Quantitative screening for fluconazole—amphotericin B antagonism in several <i>Candida albicans</i> strains by a comparative agar diffusion assay

Scheven, M.; Scheven, C.

doi:10.1111/j.1439-0507.1996.tb00111.x

Cited by 6 publications

(3 citation statements)

References 4 publications

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“…Antagonism among antifungal agents might occur in one of several ways. (i) Direct antifungal action at the same site results in decreased ability of other agents to exert their competitive effects on that site or at an altered target, as proposed for the azoles and amphotericin B (31,49,182,183,185,186,203). Azoles block the synthesis of ergosterol in the fungal cell membrane and may thus render amphotericin B inactive, since this agent exerts its activity by binding to ergosterol in the cell membrane.…”

Section: Mechanisms Of Interactions For the Antifungal Agentsmentioning

confidence: 99%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

487

368

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5 RATIONALEThe availability of new antifungal agents with novel mechanisms of action has stimulated renewed interest in combination antifungal therapies. In particular, and despite the limited clinical data, the high mortality of mold infections and the relatively limited efficacy of current agents have produced significant interest in polyene-, extended-spectrum azole-, and echinocandin-based combinations for these difficult-to-treat infections. With the recent publication of the first large randomized trial of antifungal combination therapy to be conducted in two decades (166) and the rapid proliferation of new in vitro and in vivo data on antifungal combinations, we have sought to review the recent work and future challenges in this area.The focus of this review is on the efficacy of antifungal drugs in combination with respect to the extent or rate of killing of the fungal pathogen, although other potential interactions (such as pharmacokinetic drug interactions) can impact efficacy when these agents are used together. The value of giving two drugs because each is separately effective against a group of organisms exhibiting a variety of types of resistance is not specifically discussed, but this also is an obvious and straightforward reason to use a combination of agents.It cannot be simply assumed that the use of two or more effective drugs with different mechanisms of action will produce an improved outcome compared to the results seen with a single agent. Combination antifungal therapy could reduce antifungal killing and clinical efficacy, increase potential for drug interactions and drug toxicities, and carry a much higher cost for antifungal drug expenditures without proven clinical benefit (106). Thus, it is important to critically evaluate the role of combination therapy as new data become available.Conceptual models and terminology. Methods for studying antifungal combinations in vitro and in vivo have differed considerably over time and among investigators. These tools do not differ with respect to their application to combination antibacterial or antiviral therapies and have been discussed extensively and elegantly in the landmark 1995 review by Greco (79). In brief, all approaches to evaluating combinations can be reduced to two elements: (i) a conceptual model for predicting the expected result for a combination and (ii) a set of phrases used to categorize results that are better than expected, worse than expected, or as expected. Although many subtle variations are possible, the underlying mathematical model is based on either the assumption of additive interactions or the assumption of probabilistic (multiplicative) interactions. On the basis of the terminology employed by the author who first carefully described each of these models, the two models can be usefully referred to as the Loewe additivity model and the Bliss independence model (79).The terminology used to place results into interpretive categories is often the subject of debate and confusion. Greco et al. (79) have proposed a set ...

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Section: Mechanisms Of Interactions For the Antifungal Agentsmentioning

confidence: 99%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

487

368

View full text Add to dashboard Cite

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“…Depending on the conditions, up to 100% of the preexposed cells tolerated AmB at 2 g/ml for up to 24 h. However, simultaneous exposure of C. albicans to azoles and AmB had much less effect, with only a small increase in the Candida population surviving relative to controls exposed to AmB alone. Moreover, several investigators have found synergistic interactions by simulta-neous exposure of C. albicans to azoles and AmB (13,30). One group, on the other hand, described antagonisms with preexposures of Candida to the more lipophilic azoles, such as itraconazole, but not to fluconazole (31,32).…”

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confidence: 99%

Stable Phenotypic Resistance of Candida Species to Amphotericin B Conferred by Preexposure to Subinhibitory Levels of Azoles

et al. 1998

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The fungicidal activity of amphotericin B (AmB) was quantitated for several Candida species. Candida albicans andC. tropicalis were consistently susceptible to AmB, with less than 1% survivors after 6 h of exposure to AmB. C. parapsilosis and variants of C. lusitaniae andC. guilliermondii were the most resistant, demonstrating 50 to 90% survivors in this time period and as high as 1% survival after a 24-h exposure time. All Candida species were killed (<1% survivors) after 24 h of exposure to AmB. In contrast, overnight exposure to either fluconazole or itraconazole resulted in pronounced increases in resistance to subsequent exposures to AmB. Most dramatically, C. albicans was able to grow in AmB cultures after azole preexposure. Several other Candida species did not grow in AmB but showed little or no reduction in viability after up to 24 h in AmB. Depending on the growth conditions,Candida cells preexposed to azoles may retain AmB resistance for days after the azoles have been removed. If this in vitro antagonism applies to the clinical setting, treatment of patients with certain antifungal combinations may not be beneficial. The ability of some Candida isolates to survive transient exposures to AmB was not reflected in the in vitro susceptibility changes as measured by standard MIC assays. This finding should be considered in studies attempting to correlate patient outcome with in vitro susceptibilities of clinical fungal isolates. Patients who fail to respond to AmB may be infected with isolates that are classified as susceptible by standard in vitro assays but that may be resistant to transient antifungal exposures which may be more relevant in the clinical setting.

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“…Depending on the conditions, up to 100% of the preexposed cells tolerated AmB at 2 g/ml for up to 24 h. However, simultaneous exposure of C. albicans to azoles and AmB had much less effect, with only a small increase in the Candida population surviving relative to controls exposed to AmB alone. Moreover, several investigators have found synergistic interactions by simultaneous exposure of C. albicans to azoles and AmB (13,30). One group, on the other hand, described antagonisms with preexposures of Candida to the more lipophilic azoles, such as itraconazole, but not to fluconazole (31,32).…”

mentioning

confidence: 99%