Interactions between Triazoles and Amphotericin B against
            <i>Cryptococcus neoformans</i>

Barchiesi, Francesco; Schimizzi, Anna Maria; Caselli, Francesca; Novelli, Andréa; Fallani, Stefania; Giannini, Daniele; Arzeni, Daniela; Cesare, Simona Di; Francesco, Luigi Falconi Di; Fortuna, Maria Caterina; Giacometti, Andrea; Carle, Flavia; Mazzei, Teresita; Scalise, Giorgio

doi:10.1128/aac.44.9.2435-2441.2000

Cited by 73 publications

(66 citation statements)

References 27 publications

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“…This may be related to the various sterol compositions seen with C. neoformans isolates (75). Indifferent effects have been reported most frequently (13,78,161), but synergy has also been found for combinations of ketoconazole (78,161) or posaconazole (13) and amphotericin B. While positive interactions have been most commonly reported with concurrent combinations of polyenes and azoles, sequential exposure to an azole may reduce subsequent amphotericin B activity.…”

Section: Neoformans (I) In Vitro Datamentioning

confidence: 98%

“…Polyene-azole interactions in the treatment of C. neoformans infections have been studied both with (74,140) and without (13,63,74,78,150,161) the use of flucytosine, but in vitro data are relatively scant. In contrast to the antagonism commonly observed with Candida spp.…”

Section: Neoformans (I) In Vitro Datamentioning

confidence: 99%

“…Investigations that have not confirmed synergy (78,80,161) VOL. 48,2004 MINIREVIEW 697 (14) Improved (3,50,61,157), similar (14,50,60,212), or worse (89) survival Reduced tissue burden (50,78,101,212) Combination associated with better survival than monotherapy and was consistent over a range of doses (3); effects more pronounced at lower doses (101), and single agents were very effective at higher doses alone; 5FC ϩ KTC rarely cleared tissues better than either agent alone (150); hamsters with combination did worse than with ITC alone (89); ITC ϩ 5FC performed similarly to ITC ϩ AmB and better than ITC or 5FC monotherapy in guinea pigs (212); with 10 days of treatment of mice, combination prolonged survival more than either agent alone but not when treatment was limited to 5 days (157); PSC combination not better than monotherapy in terms of survival but better than monotherapy in reducing fungal counts in brain tissue (14) Humans FLC (48,102,124,193,223) Good clinical success (48,102,193 FLC: addition of AmB to FLC had dramatic impact on yeast burden in brain tissue b , but survival with AmB was 100%; effects on survival were greatest at highest dosages of azole-AMB (2,158); improved survival at lower doses of ITC ϩ AmB, but survival was worse when higher doses were used (157); FLU preexposure did not reduce subsequent AmB activity (13) Humans-case report (47) Case report of a woman with meningitis who responded to this combination after failing AmB used lower concentrations of flucytosine and amphotericin B only or used strains with reduced susceptibility to flucytosine, which may have influenced or biased their ability to characterize the full spe...…”

Section: Neoformans (I) In Vitro Datamentioning

confidence: 99%

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Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

485

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: Neoformans (I) In Vitro Datamentioning

confidence: 98%

Section: Neoformans (I) In Vitro Datamentioning

confidence: 99%

Section: Neoformans (I) In Vitro Datamentioning

confidence: 99%

See 1 more Smart Citation

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

485

368

View full text Add to dashboard Cite

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“…A stock solution of fluconazole (2 mg/ml) (Pfizer Inc., New York, N.Y.) in sterile distilled water was used. The drug was administered intraperitoneally at a dose of 10 mg/kg/day (delivered in a 100-l volume), which is the dose found to be most effective in the murine model being used (1). In survival experiments, treatment was initiated 24 h after infection and continued for 10 days (postinfection days 1 through 10).…”

Section: Methodsmentioning

confidence: 99%

Role of AFR1 , an ABC Transporter-Encoding Gene, in the In Vivo Response to Fluconazole and Virulence of Cryptococcus neoformans

et al. 2006

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We have recently demonstrated that upregulation of the ATP binding cassette (ABC) transporter-encoding gene AFR1 in Cryptococcus neoformans is involved in the in vitro resistance to fluconazole of this yeast. In the present study, we investigated the role of AFR1 in the in vivo response to fluconazole in a mouse model of systemic cryptococcosis. Mice were infected with a wild-type fluconazole-susceptible strain of C. neoformans, strain BPY22; an afr1 mutant, BPY444, which displayed hypersusceptibility to fluconazole in vitro; or an AFR1-overexpressing strain, BPY445, which exhibited in vitro resistance to the drug. In each of the three groups, infected animals were randomly assigned to fluconazole treatment or untreated-control subgroups. As expected, fluconazole prolonged survival and reduced fungal tissue burdens (compared with no treatment) in BPY22-and BPY444-infected mice, whereas it had no significant effects in mice infected with BPY445. When the pathogenicities of these strains in mice were investigated, strain BPY445 was significantly more virulent than BPY22 following inhalational or intravenous inoculation, but mice infected with BPY444 survived significantly longer than BPY22-infected animals only when infection was acquired via the respiratory tract. In in vitro macrophage infection studies, strain BPY445 also displayed enhanced intracellular survival compared with strains BPY22 and BPY444, suggesting that its increased virulence may be due to its reduced vulnerability to the antimicrobial factors produced by phagocytic cells. These findings indicate that the upregulation of the AFR1 gene is an important factor in either determining the in vivo resistance to fluconazole or influencing the virulence of C. neoformans.Fluconazole (FLC) and other azole antifungal drugs are the agents most widely used for prevention and treatment of infections with Cryptococcus neoformans. Their confirmed efficacy and safety combined with their excellent pharmacokinetic profiles make them extremely important therapeutic options for the management of cryptococcosis at various body sites (6). In spite of their extensive use, resistance to these drugs among C. neoformans strains is apparently uncommon, although it has been implicated in several cases of treatment failure or infection relapse (3-4, 6, 20). Some authors have suggested that the frequency of resistance may have been underestimated because azole-resistant mutants of C. neoformans are often less virulent than their wild-type counterparts (6, 22). However, findings with other pathogenic yeast species demonstrate that antifungal resistance is not necessarily associated with attenuated pathogenicity (2, 44). For example, in a study of Candida albicans, Becker et al. (2) demonstrated that virulence is reduced by the disruption of the efflux pump-encoding MDR1 gene, whose overexpression leads to fluconazole resistance (36, 42). Graybill et al. (21) used a mouse model of systemic candidiasis to assess the virulences of a series of C. albicans isolates with increasing f...

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“…26 There have been favorable animal model studies with this combination and certainly an azole following polyene induction therapy in sequence has been widely and successfully used. 27 However, the combination of an azole plus polyene for induction therapy still represents second-line therapy. Similarly, the all oral combination regimen of fluconazole plus flucytosine has been studied in cryptococcal meningitis.…”

Section: Challenge Recommendationmentioning

confidence: 99%