`
`Leading articles
`
`The azale anih’m~gal drags
`
`The azole drugs constitute a large group of
`synthetic compounds whose members show a
`range of therapeutic activity encompassing
`fungal, protozoal and anaerobic bacterial
`infections, as well as immunostimulation.
`However, it is the antifungal potential of
`many of these drugs which has attracted much
`attention (Odds, 1980) and developmental
`research. Before their appearance, choice
`amongst antifungal drugs was limited. For tbe
`systemic mycoses, for instance, amphotericin
`B and flucytosine were the only alternatives
`and for some fungal infections, such as
`onychomycosis due to candida, there was no
`effective treatment. The availability of a range
`of antifungal imidazoles and, more recently
`triazoles, for both topical and systemic use has
`now widened the choice.
`The number of topical imidazoes for use in
`superficial fungal infections is large--some
`would say excessive--and there are more in
`development. Those currently available in
`Britain include clotrimazole, miconazole,
`econazole, ketoconazole, sulconazole, and
`isoconazole. The importance of these com-
`pounds lies mainly in their efficacy, confirmed
`by numerous studies, against the main super-
`ficial mycoses (dermatophytosis, candidosis
`and pityriasis versicolor). However, it has
`generally proved impossible to establish thera-
`peutic differences between them which would
`be of use in making a choice of drug (Roberts,
`1980). Recent attempts to simplify the use of
`topical antifungal therapy have shown that
`bifonazole, for instance, when used once daily
`in dermatophytosis, is as effective as the more
`usual twice daily regimen (Doting &
`Stettendorf, 1982). While this may reflect an
`inherent difference in the pharmacological
`properties of the drug, it is likely that other
`azoles will be found to behave similarly;
`indeed isoconazole shows sufficient skin
`surface retention to justify onc~ daily use
`(Dykes, Marks & Tauber, 1986). Single dose
`treatments with clotrimazole, isoconazole and
`tioconaTole are available for vaginal candi-
`dosis and produce satisfactory cure rates,
`although the chief benefit from simplification
`of topical regimens probably lies in increased
`patient compliance.
`Only a few members of this group can be
`given systemically but the imidazoles, keto-
`
`conaz~le (oral) and miconazole (intravenous),
`and the triazoles, itraconazole (oral) and
`fluconazole (oral), produce therapeutic blood
`levels. Of these only ketoconazole has been
`widely used in superficial infections and is
`effective in dermatophytosis, chronic muco-
`cutaneous candidosis (for which it has become
`the treatment of choice)’ and pityriasis
`versicolor. Comparative studies of keto-
`conazole versus griseofulvin have highlighted
`some differences such as a more rapid
`response of tinea corpofis to the former (Hay
`et al., 1985). But recovery rates of nail
`infections are similar. Early studies of
`itraconazole show that it is similarly active in
`some of these infections (Delescluse,
`Cauwenbergh & Degrecf, 1986). In sub-
`cutaneous mycoses the azoles have made a
`small but significant impact. For instance,
`ketoconazole has been found to be effective in
`mycetomas caused by Ma_.dw’.ella mycetomatis
`(Mahgnub & Gumaa, 1984) and itraconazole
`was shown to be curative in sporotriehosis
`(Restrepo et aL, 1986) although in the latter
`study only 35-3% of patients were cleared of
`the infection within 90 days of the start of
`therapy. In the case of the systemic mycoses
`objective clinical assessments have proved
`more difficult. However, in a few infections the
`effectiveness of some azoles has been
`established by small open studies. For instance
`in paracoccidioidomycosis oral miconazole,
`which is poorly absorbed, was effective in
`some cases (Lima et a/., 1977), but keto-
`conazole produced much better results and
`has since become the main treatment for this
`disease (P, estrepo et a!., 1980). The latter drug
`has also been found to be useful in some
`forms of histoplasmosis, blastomycosis and
`coccidioidomycosis (Dismukes et al., 1983),
`particularly for infections affecting soft tissues.
`The value of azole antifungals as treatment
`or prophylaxis for infections caused by
`systemic opportunists such as candida or
`aspergillus is less clear, Most of the data come
`from single case reports or, at the best, small
`series. With ketoconazole these indicate
`activity in some candida infections in non-
`neutropertic patients, such as candida endoph-
`thalmitis (Drouhet & Dupont, 1983), but, in
`accordance with the in-vitro sensitivity, little
`effect in aspergillosis. In the latter infection it
`is possible that itraconazole may prove helpful
`flits in-vitro activity (Van Cutsem et al., 1985)
`
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`ARGENTUM EX1029
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`Page 1
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`2
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`Leading articles
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`is mirrored by subsequent clinical experience
`(see, for example, Tricot et al., 1987).
`However, there are still insufficient numbers of
`critically assessed patients to establish clear
`guidelines for the use of these compounds in
`opportunistic infections even though attempts
`have been made to improve the flow of
`information by monitored release, in the case
`of intravenous miconazole (Barton, Fox &
`Waldron, 1981). A muldcentre study of
`ketoconazole in the U.S.A. has also provided
`useful data on the treatment of systemic
`infections (NIAID Mycoses Study Group,
`1985).
`Azole antifungals are not without disadvan-
`tages. For instance poor cover of aspergilius
`and zygomycete infections limits the use of
`miconazole or ketoconaz~le as empirical
`therapy in febrile neutropenic patients.
`Absorption of ketoconazole in some patients,
`particularly after bone marrow grafts, is poor
`(Hann et al., 1983) and it is not clear at
`present whether this extends to the new oral
`triazoles. In rare cases azole cross resistance
`has been reported following continuous long-
`tc~m use of ketoconazole in patients with
`chronic mucocutaneous candidosis (Ryley,
`Wilson & Barrett-Bee, 1984) or AIDS
`(Tavitian et a/., 1986). When ketoconazole has
`been used as a prophylactic agent continued
`faecal carriage of less sensitive, but potentially
`pathogenic, organisms such as Torulopsis
`(Candida) glabrata has posed clinical prob-
`lems. It has also been reported that ampho-
`tedcin B is less effective in mice with
`experimental aspergillosis if the animals are
`pretreated with ketoconazole (Schaffner &
`Frick, 1985); a similar phenomenon has not
`been recorded in human infections.
`The incidence of drug toxicity caused by
`antifungal azoles has generally been low.
`Nevertheless, miconazole, for instance, can
`cause ventricular tachycardia and anaphylaxis
`(Fainstein & Bodey, 1980) on rare occasions.
`With the wider use of ketoconazole cases of
`drug related hepatitis were reported (Lewis et
`ai., 1984; Lake-Bakaar, Scheuer & Sherlock,
`1987). At present the estimated incidence of
`the latter is approximately i in 10,000 patients
`and while the risk factors are not completely
`understood, a history of liver disease and the
`use of the drug for the treatment of
`onychomycosis are both associated with an
`increased risk of hepatitis. Unfortunately the
`mechanism appears to be idiosyncratic and
`unpredictable. Inhibition of pathways of
`steroid biosynthesis dependent on cytochrome
`P450 is thought to be responsible for the
`
`androgen blocking activity of ketoconazole at
`high dosage (Pont et al., 1984) and the
`development of azoles without affinity for the
`human enzyme is regarded as an important
`objective since toxicity of this nature neces-
`sarily limits the use of drugs for non life-
`threatening conditions.
`The oral triazoles currently in development,
`itraconazole (Van Cutsem el a/., 1985) and
`fluconazole (Richardson et al., 1985), have
`shown promise in superficial fungal infections.
`Itraconazole is absorbed in low concen-
`trations, and is avidly tissue bound. In
`contrast fluconazole is well absorbed and
`penetrates urine and cerebrospinal fluid, and
`only a small proportion is protein bound.
`Both drugs appear to have potential in deep
`mycoses including some infections such as
`aspergillosis (itraconazole) and urinary
`candidosis (fluconazole) that are not well
`covered by existing antifungals. It will be a
`challenge to devise suitable methods of
`establishing their therapeutic roles in systemic
`fungal disease.
`
`R. J. HAY
`Medical Mycology and Tropical Dermatology Unit,
`Department of Medical Microbiology,
`London School of Hygiene and Tropical Medicine,
`Keppel Street,
`London WCIE 7HT,
`England
`
`References
`
`Barton, G. J., Fox, J. J. & Waldron, H. A. (1980.
`Monitored reltm~ of intravenous miconazole in
`the United Kingdom. A report of the first 2 year’s
`experience. Royal Society of Medicine Inter-
`national Congreaa and Symposium Series 45,
`27-36.
`Delescluse, J., Cauwenbergh, G. & l:K’greef, H.
`(1986). ltraconazole, a new orally active anfi-
`fungal, in the treatment of pityriasis versioolor.
`British Journal of Dermatology 114, 701-3.
`Dismukes, W. E., Stature, A. M., Graybill, J. R.
`Craven, P. C., Stevens, D. A., Gallis, R., et al.
`(1983). Treatment of systemic mycoses with
`ketoconazole. Emphasis on toxicity and clinical
`response in 52 patients. Anna/s of Internal
`Medicine 98, 13-20.
`Doting, H. F. & Stetlendorf, S. (1982). Bifonazole---
`a new agent for the treatment of dermatomycoses.
`In International Anlifunga! SympoMum:
`Bifonazole, pp. 96-107. Excerpta Medica,
`Amsterdam.
`Drouhet, E. & Dupont, B. (1983). Laboratory and
`assessment of ketocormTnle in deep seated
`mycoses. American Journal of Medicine 74, I B
`30--47.
`Dykes, P. J., Marks, 17,. & Tauber, U. (1986). The
`retention of isoconazol¢ in the skin after once or
`
`©
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`t.,o
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`Page 2
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`Leading articles
`
`3
`
`twice daily application of !% isocouazole nitrate
`cream (Travogen) over a 14 day period. Clinical
`and Experimental Dermatology 11, 365-70.
`Fain~tein, V. & Bodey, G. P. (1980). Cardiorespira-
`tory toxicity due to rniconazole. Annals oflnternal
`Medicine 93, 432-3.
`Harm, I. M., Prentice, H. G., Corringham, R.,
`Blacklock, H. A., Keaney, M., Shannon, M. et al.
`(1983). KetoconaT~le verzua nystafin plus ampho-
`~icin B for fungal prophylaxis in ~terely
`immunocompromJsed patients. Lancet i. 826-9.
`Hay, R. J., Clayton, Y. M., Griffith~ W. A. D. &
`Dowd, P. M. (1985) A comparative double blind
`study of ketoconazole and griscofulvin in derma-
`tophytusis. British Journal of Dermato/ogy 112,
`691-6.
`Lake-Bakaar, O., Scheuer, P.J. & Sherlock, S.
`(1987). Hepatic reactions associated with
`ketoconazole In the United Kingdom. British
`Medical Journal 294, 419-22.
`Lewis, J. H., Zimlnel-ma~ H. J., Benin, G. D. &
`Ishak, K. G. (1984). Hepatic injury associated
`with ketoconazole therapy--analysis of 33 cases.
`Gastroenterology 86, 503-13.
`Lima, N. S., Tcixeira, G., Miranda, J. & do Valle,
`A. C. F. 0977). Treatment of South American
`blastomycosis (paracoccidioidomycosis) with
`mic.onazole by the oral route--an on-going study.
`Proceedings of the Royal Society of Medicine 70,
`Suppl. 1, 35-9
`Mahgoub, E. S. & Gmnaa, S. A. (1984). Keto-
`conazole in the treatment of eumycetoma due to
`Madureiln mycetomati~. Transactions of the Royal
`
`Society of Hygiene and Tropical Medicine 78,
`376-9.
`National Institutes of Allergy and Infectious Di _s~_~
`Mycoses Study Group (1985). Treatment of
`blastomycofis and histoplasmosis with
`ketoconazole. Annals of Internal Medicine 103,
`861-72.
`Odds, F. C. (1980). Laboratory evaluation of
`antifungal agents; a comparative study of five
`imidazole derivatives of clinical importance.
`Journal of Antimicrobial Chemotherapy 6, 749-61.
`Pont, A., Graybill, J. R., Craven, P. C., Galgiani,
`J. N., Dismuke~, W. E., Reitz, R. E. et at. (1984).
`High dose ketoconazole therapy and adrenal and
`testicular function in human. Arcku’ves of Internal
`Medicine i44, 2150-3.
`Rostrum, A., Stevens, D. A., Leiderman, E.,
`Fuentcs, J., Arana, A, Angel, IL et al. (1980).
`Ketoconazole in paracoccidioidomycosis;
`of prolonged oral therapy. Mycopathologia 72,
`35-45.
`Restrepo, A. Robledo, L, Gom~ I., Tabar~ A.
`M. & Gutierr~ R. (1986). Itraconazole therapy
`in lymphangific and cutaneous sporotrichosis.
`Archives of Dermatology 112, 413-7.
`Richardson, K., Brammer, K. W., Marriott, M. S.
`& Troke, P. F. (1985). Activity of UK 49858, a
`Bis-triazole derivative against experimental infec-
`tions with Candidn albican~ and Trichophyton
`mtntagrophyte& Antimicrobial A[gent3 and Chemo-
`therapy 27, 832-5.
`
`Roberts, S. O. B. (1980). The treatment of the
`superficial and subculancous mycoses. In Anti-
`fungal Chemotherapy (Speller, D. C. E., Ed.,), pp.
`225-83. John W’dey, Chichestev.
`Ryle% J. F., W’flson, R. G. & Barrett-Bee, K. J.
`(1984). Azole resistance in Cav,~,~,, a/bican~.
`Journal of Me~eM and Veterinary Mycology 22,
`53-64.
`Schaffner, A. & Frick, P. G. (1985). The effect of
`ketoconazole on amphotericin B in a model of
`disseminated ~o~ Journal of Infectious
`Diseases 152, 902-10.
`Tavifian, A., Raufman; J. P., Rose~thal, L. E.,
`Weber, J., Webber, C. A. & Dincaoy, H. P.
`(I 986). Ketoconazole resistant Candida
`csophagitis in patients with acquired immunb-
`defi~ency syndrome. Gastroenterology 90, 443-5.
`Tricot, G., Joosten, E., Boogaerts, M. A., Van de
`Pitte, J. & Cauwenbergh, G. (1987). Kctoconazole
`vs itraconazole for antifungal prophylaxis in
`patients with severe granulocytopema:
`preliminary results of two non randomized
`studies. Roiews of Infectious Diseases 9, Suppl. ],
`94-9.
`Van Cu~, J., Van ~ J., Van de Ven, M. A.,
`Borgers, M. & J~ P. A. J. (1985).
`Itraconazole, a new triazole, that is orally active
`in ~llosis. Antfmicrobial Agents and Chemo-
`therapy 26, 527-34.
`
`Pentdllin4Muced hypersensitivity vasculitides
`
`Hypersensitivity to penicillin gives rise to a
`wide variety of cfinical syndromes including
`maculopapular rashes, urticaria, angioedema,
`haemolytic anaemia, anaphylactic shock, and
`acute interstitial nephritis. Very uncommon
`manifestations of penicillin hypersensitivity
`are necrotizing angiitis, polyarteritis nodosa
`(Spring, 1951; Peters etal., 1960; Schrier,
`Bulger & Vain Arsdel, 1966; Vahanian et al.,
`1977) and, most frequently within this group
`of rare reactions, hypersensitivity vasculitis
`(McCoombs, 1965; Mullick et al., 1979).
`Necrotizing angiitides constitute a
`heterogeneous group of diseases whose
`histological common denominators are
`fibrinoid necrosis and inflammation of the
`vessel walls with a pleomorphic cellular
`infiltrate with predominant polymorpho-
`nuclear leucocytes. According to Alarcon-
`S~govia (1980), hypersensitivity vasculitides
`are defined as necrotizing but not granu-
`Iomatous vasculitides involving cutaneous or
`systemic small vessels. Hypersensitivity
`vasculitides may be associated with various
`diseases such as lupus erythematosus, mixed
`cryoglobulinaemia, neoplasia, leukaemia and
`rheumatic or intestinal inflammatory diseases.
`
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