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Antifungal drugs
James J. Fennelly
28 Amphotericin B In earlier volumes in this series, broad coverage was given to the toxic effects of amphotericin B, with particular emphasis on its nephrotoxicity. Early suggestions by Olivero e t al. (1) of a protective effect of mannitol were not supported by the subsequent paper of Appel and Neu (2). A well-documented case, however, reported by Lagariea e t al. (3) showed increasing signs of nephrotoxicity with urea rising from 20 to over 140 mg% and creatinine from 1 to 2 mg%, clearing on the introduction of mannitol on the n i n t h day of treatment. Because of the reversal of the renal toxicity it was possible to continue the amphotericin B so that the patient's pulmonary symptoms cleared completely.
Amphotericin B combined with 5-fluoroeytosine Since amphotericin B is associated with significant toxicity when given in full therapeutic dosage, many communications have dealt with the improved benefit and perhaps reduced toxicity attained by combination with 5-fluorocytosine (5-FC) in selected cases. In a paper by Bennett e t aL (4) amphotericin B alone given for ten weeks was compared to amphotericin B plus 5-FC given for six weeks to patients with cryptococcal meningitis. The combination was more effective in these carefully evaluated patients, in that more individuals responded to the combination than to amphotericin alone, and with the combination there were less relapses with more rapid sterilization of the CSF. This was associated with a lesser degree of nephrotoxicity. As pointed out in other communications amphotericin B alone produces cure in cryptococcal infections in 5 3 - 5 8 % of cases, but long treatment is needed and significant toxicity is produced (5, 6). Side effects of fluorocytosine in Ben-
Antifungal drugs nett's study appeared to present in 11 of 34 patients on combination therapy, and in one of six receiving fluorocytosine after failure of amphotericin alone, i.e. 30% in all. Nine had leukopenia or thrombocytopenia, but mild leukopenia developed in three patients receiving amphotericin alone. The mean of the two highest serum concentrations in 16 patients receiving amphotericin B was 200/amol/l (2.3 mg/dl) and in 18patients receiving the combination was 140/.tmol/1 (1.5 mg/dl). This supported the initial suggestion by Utz e t al. in 1975 (7) that this combination was most effective in cryptococcal infections. In the 10-week programme of amphotericin B the dosage was 0.4 mg/kg body weight followed by 0.8 mg/kg every other day for 28 days. This was compared to a six-week regimen of amphotericin B 0.3 g/kg/day and fluorocytosine 150 mg/kg/day divided in six hourly doses. Interpreting the data presented above and in similar papers it is still important to bear in mind the evidence discussed in earlier volumes (see SEDA-3, 236) that the combination of amphotericin B and 5-FC can in some circumstances be more toxic than the separate substances. 5-Fluorocytosine (Flucytosine) According to Kauffmann (8) the cut-off serum level for fluorocytosine toxicity is 125 mg/1, i.e. 1.25 mg/dl. In the paper by Bennett e t al. cited above fluorocytosine levels were assessed in 22 patients of whom nine had toxicity attributable to fluorocytosine; in seven the samples were assessed at the time of toxicity and six of these seven showed peak levels exceeding 100 mg/1; five patients without any toxicity, however, also showed frequent levels exceeding 100 mg/1, indicating that the blood levels are not the sole determinant of toxicity. A dosage of 150 mg/kg produced a mean blood level in patients with serum creatinine below 1.4 mg/dl or 78 mg/1 as compared to patients with a serum creatinine level of
202 1.4-1.9 mg/dl whose mean blood level was
119 mg/1. The fact that toxicity of fluorocytosine is not necessarily related to blood levels as illustrated by Bennett e t al. supports the possibility that toxicity is related to the metabolite 5-fluorouracil, as indicated by Allhadeft (9). 5-Fluorocytosine is eliminated 98% unchanged in the urine, and it seems that human cells are unable to convert 5-FC into 5-FU; in susceptible pathogenic fungi, however, 5-FC is concentrated in the protoplasm and immediately transformed into 5-FU by deaminase.
Miconazole It has been assumed that the therapeutic effect of this drug is exerted through rupture of the cell membranes. De Nollis e t al. (10) showed miconazole in yeast cells to have a strong effect on oxidative enzymes with the reduction of cytochrome C oxidase and peroxidase associated with an increased catalase level when using fungistatic doses. These enzymes are totally absent with minimal fungicidal doses, suggesting that a breakdown of these cells is associated with a release of enzymes, accumulation of NADH and a resulting excess of peroxide which may reach levels adequate to kill cells. A major advantage of miconazole is a lack of marrow suppression as compared to 5-FC and amphotericin B. This is illustrated in a report by Evers and Knoop (11): their patient, a six-year-old girl with aminophenazone-induced agranulocytosis, was successfully treated for candida sepsis with miconazole. Eruptive xanthomas developed with intravenous miconazole in a 69-year-old man (12), probably attributable to reversible hyperlipidaemia associated with parenteral miconazole (13, 14). It is likely that the carrier solution (polyethoxylated castor oil) is responsible. The patient (with disseminated cryptococcal infection) had been treated with miconazole 200 mg increasing to 800 mg every eight hours over one month. The fact that the patient was a mild diabetic might have increased his liability to this complication. In a study by Deresinski e t al. (15) 12 patients with fungal meningitis treated with intravenous or intrathecal miconazole showed a good response. The main side effects were nausea (4 of 12 patients), pruritic skin erup-
J. J. Fennelly
tions (3 of 12), phlebitis (4 of 12) and hyponatraemia (8 of 12). In one case the latter was associated with high urine osmolarity and suggestive of inappropriate ADH excretion. Of the four patients who received IntraCSF miconazole one developed a twelfth nerve palsy and one a mild third ventricle haemorrhage. Seven of 12 patients developed mild anaemia. It is indicated that this was due to depression of red cell production (16). Complications were mild and a moderate thrombocytosis caused no problems. It was concluded that miconazole given i.v. or intrathecally is well tolerated and effective in some cases with coccidioidal meningitis.
Nimorazole A nimorazole preparation with striking in vitro and in vivo trichomicidal action was studied in 20 cases of vulvovaginitis caused by T r i c h o m o n a s vaginalis. Disappearance of the parasites was apparent only after four days of treatment. No bone marrow, hepatic or renal toxic effects were noted (I 7).
Econazole This imidazole dermative (17 R) is very closely related to miconazole. High efficacy has been demonstrated in uncontrolled studies but the relative benefit as compared to other antifungal agents is unknown. In dermatological studies some 90% of fungal infections are stated to respond. From the limited studies in man 90% of topically applied econazole appears to remain on the skin surface but following vaginal application about 3 - 7 % is absorbed. In topical or vaginal use, econazole is very well tolerated with side effects in 1-4% of cases. Redness, burning and pruritis appear to occur more often with inguinal application. While addition of a glucocorticoid might reduce this reaction there is evidence of reduced antifungal activity with the combined treatment (18). In two trials 4% of patients stopped treatment because of side effects. Minimal data on parenteral treatment are available. A single oral dose of 2 g caused gastrointestinal symptoms and visual and auditory hallucinations, headache, and dizziness in four of six subjects; with a divided dose the drug was better tolerated (19, 20, 21).
Antifungal drugs
203
REFERENCES 1. Olivero, J. J. et al. (1975): Mitigation of amphotericin B nephrotoxicity by mannitol. Brit. reed. J., 1,550. 2. Appel, E.B. and Neu, H.C. (1977): Nephrotoxicity of antimicrobial agents. New Engl. J.
Med., 296,284. 3. Lagarriga, J.A., Ortiz, B.P., Rodriguez, J.A. and Castaneda, J. (1977): Nefrotoxicidad por anfotericina B. A proposito de una observacion tradada con Mannitol. Invest. Med. Intern., 4, 397. 4. Bennett, J. E. et al. (1979): A comparison of amphotericin B alone and combined with fluorocytosine in the treatment of cryptococcal meningitis. New Engl. J. Med., 301, 126. 5. Spickard, A., Butler, W. T., Andriole, V. et al. (1963): The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann. intern. Med., 58, 66. 6. Sanosi, E., Parker, J. D., Doto, I. et al. (1969): Amphotericin B in cryptococcal meningitis: longterm results of treatment. Ann. intern. Med., 71, 1079. 7. Utz, J.P., Gannignes, I., Sande, M.A. et al. (1975): Therapy of cryptococcosis with a combination of fluorocytosine and amphotericin B. J. infect. Dis., 132, 368. 8. Kauffmann, C.A. and Frame, P.T. (1977): Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob. Agents Chemo-
ther., 11,244. 9. Ahadeff, M. (1978): Mycosis. Drugs of Today, XIV, 17. 10. De NoUis, S., Van Belle, H., Goosens, F., Thone, F. and Burgers, M. (1977): Antimicrob.
Agents Chemother., 11,500. 11. Evers, K. G. and Knoop, U. F. (1978): Miconazole treatment of candida sepsis in aminophe-
nazone-induced agranulocytosis. Acta paediat.
belg., 31,151. 12. Barr, R. J., Wayne, H., Fugita, M. D. and Graham, J. H. (1978): Eruptive xanthomas associated with intravenous miconazole therapy. Arch. Derm., 114, 1544. 13. Bagnarello, A. E., Lewis, L.A. and McHenry, M. C. (1977): Unusual serum abnormalities induced by the vehicle of miconazole. New Engl. J. Med., 296, 497. 14. Niell, H.B. (1977): Miconazole carrier solution hyperlipidaemia and haematologic problems. New Engl. J. Med., 296, 1479. 15. Deresinski, S.C., Lilly, R.B. and Levine, H.B. (1977): Treatment of fungal meningitis with miconazole. Arch. intern. Med., 136, 1977. 16. Marmion, L. C., Desser, K. B., Lilly, R. B. et al. (1976): Miconazole induced thrombocytosis and anaemia. Clin. Res., 84, 35 7. 17. Pesando, P. C. and Guashino, S. (1979): Valutazione clinica sull'efficacia e sulla tollerabilit~ del trattamento della trichomoniasi vaginale con Nimorazolo. Minerva ginec., 31,155. 18. Raab, W. and Gmeiner, B. (1976): Evaluation of econazole. A broad spectrum antimycotic substance and topically active glucocorticoid. Dermatologica, 153, 14. 19. Garrel, J., Millet, P., Jeanney, J. C. and Jacquelin, R. (1976): Un nouvel antimycosique d'action polyvalente l'6conazole. Med., 4, 5. 20. Hemple, M. (1975): Klinische Erfahrungen in der lokalen Behandlung yon Dermatomykosen mit Econazol. Mykosen, 18, 213. 21. Drouhet, E. and Dupont, B. (1978): Preliminary studies on the pharmacology and therapeutic activity of p.o. and i.v. econazole. Mykosen, Suppl. 1, 192.
28 Amphotericin B In earlier volumes in this series, broad coverage was given to the toxic effects of amphotericin B, with particular emphasis on its nephrotoxicity. Early suggestions by Olivero e t al. (1) of a protective effect of mannitol were not supported by the subsequent paper of Appel and Neu (2). A well-documented case, however, reported by Lagariea e t al. (3) showed increasing signs of nephrotoxicity with urea rising from 20 to over 140 mg% and creatinine from 1 to 2 mg%, clearing on the introduction of mannitol on the n i n t h day of treatment. Because of the reversal of the renal toxicity it was possible to continue the amphotericin B so that the patient's pulmonary symptoms cleared completely.
Amphotericin B combined with 5-fluoroeytosine Since amphotericin B is associated with significant toxicity when given in full therapeutic dosage, many communications have dealt with the improved benefit and perhaps reduced toxicity attained by combination with 5-fluorocytosine (5-FC) in selected cases. In a paper by Bennett e t aL (4) amphotericin B alone given for ten weeks was compared to amphotericin B plus 5-FC given for six weeks to patients with cryptococcal meningitis. The combination was more effective in these carefully evaluated patients, in that more individuals responded to the combination than to amphotericin alone, and with the combination there were less relapses with more rapid sterilization of the CSF. This was associated with a lesser degree of nephrotoxicity. As pointed out in other communications amphotericin B alone produces cure in cryptococcal infections in 5 3 - 5 8 % of cases, but long treatment is needed and significant toxicity is produced (5, 6). Side effects of fluorocytosine in Ben-
Antifungal drugs nett's study appeared to present in 11 of 34 patients on combination therapy, and in one of six receiving fluorocytosine after failure of amphotericin alone, i.e. 30% in all. Nine had leukopenia or thrombocytopenia, but mild leukopenia developed in three patients receiving amphotericin alone. The mean of the two highest serum concentrations in 16 patients receiving amphotericin B was 200/amol/l (2.3 mg/dl) and in 18patients receiving the combination was 140/.tmol/1 (1.5 mg/dl). This supported the initial suggestion by Utz e t al. in 1975 (7) that this combination was most effective in cryptococcal infections. In the 10-week programme of amphotericin B the dosage was 0.4 mg/kg body weight followed by 0.8 mg/kg every other day for 28 days. This was compared to a six-week regimen of amphotericin B 0.3 g/kg/day and fluorocytosine 150 mg/kg/day divided in six hourly doses. Interpreting the data presented above and in similar papers it is still important to bear in mind the evidence discussed in earlier volumes (see SEDA-3, 236) that the combination of amphotericin B and 5-FC can in some circumstances be more toxic than the separate substances. 5-Fluorocytosine (Flucytosine) According to Kauffmann (8) the cut-off serum level for fluorocytosine toxicity is 125 mg/1, i.e. 1.25 mg/dl. In the paper by Bennett e t al. cited above fluorocytosine levels were assessed in 22 patients of whom nine had toxicity attributable to fluorocytosine; in seven the samples were assessed at the time of toxicity and six of these seven showed peak levels exceeding 100 mg/1; five patients without any toxicity, however, also showed frequent levels exceeding 100 mg/1, indicating that the blood levels are not the sole determinant of toxicity. A dosage of 150 mg/kg produced a mean blood level in patients with serum creatinine below 1.4 mg/dl or 78 mg/1 as compared to patients with a serum creatinine level of
202 1.4-1.9 mg/dl whose mean blood level was
119 mg/1. The fact that toxicity of fluorocytosine is not necessarily related to blood levels as illustrated by Bennett e t al. supports the possibility that toxicity is related to the metabolite 5-fluorouracil, as indicated by Allhadeft (9). 5-Fluorocytosine is eliminated 98% unchanged in the urine, and it seems that human cells are unable to convert 5-FC into 5-FU; in susceptible pathogenic fungi, however, 5-FC is concentrated in the protoplasm and immediately transformed into 5-FU by deaminase.
Miconazole It has been assumed that the therapeutic effect of this drug is exerted through rupture of the cell membranes. De Nollis e t al. (10) showed miconazole in yeast cells to have a strong effect on oxidative enzymes with the reduction of cytochrome C oxidase and peroxidase associated with an increased catalase level when using fungistatic doses. These enzymes are totally absent with minimal fungicidal doses, suggesting that a breakdown of these cells is associated with a release of enzymes, accumulation of NADH and a resulting excess of peroxide which may reach levels adequate to kill cells. A major advantage of miconazole is a lack of marrow suppression as compared to 5-FC and amphotericin B. This is illustrated in a report by Evers and Knoop (11): their patient, a six-year-old girl with aminophenazone-induced agranulocytosis, was successfully treated for candida sepsis with miconazole. Eruptive xanthomas developed with intravenous miconazole in a 69-year-old man (12), probably attributable to reversible hyperlipidaemia associated with parenteral miconazole (13, 14). It is likely that the carrier solution (polyethoxylated castor oil) is responsible. The patient (with disseminated cryptococcal infection) had been treated with miconazole 200 mg increasing to 800 mg every eight hours over one month. The fact that the patient was a mild diabetic might have increased his liability to this complication. In a study by Deresinski e t al. (15) 12 patients with fungal meningitis treated with intravenous or intrathecal miconazole showed a good response. The main side effects were nausea (4 of 12 patients), pruritic skin erup-
J. J. Fennelly
tions (3 of 12), phlebitis (4 of 12) and hyponatraemia (8 of 12). In one case the latter was associated with high urine osmolarity and suggestive of inappropriate ADH excretion. Of the four patients who received IntraCSF miconazole one developed a twelfth nerve palsy and one a mild third ventricle haemorrhage. Seven of 12 patients developed mild anaemia. It is indicated that this was due to depression of red cell production (16). Complications were mild and a moderate thrombocytosis caused no problems. It was concluded that miconazole given i.v. or intrathecally is well tolerated and effective in some cases with coccidioidal meningitis.
Nimorazole A nimorazole preparation with striking in vitro and in vivo trichomicidal action was studied in 20 cases of vulvovaginitis caused by T r i c h o m o n a s vaginalis. Disappearance of the parasites was apparent only after four days of treatment. No bone marrow, hepatic or renal toxic effects were noted (I 7).
Econazole This imidazole dermative (17 R) is very closely related to miconazole. High efficacy has been demonstrated in uncontrolled studies but the relative benefit as compared to other antifungal agents is unknown. In dermatological studies some 90% of fungal infections are stated to respond. From the limited studies in man 90% of topically applied econazole appears to remain on the skin surface but following vaginal application about 3 - 7 % is absorbed. In topical or vaginal use, econazole is very well tolerated with side effects in 1-4% of cases. Redness, burning and pruritis appear to occur more often with inguinal application. While addition of a glucocorticoid might reduce this reaction there is evidence of reduced antifungal activity with the combined treatment (18). In two trials 4% of patients stopped treatment because of side effects. Minimal data on parenteral treatment are available. A single oral dose of 2 g caused gastrointestinal symptoms and visual and auditory hallucinations, headache, and dizziness in four of six subjects; with a divided dose the drug was better tolerated (19, 20, 21).
Antifungal drugs
203
REFERENCES 1. Olivero, J. J. et al. (1975): Mitigation of amphotericin B nephrotoxicity by mannitol. Brit. reed. J., 1,550. 2. Appel, E.B. and Neu, H.C. (1977): Nephrotoxicity of antimicrobial agents. New Engl. J.
Med., 296,284. 3. Lagarriga, J.A., Ortiz, B.P., Rodriguez, J.A. and Castaneda, J. (1977): Nefrotoxicidad por anfotericina B. A proposito de una observacion tradada con Mannitol. Invest. Med. Intern., 4, 397. 4. Bennett, J. E. et al. (1979): A comparison of amphotericin B alone and combined with fluorocytosine in the treatment of cryptococcal meningitis. New Engl. J. Med., 301, 126. 5. Spickard, A., Butler, W. T., Andriole, V. et al. (1963): The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann. intern. Med., 58, 66. 6. Sanosi, E., Parker, J. D., Doto, I. et al. (1969): Amphotericin B in cryptococcal meningitis: longterm results of treatment. Ann. intern. Med., 71, 1079. 7. Utz, J.P., Gannignes, I., Sande, M.A. et al. (1975): Therapy of cryptococcosis with a combination of fluorocytosine and amphotericin B. J. infect. Dis., 132, 368. 8. Kauffmann, C.A. and Frame, P.T. (1977): Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob. Agents Chemo-
ther., 11,244. 9. Ahadeff, M. (1978): Mycosis. Drugs of Today, XIV, 17. 10. De NoUis, S., Van Belle, H., Goosens, F., Thone, F. and Burgers, M. (1977): Antimicrob.
Agents Chemother., 11,500. 11. Evers, K. G. and Knoop, U. F. (1978): Miconazole treatment of candida sepsis in aminophe-
nazone-induced agranulocytosis. Acta paediat.
belg., 31,151. 12. Barr, R. J., Wayne, H., Fugita, M. D. and Graham, J. H. (1978): Eruptive xanthomas associated with intravenous miconazole therapy. Arch. Derm., 114, 1544. 13. Bagnarello, A. E., Lewis, L.A. and McHenry, M. C. (1977): Unusual serum abnormalities induced by the vehicle of miconazole. New Engl. J. Med., 296, 497. 14. Niell, H.B. (1977): Miconazole carrier solution hyperlipidaemia and haematologic problems. New Engl. J. Med., 296, 1479. 15. Deresinski, S.C., Lilly, R.B. and Levine, H.B. (1977): Treatment of fungal meningitis with miconazole. Arch. intern. Med., 136, 1977. 16. Marmion, L. C., Desser, K. B., Lilly, R. B. et al. (1976): Miconazole induced thrombocytosis and anaemia. Clin. Res., 84, 35 7. 17. Pesando, P. C. and Guashino, S. (1979): Valutazione clinica sull'efficacia e sulla tollerabilit~ del trattamento della trichomoniasi vaginale con Nimorazolo. Minerva ginec., 31,155. 18. Raab, W. and Gmeiner, B. (1976): Evaluation of econazole. A broad spectrum antimycotic substance and topically active glucocorticoid. Dermatologica, 153, 14. 19. Garrel, J., Millet, P., Jeanney, J. C. and Jacquelin, R. (1976): Un nouvel antimycosique d'action polyvalente l'6conazole. Med., 4, 5. 20. Hemple, M. (1975): Klinische Erfahrungen in der lokalen Behandlung yon Dermatomykosen mit Econazol. Mykosen, 18, 213. 21. Drouhet, E. and Dupont, B. (1978): Preliminary studies on the pharmacology and therapeutic activity of p.o. and i.v. econazole. Mykosen, Suppl. 1, 192.