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Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from Postgraduate Medical Journal (September 1979) 55, 587-592

INTRODUCTORY ADDRESS

Antifungal therapy, 1978 G. L. BAUM M.D. Pulmonary Division, Department ofMedicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Summary of the cause of favus, both in 1839. This was the age The past 40 years have brought great advances in the of descriptive medicine and so it is natural that under- knowledge of morphology, immunology and epi- standing of effective treatments, such-as they existed, demiology of fungal in man. Each general was limited to the simple observation that these advance in the science of medicine has had its counter- treatments did, indeed, work. Again, based on part in man's improved facility to deal with these description only, it is clear why diseases of the skin infections therapeutically. Although satisfactory con- should have been so prominent among the literature trol of fungal infections of man is still of the 19th century. The list of treatments for the lacking, Protected by copyright. productive paths of investigation seem to have been wide variety of ringworm infections, for example, is found and the continued application of rigorous long and consists of unguents, lotions, and powders discipline to research efforts should provide even more all of which either discoloured the skin so badly that efficient treatment in the future. the continuously flourishing was invisible or caused the skin to peel or slough off so that, once IN SPITE of the emphasis being placed by this con- again, the physician and, even more importantly, the ference on the therapy of fungal diseases it seems to patient, could no longer see the lesion. This latter me that the understanding of where we have been approach was actually effective with 2 slight draw- and to what point we have arrived in the treatment backs: the infection frequently returned and the of this group of diseases requires us to consider the results of overuse or overconcentration of the therapy broader accomplishments of our quest for under- gave rise to skin lesions that made the fungal standing of our subject. That is to say that a simple infection a pleasure by comparison. Not to be under- recitation of what drugs, incantations, and manipu- estimated in assessing these various treatments was lations were used and are being used and the names the circumstance of remuneration to the therapist and drinking habits of the men who first published which generally was, over the period of many http://pmj.bmj.com/ on these activities simply will not do. If perspective recurrences, considerable. Considering the drama of is desired then a search for understanding is essential. apparent cure, albeit short-lived, and the comfort of I have been unable to find any citation or letters a consistent income, it is a wonder that the great to the editor to explain the rationale of what must break-through of was greeted with such have been the earliest treatment by our ancestors of enthusiasm. itchy toes; that is amputation. Nevertheless, I believe The beginnings were rather unimpressive ... and that it is clear to us all what motivated the action. surprisingly early, 1939. Oxford, Raistrick and On the other hand Hippocratic logic in using local Simonart (1939) reported discovery of the substance on September 25, 2021 by guest. bleeding as treatment for ulcers on the toes occasion- from the mould Penicillium griseofulvin and some- ally caused by fungi is a bit obscure unless one thing of its chemical nature. This period of pre- accepts the master's rationale that bleeding an area World War II was a time in the history of medicine is a means to dry it (Adams, 1971). when the beginnings of modern biochemistry of the Although Giovan Cosimo Bonomo was the first 1920s were being applied to medicine of the 1930s. to relate a human disease to the activities of a small That was the time when this biochemical approach companion, in his case scabies caused by Acarus was particularly appealing for the microbiologist scabiei, in 1787, the field of has the since the 1930s had witnessed the beginnings of the honour ofhaving given the field ofinfectious diseases chemotherapy ofbacterial diseases with the sulphon- its scientific beginnings with the discovery by amides. So it was natural that the effect of Langenbeck of the thrush and by Schoenlein biologically generated substances should be looked 0032-5473/79/0900-0587$02.00 © 1979 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from 588 G. L. Baum at as possible influences on the life cycle of micro- Ageing of humans has been given rather bad organisms. The drama of penicillin was about to publicity of late but I have to admit that it is not as explode upon society but 1939 was a little too early bad as I once thought it might be. Advantages take for anyone to try out this apparently interesting but some looking after but they do exist, and one of not important substance, griseofulvin, against fungi, them is the feeling that one has lived through great of all things! days of discovery and can report to another gener- And so the appearance of had to ation on such great moments. My first stutterings happen with great drama, seemingly as a by-product into mycological mysteries were at the knee of my of the tragedy of World War II. Antibiotics came teacher and father in medicine, Jan Schwarz, and along with empirical regularity, penicillin, strepto- our first efforts were directed towards North mycin, the first of the tetracyclines, para-amino American . Our mutual affection and , and in 1949 , discovered by enthusiasm served us both well: I learned a tre- Brown and Hazen. At the same time the first words mendous amount about medicine, especially fungus were printed about the effect of stilbamidine and diseases, from him, and he obtained translations of then 2-hydroxy stilbamide on blastomycosis; and in his words from English to English from me. As we 1956 we were given amphotericin. But more about pursued our interests in blastomycosis we were all of them later; it is back to the first discovered impressed that the available treatment using iodides griseofulvin for more detail. and various immunization programmes using blasto- In 1958 Gentles reported on this drug as having an mycin were terribly ineffective and did little to effect on experimental ringworm in guinea-pigs and improve the horrible prognosis of disseminated in the same year Williams, Marten and Sarkany disease. We toyed with a substance called ethyl (1958) reported on treatment of ringworm in man vanillate and even went so far as to treat one man for with this substance. In 1959, the flood gates were a short time with this foul potion. What stopped us

opened by Harvey Blank and the drug was off and was the unfortunate circumstances of Dr Schwarz'sProtected by copyright. running (Blank and Roth, 1959). But what gave this tasting the witch's brew one day before giving it to substance that had lain fallow for 20 years the push the hapless patient. Jan was and still is a 'chicken- into some studies that led to discovery of its exciting heart' and could not bear tormenting the poor fellow characteristics? Perhaps it was the words of the with that brackish brew with so little hope of success. authors of 1939 who wrote of this substance in the Either in spite of or because of the treatment the context of biochemistry of the mother organism and patient did not improve. We played in the laboratory thereby aroused the curiosity of a susceptible Dr with various agents and were thrilled to find a Gentles or perhaps it was something much more miracle in the form of stilbamidine which was used banal: curiosity to see what would happen if the by Dr Emanuel Schoenbach in New York for substance was cooked with the one group of patho- blastomycosis. His reports in 1948 and 1951 were the genic fungi that seemed resistant to all the newer first reporting success in the treatment of this agents that had been described up to that terrible disease (Schoenbach and Greenspan, 1948; point. After all, nearly everything except the der- Schoenbach et al., 1951). Why Dr Schoenbach was matophytes was being treated at least in the labora- working in such an area is not clear but this was a tory, so why not try it out! I am not sure what came time of intense interest in chemical interference with http://pmj.bmj.com/ first, the success clinically in guinea-pigs or the various disease processes; one has only to think of observation that the hyphae of the the plethora of agents that were being used for were curled by this substance; but, in any case, the metabolic defects or the exciting discoveries that enquiring mind was primed to make the clinical were being made in enzymology at the same time. observation and now we have a drug that works. Cell biology as we know it today was only the dream But we have now grown more sophisticated and of a few physicists and biologists but metabolic are no satisfied to say it works and and defects therein discovered preoccupied longer merely pathways on September 25, 2021 by guest. curls hyphae into the bargain. We have advanced in many investigators. Thus the aromatic diamidines the 1970s to finding a cellular biological explanation found their way into the hands of an astute clinical for all these phenomena, such as killing fungi and so investigator, and blastomycosis became treatable. we have arrived at the conclusions that griseofulvin Needless to say the toxicity was great and led to the inhibits DNA synthesis, destroys cytoplasm and use of the 2-hydroxy derivative but that was a kills the fungus. The words are impressive but I have technicality; the stroke of genius was Schoenbach's a hunch that we really do not understand it all and and the validation was found to come from another the 1980s will have to unravel how all this works, classical clinical investigator, Isadore Snapper, only what reactor sites are blocked and how it really does a few months later (Snapper and McVay, 1952). what it does. Perhaps we will start to learn here at But now we come to the big story of the last 30 this conference. years: the discovery of nystatin by 2 intrepid ladies Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from Antifungal therapy, 1978 589 who were working for the New York State Depart- Now the stage was set for the discovery by Gold, ment of Health. Drs Brown and Hazen isolated a et al. (1956) of amphotericin. As is well known, this species of on the Nourse dairy farm in substance (really 2 substances) was found to be the Fouquier County, Virginia, and from the locale came product of Strep. nodosus which had been isolated the organism's name, S. noursei. They found 2 in the Orinoco river valley. The 2 forms of ampho- substances produced by the fungus, tericin, named A and B, were separated by Steinberg, actidione and nystatin (Brown and Hazen, 1949; Jambor and Suydam (1956) and the work of Gold Hazen and Brown, 1950). The former was useful in and his colleagues (1956) was extended and sup- its own right but the primary discovery was that a ported. This was THE polyene antibiotic and it had polyene substance had unique properties, among not only in vitro effect on a wide variety of deep fungi them its ability in low concentration to inhibit the but it also worked against infections in animals and growth of several fungi in vitro and, in high con- man. As a budding student of mycology in Dr centrations, to kill them. The good news was that Schwarz's laboratory I spent many a day and night in vitro the spectrum included Candida spp., Crypto- injecting animals with amphotericin and other lesser coccocus neoformans, , Blas- substances as we, along with many other investi- tomyces dermatitidis, Paracoccidioides brasiliensis, gators, exploited the promise implied by the earlier (these latter in their forms) reports. By the late 1950s it was clearly established and a wide variety of the dermatophytes. The bad that this drug worked and, in spite of its relative news was that the substance was all but completely insolubility, it could be given intravenously, and by insoluble in water and, therefore, its use was limited this route did, indeed, fulfil its destiny as an effective to direct application to the offending fungus. clinical tool. Switching hats again I participated both Never mind, this was a major discovery both from with Dr Schwarz and with the Veterans Administra- the point of view of the direct results over the years tion Cooperative Studies in helping to demonstrate

of use ofnystatin and from the fact that it introduced that , blastomycosis, , Protected by copyright. to the investigator a new family of substances that systemic and were all has proved to be highly effective in the treatment of effectively treated with . During this deep fungus infections in man. Keeping in mind the same period, several workers in the western United time of the discovery we find ourselves in the halcyon States demonstrated the significant impact of days of the post-World War II search for new anti- amphotericin B on . biotics. The mechanism of action was found to be con- In addition to the contribution made to the sistent with that of nystatin but a stroke of genius treatment of Candida infections, nystatin has become was expressed by Kobayashi et al. (1972) when they a tool to unravel the mode of action of polyene exploited the permeability effect of amphotericin to antibiotics on the susceptible micro-organisms. the cell wall and added rifampicin to the mix and got Lampen and his colleagues (Lampen, Morgan and a considerable enhancement of the anti-DNA effect, Slocum, 1956, 1957) pointed out that nystatin apparently owing to the increased penetration of the attaches itself to the cell wall of the yeast cell and cell by rifampicin. renders it more permeable, first increasing its 02 But what of the toxicity of this drug? From a consumption and then causing it to fall to nothing, personal point of view I can add that both in my http://pmj.bmj.com/ with subsequent cell death. This latter appeared to clinical experience with patients and as a participant be due to loss of potassium through the permeable in the Cooperative Studies I found that the bark of cell membrane followed by inhibition of utilization toxicity was considerably greater than the bite. of glucose both via aerobic and anaerobic pathways Kidneys and bone marrow were found to be badly (Marini, Arnow and Lampen, 1961). damaged but, by and large, not permanently so. As a clinician, my own interests were more in the Professor Symmers stated it brilliantly by coining the area of deep fungus infections; thus I found nystatin term 'pharmacophobia', pointing out that the disappointing but in the area of surface troubles with greatest danger was in not using the drug where it on September 25, 2021 by guest. Candida in debilitated patients, for example, the was indicated (Symmers, 1973). effects of this substance were amazing. It was always These experiences were noted during the times of my feeling that it lacked only a colourful personality great achievement in cell biology, and investigations such as that of gentian violet, the treatment of of this drug were therefore carried out. To this day, another era for Candida overgrowth. I probably was we are continuing to use this substance as a cell not the first to realize that a few drops of gentian membrane-active agent and who knows what secrets violet added to the suspension of nystatin applied to may come through the cell walls thus rendered more tongue, mouth, ear, finger-tips or vaginal mucosa permeable by amphotericin B. We also learned early added tremendously to the impact of the treatment on to use the clinical trial approach to finding out if on the patient. a cure was really a cure and of course the Medical Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from 590 G. L. Baum Research Council of the U.K., the U.S. Public some of the dermatophytes, it was soon found that Health Service and the U.S. Veterans Administration blood levels were impossible to maintain even with all share the honour of developing and exploiting very high doses of the drug. The mechanism for this this method. strange phenomenon appears to be the activation, We come now to the story of 5-fluorocytosine, an after initial exposure, of liver enzymes which destroy agent which began its career in the shadow of its the drug. With , the effect has proved to more toxic cousin, 5-fluorouracil, one of the earliest be more reliable, and the drug appears to be a of the antineoplastic agents. 5-Fluorocytosine was reliable oral treatment for candidiasis, some der- discovered by Duschinski, Plevin and Heidelberger matophyte infections and, of particular note, for (1957) but its antifungal activity was first reported by coccidioidomycosis (Stevens, Levine and Deresinski, a friend of many years, Emanuel Gruneberg, and his 1976). It is in this latter role that the most dramatic colleagues (Gruneberg, Titsworth and Bennet, 1964). implications arise since disseminated coccidioidomy- I remember a meeting of the Cooperative Study cosis remains a difficult infection to treat and group of the Veterans Administration dealing with amphotericin B, although effective, is far from the fungus diseases in the early 1960s when Dr Grune- ideal agent. Only time will clarify the role of this berg mentioned his discovery; and, in the 6 months new, promising agent. between that first announcement and our next As a recent development, Dr Levine (1976) in meeting, several investigators reported anecdotal California has reported experience with a dioxolane experience with the drug. I complained to my , R-3400, which has shown promising colleagues that it was too bad that no animal work results in experimental coccidioidomycosis. Perhaps was being done to support these early in vitro claims we are about to find another effective agent in this and in the manner of many a dyspeptic non-believer, exciting chemical family. doubted the validity of the claims. As matters have In order to finish this brief encounter with the past turned out I was wrong in my conclusions even and present of antimycotic chemotherapy let me Protected by copyright. though I am convinced that my methodological deal a moment with 2 agents that were received by complaints were justified. We have come to find the world of mycologists with anticipation but which 5-fluorocytosine a useful adjunctive drug to be used faded from the scene after a brief moment of fame. with amphotericin B in the treatment particularly of These are not the only such agents to have come and cryptococcal meningitis. It is useful in its own right gone in the past 40 years but they are the ones I dealt as a treatment for candidal infections but in the case with and of which I can recount some personal of both Candida and Cryptococcus resistance reactions. develops quickly, or is already present, and this In 1961, Gruneberg, Berger and Titsworth re- limits the use of the agent as a single treatment. ported on the antibiotic they obtained from Strep. Coming along as it did as a by-product of cancer novum, x-5079-c, a name with adventurous impli- chemotherapy, we must credit the zealous search for cations but marketing limitations. Subsequently it anti-neoplastic agents as being responsible for the became known as saramycetin, named after Dr discovery of 5-fluorocytosine. That was an interest- Gruneberg's daughter. More importantly it had ing time, when millions of U.S. dollars were being significant activity against H. capsulatum, and B. spent in the race to find the cure for malignant dermatitidis and was proposed for extensive clinical http://pmj.bmj.com/ disease. In the course of studies with this agent we trials after the usual preliminary statements of learned that the effect on the yeast cell was actually success. Dr Gruneberg approached the Veterans achieved by 5-fluorouracil and the conversion of 5- Administration (V.A.) and, although they expressed fluorocytosine to 5-fluorouracil occurred within the interest, the company that manufactured the drug yeast cell. This conversion does not occur within the discontinued it owing to the high cost of production human cells because man lacks the necessary and the relatively small market potential and agreed a enzyme, very convenient difference between yeast to a franchise arrangement if someone would pay for on September 25, 2021 by guest. and human cells indeed! This, then, accounts for the the production. A grant was given by the National relative lack of toxicity in man of this drug and Cancer Institute to cover the cost of the drug, $75 000 rationalizes its use against yeast infections. for the first kilo. By this time, the Food and Drug This brings us to a family of drugs that has Administration had set up its strict procedures, and appeared since 1969. and miconazole extensive laboratory testing was required before the were both reported upon in those times (Plempel et clinical trials. When this was completed, the V.A. al., 1969, 1970; Godefroi et al., 1969). Both these was ready to start on the big test but they had used drugs were found to be active in that they increased up that first kilo and ordered a second. As the trial membrane permeability, a familiar story with anti- was about to get started the Food and Drug Admini- mycotic agents. With clotrimazole, in spite of its stration exploded their bombshell by stating that promise of activity against , Candida and with a new batch new basic data would be required. Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from Antifungal therapy, 1978 591

Such a 'crafty' approach was too much even for the References V.A. and saramycetin faded away and has not been ADAMS, F. (1971) The Genuine Works ofHippocrates, vol. II, heard of since. We must always wonder what might p. 294. William Wood & Co., New York. BLANK, H. & ROTH Jr, F.J. (1959) The treatment of derma- have been but, frankly, the early results were no tomycoses with orally administered griseofulvin. A.M.A. better than with existing treatment so perhaps we Archives of Dermatology, 79, 259. didn't lose too much. BROWN, R. & HAZEN, E.L. (1949) Annual Report, Division of Of even more personal connection was the story Laboratories and Research, p. 19. New York State Depart- of hamycin, a polyene antibiotic that was discovered ment of Health. DUSCHINSKI, R., PLEVIN, E. & HEIDELBERGER, C. (1957) in India by Thirumalachar, Menon and Bhatt (1961) The synthesis of 5-fluoropyrimidines. Journal of the and developed in the U.S. by Williams, Bennett and American Chemical Society, 79, 4559. Emmons (1965). The drug was found to be active GENTLES, J.C. (1958) Experimental ringworm in guinea-pigs: against B. dermatitidis and in clinical practice was oral treatment with griseofulvin. Nature. London, 182, 476. found to be a potential alternative to amphotericin B GODEFROT, E.F., HEERES, J., VAN CUTSEM, J.M. & JANSSEN, P.A.J. (1969) The preparation and antimycotic properties and hydroxystilbamidine in the treatment of North of derivatives of 1-phenetyl-imidazole. Journal ofMedicinal American blastomycosis. The preliminary work was Chemistry, 12, 784. done and the drug was accepted by the Food and GOLD, W., STOUT, H.A., PAGANO, J.G. & DONOVICK, R. Drug Administration for clinical trials. Again the (1956) Amphotericin A and B: antifungal antibiotics pro- V.A. was involved and it was to duced by a streptomycete. I. In vitro studies. Antibiotics my responsibility Annual, 1955-1956, p. 526. Medical Encyclopedia Incor- develop the protocol and help to organize the porated, New York. co-operating hospitals. I spent nearly a year getting GRUNEBERG, E., BERGER, J. & TITSWORTH, E. (1961) Chemo- things into good order and had arranged for the therapeutic studies on a new antifungal agent, x-5079 C, final protocol to be printed by the V.A. with the effective against systemic mycoses. American Review of I Respiratory Diseases, 84, 504. blessings of the statisticians. As a courtesy sent the GRUNEBERG, E., TITsWORTH, E. & BENNET, M. (1964) last rough copy to the drug company representatives Chemotherapeutic activity of 5-fluorocytosine. In: Anti- Protected by copyright. with whom I had been working closely. After a long microbial Agents and Chemotherapy, 1963, p. 566. silence, I was told that the company was discontinu- American Society for Microbiology, Ann Arbor. ing importation of the drug because the potential HAZEN, E.L. & BROWN, R. (1950) Two antifungal agents market did not the produced by a soil actinomycete. Science. New York, etc., seem to them to justify cost. 112, 423. Who knows what we may have lost and who can say KOBAYASHI, G.S., MEDOFF, G., SCHLESINGER, D., KWAN, what we might have learned about cell-drug inter- C.N. & MUSSER, W.E. (1972) Amphotericin B potentiation action or dynamics of organism biochemistry. of rifampicin as an antifungal agent against the yeast phase We are about to embark on a conference to hear of Histoplasma capsulatum. Science. New York, etc., 177, 709. the latest news. What has gone before was a reflec- LAMPEK, J.O., MORGAN, E.R. & SLOCUM, A.C. (1956) tion of the needs, the times but especially the Inhibition of sugar utilization by nystatin. Federation Pro- curiosity and industry of the men who did the work. ceedings, 15, 295. I have not in any way cited all the major contribu- LAMPEN, J.O., MORGAN, E.R. & SLOCUM, A.C. (1957) Effect tions made in this field but I have tried to pick out of nystatin on the utilization of substrates by yeast and some of the early discoveries. There is an American other fungi. Journal of Bacteriology, 74, 297. LEVINE, H.B. (1976) R-3400, a dioxolane imidazole in the http://pmj.bmj.com/ bias to this presentation but for this I have no therapy for experimental coccidioidomycosis: comparison excuses, only an explanation. This is but a preamble with miconazole and . Chest, 70, 755. to the conference. The one matter which we can MARINI, F., ARNOW, P. & LAMPEN, J.O. (1961) The effect of apply from past experience to future activity is monovalent cations on the inhibition of yeast metabolism the rigorous insistence on careful dissemination of by nystatin. Journal of General Microbiology, 24, 51. data and, even more, a careful interpretation of OXFORD, A.E., RAISTRICK, H. & SIMONART, P. (1939) XXIX Studies on the biochemistry of micro-organisms: LX them. Griseofulvin C18H170,C1, a metabolic product of Peni-

As we open this conference my clinical bias cillium griseofulvin Dierckx. Biochemistry Journal, 33, 240. on September 25, 2021 by guest. prompts me to express questions which I hope may PLEMPEL, M., BARTMANN, K., BEUCHEL, K.H. & REGAL, E. be touched upon. Are there in vitro indices which (1969) Experimentelle Befunde ueber ein neues oral wirk- can be used as guides to the length of antifungal sames Antimykotikum mit breiten Wirkung-spektrum. therapy? Are all known fungal infections necessarily Deutsche medizinische Wochenschrift, 94, 1356. PLEMPEL, M., BARTMANN, K., BUECHEL, K.H. & REGAL, E. to be treated with anti-fungal agents? Is the host (1970) Bay b 5097, a new orally applicable antifungal response a matter of only divine intervention, or substance with broad-spectrum activity. In: Antimicrobial may we expect more effective and longer lasting tools Agents and Chemotherapy, 1969, p. 271. American Society such as transfer factor, B.C.G., levamisole and for Microbiology, Ann Arbor. thymic hormone to be available to the clinician? Is SCHOENBACH, E.B. & GREENSPAN, E.M. (1948) The pharma- cology, mode of action and therapeutic potentialities of immunization a means significantly to reduce stilbamidine, , propamidine and other aro- morbidity and mortality from fungal infections? matic diamidines. A review. Medicine, 27, 327. Postgrad Med J: first published as 10.1136/pgmj.55.647.587 on 1 September 1979. Downloaded from 592 G. L. Baum

SCHOENBACH, E.B., MILLER, J.M., GINSBERT, M. & LONG, pharmacologic studies in man. American Journal of P.H. (1951) Systemic blastomycosis treated with stilbami- Medicine, 60, 191. dine: a preliminary report. Journal ofthe American Medical SYMMERS, W.STC. (1973) Amphotericin pharmacophobia. Association, 146, 1317. British Medical Journal, 4, 460. SNAPPER, I. & MCVAY, L.O. (1952) The treatment of North THIRUMALACHAR, M.J., MENON, S.K. & BHATT, V.V. (1961) American blastomycosis with 2-hydroxy stilbamidine. Hamycin, a new antifungal antibiotic. I. Discovery and American Journal of Medicine, 15, 603. biological studies. Hindustan Antibiotics Bulletin, 3, 136. WILLIAMS Jr, T.W., BENNETT, J.E. & EMMONS, C.W. (1965) STEINBERG, B.A., JAMBOR, W.P. & SUYDAM, L.O. (1956) Chemotherapeutic and toxic activity of hamycin in Amphotericins A and B: two new antifungal antibiotics experimental mycoses. Antimicrobial Agents and Chemo- possessing high activity against deep-seated and superficial therapy, 1964, p. 737. American Society for Microbiology, mycoses. Antibiotics Annual 1955-1956, p. 574. Ann Arbor. STEVENS, D.A., LEVINE, H.B. & DERESINSKI, S.C. (1976) WILLIAMS, D.I., MARTEN, R.H. & SARKANY, I. (1958) Oral Miconazole in coccidioidomycosis: II. Therapeutic and treatment of ringworm with griseofulvin. Lancet, ii, 1212. Protected by copyright. http://pmj.bmj.com/ on September 25, 2021 by guest.