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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.

ABSTRACT: Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy.

SUBMITTER: Rosenberg A

PROVIDER: S-EPMC6018213 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.

Rosenberg Alexander A Ene Iuliana V IV Bibi Maayan M Zakin Shiri S Segal Ella Shtifman ES Ziv Naomi N Dahan Alon M AM Colombo Arnaldo Lopes AL Bennett Richard J RJ Berman Judith J

Nature communications 20180625 1

Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, ...[more]

PMID: 29941885

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Project description:The increasing burden of candidemia and the emergence of resistance, especially among non-Candida albicans strains, represent a new threat for public health. We aimed to assess the status of surveillance and to identify publicly accessible resistance data in Candida spp. blood isolates from surveillance systems and epidemiological studies in 28 European and 4 European Free Trade Association member states. A systematic review of national and international surveillance networks, from 2015 to 2020, and peer-reviewed epidemiological surveillance studies, from 2005 to 2020, lasting for at least 12 consecutive months and with at least two centers involved, was completed to assess reporting of resistance to amphotericin B, azoles, and echinocandins in C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. auris. Only 5 (Austria, Italy, Norway, Spain, and United Kingdom) of 32 countries provided resistance data for Candida spp blood isolates. Among 322 surveillance studies identified, 19 were included from Belgium, Denmark, Iceland, Italy, Portugal, Spain, Sweden, Switzerland, and United Kingdom. C. albicans and C. glabrata were the most monitored species, followed by C. parapsilosis and C. tropicalis. C. krusei was not included in any national surveillance system; 13 studies assessed resistance. No surveillance system or study reported resistance for C. auris. Fluconazole, voriconazole, caspofungin, and amphotericin B resistance in C. albicans, C. glabrata, and C. parapsilosis were the most common drug-species combination monitored. Quality of surveillance data was poor, with only two surveillance systems reporting microbiological methods and clinical data. High heterogeneity was observed in modalities of reporting, data collection, and definitions. Surveillance of antifungal resistance in Candida spp blood-isolates is fragmented and heterogeneous, delaying the application of a translational approach to the threat of antifungal resistance and the identification of proper targets for antifungal stewardship activities. International efforts are needed to implement antifungal resistance surveillance programs in order to adequately monitor antifungal resistance.

Project description:Antifungal drug tolerance is a response distinct from resistance, in which cells grow slowly above the MIC. Here, we found that the majority (69.2%) of 133 Candida albicans clinical isolates, including standard lab strain SC5314, exhibited temperature-enhanced tolerance at 37°C and 39°C, and were not tolerant at 30°C. Other isolates were either always tolerant (23.3%) or never tolerant (7.5%) at these three temperatures, suggesting that tolerance requires different physiological processes in different isolates. At supra-MIC fluconazole concentrations (8 to 128 μg/mL), tolerant colonies emerged rapidly at a frequency of ~10-3. In liquid passages over a broader range of fluconazole concentrations (0.25 to 128 μg/mL), tolerance emerged rapidly (within one passage) at supra-MICs. In contrast, resistance appeared at sub-MICs after 5 or more passages. Of 155 adaptors that evolved higher tolerance, all carried one of several recurrent aneuploid chromosomes, often including chromosome R, alone or in combination with other chromosomes. Furthermore, loss of these recurrent aneuploidies was associated with a loss of acquired tolerance, indicating that specific aneuploidies confer fluconazole tolerance. Thus, genetic background and physiology and the degree of drug stress (above or below the MIC) influence the evolutionary trajectories and dynamics with which antifungal drug resistance or tolerance emerges. IMPORTANCE Antifungal drug tolerance differs from drug resistance: tolerant cells grow slowly in drug, while resistant cells usually grow well, due to mutations in a few known genes. More than half of Candida albicans clinical isolates have higher tolerance at body temperature than they do at the lower temperatures used for most lab experiments. This implies that different isolates achieve drug tolerance via several cellular processes. When we evolved different strains at a range of high drug concentrations above inhibitory levels, tolerance emerged rapidly and at high frequency (one in 1,000 cells) while resistance appeared only later at very low drug concentrations. An extra copy of all or part of chromosome R was associated with tolerance, while point mutations or different aneuploidies were seen with resistance. Thus, genetic background and physiology, temperature, and drug concentration all influence how drug tolerance or resistance evolves.

Project description:The prevalence of intrinsic and acquired resistance among colonizing Candida isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or ≥ 7 days. Species identification was confirmed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined by FKS sequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for ≥ 7 days (n = 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularly Candida glabrata) among oral isolates than among initial blood isolates (36.6% versus 12.9%; P < 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for ≥ 7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates; P > 0.5). Acquired resistance in Candida albicans was rare (<5%). However, acquired resistance to fluconazole (29.4%; P < 0.05) and anidulafungin (21.6%; P < 0.05) was common in C. glabrata isolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistant Candida species, especially C. glabrata, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal drugs.

Project description:BackgroundData on persistent candidemia (PC), a recognized complication of candidemia, are lacking in China. This study aimed to investigate the clinical characteristics and risk factors for the mortality of PC among adults in China.MethodsThis 6-year retrospective study analyzed the prevalence, species distribution, antifungal susceptibility, risk factors, and patient mortality of PC among adults in three regional tertiary teaching hospitals in China from 2016 to 2021. We collected electronic laboratory records data of PC and non-PC patients and used the Student test or Mann-Whitney U test for a retrospective study. Logistic regression was used to identify risk factors associated with persistent candidemia.ResultsThe definition of PC was fulfilled by 36 patients (13.7%, 36/263). The mean age of the patients was 59.9 years (60 years for patients with PC; 59.8 years for those with non-PC; P > 0.05) and 131 (60.1%) were men [16 with PC (44.4%), 115 with non-PC (63.2%), P < 0.05]. The mean annual incidence was 0.15/1000 admissions (including PC 0.03/1000 admissions vs. non-PC 0.12/1000 admissions, P < 0.05). Candida parapsilosis (14/36, 38.9%) and Candida albicans (81/182, 44.5%) were the predominant pathogens in patients with PC and non-PC, respectively. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.5%), and the activity of antifungal agents against Candida species was not statistically significantly different between patients with PC and non-PC (P > 0.05). The 30-day mortality rate was 20.2% (16.7% with PC vs. 20.9% with non-PC, P > 0.05). Multivariable regression analysis showed that use of broad-spectrum antibiotics (odds ratio (OR), 5.925; 95% confidence interval (CI), 1.886-18.616, P = 0.002), fluconazole (OR, 3.389; 95% CI, 1.302-8.820, P = 0.012) and C. parapsilosis infection (OR, 6.143; 95% CI, 2.093-18.031, P = 0.001) were independent predictors of PC, sex (male) (OR, 0.199; 95% CI, 0.077-0.518, P = 0.001) was the protective factor for PC. Respiratory dysfunction (OR, 5.763; 95% CI, 1.592-20.864, P = 0.008) and length of hospital stay(OR, 0.925; 95% CI, 0.880-0.973, P = 0.002) were independent predictors of 30-day mortality in patients with non-PC. C. tropicalis bloodstream infection (OR, 12.642; 95% CI, 1.059-150.951; P = 0.045) was an independent predictor of 30-day mortality in patients with PC.ConclusionsThe epidemiological data of patients with PC and non-PC were different in the distribution of Candida species, the mean annual incidence and independent predictors of 30-day mortality. Flucytosine and amphotericin B could be used as first-choice drugs in the presence of PC infections.

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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.

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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.

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