Azole Antifungal Drugs: Old and New

Dismukes, William E.

doi:10.7326/0003-4819-109-3-177

Cited by 92 publications

(18 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, the fluconazole MIC end points obtained for susceptible organisms (0.25 ,ug/ml) by using this method correspond to achievable levels of fluconazole in blood and tissue of humans and experimental animals and are in agreement with the known in vivo activity of the drug in the setting of human and experimental candidiasis (7,17,18,20,25). Additional experiments are currently ongoing to correlate our in vitro findings with in vivo results of treatment in a murine model of systemic candidiasis.…”

Section: Resultssupporting

confidence: 53%

“…MICs of fluconazole obtained by direct visual reading without agitation, however, were difficult to read and were in the resistant range (MIC for 50% of the isolates tested [MIC50], >64 ,ug/ml; range, 16 to >64 ,ug/ml) (Table 1), not in keeping with the known activity of this drug in experimental and human candidiasis (7,13,17,18,20). Before agitation, the visible growth for the susceptible strains was noted at 64 ,ug/ml, gradually increasing as the drug concentration fell to 0.125 ,ug/ml but without any significant differences between consecutive wells, which would have allowed end point determination (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Fluconazole susceptibility testing of Candida albicans: microtiter method that is independent of inoculum size, temperature, and time of reading

Anaissie

Paetznick

Bodey

1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

In vitro antifungal susceptibility testing generally remains unstandardized and unreliable for directing therapy. When azoles are tested, this problem is further compounded by the lack of definite reading end points. We determined the in vitro susceptibility of 50 Candida albicans isolates (including 10 reference strains) to fluconazole by using a microbroth dilution method in which microtiter plates were agitated immediately before reading. Six fungal inoculum sizes (ranging from 2 x 102 to 4 x 105 CFU/ml), three different times of reading (24, 48, and 72 h) Over the past several years, we have witnessed an increasing number of opportunistic fungal infections in immunocompromised patients (1,5,14,28). In addition, fungi previously considered harmless colonizers have now emerged as significant pathogens, and many of them are resistant to available drugs (4,19,24). At the same time, several new antifungal agents have become available, resulting in a great demand for in vitro susceptibility testing (9,13,20,23,25,26). Although major advances in antifungal susceptibility testing have been achieved, particularly through the efforts of the National Committee for Clinical Laboratory Standards (NCCLS) (2, 6, 8-10, 21, 22), currently available methods remain difficult to duplicate and cannot be relied upon for directing therapy (6,9,10,26). This problem is particularly relevant to tests of susceptibility to azoles because of the lack of definite reading end points due to the "trailing effect." In this report, we present results of our determination of the in vitro susceptibility of 50 Candida albicans isolates to fluconazole by using a microbroth dilution method with agitation of the plates immediately before reading. This method resulted in clear-cut visual end points that were reproducible; that were independent of inoculum size, time of reading, and incubation temperature; and that correlated with the degree of fungal inhibition as determined by turbidity studies. MATERIALS AND METHODSAntifungal agent. Fluconazole (Pfizer, Sandwich, United Kingdom) was rendered soluble in 100% dimethyl sulfoxide (Sigma Chemical Co., St. Louis, Mo.) at a starting concentration of 6,400 ,ug/ml. Fluconazole was diluted with assay medium to the highest drug concentration of 64 pg/ml (4% dimethyl sulfoxide). Twofold dilutions were made for the remaining wells according to the NCCLS's modification of Ericsson and Sherris' method of dilution (8).Assay medium. RPMI 1640 medium powder with L-glu-* Corresponding author. tamine and without phosphate buffer (Sigma Chemical Co.) was used as the assay medium. Preweighed aliquots of 10.4 g of medium were mixed with 1,000 ml of deionized water buffered with morpholinepropanesulfonic acid (MOPS; Sigma Chemical Co.). The buffer solution was prepared with 34.53 g of MOPS (0.165 M) per 1,000 ml of water. Clear solutions of both the buffer powder-water and medium powder-buffered water combinations were obtained by using magnetic spin bars at room temperature. The solutions were titrated by using 10 N sod...

show abstract

Section: Resultssupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Fluconazole susceptibility testing of Candida albicans: microtiter method that is independent of inoculum size, temperature, and time of reading

Anaissie

Paetznick

Bodey

1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…ker- Woudenberg and Roerdink, 1986;Bakker-Woudenberg et al, 1993Lopez-Berestein, 1987; Since the rise i n the number Of newer azole antifungal compounds have been synthesized and evaluated in vivo, alone [Clemons et al, 1995;Como and Dismukes, 1994;Dismukes, 1988;Fromtling, 1988;Georgiev, 1993;Hay, 1994;Kauffman, 1994;Peng and Galgiani, 19931 or associated with liposomes [Brasseur et al, 1991;Le Conte et al, 1991;Singh et al, 19931 or cyclodextrins [Hostetler et al, 1992;Van Doorne et al, 19881. Particular interest has been focused on the new triazole derivative itraconazole ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Freeze-drying of itraconazole-loaded nanosphere suspensions: a feasibility study

et al. 1996

View full text Add to dashboard Cite

“…Consequently, there is a need for effective and less toxic drugs for the treatment of patients with these infections. One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37).…”

mentioning

confidence: 99%

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

Etten

Rhee

Kampen

et al. 1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans were studied. With respect to the extracellular growth of C. albicans, antifungal activity was measured in terms of MICs and minimal fungicidal concentrations as well as by determination of the concentration that effectively killed (>99.9%) C. albicans in the absence or presence (amphotericin B only) of serum. Amphotericin B was highly active in terms of killing, even at an increased inoculum size. In the presence of serum, amphotericin B activity was substantially reduced. For fluconazole, activity was restricted to inhibition of fungal growth, even after the inoculum size was reduced. With respect to the intracellular growth of C. albicans, antifungal activity was measured by using monolayers of murine peritoneal macrophages infected with C. albicans and was measured in terms of inhibition of germ tube formation as well'as effective killing (>99%) of C. albicans. Amphotericin B was highly active against C. albicans. At an increased ratio of infection, amphotericin B activity was slightly reduced. Fluconazole had no antifungal activity. Neither a reduction in the ratio of infection nor exposure of C. albicans to fluconaz'ole prior to macrophage ingestion resulted in activity against intracellular C. albicans by fluconazole. Previous exposure of C. albicans to amphotericin B resulted in increased intracellular activity of amphotericin B. The. intracellular antifungal activity of the combination of fluconazole with amphotericin B was les than that of amphotericin B alone. Amphotericin B showed fungicidal activity against C. albicans growing both extracellularly and intracellularly, whereas fluconazole inhibited growth only of extracellular C. albicans. A slight antagonistic effect between fluconazole and aiflphotericin B was found with respect to intracellular as well as extracellular C. albicans.Deep-seated candidal infections are an important cause of morbidity and mortality in immunocompromised patients (15,21,22). The current drug of choice for most systemic mycoses is still amphotericin B (AmB), but its use is restricted by a variety of toxic side effects (6,13,15,21,22). Consequently, there is a need for effective and less toxic drugs for the treatment of patients with these infections. One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37). Recently, the antifungal efficacy of Flu was demonstrated in persistently granulocytopenic rabbits when it was used for prevention or early treatment (39,40). Little is still known, however, on the role of Flu in the treatment of systemic candidiasis in immunocompromised patients. Since the host defense mechanisms in these patients are severely impaired, the intrinsic antifungal activity of the antifungal agent is of great importance for effective treatment. Unfortunately, standardized in vitro methods for assessment of ...

show abstract

Azole Antifungal Drugs: Old and New

Cited by 92 publications

References 16 publications

Fluconazole susceptibility testing of Candida albicans: microtiter method that is independent of inoculum size, temperature, and time of reading

Fluconazole susceptibility testing of Candida albicans: microtiter method that is independent of inoculum size, temperature, and time of reading

Freeze-drying of itraconazole-loaded nanosphere suspensions: a feasibility study

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

Contact Info

Product

Resources

About