scholarly journals Postantifungal Effects of Echinocandin, Azole, and Polyene Antifungal Agents against Candida albicans andCryptococcus neoformans

2000 ◽  
Vol 44 (4) ◽  
pp. 1108-1111 ◽  
Author(s):  
Erika J. Ernst ◽  
Michael E. Klepser ◽  
Michael A. Pfaller
Keyword(s):  
Candida Albicans ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Postantifungal Effect

ABSTRACT The postantifungal effect (PAFE) of fluconazole, MK-0991, LY303366, and amphotericin B was determined against isolates of Candida albicans and Cryptococcus neoformans. Concentrations ranging from 0.125 to 4 times the MIC were tested following exposure to the antifungal for 0.25 to 1 h. Combinations of azole and echinocandin antifungals (MK-0991 and LY303366) were tested againstC. neoformans. Fluconazole displayed no measurable PAFE against Candida albicans or Cryptococcus neoformans, either alone or in combination with either echinocandin antifungal. MK-0991, LY303366, and amphotericin B displayed a prolonged PAFE of greater than 12 h againstCandida spp. when tested at concentrations above the MIC for the organism and 0 to 2 h when tested at concentrations below the MIC for the organism.

scholarly journals Sublethal Injury and Resuscitation of Candida albicans after Amphotericin B Treatment

2003 ◽  
Vol 47 (4) ◽  
pp. 1200-1206 ◽  
Author(s):  
Robert S. Liao ◽  
Robert P. Rennie ◽  
James A. Talbot
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Sybr Green ◽  
Sequential Treatment ◽  
Tetrazolium Salt ◽  
Fungal Cell ◽  
Sublethal Injury

ABSTRACT Amphotericin B treatment was previously shown to inhibit Candida albicans reproduction and reduce the fluorescence of vitality-specific dyes without causing a corresponding increase in the fluorescence of the mortality-specific dyes bis-(1,3-dibutylbarbituric acid)trimethine oxonol and SYBR Green Ι. In the present study, we have confirmed these results and have shown that the numbers of CFU are reduced by 99.9% by treatment with 0.5 μg of amphotericin B per ml for 10 h at 35°C. This reduction was not due to fungal cell death. First, the level of reduction of the tetrazolium salt 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide increased in the presence of concentrations of amphotericin B that caused greater than 90% reductions in the numbers of CFU. Second, fungal cells treated with amphotericin B at a concentration of 0.5 μg/ml were resuscitated by further incubation at 22°C for 15 h in the continued presence of amphotericin B. Third, recovery of the ability to replicate was prevented by sequential treatment with 20 μg of miconazole per ml, which also increased the fluorescence of mortality-specific dyes to near the maximal levels achieved with 0.9 μg of amphotericin B per ml. Sequential treatment with fluconazole and flucytosine did not increase the levels of staining with the mortality-specific dyes. Itraconazole was less effective than ketoconazole, which was less effective than miconazole. The practice of equating the loss of the capacity of C. albicans to form colonies with fungal cell death may give incorrect results in assays with amphotericin B, and the results of assays with caution with other antifungal agents that are lipophilic or that possess significant postantifungal effects may need to be interpreted.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

scholarly journals Genotypic variation and antifungal susceptibilities of Candida pelliculosa clinical isolates

2005 ◽  
Vol 54 (3) ◽  
pp. 279-285 ◽  
Author(s):  
F Barchiesi ◽  
A M Tortorano ◽  
L Falconi Di Francesco ◽  
A Rigoni ◽  
A Giacometti ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Drug Therapy ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Yeast Species ◽  
Genotypic Variation ◽  
Optimal Drug ◽  
Typing Methods ◽  
Dna Types

At the Istituto Ricovero Cura Carattere Scientifico, Ospedale Maggiore di Milano, Italy, Candida pelliculosa accounted for 3.3 and 4.4 % of all Candida species other than Candida albicans collected during 1996 and 1998, respectively. Genetic variability was investigated by electrophoretic karyotyping and inter-repeat PCR, and the susceptibility to five antifungal agents of 46 strains isolated from 37 patients during these 2 years was determined. Combination of the two typing methods yielded 14 different DNA types. Although the majority of DNA types were randomly distributed among different units, one DNA type was significantly more common in patients hospitalized in a given unit compared with those from other wards (P = 0.034), whereas another DNA type was more frequently isolated in patients hospitalized during 1996 than in those hospitalized during 1998 (P = 0.002). Fluconazole, itraconazole and posaconazole MIC90 values were 16, 1 and 4 μg ml−1, respectively. All isolates but three were susceptible in vitro to flucytosine. All isolates were susceptible in vitro to amphotericin B. These data suggest that there are possible relationships among strains of C. pelliculosa, wards and time of isolation. Amphotericin B seems to be the optimal drug therapy in infections due to this yeast species.

scholarly journals In Vitro Pharmacodynamic Properties of Three Antifungal Agents against Preformed Candida albicans Biofilms Determined by Time-Kill Studies

2002 ◽  
Vol 46 (11) ◽  
pp. 3634-3636 ◽  
Author(s):  
Gordon Ramage ◽  
Kacy VandeWalle ◽  
Stefano P. Bachmann ◽  
Brian L. Wickes ◽  
José L. López-Ribot
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Pharmacokinetic Properties ◽  
Time Kill ◽  
Candida Albicans Biofilms

ABSTRACT We have examined the in vitro activities of fluconazole, amphotericin B, and caspofungin against Candida albicans biofilms by time-kill methodology. Fluconazole was ineffective against biofilms. Killing of biofilm cells was suboptimal at therapeutic concentrations of amphotericin B. Caspofungin displayed the most effective pharmacokinetic properties, with ≥99% killing at physiological concentrations.

scholarly journals Combination of antifungal drugs and protease inhibitors prevent Candida albicans biofilm formation and disrupt mature biofilms

2020 ◽  
Author(s):  
Matthew B. Lohse ◽  
Megha Gulati ◽  
Charles S. Craik ◽  
Alexander D. Johnson ◽  
Clarissa J. Nobile
Keyword(s):  
Candida Albicans ◽  
Protease Inhibitors ◽  
Amphotericin B ◽  
Biofilm Formation ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Aspartyl Protease ◽  
Abiotic Surfaces ◽  
Drug Concentrations ◽  
Aspartyl Protease Inhibitors

AbstractBiofilms formed by the fungal pathogen Candida albicans are resistant to many of the antifungal agents commonly used in the clinic. Previous reports suggest that protease inhibitors, specifically inhibitors of aspartyl proteases, could be effective antibiofilm agents. We screened three protease inhibitor libraries, containing a total of 80 compounds for the abilities to prevent C. albicans biofilm formation and to disrupt mature biofilms. The compounds were screened individually and in the presence of subinhibitory concentrations of the most commonly prescribed antifungal agents for Candida infections: fluconazole, amphotericin B, or caspofungin. Although few of the compounds affected biofilms on their own, seven aspartyl protease inhibitors inhibited biofilm formation when combined with amphotericin B or caspofungin. Furthermore, nine aspartyl protease inhibitors disrupted mature biofilms when combined with caspofungin. These results suggest that the combination of standard antifungal agents together with specific protease inhibitors may be useful in the prevention and treatment of C. albicans biofilm infections.ImportanceCandida albicans is one of the most common pathogens of humans. C. albicans forms biofilms, structured communities of cells several hundred microns thick, on both biotic and abiotic surfaces. These biofilms are typically resistant to antifungal drugs at the concentrations that are normally effective against free-floating cells, thus requiring treatment with higher drug concentrations that often have significant side effects. Here, we show that certain combinations of existing antifungal agents with protease inhibitors, including several drugs already commonly used to treat HIV patients, are effective at inhibiting biofilm formation by C. albicans and/or at disrupting mature C. albicans biofilms.

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

2001 ◽  
Vol 45 (11) ◽  
pp. 3065-3069 ◽  
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.

scholarly journals In vitroactivities of antifungals alone and in combination with tigecycline againstCandida albicansbiofilms

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5263 ◽  
Author(s):  
Mayram Hacioglu ◽  
Ayse Seher Birteksoz Tan ◽  
Sibel Dosler ◽  
Nese Inan ◽  
Gulten Otuk
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Biofilm Formation ◽  
Antifungal Agents ◽  
Synergistic Effects ◽  
Planktonic Cells ◽  
Effective Agent ◽  
Highly Active ◽  
Highly Effective ◽  
Anti Fungal

BackgroundCandidamay form biofilms, which are thought to underlie the most recalcitrant infections.MethodsIn this study, activities of antifungal agents alone and in combination with tigecycline against planktonic cells and mature and developing biofilms ofCandida albicansisolates were evaluated.ResultsAmphotericin B and echinocandins were found to be the most effective agents against mature biofilms, whereas the least effective agent was fluconazole. Furthermore, the most effective anti-fungal monotherapies against biofilm formation were amphotericin B and anidulafungin, and the least effective monotherapy was itraconazole. The combination of tigecycline and amphotericin B yielded synergistic effects, whereas combinations containing itraconazole yielded antagonist effects against planktonic cells. The combination of tigecycline and caspofungin exhibited maximum efficacy against mature biofilms, whereas combinations containing itraconazole exhibited minimal effects. Combinations of tigecycline with amphotericin B or anidulafungin were highly effective againstC. albicansbiofilm formation.DiscussionIn summary, tigecycline was highly active againstC. albicansparticularly when combined with amphotericin B and echinocandins.

scholarly journals Susceptibility of Cryptococcus neoformans Biofilms to Antifungal Agents In Vitro

2006 ◽  
Vol 50 (3) ◽  
pp. 1021-1033 ◽  
Author(s):  
Luis R. Martinez ◽  
Arturo Casadevall
Keyword(s):  
Confocal Microscopy ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Biofilm Formation ◽  
Antifungal Agents ◽  
Capsular Polysaccharide ◽  
Antifungal Drugs ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sequence Of Events ◽  
Biofilm Development

ABSTRACT Microbial biofilms contribute to virulence and resistance to antibiotics by shielding microbial cells from host defenses and antimicrobial drugs, respectively. Cryptococcus neoformans was demonstrated to form biofilms in polystyrene microtiter plates. The numbers of CFU of disaggregated biofilms, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide reduction, and light and confocal microscopy were used to measure the fungal mass, the metabolic activity, and the appearance of C. neoformans biofilms, respectively. Biofilm development by C. neoformans followed a standard sequence of events: fungal surface attachment, microcolony formation, and matrix production. The susceptibilities of C. neoformans cells of the biofilm and planktonic phenotypes to four antifungal agents were examined. The exposure of C. neoformans cells or preformed cryptococcal biofilms to fluconazole or voriconazole did not result in yeast growth inhibition and did not affect the metabolic activities of the biofilms, respectively. In contrast, both C. neoformans cells and preformed biofilms were susceptible to amphotericin B and caspofungin. However, C. neoformans biofilms were significantly more resistant to amphotericin B and caspofungin than planktonic cells, and their susceptibilities to these drugs were further reduced if cryptococcal cells contained melanin. A spot enzyme-linked immunosorbent assay and light and confocal microscopy were used to investigate how antifungal drugs affected C. neoformans biofilm formation. The mechanism by which amphotericin B and caspofungin interfered with C. neoformans biofilm formation involved capsular polysaccharide release and adherence. Our results suggest that biofilm formation may diminish the efficacies of some antifungal drugs during cryptococcal infection.

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