Antifungal combination treatment: a future perspective

Fohrer, Cécile; Fornecker, Luc; Nivoix, Yasmine; Cornila, Corina; Marinescu, Cristina; Herbrecht, Raoul

doi:10.1016/j.ijantimicag.2006.03.016

Cited by 35 publications

(19 citation statements)

References 40 publications

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“…The combined use of antifungal compounds that belong to different pharmacological classes and possess different mechanisms of action is an attractive approach. Combination antifungal therapy may increase the extent and rate of pathogen killing even in difficult-to-treat anatomical sites of infections, lower the risk of acquired resistance, shorten the recovery time, reduce undesirable side effects by using smaller drug doses, overcome the problem of subtherapeutic drug levels, and expand the antifungal spectrum to cover mixed infections (3). However, there are risks which may outweigh the value of combination therapy and limit its use, such as a reduced efficacy due to antagonistic interactions, increasing toxicity with the use of both drugs, and the higher cost of treatment, especially when new compounds are combined (4).…”

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confidence: 99%

Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

Siopi

Siafakas

Vourli

et al. 2015

Antimicrob Agents Chemother

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Although amphotericin B-azole combination therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional in vitro tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of amphotericin B and voriconazole in an in vitro dialysis/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an azole-resistant and an azole-susceptible Aspergillus fumigatus isolate, using Bliss independence and canonical mixture response surface analyses. Amphotericin B dosing regimens with the drug administered every 24 h (q24h) were combined with voriconazole q12h dosing regimens. In vitro PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low amphotericin B-high voriconazole exposures, whereas antagonism (؊6 to ؊16%) was found at high amphotericin B-low voriconazole exposures for both isolates. Combination therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with voriconazole/amphotericin B MICs of 1 to 4 mg/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of drug in serum (tC min )/MIC ratio for voriconazole and a 0.5 total maximum concentration of drug in serum (tC max )/MIC ratio for amphotericin B, whereas the equally effective monotherapy regimens required a voriconazole tC min /MIC ratio of 1.8 and an amphotericin B tC max /MIC ratio of 2.8. Amphotericin B-voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic drug monitoring can be employed to optimize antifungal combination therapy with low-dose (<0.6 mg/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity. Invasive aspergillosis is a serious life-threatening complication in immunocompromised patients. The main pathogen is Aspergillus fumigatus (1). The poor prognosis, the unsatisfactory response to first-line treatment, and the emergence of resistance among clinical isolates have raised interest in the use of combination therapy as an alternative therapeutic approach in an attempt to increase antifungal efficacy, particularly against difficult-to-treat infections (2). The combined use of antifungal compounds that belong to different pharmacological classes and possess different mechanisms of action is an attractive approach. Combination antifungal therapy may increase the extent and rate of pathogen killing even in difficult-to-treat anatomical sites of infections, lower the risk of acquired resistance, shorten the recovery time, reduce undesirable side effects by using smaller d...

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Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

Siopi

Siafakas

Vourli

et al. 2015

Antimicrob Agents Chemother

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“…Current practices are evolving to use the newer drugs in combinations either with or after a more established therapeutic regimen for the treatment of serious yeast infections (18,26,35,37,43,50). Potential benefits of using these antifungal drugs in combinations against serious infections include a broader spectrum, reduced toxicity, lower likelihood of the emergence of acquired resistance, and synergistic or additive interactions (7,15,19,24,28,33).…”

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Multilaboratory Testing of Two-Drug Combinations of Antifungals against Candida albicans , Candida glabrata , and Candida parapsilosis

Chaturvedi

Ramani

Andes

et al. 2011

Antimicrob Agents Chemother

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“…5) However, in most cases the limited diversity of the mechanisms of action among the currently available drugs and the controversial results of the studies of combination therapies have failed to offer sufficient evidence to make them major treatments. 6,7) On the other end of the scale, although mucosal fungal infections are generally not fatal, the emergence of resistant species and strains as well as frequent recurrences, especially in the case of vaginal candidiasis, has become problematic. 3,8) Oral administration of fluconazole is frequently prescribed for recurrent vulvovaginal candidiasis mainly because of its good penetration in the vaginal tissue and high tolerance.…”

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confidence: 99%

In Vitro Antifungal Activities of D11-2040, a .BETA.-1,6-Glucan Inhibitor, with or without Currently Available Antifungal Drugs

Kitamura

Someya

Okumura

et al. 2010

Biological & Pharmaceutical Bulletin

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We recently reported our discovery of small molecule b b-1,6-glucan inhibitor named D75-4590 and the antiCandida activity of its derivatives D11-2040 and D21-6076. In this study, we further evaluated the antifungal profile of D11-2040. It alone strongly inhibited the vegetative growth and/or hyphal development of various Candida species, but no significant activity was observed against Cryptococcus neoformans or any of the filamentous fungi tested. Synergism was detected for C. albicans in the interaction of D11-2040 and caspofungin by the chequerboard method and in that of D11-2040 and fluconazole by the time-kill method. Slight but positive interactions were observed in several combinations for C. neoformans and Aspergillus fumigatus as well. These results suggested that b b-1,6-glucan inhibitors have promising potential as single drugs as well as concomitants.

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Antifungal combination treatment: a future perspective

Cited by 35 publications

References 40 publications

Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

Multilaboratory Testing of Two-Drug Combinations of Antifungals against Candida albicans , Candida glabrata , and Candida parapsilosis

In Vitro Antifungal Activities of D11-2040, a .BETA.-1,6-Glucan Inhibitor, with or without Currently Available Antifungal Drugs

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