Combined Flucytosine — Amphotericin B Treatment of Cryptococcosis

Utz, John P.; Garriques, I. L.; Sande, Merle A.; Warner, John F.; Mandell, Gerald L.; Mcgehee, Read F.; Duma, Richard J.; Shadomy, Smith

doi:10.1007/978-1-4684-3129-2_22

Cited by 3 publications

(6 citation statements)

References 12 publications

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“…Relapses, development of drug resistance, and significant bone marrow toxicity were common (96,97). Utz et al (98) used low doses of amphotericin B (20 mg daily) in combination with flucytosine to successfully treat a small number of patients with cryptococcal meningitis. Subsequently, a cooperative trial evaluated combination therapy (99).…”

Section: Treatmentmentioning

confidence: 98%

Current concepts in Cryptococcosis

Patterson

Andriole

1989

Eur. J. Clin. Microbiol. Infect. Dis.

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Cryptococcus neoformans has become an increasingly important pathogen. Cryptococcosis is an important cause of morbidity and mortality in immunocompromised hosts and is the second most common fungal infection complicating AIDS. In recent years, research has focused on the host defenses against Cryptococcus and has led to an improved understanding of the capsular virulence of the organism, the mechanisms of T-cell defenses, and the role of phagocytic cells in the fungistasis and killing of cryptocci. Amphotericin B with or without flucytosine has clearly improved treatment of cryptococcosis, but therapy is associated with significant toxicity. Current investigation is focused on the triazoles, which may offer improved therapy for cryptococcosis. In this report, we review recent developments in the understanding of the host defenses against Cryptococcocus and discuss current recommendations for the management of cryptococcosis.

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Section: Treatmentmentioning

confidence: 98%

Current concepts in Cryptococcosis

Patterson

Andriole

1989

Eur. J. Clin. Microbiol. Infect. Dis.

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“…Combination therapy with oral 5-FC and intravenous amphotericin B has been most successfully applied to human systemic candidiasis for suppressing the occurrence of 5-FC-resistant mutants of Candida spp. (103,142,144,151,159,167,174). The superiority of this combination therapy to 5-FC monotherapy or to amphotericin B monotherapy has also been proven or suggested for the treatment of cryptococcal meningitis with regard to fungal suppression and symptomatic improvement (14,60,66,129,153,161,174).…”

Section: Flucytosine Resistancementioning

confidence: 99%

Drug resistance in human pathogenic fungi

Iwata

1992

Eur J Epidemiol

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Since the therapy of the mycoses, particularly the systemic mycoses, is relatively long-term in nature, emergence of resistance to antifungal drugs during the treatment of period would be of considerable clinical importance. However, most reports of resistance to antifungal agents among human pathogenic fungi indicate that naturally-occurring resistance is very rare, and that the induction of resistant mutants or variants is much more difficult to achieve in vitro and in vivo than with bacteria. As a matter of fact, amphotericin B and some other classic antifungals have not as yet posed a broadly significant problem relative to drug resistance despite their widespread and frequent use. Fungal resistance has thus received little attention, in contrast to the critical importance of bacterial resistance frequently caused by a variety of antibacterial chemotherapeutic agents, until a single exception to this generalization arose with the advent of flucytosine. This new development has aroused great interest in the problem of fungal resistance among the scientists involved with medical mycology. It is generally believed that fungi, like bacteria, are intrinsically capable of developing resistance to antifungal agents. As illustrated by flucytosine, inherently resistant mutants to antifungals occur within sensitive strains of human pathogenic fungi with significant frequency. Given the relatively high degree of such primary resistance, these mutants should develop secondary resistance during therapy, thus resulting in considerable limitations in the clinical usefulness of the antifungals. Virtually, all unsuccessful cases of mycoses treated with some of the recently exploited antifungal drugs, albeit scarce to date, would obviously be attributable to the occurrence of secondary resistance. The exploitation of new antifungal drugs thus requires investigations of their resistance as one of the most important research projects to be undertaken before receiving approval for use on humans. This paper reviews from various aspects the literature on resistance to various classic and novel antifungal agents among human pathogenic fungi. The resistance of some nonpathogenic fungi to these agents will also be described from genetic and biochemical points of view.

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“…Combined chemotherapy with AmphB and 5-FC showed advantages over the che motherapy with AmphB alone, or with either AmphB or 5-FC alone, in human CNS cryptococcosis [4,21,38], and this com bination was used successfully also for severe cases of human candidiasis and invasive aspergillosis [see e.g. 8,9,14,35,39,40], although superiority over AmphB alone was not assessed.…”

Section: Combination Amphb Plus 5-fcmentioning

confidence: 99%

“…A substantial number of the failures of 5-FC monotherapy in human mycoses (particularly CNS cryptococcosis and asper gillosis) was explained by the emergence of 5-FC resistance [see e.g. 34], whereas sec ondary 5-FC resistance was not or only rarely observed with the combination AmphB plus 5-FC [4,38], In most of the animal models used for antifungal chemo therapy including ours, the treatment period was too short for a selection of resistant mutants. (In unpublished experiments using the same treatment schedule is in the pres ent study, we did not find any increase of resistant mutants in the organ cultures from animals dying in spite of 5-FC mono therapy.)…”

Section: Combination Amphb Plus 5-fcmentioning

confidence: 99%

“…Not sur prisingly, there has been an increasing in terest in drug combinations, with the hope that they may offer advantages such as smaller dosage of the partners, reduced in cidence of resistance, and complementary pharmacokinetics of the 2 drugs, particu larly with respect to penetration. Several clinical studies exist indicating that the one or the other of these expectations was ful filled by combining amphotericin B and 5-fluorocytosine, especially in cryptococcal meningitis [4,21,38], Candida endocarditis [39] and invasive aspergillosis [23,35]. Clinical experience with combinations of the most recent drug, kétoconazole, with any of the older antimycotics is still scarce.…”

Section: Introductionmentioning

confidence: 99%

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Combination Therapy of Experimental Candidiasis, Cryptococcosis and Aspergillosis in Mice

Polak¹,

Scholer²,

Wall

1982

Chemotherapy

120

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Combination pairs of the major systematic antimycotic drugs, amphotericin B (AmphB), 5-fluorocytosine (5-FC) and ketoconazole (Ktz) were administered to mice with experimental candidiasis, cryptococcosis and aspergillosis at a variety of combination ratios. The 3 mycoses were produced with 3 strains each of Candida albicans, Cryptococcusneoformans, and Aspergillus jumigatus, respectively, which were preselected to represent 3 different degrees of 5-FC sensitivity (‘normally sensitive’, ‘moderately resistant’, and ‘definitely resistant’). The life-prolonging effect of the combinations was compared with the effect of each partner administered alone at the same and at the double dosage. Using the U test of Mann and Whitney and setting limits which on the whole were more rigorous than those of the isobole methods commonly applied to the study of drug interactions, the effects of the concentrations were classified as ‘synergistic’, ‘additive’, ‘indifferent’ or ‘antagonistic’. The combination AmphB plus 5-FC was definitely synergistic or definitely additive in all 3 candidiasis models, the most pronounced synergism occurring in the infection with the ‘definitely 5-FC-resistant’ C. albicans strain; in cryptococcosis produced by any of the 3 C. neoformans strains the effect was definitely additive, but only slightly additive or indifferent in the 3 aspergillosis models. The combination AmphBplus Ktz was slightly synergistic in candidiasis produced by one C. albicans strain, but definitely antagonistic in this mycosis produced by the remaining 2 strains of the same species; the combination was definitely additive or, even, slightly synergistic in the 3 cryptococcus models, but, again, antagonistic in aspergillosis produced by all 3 strains of A. fumigatus. 5-FC plus Ktz was additive or indifferent in the 3 candidiasis models, but throughout indifferent in cryptococcosis and aspergillosis.

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Combined Flucytosine — Amphotericin B Treatment of Cryptococcosis

Cited by 3 publications

References 12 publications

Current concepts in Cryptococcosis

Current concepts in Cryptococcosis

Drug resistance in human pathogenic fungi

Combination Therapy of Experimental Candidiasis, Cryptococcosis and Aspergillosis in Mice

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