Effects of environmental factors on sensitivity of <i>Cryptococcus neoformans</i> to fluconazole and amphotericin B

Carlson, Tyler; Lupinacci, Emily; Moseley, Katie; Chandrasekaran, Srikripa

doi:10.1093/femsle/fnab040

Cited by 13 publications

(12 citation statements)

References 43 publications

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“…Another study recently confirmed the connection between resistance acquisition and lower temperature as they proved that adaptation in drugs as fluconazole and amphotericin B at lower temperatures selects resistance to these drugs in C . neoformans , which does not happen at a higher temperature [ 177 ]. Overall, temperature probably influences the survival and adaptation of Cryptococcus spp.…”

Section: Cryptococcus Sppmentioning

confidence: 99%

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

et al. 2021

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Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.

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Section: Cryptococcus Sppmentioning

confidence: 99%

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

et al. 2021

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“…Several factors have been found to affect the susceptibility of Cryptococcus spp. isolates to antifungal drugs, which include the prolonged use of FCZ as a suppressive monotherapy, low bioavailability of FCZ in the infected tissue, fungistatic action of azoles, increased tolerance to FCZ due to replicative aging, low glucose growth condition and limited nutrients, and intrinsic resistance, such as the hetero-resistance of C. neoformans and C. gattii to azoles [ 11 , 13 , 14 , 15 ]. The environmental triazole (tebuconazole) used as an agrochemical pesticide may induce cross-resistance to clinically available azoles in C. neoformans and C. gattii [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Epidemiological and Clinical Characteristics, Antifungal Susceptibility, and MLST-Based Genetic Analysis of Cryptococcus Isolates in Southern Taiwan in 2013–2020

Chen

Kuo

Lin

et al. 2022

JoF

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Cryptococcal meningoencephalitis (CM) is a treatable condition, but it leads to excessive morbidity and mortality. We collected 115 non-duplicated Cryptococcus clinical isolates during 2013–2020 in southern Taiwan to perform antifungal susceptibility testing. Multi-locus sequence typing was performed on 96 strains from patients with CM (n = 47) or cryptococcemia (n = 49). In addition, the epidemiological and clinical characteristics of patients with CM during 2013–2020 (n = 47) were compared with those during 2000–2010 (n = 46). During 2013–2020, only one C. neoformans isolate (0.9%) had a fluconazole minimum inhibitory concentration of >8 μg/mL. Amphotericin B (AMB), flucytosine (5FC), and voriconazole were highly active against all C. neoformans/C. gattii isolates. The most common sequence type was ST5. Among these 47 patients with CM, cerebrospinal fluid cryptococcal antigen (CSF CrAg) titer >1024 was a significant predictor of death (odds ratio, 48.33; 95% CI, 5.17–452.06). A standard induction therapy regimen with AMB and 5FC was used for all patients during 2013–2020, but only for 2.2% of patients in 2000–2010. The in-hospital CM mortality rate declined from 39.1% during 2000–2010 to 25.5% during 2013–2020, despite there being significantly younger patients with less CSF CrAg >1024 during 2000–2010. The study provides insight into the genetic epidemiology and antifungal susceptibility of Cryptococcus strains in southern Taiwan. The recommended antifungal drugs, AMB, 5FC, and FCZ, remained active against most of the Cryptococcus strains. Early diagnosis of patients with CM and adherence to the clinical practice guidelines cannot be overemphasized to improve the outcomes of patients with CM.

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“…Fluconazole tolerance may be underestimated when MICs are performed in 2% glucose due to the ability of Cryptococcus spp. to exhibit in vivo fluconazole tolerance in the low glucose host environment [ 37 , 38 ]. In addition, host factors such as patient drug adherence, pharmacokinetic data [ 4 ] and host-specific immune reconstitution inflammatory syndrome [ 39 ] can collectively cause treatment failure.…”

Section: Discussionmentioning

confidence: 99%

Lack of Association between Fluconazole Susceptibility and ERG11 Nucleotide Polymorphisms in Cryptococcus neoformans Clinical Isolates from Uganda

Atim

Meya

Gerlach

et al. 2022

JoF

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Fluconazole is the drug of choice for cryptococcal meningitis (CM) monoprophylaxis in resource-limited settings such as Uganda. Emerging fluconazole resistance linked to mutations in the Cryptococcus neoformans ERG11 gene (CYP51) has been observed in clinical isolates. Currently, the single nucleotide polymorphisms [SNPs] in the Cryptococcus spp. ERG11 gene that could be responsible for fluconazole resistance are poorly characterized within Ugandan C. neoformans clinical isolates. If available, this information would be useful in the management of cryptococcosis among HIV patients. This cross-sectional study investigates the SNPs present in the coding region of the C. neoformans ERG11 gene to determine the relationship between the SNPs identified and fluconazole susceptibility of the clinical isolates. 310 C. neoformans isolates recovered from the Cerebrospinal Fluid (CSF) of patients with HIV and cryptococcal meningitis were examined. The fluconazole half-maximal inhibitory concentrations (IC50 range: 0.25–32 μg/mL) was determined using the microbroth dilution method. A total of 56.1% of the isolates had low IC50 values of <8 μg/mL while 43.9% had high IC50 values ≥ 8 μg/mL. We amplified and sequenced 600 bp of the ERG11 coding sequence from 40 of the clinical isolates. Novel synonymous and 2 missense mutations, S460T and A457V, were identified in the ERG11 gene. The identified SNPs were not associated with differences in fluconazole IC50 values in vitro (p = 0.179).

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Effects of environmental factors on sensitivity of Cryptococcus neoformans to fluconazole and amphotericin B

Cited by 13 publications

References 43 publications

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

Epidemiological and Clinical Characteristics, Antifungal Susceptibility, and MLST-Based Genetic Analysis of Cryptococcus Isolates in Southern Taiwan in 2013–2020

Lack of Association between Fluconazole Susceptibility and ERG11 Nucleotide Polymorphisms in Cryptococcus neoformans Clinical Isolates from Uganda

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