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Antifungal drugs
V.K. Lepakhin and A.V. Astakhova
28
Antifungal drugs
During the last year a series of new reviews on treatment with antifungal drugs has been published, but few of them provide new information on side effects. Among them, one would mention particularly the review by Cleary et al (1 r) who compared the efficacy of and reactions to different conazoles. Graybill (2r) in his overview on 'new' antifungal drugs concluded that the toxicity of all azole compounds is less than that of amphotericin B, and that these newer agents offer a remarkable increase in potency and a decrease in gastrointestinal and endocrine adverse reactions. Hepatotoxicity may be common to all of them. As with any new agent, novel forms of toxicity may yet be discovered.
Amphotericin B (SED-11, 568; SEDA-12, 226; SEDA-13, 230; SEDA-14, 229) Blood dyscrasias The majority of patients receiving amphotericin B appear to develop anemia, presumably caused by suppression of red blood cell production. Immune hemolytic anemia associated with amphotericin B has, so far as we know, not been described earlier. Salama et al (3 c) now report on an 8-year-old boy in whom the drug caused acute intravascular hemolysis and subsequently a delayed hemolytic transfusion reaction due to alloantibodies. The patient's serum contained a hemagglutinating IgM antibody that reacted with all red blood cells when tested in the presence of plasma obtained from patients receiving amphotericin B, but not in the presence of their urine, of the drug itself, or of amphotericin B-pretreated red blood cells. In the authors' opinion, these findings indicate that the causative antibody was directed against a degradation product of amphotericin B,
9 1991 Elsevier Science Publishers B.V.
Side Effects of Drugs Annual 15 M.N.G. Dukes and J.K. Aronson, editors
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presumably a trace metabolite, that has not yet been identified. Serial hemoglobin, hematocrit, amphotericin B, and erythropoietin levels were determined by Lin et al (4C) before, during and after completion of amphotericin B therapy in 3 patients without significant renal disease or active hematological malignancy. Patients with systemic fungal diseases treated with traconazole served as controls. Serum erythropoietin levels were determined by radioimmunoassay and amphotericin B by high-performance liquid chromatography. Although there was anemia in all the amphotericin B-treated patients, erythropoietin levels declined or remained relatively constant during therapy, while erythropoietin levels in controls were appropriate for the degree of anemia. Within 2 weeks of completion of amphotericin B treatment, 2 patients showed increasing erythropoietin levels in response to their anemia. Amphotericin B appears to suppress but not abolish the erythropoietin response to anemia; this effect disappears quickly after discontinuation of the drug.
Nephrotoxicity Inprevious studies it has been shown that concomitant administration of sodium can protect against nephrotoxicity in patients receiving amphotericin B. Earlier work did not render it possible, however, to distinguish the effects of ticarcillin from those of sodium. The study of Stein and Alexander (5 C) supports the hypothesis that it is the sodium in sodium ticarcillin that is protective, since sodium chloride and sodium ticarcillin had similar effects. The authors consider that administration of sodium alone, 90 mEq/d, given daily during treatment with amphotericin B, is effective in decreasing the risk of nephrotoxicity associated with amphotericin B therapy and should be administered unless there is a definite medical contraindication to supplemental sodium. Antoniskis and Larsen (6c) have identified 4
Antifungal drugs Chapter 28 patients who developed severe acute renal failure while receiving combination therapy with amphotericin B and parenteral pentamidine isethionate and whose renal failure was fully reversible on discontinuation of both medications. Until prospective trials are conducted to determine the true incidence of this severe drug interaction, caution should be used when these 2 nephrotoxic agents are given concomitantly. Ocular toxicity Li and Lai (7 C) report a case o f acute visualloss after a test dose (I mg) of intravenous amphotericin B was administered to a patient with systemic lupus erythematosus and cryptococcal meningitis. This is the first report of an intravenous test dose of amphotericin B leading to ocular toxicity in cryptococcal meningitis. The patient's visual acuity was normal prior to the injection of amphotericin B. A 26-year-old woman developed fever, chills, and a rigor after receiving the test dose, so amphotericin B was withheld. Ten hours later the patient complained of bilateral visual impairment. Within 24 hours she developed acute bilateral blindness. Four days tater she developed ophthalmoplegia, with failure of abduction of both eyes and impaired upward and downward gaze of the left eye. Her ophthalmoplegia subsided 5 weeks after treatment. The visual failure persisted, with no light perception and loss of light reflexes bilaterally. Bilateral optic atrophy developed 10 weeks after the administration of amphotericin B. " Blurring of vision is a well-recognized but u n c o m m o n complication of intravenous amphotericin B, but acute blindness has never been reported. The authors cannot prove that the amphotericin B was the culprit, but a possible idiosyncratic reaction of optic nerves towards the drug is highly likely in view of the temporal relation between the acute onset of blindness and the administration of the test dose. Cryptococcus neoformans may occasionally invade the optic nerve; wether this would predispose the optic nerve to further injury by amphotericin B remains speculative. Since such a low test dose could cause acute blindness in patients with cryptococcal meningitis, extreme caution should be exercised in administering it to these patients. The authors suggest that it should not be used as a first-line drug in patients with possible optic nerve involvement,
277 Pulmonary reactions Pulmonary toxicity is a rare and much-debated possible side effect of amphotericin B. Those who support a causal relationship have noted that the complication only occurred when the drug was administered concomitantly with leukocyte transfusions or other blood components. Krimerman and Barak (8 c ) have however recently described a patient who developed the adult respiratory distress syndrome (ARDS) after amphotericin administration without receiving transfusions. The complication appeared in a 24-year-old woman who had begun to receive amphotericin B in a dose of 0.4 mg/kg. Within a few hours, severe respiratory distress developed. On the 4th hospital day she inadvertently received 2 doses of amphotericin B, each followed by increasing shortness of breath. Because of a presumed causal association between amphotericin and ARDS, the drug was stopped for 1 day, resulting in marked clinical improvement. The patient did not require blood component transfusions. Amphotericin (25 mg/d) was reinstituted without further respiratory complications. The authors of this report believe that the major trigger for A R D S in this case was amphotericin; the dose and timing of administration are clearly temporally related to the development o f A R D S .
Prevention of amphotericin B toxicity
Burnett and Reents (9 C) in their report evaluate the premedication measures needed to reduce the risk of amphotericin B-induced chills. A typical premedication regimen was hydrocortisone 25 mg i.v. (as the sodium succinate salt), diphenhydramine hydrochloride 50 mg i.v., and acetaminophen 650 mg orally. The only agents previously proving effective in certain controlled trials for preventing amphotericin B-induced chills are ibuprofen 10 m g / k g given orally 30 minutes before amphotericin B infusion and hydrocortisone 25 mg given i.v. before infusion. Concurrent premedication with diphenydramine and hydrocortisone is no more effective than the use of hydrocortisone alone. Meperidine, given i.v., is helpful in the treatment but not the prevention of shaking chills caused by amphotericin B infusion. The use of dantrolene as a premedication has been described but because of the high cost of the drug and the lack of controlled studies proving efficacy, clinicians should consider using dantrolene on-
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ly when other drugs have failed. In addition, the effectiveness o f dantrolene has been questioned. In the opinion o f the authors o f the above paper, who view the issue f r o m the pharmaceutical point o f view, pharmacists should encourage physicians to prescribe premedication only when the patient has earlier has chills associated with amphotericin B infusion. In addition, pharmacists should r e c o m m e n d only those drugs which have proved effective in decreasing the frequency and severity o f shaking chills induced by a m p h o t e r i c i n B. L a b o r a t o r y studies and early clinical experience with liposomal amphotericin B have indicated that this galenic p r e p a r a t i o n decreased the toxicity o f A m B while m a i n t a i n i n g its effectiveness. Two reports cited below seem to c o n f i r m this opinion.
Safe dosage schedules C o n v e n t i o n a l schedules o f a m p h o t e r i c i n B therapy r e c o m m e n d that the drug he delivered as a short infusion over a 4 - 6 hour period with gradual daily increases in dose until 1 - 1.5 m g / k g daily is reached. Increases o f 0.25 m g / k g or 5 - 10 mg daily are suggested to minimize the acute toxicity o f amphotericin B. However, these schedules may delay attaining therapeutic levels, and signs o f acute toxicity (fever and chills) may still be observed in over half o f the patients. Based on previously r e p o r t e d work relating to continous infusion o f amphotericin B (CI-AmB) in a murine model, which pointed to i m p r o v e d drug delivery with decreased toxicity, a pilot study was intitiated by C h a b o t et al (12 c ) to investigate the pharmacokinetics and toxicity o f CIAmB.
Liposomal amphotericin B for treatment of pulmonary aspergillosis in a heart transplant patient was used by Katz et al (10c). They administered liposomal amphotericin B preparation as a continuous infusion over 1 hour. This was a considerably shorter period than the 6-hour infusion time that others have used for infusion of conventional amphotericin B. Generally the dose of amphotericin B in the conventional form has been limited by its toxicity, and a total dose of 2 - 6 g has been considered an adequate course. With the low toxicity of the liposomal preparation and the patient's improvement in kidney function with institution of the liposomal preparation, the authors administered a total dose of 3 g, 2.5 g being the liposomal preparation. The liposomal amphotericin B preparation was administered at a higher dose than the conventional preparation (1 vs. 0.6 mg/kg/d), and the total dose could be completed in 34 days. They did not observe side effects such as fever or chills in their patient. The pharmacokinetic measurements indicate that liposomal amphotericin B administration provides a 10-fold higher plasma level than with the free drug. This may be an important determinant of enhanced therapeutic efficacy. This case and the early experience suggest that liposomal amphotericin B represents an important advance in the treatment of pulmonary aspergillosis and is particularly advantageous in heart transplant patients. Sculier et al (11 c) report on successful treatment with liposomal amphotericin B in 2 patients with persisting fungemia. Liposomal amphotericin B was tolerated much better than the deoxycholate preparation. The only significant side effect observed in their patients was reversible distal tubular acidosis with hypokalemia, requiring intravenous administration of potassium, but without renal failure. Chills and fever were only during the first infusion.
The CI-AmB was administered with lomustine, doxorubicin, and cyclophosphamide as a continuous infusion over a period of 52 - 120 hour to 14 patients (26 courses) with advanced carcinoma. CI-AmB was delivered at a rate of 0.5-0.8 mg/kg/d. This study was performed as part of a project examining the biochemical modulation of antineoplastic drugs by AmB. With CI-AmB, potentially effective plateau plasma concentrations were attained within 1 day and maintained within the antifungal pharmacological range (0.5 - 2 mg/ml) throughout the infusion time. Such serum levels are reached only after several days when conventional short-term infusions are employed. The use of CI-AmB allowed immediate delivery of therapeutic doseg, avoiding the daily dose increase required to reach therapeutic dose in conventional AmB delivery. Acute toxicities of fever and chills were encountered less frequently with CI-AmB than with conventional short infusions. Mild chills were observed in only 3 of 26 courses (12070) and fever was noted in 1 course (4%). In this study, patients were not pretreated with diphenhydramine, corticosteroids, or acetaminophen. However, 3 patients who experienced mild acute symptoms were treated with diphenydramine and steroids and showed symptomatic improvement. Clinical studies of short infusions demonstrated higher incidences of acute toxicity. The approach did not provide a firm answer as regards renal toxicity; approximately 80070 of patients receiving conventional AmB will develop decreased renal function though such toxicity is usually transient and reversible. In this study using CI-AmB renal toxicity was observed in 23 of 26 courses but was rapidly reversible. The creatinine levels generally returned to baseline within 1 week following the cessation of CI-AmB. The authors consider that future development of continuous infusion AmB will need to address the influence of total dose and dura-
Antifungal drugs Chapter 28 tion of infusion on renal function. The AmB plasma disposition was biphasic, with mean half-lives of 17 hours for the first phase and l 1 days for the terminal phase, and a mean residence time of 12 days. Biochemical modulation of antineoplastic agents (lomustine, doxorubicin, cyclophosphamide) by CIAraB was not demonstrated clinically. Although the above study demonstrated distinct differences between conventional short infusions and CI-AmB, a Phase I study using continuous infusion is required to define the maximum tolerated dose and duration of infusion, and more clearly delineate the toxicity of C1-AmB.
I M I D A Z O L E DERIVATIVES (SED-11, 572;
SEDA-12, 228," SEDA-13, 232; SEDA-14, 233) Contact dermatitis with various topical midazole antifungals is mentioned below; it remains a relatively rare problem with most such substances. Fifteen such cases, occurring over a 12-year period, have been discussed by Jelen and Tennstedi (32c); results are discussed particularly with regard to imidazole cross reactions and to sensitization to topicals combining miconazole and hydrocortisone. Ketoconazole (SED-11, 572; SEDA-12, 228; SEDA-13, 232; SEDA-14, 233) A review by Seetharam and Pasricha (13 r) provides a useful view of ketoconazole use in dermatology. Insofar as toxicity is concerned it provides no new data. With topical ketoconazole the side effects are few and occur in 5% of the cases. The authors do stress however that ketoconazole is excreted in breast milk. It should not be given to lactating mothers and it is not safe to use ketoconazole in children less than 2 years of age. Endocrine effects It was established earlier that high-dose ketoconazole effectively reduces testosterone production. Turning an adverse effect to advantage, its use in the management of (metastatic) prostate cancer has been advocated. A study of Witjes et al (14 cr) shows that, even in patients relapsing after previous antiandrogen therapy, high-dose ketoconazole might be of some benefit.
279 Twenty-eight relapsing patients, of whom 15 were evaluable at 3 months have been treated with high-dose ketoconazole. Patients were randomized in 2 treatment programs: 400 mg every 8 hours or 600 mg every 12 hours of a ketoconazole suspension. The findings showed, as the author remarks, that the side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole. Seven patients had to discontinue the therapy after an average period of 12 days ( 3 - 28) because of severe gastrointestinal intolerance. Four of these patients died within 2 months. In 3 cases a temporary dose reduction, and in one the use of an antiemetic rendered it possible to continue therapy. Other side effects were rare. Skin symptoms (itching, dry skin) occurred in 3 cases. Impotence was not assessable as a side effect because all patients were already impotent as a result of previous therapy. No complications resulting from the adrenal suppression were observed. The authors conclude that ketoconazole high dose cannot be advised as first line treatment for patients with metastatic prostate cancer. The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens by Weber et at (15cr). In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all the androgens measured. The mean reduction in serum levels of dehydroepiandrosterone bulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43 %; mean serum levels of cortisol fell by only 19%. The reduction of serum androgen levels was first significant 24 hours after beginning of treatment and persisted as long as the drug was administered. The authors conclude that ketoconazole inhibits adrenal androgen biosynthesis more markedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion. Four patients showed minor drug-related side effects. In 1 patient ketoconazole had to be discontinued because of rising transaminases in association with considerable alcohol consumption. Two others showed minor and transient changes in liver enzymes and 1 patient complained of loss of scalp hair, burning feeling in feet, and abdominal distress.
280
Hepatotoxicity Four cases of toxic hepatitis due to ketoconazole were described by Vilela et al (16c). All patients were female and were given the drug for periods ranging from 8 to 16 weeks (200 mg/d). The clinical condition of the 4 patients was similar to that of viral hepatitis. Normalization of clinical and laboratory findings occurred 6 0 - 9 0 days after discontinuation of the drug and no patient died. One patient received ketoconazole again after her clinical and laboratory results were normalized, and a new toxic hepatitis appeared within 15 days; the second discontinuation of the drug lead to cure of the hepatitis. Blood disorders An observation by Barraviera et al (17cr) confirms previous findings reported by different authors who suggested that ketoconazole is an oxidant drug in addition to being an inhibitor of antioxidant erythrocyte enzymes. Hemoglobin rates, hematocrit and glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase activities were measured in 38 patients with paracoccidioidomycosis treated with ketoconazole or sulfadoxin, and in 13 normal individuals. Ketoconazole-treated patients showed reduced G6PD and glutathione reductase activities. One of these patients was found to be G6PDdeficient and suffered a hemolytic episode during treatment, which, however, did not require interruption of therapy. The authors suggest that patients showing an erythrocyte enzyme defect should be monitored hematologically during treatment with ketoconazole. Hypertension Leal-Cerro et al (18C) report 2 of 14 patients with Cushing's syndrome who became hypertensive during chronic ketoconazole therapy. Both patients were given ketoconazole in a dose of 200 mg 4 times a day. In both cases normal plasma and urinary free cortisol levels had been achieved following ketoconazole therapy, yet continuous blood pressure monitoring demonstrated hypertension some 31 weeks (patient 1) and 52 weeks (patient 2) after treatment. In patient 1, plasma levels of deoxycorticosterone and ll-deoxycortisol were elevated. In patient 2, in addition to an increase in both deoxycorticosterone and l l-deoxycortisol levels, plasma aldosterone values were raised, with a concomitant suppression of renin levels. These findings show that
Chapter 28
V.K. Lepakhin and A. V. Astakhova
long-term treatment with high doses of ketoconazole may induce enzyme blockade leading to mineralocorticoid-related hypertension. Therefore, blood pressure monitoring should be included in the assessment of patients treated with ketoconazole on a long-term basis.
Bifonazole (SED-11, 576; SEDA-12, 232) Piantoni et al (19cr) report on their experience with 1~ bifonazole lotion in 23 patients suffering from otomycoses. The drug was used for a period of 4 - 1 5 days. Two days before the end of the treatment, complete resolution of the clinical picture in 23/23 patients was observed. The tolerability of bifonazole was satisfactory in all cases but 1, who interrupted treatment because of pain and local hyperemia where the lotion had been applied. In some patients suffering from chronic otitis application of the lotion caused slight and short-lasting pain and burning of the ear.
Butoconazole (SEDA-12, 232) Some imidazoles have been shown to cause thrombocytopenia. Butoconazole is an imidazole derivative structurally related to other drugs in this class such as clotrimazole, enconazole, ketoconazole, miconazole and terconazole. Maloley et al (20C) report on the occurrence of lifethreatening thrombocytopenia complicating vaginal therapy with this compound. The effect developed 1 week after beginning therapy and was complicated by upper gastrointestinal hemorrhage that probably resulted from concomitant ibuprofen and methotrexate therapy. Sepsis, myelophthisic anemia and other potential etiologies were ruled out. Once stabilized, the patient was rechallenged with other medications without incident. These findings indicate that a potentially serious thrombocytopenia may result from the administration of butoconazole vaginal cream or in combination with methotrexate and/or ibuprofen. It appears likely that this is an idiosyncratic reaction related to the chemical structure of this class of compounds.
Fluconazole (SEDA-14, 234) Fluconazole (UK-49.858) is a new bistriazole antifungal drug that can be administered both
Antifungal drugs Chapter 28 orally and intravenously. Van 't W o u t et al (21 c ) conducted an open clinical trial o n the efficacy o f fluconazole ( 5 0 - 100 mg) once daily in 20 n o n - n e u t r o p e n i c patients with deep-seated fungal infections. Seventeen patients could be evaluated clinically. The median duration of treatment was 33 days (range 8 - 1 9 4 days). Clinical cure or improvement was achieved in 14 out of 17 patients (82070). No serious side effects of fluconazole were encountered. In general, fluconazole was well tolerated by the patients, although the seriousness of the underlying conditions did not allow evaluation of minor side effects such as nausea. In 2 patients transient mild elevation of alkaline phosphatase and gamma-glutamate transferase levels occurred and these changes may have been due to treatment with fluconazole. The authors conclude that it is necessary to detect liver function during fluconazole treatment. The p u r p o s e o f a further study, by Kujath and Lerch (22cr), was to investigate the significance o f mycotic infections in a surgical clinic a n d to carry out a trial o f the atimycotic agent fluconazole. Twenty-six patients with severe internal mycotic infections were treated with fluconazole at a dose of 200-400 mg daily for at least 10 days: 22 out of 26 patients were cured of their infections. Fluconazole was well tolerated and seemed to be entirely suitable for use in surgical patients. The authors observed mild unwanted effects but, in view of the wide range of other therapies given and the various underlying diseases of patients in this series, there is no certainty that they are in fact due to fluconazole. They comprise increases in alkaline phosphatase and SGOT to 3 times the normal level in I patient, 4 cases of nausea, 2 of vomiting, 2 of thrombocytosis and 1 of anorexis.
Fenticonazole Fenticonazole, another new m e m b e r o f the imidazole family, is one o f m o r e active and well-tolerated antimycotic c o m p o u n d s . It possesses an interesting fungicidal, in addition to fungistatic, activity. The m e c h a n i s m o f action o f the c o m p o u n d is similar to that o f the other imidazole antimycotics. In most clinical studies published to date the c o m p o u n d has been tested utilizing multiple (mainly twice) daily application schedules, while a recent report appears to indicate that once-daily application has a c o m p a r a b l e degree o f efficacy, at least in
281 the case o f the cream formulation. O d e h et al (23 c) therefore sought to verify in 185 patients in a double-blind c o m p a r i s o n o f fenticonazole and econazole whether goot antimycotic activity could also be obtained utilizing a single daily application o f the lotion; this seemed to be the case. Two patients in the fenticonazole g r o u p c o m p l a i n e d o f side effects: 1 patient interrupted treatment 4 days after beginning because o f severe redness and itching; the second patient c o m p l a i n e d o f local burning sensation o f mild intensity after 4 days, which lasted for 7 days. This side effect was possibly correlated to the drug, but in this case t r e a t m e n t was not stopped.
Itraconazole (SEDA-12, 233; SEDA-13, 235) The activity o f itraconazole has been confirmed in m a n y open a n d comparative clinical trials in vaginal candidiasis and dermatomycosis. In these studies, the suggested t r e a t m e n t schedules were a 1-day t r e a t m e n t at 200 mg twice daily or a 3-day treatment at 200 mg daily in vaginal candidiasis and a 15- to 30day t r e a t m e n t period at 100 mg daily in derm a t o p h y t o s i s . The aim o f the study o f Alcantara and Garibay (24 c ) was to confirm these results in a large population and to obtain m o r e i n f o r m a t i o n a b o u t the adverse effects profile o f these t r e a t m e n t schedules. A total of 3476 patients with different types of vaginal candidiasis were treated with 200 nag itraconazole once-daily for 3 days. Dermatomycosis was treated with itraconazole for 15 - 30 days at 100 mg once daily in 2741 patients. The total incidence of adverse effects was comparable for the gynecological and dermatological indications: 7.7o70 in vaginal candidiasis and 8.3~ in dermatomycosis (Table 1). As is evident from the figures, gastrointestinal complaints, headache, and dizziness were the most frequently recorded adverse effects. There was no difference in incidence when both groups were compared. The nature of the reported adverse effects does not indicate a specific adverse effects profile for itraconazole. The reporting of dermatological adverse effects was higher in dermatomycosis than in vaginal candidiasis, and the reverse was seen for gynecological complaints. This observation indicates that these adverse effects may not be related to itraconazole, but to the condition treated. There appeares to be no difference between the 3-day 200 mg once daily schedule and the 15- or 30-day course of therapy at 100 mg daily. The authors note that all the
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Table 1. Adverse effects profile o f itraconazole in the 3-day 100 mg twice-daily treatment o f vaginal candidiasis and the 15- to 30-day treatment at 100 mg daily in dermatomycosis
Adverse effects
Vaginal candidiasis 3-day treatment (n = 3476)
Dermatomycosis 15-day treatment/30-day treatment (n = 2741)
Number
Percent
Number
Percent
Gastrointestinal complaints Nausea Pyrosis Gastritis Gastric complaints, other Headache Dermatological complaints Dizziness Somnolence Gynecological complaints Other minor complaints
163 88 15 12 11 36 4 34 5 4 23
4.86 2.53 0.43 0.35 0.32 1.04 0.12 1.00 0.14 0.12 0.66
115 44 12 15 6 33 25 20 11 1 23
4.19 1.60 0.44 0.55 0.22 1.20 0.91 0.73 0.40 0.04 0.84
Total
269
7.74
228
8.32
treatment schedules studies appear to be very effective in these conditions and devoid of major adverse effects. An open study of Gutierrez et al (25 c) was devoted to the evaluation of efficacy of itraconazole in the treatment of superficial mycoses in 31 patients, using 100 mg itraconazole orally once daily for a period ranging from 2 to 6 weeks. Overall, clinical and mycological response rates were excellent. No m a j o r adverse reactions or hematological or biochemical abnormalities were observed. Only 1 of the 31 patients included in the study reported an adverse reaction; towards the second week of therapy, a 42-year-old male complained of dryness o f the m o u t h with a bitter taste. No other reactions were noted. A series of 114 evaluable patients with tinea pedis or tinea m a n u m have been analyzed in a double-blind study between itraconazole and griseofulvin by van Hecke and van Cutsem (26c). It was concluded that itraconazole 100 mg orally once daily for 30 days was micologically more effective than griseofulvin 500 mg once daily for 30 days in the treatment of tinea pedis and tinea m a n u m . Both drugs were well tolerated and appeared to be safe for use. Five patients out of 75 of the griseofulvin group
(exanthema, nausea, headache, pyrosis, abdominal cramps) and 9 patients out of 74 (abdominal cramps and pain, fatique, headache, bladder pain, dishidrosis) o f the itraconazole group reported side effects. Treatment was discontinued in 1 itraconazole patient because of abdominal cramps. Omoconazole O m o c o n a z o l e (CM 8282) is a novel molecule but still belongs to the imidazole class. According to an extensive review (27 c) the principal undesired effects noted with dermatological formulations are local burning sensations and irritation. They are usually mild and transient. The main undesired effects with pessaries are burning sensations or pruritus, but these too are usually transient and of moderate intensity. Sulconazole The safety and efficacy of sulconazole nitrate 1 ~ ointment administered for 4 weeks to 40 patients with tinea pedis were studied by Arenas and Castavantes (28c). Clinical and mycological improvement was observed in almost all cases; 2.5o7o of the patients treated developed contact dermatitis as an adverse reaction.
Antifungal drugs Chapter 28
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Terconazole (SEDA-13, 236)
Croconazole
Moebius (29 k) summarizes the data on apparently immunoallergic complications which occur during terconazole treatment, noting that the G e r m a n Federal Health Office had received reports f r o m doctors o f an influenza-like synd r o m e associated with terconazole, 160 mg as single-dose treatment. The s y n d r o m e includes fever, chills, headache, a n d / o r hypotension. Within 1 hour after intravaginal application o f terconazole the s y n d r o m e starts with chills. A f t e r 2 hours the temperature can reach 3 8 . 0 40.2~ The complaints disappear after 1 0 - 48 hours.
S h o n o et al (33 C) report 6 cases o f contact sensitivity to croconazole hydrochloride, a new imidazole antimycotic drug introduced to the J a p a n e s e market in 1986, and available as 1%0 gel and cream. Six sensitized patients reacted on p a t c h testing to croconazole h y d r o c h l o r i d e d o w n to 0 . 5 - 0 . 1 % pet, and 3 appeared to be cross-sensitized to sulconazole nitrate. In J a p a n , allergic contact dermatitis to this drug has now been detected in 12 cases, including these 6. The authors underline that prescribers should be aware o f contact sensitivity to this drug.
In a typical case, a 56-year-old woman (weight 55 kg) was treated by a gynecologist for a genital mycosis; 2 - 3 hours after starting terconazole 160 mg she was observed to have vertigo, nausea, and a temperature of 38.5~ The patient collapsed twice and recovered within 1 day. The reaction lasted for about 10 hours and was observed by a general practitioner. The m a n u f a c t u r e r s have received at least 46 similar reports f r o m West G e r m a n y and the U . S . A . Moebius considers that the use o f terconazole involves an avoidable risk because imidazole derivatives which have p r o v e d better are available for gynecological use.
Tioconazole (SED-11, 235; SEDA-12, 235)
Contact sensitivity to topical ticonazol, a new imidazole for topical treatment o f fungal nail infections, is today well recognized. Further reports by Haustein et al (30 c) and J o n e s and K e n n e d y (31 C) c o n f i r m the p h e n o m e n o n . Haustin et al (30c) used lotion or cream of Micontral, which contains 1% tioconazole, in 73 patients with fungal infections due to dermatophytes, yeasts. Side effects such as slight redness, transient burning and pruritus on the eroded skin in the initial phase in 8 patients (11%) were observed. Jones and Kennedy (31 c) observed redness, swelling and blistering of the toes in the area of application of tioconazole nail solution. The contact dermatitis from tioconazole appeared after the third course of therapy, within 36 hours of application. The patient did not show crossreactivity with sulconazole, miconazole or clotrimazole, but reacted to topical ketoconazole. As there was no history to suggest primary sensitisation by ketoconazole, this presumably represents crossreactivity.
OTHER ANTIFUNGAL DRUGS Griseofulvin (SED-11, 567; SEDA-12, 236;
SEDA-13, 236) Lecky (34 C) reports a case o f griseofulvininduced neuropathy. A 76-year-old woman was treated with griseofulvin, 500 mg daily for 4 months, in 1987 and 6 months in 1988 for fungal nail infection. The second treatment was discontinued after parestbesia developed in all fingers, followed by numbness of the feet and a sensation of 'walking on cottonwool'. 4 months after the onset of neurological symptoms ankle jerks were absent and she had bilateral loss of vibration sense at the hallux. Nerve conduction studies showed a severe but very distal motor and sensory neuropathy. Laboratory investigation, including cerebrospinal fluid examination, were negative. Four months later her sensory symptoms had resolved and there were no neurological signs. Nerve conduction had substantially improved. It seems likely that the neuropathy was caused by griseofulvin. By 1989, the U.K. C o m m i t t e e on Safety o f Medicines had reports o f 5 cases o f ' n e u r o p a t h y ' and 6 cases o f 'paresthesia' occurring in association with griseofulvin treatm e n t , but n o n e seemed to have been well documented. Griseofulvin is a k n o w n photosensitizer, and
exacerbation of systemic lupus erythematosus or unmasking of lupus diathesis has been reported after its oral administration. Miyagawa et al (35 C) report a case o f systemic lupus erythematosus in which griseofulvin was associated with eruptions with clinical and
284 laboratory features similar to those o f subacute cutaneous lupus erythematosus. A 35-year-old woman with a 10-month history of dermatomyositis was admitted to hospital because, a few days before admission and following 2 weeks of continuous oral therapy with griseofulvin (375 mg/d) for onychomycosis of the fingernails and toenails, severe eruptions had appeared. The patient had anti-
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bodies against SSA/RO and SSB/La antigens. The clinical resolution of the skin lesions after discontinuation of griseofulvin and recurrence on challenge with the drug stongly implies that this drug was associated with the clinical and histologic epidermal changes in the patient. Subacute cutaneous lupus erythematosus lesions developed on challenge with griseofulvin despite the patient's careful avoidance of direct sun exposure during hospitalization.
REFERENCES 1. Cleary JD, Taylor JW, Chapman SW (1990) Imidazoles and triazoles in antifungal therapy. DICP Ann. Pharmacother., 24, 148. 2. Graybill JR (1989) New antifungal agents. Eur. J. Clin. Microbiol. Infect. Dis., 8, 5. 3. Salama A, Burger M, Mueller-Eckhardt C (1989) Acute immune hemolysis induced by a degradation product of amphotericin B. Blur, 58, 59. 4. Lin AC, Goldwasser E, Bernard EM, Chapman SW (1990) Amphotericin B blunts erythropoietin response to anemia. J. Infect. Dis., 161, 348. 5. Stein RS, Alexander JA (1989) Sodium protects against nephrotoxicity in patients receiving amphotericin B. Am. J. Med. Sci., 298, 5. 6. Antoniskis D, Larsen RA (1990) Acute, rapidly progressive renal failure with simultaneous use of amphotericin B and pentamidine. Antirnicrob. Agents Chemother., 34, 3. 7. Li PK, Lai KN (1989) Amphotericin B induced ocular toxicity in cryptococcal meningitis. Br. J. Ophthalmol., 73, 397. 8. Krimerman S, Barak A (1989) Pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. Crit. Care Med., 17, 1081. 9. Burnett R, Reents SB (1989) Premedication for amphotericin B-induced chills. Clin. Pharm., 8, 836. 10. Katz N, Pierce PF, Anzeek RA et al (1990) Liposomal amphotericin B for treatment of pulmonary aspergillosis in a heart transplant patient. J. Heart TranspL, 9, 1. 11. Sculier JP, Bron D, Coune A, Meunier F (1989) Successful treatment with liposomal amphotericin B in two patients with persisting fungemia. Eur. J. Clin. Microbiol. Infect. Dis., 8, 903. 12. Chabot GG, Pazdur R, Valeriote FA, Baker LH (1989) Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. J. Pharm. Sci., 78, 4. 13. Seetharam KA, Pasricha JS (1988) Ketoconazole in dermatology. Indian J. DermatoL Venereol. LeproL, 54, 67. 14. Witjes FJ, Debruyne FM, Moral PF, Geboers ADH (1989) Ketoconazole high dose in manage-
ment of hormonally pretreated patients with progressive metastatic prostate cancer. Urology, 33, 5. 15. Weber MM, Luppa P, Engelhardt D (1989) Inhibition of human adrenal androgen secretion by ketoconazole. Klin. Wochenschr., 67, 707. 16. Vilela MP, Ferraz ML, Franco DR (1989) Hepatite toxica causada por ketoconazol: relato de quatro casos. Rev. Paul Med., 107, 1. 17. Barraviera B, Mendes RP, Pereira PCM et al (1988) Measurement of glucose-6-phosphate dehydrogenase and glutathione reductase activity in patients with paracoccidioidomycosis treated, with ketoconazole. Mycopathologia, 104, 87. 18. Leal-Cerro A, Garcia-Lund PP, Villar J e t al (1989) Arterial hypertension as a complication of prolonged ketoconazole treatment. J. Hypertens., 6 (Suppl. 6), $212. 19. Piantoni S, Narne S, Bottin R et al (1989) Bifonazole lozione 1% nella terapia delle otomicosi. Clin. Ter., 130, 23. 20. Maloley P, Nelson E, Montgomery HA, Campbell JR (1990) Severe reversible thrombocytopenia resulting from butoconazole cream. Ann. Pharrnacotherapy, 24, 143. 21. Van 't Wout JW, Mattie H, Furth R (1988) A prospective study of the efficacy of fluconazole (UK-49, 858) against deep-seated fungal infections. J. Antimicrob. Chemother., 21, 665. 22. Kujath P, Lerch K (1989) Secondary mycosis in surgery: treatment with fluconazole. Infection, 17, 111. 23. Odeh F, Fabry H, Kuklwein A et al (1990) A double blind clinical trial with a single daily application of fenticonazole lotion versus econazole lotion in patients with cutaneous mycosis. Curr. Ther. Res., 47, 1. 24. Alcantara R, Garibay JM (1988) Itraconazole therapy in dermatomycosis and vaginal candidiasis: efficacy and adverse effects profile in a large multicenter study. Adv. Ther., 5, 6. 25. Gutierrez GT, Enrile-Monsanto EC, Valencia CI et al (1989) Itraconazole in the treatment of superficial mycosis in Filipinos. Philipp. J. lntern. Med., 27, 179. 26. van Hecke E, van Cutsem J (1988) Double-blind
Antifungal drugs
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comparison of itraconazole with griseofulvin in the treatment of tinea pedis and tinea manuum. Mycoses, 31, 12. 27. Anonymous (1989) Omoconazole nitrate. Drugs Today, 25, 7. 28. Arenas R, Casavantes LC (1989) The safety and efficacy of sulconazole ointment in patients with tinea pedis. Dermatol. Rev. Mex., 33, 85. 29. Moebius VM (1988) Influenza-like syndrome after terconazole. Lancet, 2, 1192. 30. Haustein VF, Seebacher C, Taube KM (1989) Behandlung von Pilzinfektionen der Haut mit Tioconazol (Mykontral). Dermatol. Monatsschr., 175, 12.
285 31. Jones S, Kennedy TC (1990) Contact dermatitis from tioconazole. Contact Dermatitis, 22, 122. 32. Jelen G, Tennstedt D (1989) Contact dermatitis from topical imidazole antifungals: 15 new cases. Contact Dermatitis, 21, 6. 33. Shono M, Hayashi K, Sugimoto R (1989) Allergic contact dermatitis from croconazole hydrochloride. Contact Dermatitis, 21, 225. 34. Lecky BRF (1990) Griseofulvin-induced neuropathy. Lancet, 335, 230. 35. Miyagawa S, Okuchi T, Shiomi Y, Sakamoto K (1989) Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J. Am. Acad. Dermatol., 21, 2.
28
Antifungal drugs
During the last year a series of new reviews on treatment with antifungal drugs has been published, but few of them provide new information on side effects. Among them, one would mention particularly the review by Cleary et al (1 r) who compared the efficacy of and reactions to different conazoles. Graybill (2r) in his overview on 'new' antifungal drugs concluded that the toxicity of all azole compounds is less than that of amphotericin B, and that these newer agents offer a remarkable increase in potency and a decrease in gastrointestinal and endocrine adverse reactions. Hepatotoxicity may be common to all of them. As with any new agent, novel forms of toxicity may yet be discovered.
Amphotericin B (SED-11, 568; SEDA-12, 226; SEDA-13, 230; SEDA-14, 229) Blood dyscrasias The majority of patients receiving amphotericin B appear to develop anemia, presumably caused by suppression of red blood cell production. Immune hemolytic anemia associated with amphotericin B has, so far as we know, not been described earlier. Salama et al (3 c) now report on an 8-year-old boy in whom the drug caused acute intravascular hemolysis and subsequently a delayed hemolytic transfusion reaction due to alloantibodies. The patient's serum contained a hemagglutinating IgM antibody that reacted with all red blood cells when tested in the presence of plasma obtained from patients receiving amphotericin B, but not in the presence of their urine, of the drug itself, or of amphotericin B-pretreated red blood cells. In the authors' opinion, these findings indicate that the causative antibody was directed against a degradation product of amphotericin B,
9 1991 Elsevier Science Publishers B.V.
Side Effects of Drugs Annual 15 M.N.G. Dukes and J.K. Aronson, editors
276
presumably a trace metabolite, that has not yet been identified. Serial hemoglobin, hematocrit, amphotericin B, and erythropoietin levels were determined by Lin et al (4C) before, during and after completion of amphotericin B therapy in 3 patients without significant renal disease or active hematological malignancy. Patients with systemic fungal diseases treated with traconazole served as controls. Serum erythropoietin levels were determined by radioimmunoassay and amphotericin B by high-performance liquid chromatography. Although there was anemia in all the amphotericin B-treated patients, erythropoietin levels declined or remained relatively constant during therapy, while erythropoietin levels in controls were appropriate for the degree of anemia. Within 2 weeks of completion of amphotericin B treatment, 2 patients showed increasing erythropoietin levels in response to their anemia. Amphotericin B appears to suppress but not abolish the erythropoietin response to anemia; this effect disappears quickly after discontinuation of the drug.
Nephrotoxicity Inprevious studies it has been shown that concomitant administration of sodium can protect against nephrotoxicity in patients receiving amphotericin B. Earlier work did not render it possible, however, to distinguish the effects of ticarcillin from those of sodium. The study of Stein and Alexander (5 C) supports the hypothesis that it is the sodium in sodium ticarcillin that is protective, since sodium chloride and sodium ticarcillin had similar effects. The authors consider that administration of sodium alone, 90 mEq/d, given daily during treatment with amphotericin B, is effective in decreasing the risk of nephrotoxicity associated with amphotericin B therapy and should be administered unless there is a definite medical contraindication to supplemental sodium. Antoniskis and Larsen (6c) have identified 4
Antifungal drugs Chapter 28 patients who developed severe acute renal failure while receiving combination therapy with amphotericin B and parenteral pentamidine isethionate and whose renal failure was fully reversible on discontinuation of both medications. Until prospective trials are conducted to determine the true incidence of this severe drug interaction, caution should be used when these 2 nephrotoxic agents are given concomitantly. Ocular toxicity Li and Lai (7 C) report a case o f acute visualloss after a test dose (I mg) of intravenous amphotericin B was administered to a patient with systemic lupus erythematosus and cryptococcal meningitis. This is the first report of an intravenous test dose of amphotericin B leading to ocular toxicity in cryptococcal meningitis. The patient's visual acuity was normal prior to the injection of amphotericin B. A 26-year-old woman developed fever, chills, and a rigor after receiving the test dose, so amphotericin B was withheld. Ten hours later the patient complained of bilateral visual impairment. Within 24 hours she developed acute bilateral blindness. Four days tater she developed ophthalmoplegia, with failure of abduction of both eyes and impaired upward and downward gaze of the left eye. Her ophthalmoplegia subsided 5 weeks after treatment. The visual failure persisted, with no light perception and loss of light reflexes bilaterally. Bilateral optic atrophy developed 10 weeks after the administration of amphotericin B. " Blurring of vision is a well-recognized but u n c o m m o n complication of intravenous amphotericin B, but acute blindness has never been reported. The authors cannot prove that the amphotericin B was the culprit, but a possible idiosyncratic reaction of optic nerves towards the drug is highly likely in view of the temporal relation between the acute onset of blindness and the administration of the test dose. Cryptococcus neoformans may occasionally invade the optic nerve; wether this would predispose the optic nerve to further injury by amphotericin B remains speculative. Since such a low test dose could cause acute blindness in patients with cryptococcal meningitis, extreme caution should be exercised in administering it to these patients. The authors suggest that it should not be used as a first-line drug in patients with possible optic nerve involvement,
277 Pulmonary reactions Pulmonary toxicity is a rare and much-debated possible side effect of amphotericin B. Those who support a causal relationship have noted that the complication only occurred when the drug was administered concomitantly with leukocyte transfusions or other blood components. Krimerman and Barak (8 c ) have however recently described a patient who developed the adult respiratory distress syndrome (ARDS) after amphotericin administration without receiving transfusions. The complication appeared in a 24-year-old woman who had begun to receive amphotericin B in a dose of 0.4 mg/kg. Within a few hours, severe respiratory distress developed. On the 4th hospital day she inadvertently received 2 doses of amphotericin B, each followed by increasing shortness of breath. Because of a presumed causal association between amphotericin and ARDS, the drug was stopped for 1 day, resulting in marked clinical improvement. The patient did not require blood component transfusions. Amphotericin (25 mg/d) was reinstituted without further respiratory complications. The authors of this report believe that the major trigger for A R D S in this case was amphotericin; the dose and timing of administration are clearly temporally related to the development o f A R D S .
Prevention of amphotericin B toxicity
Burnett and Reents (9 C) in their report evaluate the premedication measures needed to reduce the risk of amphotericin B-induced chills. A typical premedication regimen was hydrocortisone 25 mg i.v. (as the sodium succinate salt), diphenhydramine hydrochloride 50 mg i.v., and acetaminophen 650 mg orally. The only agents previously proving effective in certain controlled trials for preventing amphotericin B-induced chills are ibuprofen 10 m g / k g given orally 30 minutes before amphotericin B infusion and hydrocortisone 25 mg given i.v. before infusion. Concurrent premedication with diphenydramine and hydrocortisone is no more effective than the use of hydrocortisone alone. Meperidine, given i.v., is helpful in the treatment but not the prevention of shaking chills caused by amphotericin B infusion. The use of dantrolene as a premedication has been described but because of the high cost of the drug and the lack of controlled studies proving efficacy, clinicians should consider using dantrolene on-
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ly when other drugs have failed. In addition, the effectiveness o f dantrolene has been questioned. In the opinion o f the authors o f the above paper, who view the issue f r o m the pharmaceutical point o f view, pharmacists should encourage physicians to prescribe premedication only when the patient has earlier has chills associated with amphotericin B infusion. In addition, pharmacists should r e c o m m e n d only those drugs which have proved effective in decreasing the frequency and severity o f shaking chills induced by a m p h o t e r i c i n B. L a b o r a t o r y studies and early clinical experience with liposomal amphotericin B have indicated that this galenic p r e p a r a t i o n decreased the toxicity o f A m B while m a i n t a i n i n g its effectiveness. Two reports cited below seem to c o n f i r m this opinion.
Safe dosage schedules C o n v e n t i o n a l schedules o f a m p h o t e r i c i n B therapy r e c o m m e n d that the drug he delivered as a short infusion over a 4 - 6 hour period with gradual daily increases in dose until 1 - 1.5 m g / k g daily is reached. Increases o f 0.25 m g / k g or 5 - 10 mg daily are suggested to minimize the acute toxicity o f amphotericin B. However, these schedules may delay attaining therapeutic levels, and signs o f acute toxicity (fever and chills) may still be observed in over half o f the patients. Based on previously r e p o r t e d work relating to continous infusion o f amphotericin B (CI-AmB) in a murine model, which pointed to i m p r o v e d drug delivery with decreased toxicity, a pilot study was intitiated by C h a b o t et al (12 c ) to investigate the pharmacokinetics and toxicity o f CIAmB.
Liposomal amphotericin B for treatment of pulmonary aspergillosis in a heart transplant patient was used by Katz et al (10c). They administered liposomal amphotericin B preparation as a continuous infusion over 1 hour. This was a considerably shorter period than the 6-hour infusion time that others have used for infusion of conventional amphotericin B. Generally the dose of amphotericin B in the conventional form has been limited by its toxicity, and a total dose of 2 - 6 g has been considered an adequate course. With the low toxicity of the liposomal preparation and the patient's improvement in kidney function with institution of the liposomal preparation, the authors administered a total dose of 3 g, 2.5 g being the liposomal preparation. The liposomal amphotericin B preparation was administered at a higher dose than the conventional preparation (1 vs. 0.6 mg/kg/d), and the total dose could be completed in 34 days. They did not observe side effects such as fever or chills in their patient. The pharmacokinetic measurements indicate that liposomal amphotericin B administration provides a 10-fold higher plasma level than with the free drug. This may be an important determinant of enhanced therapeutic efficacy. This case and the early experience suggest that liposomal amphotericin B represents an important advance in the treatment of pulmonary aspergillosis and is particularly advantageous in heart transplant patients. Sculier et al (11 c) report on successful treatment with liposomal amphotericin B in 2 patients with persisting fungemia. Liposomal amphotericin B was tolerated much better than the deoxycholate preparation. The only significant side effect observed in their patients was reversible distal tubular acidosis with hypokalemia, requiring intravenous administration of potassium, but without renal failure. Chills and fever were only during the first infusion.
The CI-AmB was administered with lomustine, doxorubicin, and cyclophosphamide as a continuous infusion over a period of 52 - 120 hour to 14 patients (26 courses) with advanced carcinoma. CI-AmB was delivered at a rate of 0.5-0.8 mg/kg/d. This study was performed as part of a project examining the biochemical modulation of antineoplastic drugs by AmB. With CI-AmB, potentially effective plateau plasma concentrations were attained within 1 day and maintained within the antifungal pharmacological range (0.5 - 2 mg/ml) throughout the infusion time. Such serum levels are reached only after several days when conventional short-term infusions are employed. The use of CI-AmB allowed immediate delivery of therapeutic doseg, avoiding the daily dose increase required to reach therapeutic dose in conventional AmB delivery. Acute toxicities of fever and chills were encountered less frequently with CI-AmB than with conventional short infusions. Mild chills were observed in only 3 of 26 courses (12070) and fever was noted in 1 course (4%). In this study, patients were not pretreated with diphenhydramine, corticosteroids, or acetaminophen. However, 3 patients who experienced mild acute symptoms were treated with diphenydramine and steroids and showed symptomatic improvement. Clinical studies of short infusions demonstrated higher incidences of acute toxicity. The approach did not provide a firm answer as regards renal toxicity; approximately 80070 of patients receiving conventional AmB will develop decreased renal function though such toxicity is usually transient and reversible. In this study using CI-AmB renal toxicity was observed in 23 of 26 courses but was rapidly reversible. The creatinine levels generally returned to baseline within 1 week following the cessation of CI-AmB. The authors consider that future development of continuous infusion AmB will need to address the influence of total dose and dura-
Antifungal drugs Chapter 28 tion of infusion on renal function. The AmB plasma disposition was biphasic, with mean half-lives of 17 hours for the first phase and l 1 days for the terminal phase, and a mean residence time of 12 days. Biochemical modulation of antineoplastic agents (lomustine, doxorubicin, cyclophosphamide) by CIAraB was not demonstrated clinically. Although the above study demonstrated distinct differences between conventional short infusions and CI-AmB, a Phase I study using continuous infusion is required to define the maximum tolerated dose and duration of infusion, and more clearly delineate the toxicity of C1-AmB.
I M I D A Z O L E DERIVATIVES (SED-11, 572;
SEDA-12, 228," SEDA-13, 232; SEDA-14, 233) Contact dermatitis with various topical midazole antifungals is mentioned below; it remains a relatively rare problem with most such substances. Fifteen such cases, occurring over a 12-year period, have been discussed by Jelen and Tennstedi (32c); results are discussed particularly with regard to imidazole cross reactions and to sensitization to topicals combining miconazole and hydrocortisone. Ketoconazole (SED-11, 572; SEDA-12, 228; SEDA-13, 232; SEDA-14, 233) A review by Seetharam and Pasricha (13 r) provides a useful view of ketoconazole use in dermatology. Insofar as toxicity is concerned it provides no new data. With topical ketoconazole the side effects are few and occur in 5% of the cases. The authors do stress however that ketoconazole is excreted in breast milk. It should not be given to lactating mothers and it is not safe to use ketoconazole in children less than 2 years of age. Endocrine effects It was established earlier that high-dose ketoconazole effectively reduces testosterone production. Turning an adverse effect to advantage, its use in the management of (metastatic) prostate cancer has been advocated. A study of Witjes et al (14 cr) shows that, even in patients relapsing after previous antiandrogen therapy, high-dose ketoconazole might be of some benefit.
279 Twenty-eight relapsing patients, of whom 15 were evaluable at 3 months have been treated with high-dose ketoconazole. Patients were randomized in 2 treatment programs: 400 mg every 8 hours or 600 mg every 12 hours of a ketoconazole suspension. The findings showed, as the author remarks, that the side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole. Seven patients had to discontinue the therapy after an average period of 12 days ( 3 - 28) because of severe gastrointestinal intolerance. Four of these patients died within 2 months. In 3 cases a temporary dose reduction, and in one the use of an antiemetic rendered it possible to continue therapy. Other side effects were rare. Skin symptoms (itching, dry skin) occurred in 3 cases. Impotence was not assessable as a side effect because all patients were already impotent as a result of previous therapy. No complications resulting from the adrenal suppression were observed. The authors conclude that ketoconazole high dose cannot be advised as first line treatment for patients with metastatic prostate cancer. The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens by Weber et at (15cr). In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all the androgens measured. The mean reduction in serum levels of dehydroepiandrosterone bulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43 %; mean serum levels of cortisol fell by only 19%. The reduction of serum androgen levels was first significant 24 hours after beginning of treatment and persisted as long as the drug was administered. The authors conclude that ketoconazole inhibits adrenal androgen biosynthesis more markedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion. Four patients showed minor drug-related side effects. In 1 patient ketoconazole had to be discontinued because of rising transaminases in association with considerable alcohol consumption. Two others showed minor and transient changes in liver enzymes and 1 patient complained of loss of scalp hair, burning feeling in feet, and abdominal distress.
280
Hepatotoxicity Four cases of toxic hepatitis due to ketoconazole were described by Vilela et al (16c). All patients were female and were given the drug for periods ranging from 8 to 16 weeks (200 mg/d). The clinical condition of the 4 patients was similar to that of viral hepatitis. Normalization of clinical and laboratory findings occurred 6 0 - 9 0 days after discontinuation of the drug and no patient died. One patient received ketoconazole again after her clinical and laboratory results were normalized, and a new toxic hepatitis appeared within 15 days; the second discontinuation of the drug lead to cure of the hepatitis. Blood disorders An observation by Barraviera et al (17cr) confirms previous findings reported by different authors who suggested that ketoconazole is an oxidant drug in addition to being an inhibitor of antioxidant erythrocyte enzymes. Hemoglobin rates, hematocrit and glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase activities were measured in 38 patients with paracoccidioidomycosis treated with ketoconazole or sulfadoxin, and in 13 normal individuals. Ketoconazole-treated patients showed reduced G6PD and glutathione reductase activities. One of these patients was found to be G6PDdeficient and suffered a hemolytic episode during treatment, which, however, did not require interruption of therapy. The authors suggest that patients showing an erythrocyte enzyme defect should be monitored hematologically during treatment with ketoconazole. Hypertension Leal-Cerro et al (18C) report 2 of 14 patients with Cushing's syndrome who became hypertensive during chronic ketoconazole therapy. Both patients were given ketoconazole in a dose of 200 mg 4 times a day. In both cases normal plasma and urinary free cortisol levels had been achieved following ketoconazole therapy, yet continuous blood pressure monitoring demonstrated hypertension some 31 weeks (patient 1) and 52 weeks (patient 2) after treatment. In patient 1, plasma levels of deoxycorticosterone and ll-deoxycortisol were elevated. In patient 2, in addition to an increase in both deoxycorticosterone and l l-deoxycortisol levels, plasma aldosterone values were raised, with a concomitant suppression of renin levels. These findings show that
Chapter 28
V.K. Lepakhin and A. V. Astakhova
long-term treatment with high doses of ketoconazole may induce enzyme blockade leading to mineralocorticoid-related hypertension. Therefore, blood pressure monitoring should be included in the assessment of patients treated with ketoconazole on a long-term basis.
Bifonazole (SED-11, 576; SEDA-12, 232) Piantoni et al (19cr) report on their experience with 1~ bifonazole lotion in 23 patients suffering from otomycoses. The drug was used for a period of 4 - 1 5 days. Two days before the end of the treatment, complete resolution of the clinical picture in 23/23 patients was observed. The tolerability of bifonazole was satisfactory in all cases but 1, who interrupted treatment because of pain and local hyperemia where the lotion had been applied. In some patients suffering from chronic otitis application of the lotion caused slight and short-lasting pain and burning of the ear.
Butoconazole (SEDA-12, 232) Some imidazoles have been shown to cause thrombocytopenia. Butoconazole is an imidazole derivative structurally related to other drugs in this class such as clotrimazole, enconazole, ketoconazole, miconazole and terconazole. Maloley et al (20C) report on the occurrence of lifethreatening thrombocytopenia complicating vaginal therapy with this compound. The effect developed 1 week after beginning therapy and was complicated by upper gastrointestinal hemorrhage that probably resulted from concomitant ibuprofen and methotrexate therapy. Sepsis, myelophthisic anemia and other potential etiologies were ruled out. Once stabilized, the patient was rechallenged with other medications without incident. These findings indicate that a potentially serious thrombocytopenia may result from the administration of butoconazole vaginal cream or in combination with methotrexate and/or ibuprofen. It appears likely that this is an idiosyncratic reaction related to the chemical structure of this class of compounds.
Fluconazole (SEDA-14, 234) Fluconazole (UK-49.858) is a new bistriazole antifungal drug that can be administered both
Antifungal drugs Chapter 28 orally and intravenously. Van 't W o u t et al (21 c ) conducted an open clinical trial o n the efficacy o f fluconazole ( 5 0 - 100 mg) once daily in 20 n o n - n e u t r o p e n i c patients with deep-seated fungal infections. Seventeen patients could be evaluated clinically. The median duration of treatment was 33 days (range 8 - 1 9 4 days). Clinical cure or improvement was achieved in 14 out of 17 patients (82070). No serious side effects of fluconazole were encountered. In general, fluconazole was well tolerated by the patients, although the seriousness of the underlying conditions did not allow evaluation of minor side effects such as nausea. In 2 patients transient mild elevation of alkaline phosphatase and gamma-glutamate transferase levels occurred and these changes may have been due to treatment with fluconazole. The authors conclude that it is necessary to detect liver function during fluconazole treatment. The p u r p o s e o f a further study, by Kujath and Lerch (22cr), was to investigate the significance o f mycotic infections in a surgical clinic a n d to carry out a trial o f the atimycotic agent fluconazole. Twenty-six patients with severe internal mycotic infections were treated with fluconazole at a dose of 200-400 mg daily for at least 10 days: 22 out of 26 patients were cured of their infections. Fluconazole was well tolerated and seemed to be entirely suitable for use in surgical patients. The authors observed mild unwanted effects but, in view of the wide range of other therapies given and the various underlying diseases of patients in this series, there is no certainty that they are in fact due to fluconazole. They comprise increases in alkaline phosphatase and SGOT to 3 times the normal level in I patient, 4 cases of nausea, 2 of vomiting, 2 of thrombocytosis and 1 of anorexis.
Fenticonazole Fenticonazole, another new m e m b e r o f the imidazole family, is one o f m o r e active and well-tolerated antimycotic c o m p o u n d s . It possesses an interesting fungicidal, in addition to fungistatic, activity. The m e c h a n i s m o f action o f the c o m p o u n d is similar to that o f the other imidazole antimycotics. In most clinical studies published to date the c o m p o u n d has been tested utilizing multiple (mainly twice) daily application schedules, while a recent report appears to indicate that once-daily application has a c o m p a r a b l e degree o f efficacy, at least in
281 the case o f the cream formulation. O d e h et al (23 c) therefore sought to verify in 185 patients in a double-blind c o m p a r i s o n o f fenticonazole and econazole whether goot antimycotic activity could also be obtained utilizing a single daily application o f the lotion; this seemed to be the case. Two patients in the fenticonazole g r o u p c o m p l a i n e d o f side effects: 1 patient interrupted treatment 4 days after beginning because o f severe redness and itching; the second patient c o m p l a i n e d o f local burning sensation o f mild intensity after 4 days, which lasted for 7 days. This side effect was possibly correlated to the drug, but in this case t r e a t m e n t was not stopped.
Itraconazole (SEDA-12, 233; SEDA-13, 235) The activity o f itraconazole has been confirmed in m a n y open a n d comparative clinical trials in vaginal candidiasis and dermatomycosis. In these studies, the suggested t r e a t m e n t schedules were a 1-day t r e a t m e n t at 200 mg twice daily or a 3-day treatment at 200 mg daily in vaginal candidiasis and a 15- to 30day t r e a t m e n t period at 100 mg daily in derm a t o p h y t o s i s . The aim o f the study o f Alcantara and Garibay (24 c ) was to confirm these results in a large population and to obtain m o r e i n f o r m a t i o n a b o u t the adverse effects profile o f these t r e a t m e n t schedules. A total of 3476 patients with different types of vaginal candidiasis were treated with 200 nag itraconazole once-daily for 3 days. Dermatomycosis was treated with itraconazole for 15 - 30 days at 100 mg once daily in 2741 patients. The total incidence of adverse effects was comparable for the gynecological and dermatological indications: 7.7o70 in vaginal candidiasis and 8.3~ in dermatomycosis (Table 1). As is evident from the figures, gastrointestinal complaints, headache, and dizziness were the most frequently recorded adverse effects. There was no difference in incidence when both groups were compared. The nature of the reported adverse effects does not indicate a specific adverse effects profile for itraconazole. The reporting of dermatological adverse effects was higher in dermatomycosis than in vaginal candidiasis, and the reverse was seen for gynecological complaints. This observation indicates that these adverse effects may not be related to itraconazole, but to the condition treated. There appeares to be no difference between the 3-day 200 mg once daily schedule and the 15- or 30-day course of therapy at 100 mg daily. The authors note that all the
282
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V.K. Lepakhin and A. V. Astakhova
Table 1. Adverse effects profile o f itraconazole in the 3-day 100 mg twice-daily treatment o f vaginal candidiasis and the 15- to 30-day treatment at 100 mg daily in dermatomycosis
Adverse effects
Vaginal candidiasis 3-day treatment (n = 3476)
Dermatomycosis 15-day treatment/30-day treatment (n = 2741)
Number
Percent
Number
Percent
Gastrointestinal complaints Nausea Pyrosis Gastritis Gastric complaints, other Headache Dermatological complaints Dizziness Somnolence Gynecological complaints Other minor complaints
163 88 15 12 11 36 4 34 5 4 23
4.86 2.53 0.43 0.35 0.32 1.04 0.12 1.00 0.14 0.12 0.66
115 44 12 15 6 33 25 20 11 1 23
4.19 1.60 0.44 0.55 0.22 1.20 0.91 0.73 0.40 0.04 0.84
Total
269
7.74
228
8.32
treatment schedules studies appear to be very effective in these conditions and devoid of major adverse effects. An open study of Gutierrez et al (25 c) was devoted to the evaluation of efficacy of itraconazole in the treatment of superficial mycoses in 31 patients, using 100 mg itraconazole orally once daily for a period ranging from 2 to 6 weeks. Overall, clinical and mycological response rates were excellent. No m a j o r adverse reactions or hematological or biochemical abnormalities were observed. Only 1 of the 31 patients included in the study reported an adverse reaction; towards the second week of therapy, a 42-year-old male complained of dryness o f the m o u t h with a bitter taste. No other reactions were noted. A series of 114 evaluable patients with tinea pedis or tinea m a n u m have been analyzed in a double-blind study between itraconazole and griseofulvin by van Hecke and van Cutsem (26c). It was concluded that itraconazole 100 mg orally once daily for 30 days was micologically more effective than griseofulvin 500 mg once daily for 30 days in the treatment of tinea pedis and tinea m a n u m . Both drugs were well tolerated and appeared to be safe for use. Five patients out of 75 of the griseofulvin group
(exanthema, nausea, headache, pyrosis, abdominal cramps) and 9 patients out of 74 (abdominal cramps and pain, fatique, headache, bladder pain, dishidrosis) o f the itraconazole group reported side effects. Treatment was discontinued in 1 itraconazole patient because of abdominal cramps. Omoconazole O m o c o n a z o l e (CM 8282) is a novel molecule but still belongs to the imidazole class. According to an extensive review (27 c) the principal undesired effects noted with dermatological formulations are local burning sensations and irritation. They are usually mild and transient. The main undesired effects with pessaries are burning sensations or pruritus, but these too are usually transient and of moderate intensity. Sulconazole The safety and efficacy of sulconazole nitrate 1 ~ ointment administered for 4 weeks to 40 patients with tinea pedis were studied by Arenas and Castavantes (28c). Clinical and mycological improvement was observed in almost all cases; 2.5o7o of the patients treated developed contact dermatitis as an adverse reaction.
Antifungal drugs Chapter 28
283
Terconazole (SEDA-13, 236)
Croconazole
Moebius (29 k) summarizes the data on apparently immunoallergic complications which occur during terconazole treatment, noting that the G e r m a n Federal Health Office had received reports f r o m doctors o f an influenza-like synd r o m e associated with terconazole, 160 mg as single-dose treatment. The s y n d r o m e includes fever, chills, headache, a n d / o r hypotension. Within 1 hour after intravaginal application o f terconazole the s y n d r o m e starts with chills. A f t e r 2 hours the temperature can reach 3 8 . 0 40.2~ The complaints disappear after 1 0 - 48 hours.
S h o n o et al (33 C) report 6 cases o f contact sensitivity to croconazole hydrochloride, a new imidazole antimycotic drug introduced to the J a p a n e s e market in 1986, and available as 1%0 gel and cream. Six sensitized patients reacted on p a t c h testing to croconazole h y d r o c h l o r i d e d o w n to 0 . 5 - 0 . 1 % pet, and 3 appeared to be cross-sensitized to sulconazole nitrate. In J a p a n , allergic contact dermatitis to this drug has now been detected in 12 cases, including these 6. The authors underline that prescribers should be aware o f contact sensitivity to this drug.
In a typical case, a 56-year-old woman (weight 55 kg) was treated by a gynecologist for a genital mycosis; 2 - 3 hours after starting terconazole 160 mg she was observed to have vertigo, nausea, and a temperature of 38.5~ The patient collapsed twice and recovered within 1 day. The reaction lasted for about 10 hours and was observed by a general practitioner. The m a n u f a c t u r e r s have received at least 46 similar reports f r o m West G e r m a n y and the U . S . A . Moebius considers that the use o f terconazole involves an avoidable risk because imidazole derivatives which have p r o v e d better are available for gynecological use.
Tioconazole (SED-11, 235; SEDA-12, 235)
Contact sensitivity to topical ticonazol, a new imidazole for topical treatment o f fungal nail infections, is today well recognized. Further reports by Haustein et al (30 c) and J o n e s and K e n n e d y (31 C) c o n f i r m the p h e n o m e n o n . Haustin et al (30c) used lotion or cream of Micontral, which contains 1% tioconazole, in 73 patients with fungal infections due to dermatophytes, yeasts. Side effects such as slight redness, transient burning and pruritus on the eroded skin in the initial phase in 8 patients (11%) were observed. Jones and Kennedy (31 c) observed redness, swelling and blistering of the toes in the area of application of tioconazole nail solution. The contact dermatitis from tioconazole appeared after the third course of therapy, within 36 hours of application. The patient did not show crossreactivity with sulconazole, miconazole or clotrimazole, but reacted to topical ketoconazole. As there was no history to suggest primary sensitisation by ketoconazole, this presumably represents crossreactivity.
OTHER ANTIFUNGAL DRUGS Griseofulvin (SED-11, 567; SEDA-12, 236;
SEDA-13, 236) Lecky (34 C) reports a case o f griseofulvininduced neuropathy. A 76-year-old woman was treated with griseofulvin, 500 mg daily for 4 months, in 1987 and 6 months in 1988 for fungal nail infection. The second treatment was discontinued after parestbesia developed in all fingers, followed by numbness of the feet and a sensation of 'walking on cottonwool'. 4 months after the onset of neurological symptoms ankle jerks were absent and she had bilateral loss of vibration sense at the hallux. Nerve conduction studies showed a severe but very distal motor and sensory neuropathy. Laboratory investigation, including cerebrospinal fluid examination, were negative. Four months later her sensory symptoms had resolved and there were no neurological signs. Nerve conduction had substantially improved. It seems likely that the neuropathy was caused by griseofulvin. By 1989, the U.K. C o m m i t t e e on Safety o f Medicines had reports o f 5 cases o f ' n e u r o p a t h y ' and 6 cases o f 'paresthesia' occurring in association with griseofulvin treatm e n t , but n o n e seemed to have been well documented. Griseofulvin is a k n o w n photosensitizer, and
exacerbation of systemic lupus erythematosus or unmasking of lupus diathesis has been reported after its oral administration. Miyagawa et al (35 C) report a case o f systemic lupus erythematosus in which griseofulvin was associated with eruptions with clinical and
284 laboratory features similar to those o f subacute cutaneous lupus erythematosus. A 35-year-old woman with a 10-month history of dermatomyositis was admitted to hospital because, a few days before admission and following 2 weeks of continuous oral therapy with griseofulvin (375 mg/d) for onychomycosis of the fingernails and toenails, severe eruptions had appeared. The patient had anti-
Chapter 28
V.K. Lepakhin and A. V. Astakhova
bodies against SSA/RO and SSB/La antigens. The clinical resolution of the skin lesions after discontinuation of griseofulvin and recurrence on challenge with the drug stongly implies that this drug was associated with the clinical and histologic epidermal changes in the patient. Subacute cutaneous lupus erythematosus lesions developed on challenge with griseofulvin despite the patient's careful avoidance of direct sun exposure during hospitalization.
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ment of hormonally pretreated patients with progressive metastatic prostate cancer. Urology, 33, 5. 15. Weber MM, Luppa P, Engelhardt D (1989) Inhibition of human adrenal androgen secretion by ketoconazole. Klin. Wochenschr., 67, 707. 16. Vilela MP, Ferraz ML, Franco DR (1989) Hepatite toxica causada por ketoconazol: relato de quatro casos. Rev. Paul Med., 107, 1. 17. Barraviera B, Mendes RP, Pereira PCM et al (1988) Measurement of glucose-6-phosphate dehydrogenase and glutathione reductase activity in patients with paracoccidioidomycosis treated, with ketoconazole. Mycopathologia, 104, 87. 18. Leal-Cerro A, Garcia-Lund PP, Villar J e t al (1989) Arterial hypertension as a complication of prolonged ketoconazole treatment. J. Hypertens., 6 (Suppl. 6), $212. 19. Piantoni S, Narne S, Bottin R et al (1989) Bifonazole lozione 1% nella terapia delle otomicosi. Clin. Ter., 130, 23. 20. Maloley P, Nelson E, Montgomery HA, Campbell JR (1990) Severe reversible thrombocytopenia resulting from butoconazole cream. Ann. Pharrnacotherapy, 24, 143. 21. Van 't Wout JW, Mattie H, Furth R (1988) A prospective study of the efficacy of fluconazole (UK-49, 858) against deep-seated fungal infections. J. Antimicrob. Chemother., 21, 665. 22. Kujath P, Lerch K (1989) Secondary mycosis in surgery: treatment with fluconazole. Infection, 17, 111. 23. Odeh F, Fabry H, Kuklwein A et al (1990) A double blind clinical trial with a single daily application of fenticonazole lotion versus econazole lotion in patients with cutaneous mycosis. Curr. Ther. Res., 47, 1. 24. Alcantara R, Garibay JM (1988) Itraconazole therapy in dermatomycosis and vaginal candidiasis: efficacy and adverse effects profile in a large multicenter study. Adv. Ther., 5, 6. 25. Gutierrez GT, Enrile-Monsanto EC, Valencia CI et al (1989) Itraconazole in the treatment of superficial mycosis in Filipinos. Philipp. J. lntern. Med., 27, 179. 26. van Hecke E, van Cutsem J (1988) Double-blind
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comparison of itraconazole with griseofulvin in the treatment of tinea pedis and tinea manuum. Mycoses, 31, 12. 27. Anonymous (1989) Omoconazole nitrate. Drugs Today, 25, 7. 28. Arenas R, Casavantes LC (1989) The safety and efficacy of sulconazole ointment in patients with tinea pedis. Dermatol. Rev. Mex., 33, 85. 29. Moebius VM (1988) Influenza-like syndrome after terconazole. Lancet, 2, 1192. 30. Haustein VF, Seebacher C, Taube KM (1989) Behandlung von Pilzinfektionen der Haut mit Tioconazol (Mykontral). Dermatol. Monatsschr., 175, 12.
285 31. Jones S, Kennedy TC (1990) Contact dermatitis from tioconazole. Contact Dermatitis, 22, 122. 32. Jelen G, Tennstedt D (1989) Contact dermatitis from topical imidazole antifungals: 15 new cases. Contact Dermatitis, 21, 6. 33. Shono M, Hayashi K, Sugimoto R (1989) Allergic contact dermatitis from croconazole hydrochloride. Contact Dermatitis, 21, 225. 34. Lecky BRF (1990) Griseofulvin-induced neuropathy. Lancet, 335, 230. 35. Miyagawa S, Okuchi T, Shiomi Y, Sakamoto K (1989) Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J. Am. Acad. Dermatol., 21, 2.