scholarly journals Development of Secondary Resistance to Fluconazole in Cryptococcus neoformans Isolated from a Patient with AIDS

1997 ◽  
Vol 39 (6) ◽  
pp. 359-362 ◽  
Author(s):  
Sydney H. ALVES ◽  
Jorge O. LOPES ◽  
Jane M. COSTA ◽  
Clóvis KLOCK
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Candida Species ◽  
Pneumocystis Carinii ◽  
Initial Therapy ◽  
Antifungal Drugs ◽  
Secondary Resistance ◽  
Immunodeficiency Virus ◽  
The Usa ◽  
Simplex Virus

Cryptococcus neoformans is the fifth most common opportunistic agent of infection in patients with AIDS in the USA, exceeded only by Candida species, Pneumocystis carinii, cytomegalovirus and Mycobacterium avium1, 2, 6, 10, 11. In Brazil is the sixth, exceeded by Candida species, P. carinii, Mycobacterium species, Toxoplasma gondii, and herpes simplex virus (AIDS, Boletim Epidemiológico, set/nov 96, Ministério da Saúde, Brasil). During 30 years, the treatment of C. neoformans meningitis was based on the use of amphotericin B with or without flucytosine13. Nowadays, with the immunodepression caused by human immunodeficiency virus (HIV) infection and the availability of new antifungal drugs as the triazoles, the concept related to cure and relapses of cryptococcosis has been altered7, 20. Patients are treated with amphotericin B with or without flucytosine as initial therapy, but maintenance therapy is always necessary in AIDS patients with C. neoformans infections

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 Darunavir inhibits Cryptococcus neoformans/Cryptococcus gattii species complex growth and increases the susceptibility of biofilms to antifungal drugs

2020 ◽  
Vol 69 (6) ◽  
pp. 830-837
Author(s):  
Raimunda Sâmia Nogueira Brilhante ◽  
José Alexandre Telmos Silva ◽  
Géssica dos Santos Araújo ◽  
Vandbergue Santos Pereira ◽  
Wilker Jose Perez Gotay ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
Species Complex ◽  
Cryptococcus Gattii ◽  
Antifungal Drugs ◽  
Planktonic Cells ◽  
Species Activity ◽  
Checkerboard Assay

Introduction. Cryptococcus species are pathogens commonly associated with cases of meningoencephalitis in individuals who are immunosuppressed due to AIDS. Aim. The aim was to evaluate the effects of the antiretroviral darunavir alone or associated with fluconazole, 5-flucytosine and amphotericin B against planktonic cells and biofilms of Cryptococcus species. Methodology. Susceptibility testing of darunavir and the common antifungals against 12 members of the Cryptococcus neoformans/Cryptococcus gattii species complex was evaluated by broth microdilution. The interaction between darunavir and antifungals against planktonic cells was tested by a checkerboard assay. The effects of darunavir against biofilm metabolic activity and biomass were evaluated by the XTT reduction assay and crystal violet staining, respectively. Results. Darunavir combined with amphotericin B showed a synergistic interaction against planktonic cells. No antagonistic interaction was observed between darunavir and the antifungals used. All Cryptococcus species strains were strong biofilm producers. Darunavir alone reduced biofilm metabolic activity and biomass when added during and after biofilm formation (P<0.05). The combination of darunavir with antifungals caused a significant reduction in biofilm metabolic activity and biomass when compared to darunavir alone (P<0.05). Conclusion. Darunavir presents antifungal activity against planktonic cells of Cryptococcus species and synergism with amphotericin B. In addition, darunavir led to reduced biofilm formation and showed activity against mature biofilms of Cryptococcus species. Activity of the antifungals against mature biofilms was enhanced in the presence of darunavir.

scholarly journals Effect of Amphotericin B on Capsule and Cell Size in Cryptococcus neoformans during Murine Infection

2005 ◽  
Vol 49 (10) ◽  
pp. 4358-4361 ◽  
Author(s):  
Oscar Zaragoza ◽  
Coralia Mihu ◽  
Arturo Casadevall ◽  
Joshua D. Nosanchuk
Keyword(s):  
Cryptococcus Neoformans ◽  
Cell Size ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Cellular Morphology ◽  
Additional Mechanism ◽  
Capsule Size

ABSTRACT Antifungal drugs can affect the cellular morphology of Cryptococcus neoformans in culture, which alters its interactions with phagocytes. We examined the effects of amphotericin B on C. neoformans during murine infection. The antifungal reduced capsule size and serum polysaccharide, which suggests an additional mechanism for amphotericin B's efficacy in cryptococcosis.

scholarly journals Effect of antimycotic agents on the activity of aspartyl proteinases secreted by Candida albicans

2003 ◽  
Vol 52 (3) ◽  
pp. 247-249 ◽  
Author(s):  
Martin Schaller ◽  
Nikola Krnjaic ◽  
Markus Niewerth ◽  
Gerald Hamm ◽  
Bernhard Hube ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Proteinase Inhibitors ◽  
Inhibitory Effect ◽  
Antifungal Drugs ◽  
Immunodeficiency Virus ◽  
Antimycotic Agent ◽  
Pepstatin A ◽  
Aspartyl Proteinases

The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.

scholarly journals Eugenol and Isoeugenol In Association with Antifungal Against Cryptococcus neoformans

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Pinheiro L. S. ◽  
Sousa J. P. ◽  
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.

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.

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

1996 ◽  
Vol 40 (3) ◽  
pp. 822-824 ◽  
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.

scholarly journals Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro.

1997 ◽  
Vol 41 (3) ◽  
pp. 617-623 ◽  
Author(s):  
G P Moran ◽  
D J Sullivan ◽  
M C Henman ◽  
C E McCreary ◽  
B J Harrington ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amphotericin B ◽  
Oral Candidiasis ◽  
Antifungal Drugs ◽  
Candida Dubliniensis ◽  
Fluconazole Resistance ◽  
Immunodeficiency Virus ◽  
Fluconazole Resistant ◽  
Hiv Negative

Candida dubliniensis is a recently described species of Candida associated with oral candidiasis in human immunodeficiency virus (HIV)-infected individuals. Nineteen oral isolates of C. dubliniensis recovered from 10 HIV-positive and 4 HIV-negative individuals and one vaginal isolate from an additional HIV-negative subject were assessed for fluconazole susceptibility by broth microdilution (BMD), hyphal elongation assessment, and Etest. The susceptibilities of these 20 isolates to itraconazole and amphotericin B and of 10 isolates to ketoconazole were also determined by BMD only. Sixteen of the C. dubliniensis isolates were susceptible to fluconazole (MIC range, 0.125 to 1.0 microgram ml-1), and four (recovered from two AIDS patients) were fluconazole resistant (MIC range, 8 to 32 micrograms ml-1). Fluconazole susceptibility data obtained by hyphal elongation assessment correlated well with results obtained by BMD, but the corresponding Etest MIC results were one to four times higher. All of the isolates tested were found to be sensitive to itraconazole, ketoconazole, and amphotericin B. Sequential exposure of two fluconazole-sensitive (MIC, 0.5 microgram ml-1) C. dubliniensis isolates to increasing concentrations of fluconazole in agar medium resulted in the recovery of derivatives which expressed a stable fluconazole-resistant phenotype (BMD-determined MIC range, 16 to 64 micrograms ml-1), even after a minimum of 10 consecutive subcultures on drug-free medium and following prolonged storage at -70 degrees C. The clonal relationship between the parental isolates and their respective fluconazole-resistant derivatives was confirmed by genomic DNA fingerprinting and karyotype analysis. The results of this study demonstrate that C. dubliniensis is inherently susceptible to commonly used antifungal drugs, that fluconazole resistance does occur in clinical isolates, and that stable fluconazole resistance can be readily induced in vitro following exposure to the drug.

scholarly journals In vitro Antifungal Susceptibility Profiles of Cryptococcus neoformans var. grubii and Cryptococcus gattii Clinical Isolates in Guangxi, Southern China

2021 ◽  
Vol 12 ◽  
Author(s):  
Najwa Al-Odaini ◽  
Xiu-ying Li ◽  
Bing-kun Li ◽  
Xing-chun Chen ◽  
Chun-yang Huang ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Southern China ◽  
Antifungal Susceptibility ◽  
Sensu Stricto ◽  
Cryptococcus Gattii ◽  
Antifungal Drugs ◽  
In Vitro Antifungal Susceptibility ◽  
Susceptibility Profiles

This study analyzed the in vitro drug sensitivity of Cryptococcus spp. from Guangxi, Southern China. One hundred three strains of Cryptococcus were recovered from 86 patients; 14 were HIV positive and 72 were HIV negative. Ninety-two strains were identified as Cryptococcus neoformans var. grubii, while 11 strains were identified as Cryptococcus gattii (5 C. gattii sensu stricto and 6 Cryptococcus deuterogattii). The recovered strains were tested against commonly used antifungal drugs (fluconazole, amphotericin B, 5-fluorocytosine, itraconazole, and voriconazole) and to novel antifungal drugs (posaconazole and isavuconazole) using CLSI M27-A4 method. The results showed that all isolates were susceptible to most antifungal drugs, of which the minimum inhibitory concentration (MIC) ranges were as follows: 0.05–4 μg/ml for fluconazole, 0.25–1 μg/ml for amphotericin B; 0.0625–2 μg/ml for 5-fluorocytosine, 0.0625–0.25 μg/ml for itraconazole, 0.0078–0.25 μg/ml for voriconazole, 0.0313–0.5 μg/ml for posaconazole, 0.0020–0.125 μg/ml for isavuconazole for C. neoformans var. grubii isolates, and 1–16 μg/ml for fluconazole, 0.125–1 μg/ml for 5-fluorocytosine, 0.25–1 μg/ml for amphotericin B, 0.0625–0.25 μg/ml for itraconazole, 0.0156–0.125 μg/ml for voriconazole, 0.0156–0.25 μg/ml for posaconazole, and 0.0078–0.125 μg/ml for isavuconazole for C. gattii isolates. Furthermore, some C. neoformans var. grubii isolates were found to be susceptible-dose dependent to 5-fluorocytosine and itraconazole. In addition, a reduction in the potency of fluconazole against C. gattii is possible. We observed no statistical differences in susceptibility of C. neoformans var. grubii and C. gattii in the tested strains. Continuous observation of antifungal susceptibility of Cryptococcus isolates is recommended to monitor the emergence of resistant strains.

scholarly journals In vitro interactions of amphotericin B and non-antifungal compounds against opportunistic human pathogen Cryptococcus neoformans

2020 ◽  
Vol 63 (2) ◽  
pp. 181-184
Author(s):  
Bettina Szerencsés ◽  
Anna Mülbacher ◽  
Csaba Vágvölgyi ◽  
Ilona Pfeiffer
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Combined Therapy ◽  
Antifungal Drugs ◽  
Human Pathogen ◽  
Recommended Treatment ◽  
Amphotericin B Deoxycholate ◽  
Spectrum Activity ◽  
Opportunistic Human Pathogen

The incidence of opportunistic human pathogen Cryptococcus neoformans caused infections have been higher during the last few decades along with the increasing number of susceptible individuals around the world. Recommended treatment of cryptococcal meningoencephalitis is a combined therapy with amphotericin B deoxycholate and flucytosine. Despite of the efficiency of this drug combination, the mortality rate of the disease is high due to the limited accessibility and the high cost of these antifungals in the most severely affected areas. The broad-spectrum activity of non-antifungal drugs and their potential to enhance the efficiency of conventional antifungal agents have been recognised previously. In this study, the in vitro activity of amantadine, valproic acid, trifluoperazine and chlorpromazine was tested against five C. neoformans strains individually and in combination with amphotericin B. All the four compounds exerted slight antifungal activity against the studied C. neoformans strains. Their combination with amphotericin B revealed additive and synergistic interactions.

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