as trimethoprim-sulphamethoxazole in

clearing P. carinii infection and in reducing histological

scores, and more effective using these parameters thaneither atovaquone or albendazole. If these data can be

con®rmed, terbina®ne may come to be seen as a useful

therapy for this life-threatening disease.

Terbina®ne in cutaneous leishmaniasis

In an open study13 undertaken in Saudi Arabia, 27patients with cutaneous leishmaniasis due to Leishma-

nia tropica were divided into two groups: those aged 5±

15 years received terbina®ne 250 mg/day for 4 weeks,while those over 15 years received 500 mg/day for

4 weeks. Of the 14 patients evaluable at the end of the

study, four showed clinical cure, six showed more than60% improvement, but four failed therapy. These encoura-

ging results suggest that a controlled clinical trial of

38 R.J.HAY

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 36±40

Table 2. Terbina®ne in an experimental model of Pneumocystis carinii pneumonia. (Data from Reference 12)

Rats infected byTreatment group Survivala P. carinii (%)b Infectivity scorec

Terbina®ne (40 mg/kg/day) 11 27´2 6´0 6 0´3

Terbina®ne (80 mg/kg/day) 11 18´1 6´0 6 1´5

Trimethoprim (12´5 mg/kg/day) plus

Sulphamethoxazole (62´5 mg/kg/day) 12 15´3 8´0 6 1´1Atovaquone (100 mg/kg/day) 11 45´4 23´0 6 2´1

Albendazole (600 mg/kg/day) 13 58´3 19´4 6 7´1

Control (cortisone acetate 25 mg twice weekly, subcutaneously) 10 90´0 78´0 6 3´2

aNumber of rats surviving at end of study; n�15 per group exposed at start. bPercentage of surviving rats infected with Pneumocystis carinii at end of

study. cInfectivity score was calculated from lung smears stained with methenamine silver in which P. carinii cysts were counted by two independent

examiners. Values are the mean 6 SD. Scores in the terbina®ne groups are signi®cantly less than in the control (P<0´001).

terbina®ne in this indication, and for both old and newworld forms of leishmaniasis, is urgently required.

Discussion

It is clear that the therapeutic potential of terbina®ne

extends well beyond its current use in acute and chronicdermatophytoses to include a wide range of subcuta-

neous and systemic mycoses. What remains unclear is

the optimal dose of terbina®ne for each condition, andwhether combination therapy with another agent

would in some circumstances achieve better results.

These questions can be resolved by dose-®nding andother clinical studies, but it seems likely that doses of

500±1000 mg/day or more may well be needed for

systemic or deep-seated mycoses. For an agent with sucha broad spectrum of activity across a wide variety of

super®cial, subcutaneous, and systemic mycoses, terbina-

®ne is remarkably free of adverse events. As terbina®ne isfungicidally active in vitro against pathogenic mould fungi

such as Aspergillus and dimorphic fungi, it is particularly

important to assess its ef®cacy in vivo, as these infectionscause considerable morbidity and mortality in severely

immunocompromised patients, in whom the use of a

fungicidal drug has potential advantages.In addition to the bene®cial effects of terbina®ne in

the conditions discussed above, data are available tosuggest that terbina®ne may also be effective in sub-

cutaneous and deep-seated phaeohyphomycosis. Seven

cases have been reported, with one patient showingcure, three showing marked improvement, and two

showing moderate improvement. Other infections

known to have responded to terbina®ne includemucocutaneous paracoccidioidomycosis, cutaneous

mucormycosis, subcutaneous zygomycosis due to

Conidiobolus, and refractory pulmonary infection dueto Scedosporium.

Drug combinations are often used in the treatment of

bacterial and viral infections, but have to date been littleused in mycology, apart from amphotericin B plus

¯ucytosine. However, the rising incidence of oppor-

tunistic fungal infections in immunosuppressedpatients, together with the problem of acquired azole

resistance, suggests that combination therapy will

become increasingly important.Investigation of potential synergy between antifungal

agents has focused particularly on Candida species, due

to the growing problem of acquired resistance to azoles,particularly ¯uconazole. Several studies have shown

in vitro synergy between terbina®ne and either ¯uco-

nazole or itraconazole, using clinical isolates of

C. albicans, C. glabrata, C. krusei and C. tropicalis resistant

to triazoles (N.S. Ryder, personal communication;A.W. Fothergill, personal communication; L. Rodero,

personal communication).2,14 Terbina®ne, in combina-tion with ¯uconazole and itraconazole, was tested

against a battery of 70 yeast isolates (N.S. Ryder,

personal communication; Table 3). In another in vitrostudy,14 30 isolates of C. albicans from patients with

AIDS were tested for synergy (at 24 and 48 h) to

terbina®ne when given in combination with ampho-tericin B, itraconazole or ¯uconazole. The results (Fig. 1)

show that, at 24 h, 95% of isolates show synergistic

activity between terbina®ne and amphotericin B, butthis percentage falls to about 30% at 48 h. By contrast,

synergistic activity between terbina®ne and both triazoles

TERBINAFINE IN SUBCUTANEOUS AND SYSTEMIC MYCOSES 39

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141: (Suppl. 56) 36±40

Table 3. Synergy between terbina®ne and azoles in azole-resistant

Candida. (Data from N.S. Ryder, personal communication)

Percentage of strains

Pathogen Resistance to: showing synergy

C. albicans Fluconazole 50C. albicans Itraconazole/Fluconazole 70/90

C. tropicalis Fluconazole 100

C. krusei Fluconazole 25

Figure 1. Percentage of isolates (n�30) from patients with AIDS and

C. albicans infection showing synergy to terbina®ne when combinedwith amphotericin B, ¯uconazole, or itraconazole at 24 (open bars) or

48 h (shaded bars). (Data from reference 14.)

was seen in about 50% of isolates at both time points.These interesting observations suggest that the

synergistic effects of the available antifungal agents

should be more closely assessed, particularly in viewof the increasing resistance of Candida species to

azoles.

Chairman's overview

Terbina®ne has documented activity in other super®cial

mycoses, such as tinea pedis, tinea corporis/cruris, tinea

capitis and pityriasis versicolor. Of equal signi®cance,studies reported by Professor Hay have suggested that

terbina®ne is bene®cial across a broad spectrum of

severe and life-threatening subcutaneous and systemicmycoses, either as monotherapy or in combination with

other agents.

Con¯ict of interest: Professor Hay and his department

have received funds for clinical research from NovartisPharma and Janssen Research Foundation.

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40 R.J.HAY

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 36±40