ATI-2307 Exhibits Equivalent Antifungal Activity in Cryptococcus neoformans Clinical Isolates With High and Low Fluconazole IC50

Half maximal inhibitory concentrations (IC50) to the experimental drug ATI-2307 and complete inhibition (IC90) of the common clinically used antifungal drug amphotericin B were determined by microbroth dilution assay for a collection of 69 clinical isolates of Cryptococcus neoformans from Uganda that had high fluconazole IC50 values. The majority of the clinical isolates tested had fluconazole IC50 at or above 8 µg/mL, but were susceptible to both amphotericin B (IC90 ≤1 μg/mL) and ATI-2307 (IC50 ≤0.0312 µg/mL). No correlation between increased fluconazole minimum inhibitory concentration (MIC) and ATI-2307 or amphotericin B MIC was observed, suggesting that the cellular changes impacting fluconazole susceptibility did not impact the effectiveness of ATI-2307. Our results suggest that ATI-2307 is a promising new antifungal drug for use in the context of high fluconazole or other antifungal drug MICs and/or in combination drug therapy regimens.

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Effect of antifungals on itraconazole resistant Candida glabrata

Open Life Sciences ◽

10.2478/s11535-010-0021-5 ◽

2010 ◽

Vol 5 (3) ◽

pp. 318-323 ◽

Cited By ~ 1

Author(s):

Soňa Kucharíková ◽

Patrick Dijck ◽

Magdaléna Lisalová ◽

Helena Bujdáková

Keyword(s):

Amphotericin B ◽

Biofilm Formation ◽

Candida Glabrata ◽

Antifungal Agents ◽

Inhibitory Concentration ◽

Clinical Isolates ◽

Azole Resistance ◽

Low Concentrations ◽

Reduction Assay ◽

Very High

AbstractIn the last decade, infections caused by Candida glabrata have become more serious, particularly due to its decreased susceptibility to azole derivatives and its ability to form biofilm. Here we studied the resistance profile of 42 C. glabrata clinical isolates to different azoles, amphotericin B and echinocandins. This work was also focused on the ability to form biofilm which plays a role in the development of antifungal resistance. The minimal inhibitory concentration testing to antifungal agents was performed according to the CLSI (Clinical and Laboratory Standards Institute) M27-A3 protocol. Quantification of biofilm was done by XTT reduction assay. All C. glabrata clinical isolates were resistant to itraconazole and sixteen also showed resistance to fluconazole. All isolates remained susceptible to voriconazole. Amphotericin B was efficient in a concentration range of 0.125–1 mg/L. The most effective antifungal agents were micafungin and caspofungin with the MIC100 values of ≤0.0313–0.125 mg/L. Low concentrations of these agents reduced biofilm formation as well. Our results show that resistance of different C. glabrata strains is azole specific and therefore a single azole resistance cannot be assumed to indicate general azole resistance. Echinocandins proved to have very high efficacy against clinical C. glabrata strains including those with ability to form biofilm.

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Eugenol and Isoeugenol In Association with Antifungal Against Cryptococcus neoformans

International Journal of Pharmacognosy and Phytochemical Research ◽

10.25258/phyto.v9i4.8133 ◽

2017 ◽

Vol 9 (4) ◽

Author(s):

Pinheiro L. S. ◽

Sousa J. P. ◽

Barreto N. A. ◽

Dantas T B ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Inhibitory Concentration ◽

Synergistic Effects ◽

Antagonistic Effect ◽

Antifungal Drugs ◽

Antifungal Effect ◽

Beneficial Effects ◽

Combined Use ◽

Antifungal Effects

The antifungal therapy combined is used in clinical practice of several mycoses as it may increase the efficacy of the treatment. The use of natural products (phytochemicals) in combination with conventional antifungal drugs has been related to beneficial effects, mainly synergistic effects. The aim of this study was to evaluate the effect of the combined use of eugenol / isoeugenol, compounds with recognized antimicrobial activity, in association with antifungal amphotericin B against strains of Cryptococcus neoformans. The combined antifungal effect were be determined from the Fraction Inhibitory Concentration index - checkerboard technique. The results obtained in this study showed that eugenol in combination with amphotericin B had antagonistic effect against the strains of C. neoformans, LM 615 and INCQS 40221 (FIC index 6.0 and 4.0), respectively. The combination of the isoeugenol and amphotericin B also showed antagonistic effects for both the LM 615 strain and INCQS 40221 (FIC index 6.0 and 5.0), respectively. This study contributed to the understanding of the antifungal effects of the association of phenylpropanoids (eugenol / isoeugenol) with amphotericin B. Further studies are needed to evaluate and compare the effects of the association of these phytochemicals with other conventional antifungal drugs used against C. neoformans.

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Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates in the United States: 1992 to 1994 and 1996 to 1998

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.11.3065-3069.2001 ◽

2001 ◽

Vol 45 (11) ◽

pp. 3065-3069 ◽

Cited By ~ 88

Author(s):

Mary E. Brandt ◽

Michael A. Pfaller ◽

Rana A. Hajjeh ◽

Richard J. Hamill ◽

Peter G. Pappas ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Antifungal Agents ◽

Clinical Laboratory ◽

The United States ◽

Drug Susceptibility ◽

Antifungal Drug ◽

National Committee ◽

Broth Microdilution Method

ABSTRACT The antifungal drug susceptibilities of two collections ofCryptococcus neoformans isolates obtained through active laboratory-based surveillance from 1992 to 1994 (368 isolates) and 1996 to 1998 (364 isolates) were determined. The MICs of fluconazole, itraconazole, and flucytosine were determined by the National Committee for Clinical Laboratory Standards broth microdilution method; amphotericin B MICs were determined by the E-test. Our results showed that the MIC ranges, the MICs at which 50% of isolates are inhibited (MIC50s), and the MIC90s of these four antifungal agents did not change from 1992 to 1998. In addition, very small numbers of isolates showed elevated MICs suggestive of in vitro resistance. The MICs of amphotericin B were elevated (≥2 μg/ml) for 2 isolates, and the MICs of flucytosine were elevated (≥32 μg/ml) for 14 isolates. Among the azoles, the fluconazole MIC was elevated (≥64 μg/ml) for 8 isolates and the itraconazole MIC (≥1 μg/ml) was elevated for 45 isolates. Analysis of 172 serial isolates from 71 patients showed little change in the fluconazole MIC over time. For isolates from 58 patients (82% of serial cases) there was either no change or a twofold change in the fluconazole MIC. In contrast, for isolates from seven patients (12% of serial cases) the increase in the MIC was at least fourfold. For isolates from another patient there was a 32-fold decrease in the fluconazole MIC over a 1-month period. We conclude that in vitro resistance to antifungal agents remains uncommon in C. neoformans and has not significantly changed with time during the past decade.

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Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01299-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7197-7204 ◽

Cited By ~ 89

Author(s):

Kyle D. Smith ◽

Beatrice Achan ◽

Kathy Huppler Hullsiek ◽

Tami R. McDonald ◽

Laura H. Okagaki ◽

...

Keyword(s):

Amphotericin B ◽

Low Income ◽

Low Cost ◽

Drug Susceptibility ◽

Antifungal Drug ◽

Clinical Isolates ◽

Hiv Care ◽

Low Income Countries ◽

Broth Microdilution ◽

Content Type

ABSTRACTCryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/μl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC50of 4 μg/ml and an MIC90of 8 μg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC50to 8 μg/ml and an MIC90value of 32 μg/ml, with 31% of isolates with a fluconazole MIC of ≥16 μg/ml. We observed an amphotericin B MIC50of 0.5 μg/ml and an MIC90of 1 μg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzedCryptococcussusceptibility to sertraline, with an MIC50of 4 μg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P= 0.52).

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In vitro susceptibilities of clinical and environmental isolates of Cryptococcus neoformans to five antifungal drugs.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.3.822 ◽

1996 ◽

Vol 40 (3) ◽

pp. 822-824 ◽

Cited By ~ 35

Author(s):

S P Franzot ◽

J S Hamdan

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Clinical Laboratory ◽

Antifungal Drugs ◽

Clinical Isolates ◽

National Committee ◽

Environmental Isolates ◽

Susceptibility Data

A total of 53 Cryptococcus neoformans strains, including clinical and environmental Brazilian isolates, were tested for their susceptibilities to amphotericin B, 5-flucytosine, ketoconazole, fluconazole, and itraconazole. The tests were performed according to the National Committee of Clinical Laboratory Standards recommendations (document M27-P). In general, there was a remarkable homogeneity of results for all strains, and comparable MICs were found for environmental and clinical isolates. This paper represents the first contribution in which susceptibility data for Brazilian C. neoformans isolates are provided.

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Time-Kill Curves Studies with Amphotericin B Against Cryptococcus neoformans/C. gattii Species Complex Clinical Isolates

Current Fungal Infection Reports ◽

10.1007/s12281-017-0296-3 ◽

2017 ◽

Vol 11 (4) ◽

pp. 158-162 ◽

Cited By ~ 1

Author(s):

Lidiane de Oliveira ◽

Dayane Cristina Silva Santos ◽

Marilena dos Anjos Martins ◽

Maria Walderez Szeszs ◽

Marcia Souza Carvalho Melhem

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Species Complex ◽

Clinical Isolates ◽

Time Kill

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In vitro susceptibility to antifungal agents of clinical and environmental Cryptococcus neoformans isolated in Southern of Brazil

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652001000500006 ◽

2001 ◽

Vol 43 (5) ◽

pp. 267-270 ◽

Cited By ~ 14

Author(s):

Sydney Hartz ALVES ◽

Loiva T. OLIVEIRA ◽

Jane M. COSTA ◽

Irina LUBECK ◽

Agnes Kiesling CASALI ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Antifungal Agents ◽

Susceptibility Testing ◽

Clinical Isolates ◽

Environmental Isolates ◽

Aids Patients ◽

In Vitro Susceptibility ◽

Minimal Inhibitory Concentrations

The purpose of the present study was to compare the susceptibility to four antifungal agents of 69 Cryptococcus neoformans strains isolated from AIDS patients with that of 13 C. neoformans strains isolated from the environment. Based on the NCCLS M27-A methodology the Minimal Inhibitory Concentrations (MICs) obtained for amphotericin B, itraconazole and ketoconazole were very similar for clinical and environmental isolates. Clinical isolates were less susceptible to fluconazole than environmental isolates. The significance of these findings and aspects concerning the importance, role and difficulties of C. neoformans susceptibility testing are also discussed.

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Susceptibility of clinical isolates of Cryptococcus neoformans to amphotericin B using time–kill methodology

Diagnostic Microbiology and Infectious Disease ◽

10.1016/j.diagmicrobio.2009.02.007 ◽

2009 ◽

Vol 64 (2) ◽

pp. 146-151 ◽

Cited By ~ 13

Author(s):

Mara C.S.M. Pappalardo ◽

Maria Walderez Szeszs ◽

Marilena A. Martins ◽

Liliana B. Baceti ◽

Lucas X. Bonfietti ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Clinical Isolates ◽

Time Kill

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In Vitro Interaction of Flucytosine with Conventional and New Antifungals against Cryptococcus neoformans Clinical Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.10.3361-3364.2003 ◽

2003 ◽

Vol 47 (10) ◽

pp. 3361-3364 ◽

Cited By ~ 27

Author(s):

Patrick Schwarz ◽

Françoise Dromer ◽

Olivier Lortholary ◽

Eric Dannaoui

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Clinical Isolates ◽

In Vitro Interaction

ABSTRACT Combinations of flucytosine with conventional and new antifungals were evaluated in vitro against 30 clinical isolates of Cryptococcus neoformans. Synergy determined by checkerboard analysis was observed with combinations of fluconazole, itraconazole, voriconazole, amphotericin B, and caspofungin with flucytosine against 77, 60, 80, 77, and 67% of the isolates, respectively. Antagonism was never observed. Killing curves showed indifferent interactions between triazoles and flucytosine and synergy between amphotericin B and flucytosine.

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