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Purpose <p><i>Candidozyma (Candida) auris</i> has emerged as a multidrug-resistant pathogen with the capacity to persist in healthcare environments. This study investigated bidirectional interactions between biocidal exposure and antifungal susceptibility, including both minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs), in a real-life disinfection scenario, and further evaluated membrane dynamics and efflux pump activity using rhodamine 6G (R6G) uptake/efflux assays.</p> Methods <p>Four clinical isolates and one reference strain were exposed to ethanol (EtOH), chlorine (CHLOR), chlorhexidine (CHX), and triclosan (TRC) for 30&#xa0;s, 5&#xa0;min, and 24&#xa0;h. Post-exposure MIC and MFC values were determined for antifungals-amphotericin B (AMB), voriconazole (VOR), and anidulafungin (ANI)-as well as for the same biocides, following CLSI M27-A3 guidelines. Data were expressed as log₂ fold changes relative to baseline. All experiments were performed in technical triplicates to ensure reproducibility of MIC/MFC measurements. Statistical analyses were conducted using biological comparisons across the five parental isolates and their corresponding post-exposure derivatives.</p> Results <p>In this exploratory proof-of-concept study, a total of 64 isolate-condition datasets derived from five parental <i>C. auris</i> isolates were evaluated under 12 biocidal exposure conditions, allowing assessment of time-dependent adaptive susceptibility shifts across multiple exposure scenarios. In total, 30 short-term (30&#xa0;s / 5&#xa0;min) and 2 long-term (24&#xa0;h) derivatives were generated from 4 different biocides (EtOH, CHX, TRC, and limited CHLOR data). All 32 biocide-exposed isolates underwent MIC/MFC testing against three antifungals (AMB, VOR, ANI) and three main biocides (EtOH, CHX, TRC), followed by biocide-free serial passaging to assess stability.</p> <p>Baseline MIC distributions were as follows: AMB 0.25-2 µg/mL, VOR 4-16 µg/mL, and ANI 0.01-0.25 µg/mL. After exposure, VOR MICs showed significant reduction to 3.05-4.22 mg/L with TRC exposure being nominally significant before FDR adjustment (raw p=0.043). AMB remained stable (0.47-0.67 mg/L, all p&gt;0.05), while ANI showed non-significant variability in MIC values to 0.04-0.09 mg/L (non-significant, p&gt;0.05). Biocidal MICs also showed changes: EtOH remained heterogeneous (p&gt;0.05), CHX decreased significantly with CHX pre-exposure (p=0.042), and TRC showed non-significant increases.</p> <p>Biocidal exposure produced agent-specific antifungal effects: ANI demonstrated modest non-significant directional shifts in MIC values across all biocides, AMB remained stable with heterogeneous responses, and VOR displayed significant MIC reduction only with TRC exposure. TRC and CHX yielded the most consistent effects in both antifungal and biocidal susceptibility. R6G assays suggested alterations in efflux activity after TRC and CHX exposure, whereas EtOH impaired efflux. Most changes decreased after drug-free passages, indicating adaptive rather than fixed resistance.</p> Conclusion <p><i>C. auris</i> demonstrates dynamic and mostly reversible tolerance patterns affecting both antifungals and biocides. R6G assays provided indirect functional observations consistent with altered membrane transport dynamics following biocidal exposure, which may have contributed to the observed adaptive susceptibility shifts. The observed susceptibility shifts highlights the adaptive potential of this pathogen under disinfection stress and underscores the need to consider cross-tolerance when designing infection control strategies in healthcare settings.</p> Graphic abstract of the study <p></p>

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Adaptive susceptibility shifts in Candidozyma auris following biocidal exposure: Exploratory effects on antifungal and biocidal susceptibility

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Handenur Ulukan,
  • Rufig Hasanli,
  • Dilan Cumert,
  • Sena Algın,
  • Sidre Erganiş,
  • Elif Ayça Şahin,
  • Fatma Bozdağ,
  • Sultan Pınar Çetintepe,
  • Ayse Kalkanci

摘要

Purpose

Candidozyma (Candida) auris has emerged as a multidrug-resistant pathogen with the capacity to persist in healthcare environments. This study investigated bidirectional interactions between biocidal exposure and antifungal susceptibility, including both minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs), in a real-life disinfection scenario, and further evaluated membrane dynamics and efflux pump activity using rhodamine 6G (R6G) uptake/efflux assays.

Methods

Four clinical isolates and one reference strain were exposed to ethanol (EtOH), chlorine (CHLOR), chlorhexidine (CHX), and triclosan (TRC) for 30 s, 5 min, and 24 h. Post-exposure MIC and MFC values were determined for antifungals-amphotericin B (AMB), voriconazole (VOR), and anidulafungin (ANI)-as well as for the same biocides, following CLSI M27-A3 guidelines. Data were expressed as log₂ fold changes relative to baseline. All experiments were performed in technical triplicates to ensure reproducibility of MIC/MFC measurements. Statistical analyses were conducted using biological comparisons across the five parental isolates and their corresponding post-exposure derivatives.

Results

In this exploratory proof-of-concept study, a total of 64 isolate-condition datasets derived from five parental C. auris isolates were evaluated under 12 biocidal exposure conditions, allowing assessment of time-dependent adaptive susceptibility shifts across multiple exposure scenarios. In total, 30 short-term (30 s / 5 min) and 2 long-term (24 h) derivatives were generated from 4 different biocides (EtOH, CHX, TRC, and limited CHLOR data). All 32 biocide-exposed isolates underwent MIC/MFC testing against three antifungals (AMB, VOR, ANI) and three main biocides (EtOH, CHX, TRC), followed by biocide-free serial passaging to assess stability.

Baseline MIC distributions were as follows: AMB 0.25-2 µg/mL, VOR 4-16 µg/mL, and ANI 0.01-0.25 µg/mL. After exposure, VOR MICs showed significant reduction to 3.05-4.22 mg/L with TRC exposure being nominally significant before FDR adjustment (raw p=0.043). AMB remained stable (0.47-0.67 mg/L, all p>0.05), while ANI showed non-significant variability in MIC values to 0.04-0.09 mg/L (non-significant, p>0.05). Biocidal MICs also showed changes: EtOH remained heterogeneous (p>0.05), CHX decreased significantly with CHX pre-exposure (p=0.042), and TRC showed non-significant increases.

Biocidal exposure produced agent-specific antifungal effects: ANI demonstrated modest non-significant directional shifts in MIC values across all biocides, AMB remained stable with heterogeneous responses, and VOR displayed significant MIC reduction only with TRC exposure. TRC and CHX yielded the most consistent effects in both antifungal and biocidal susceptibility. R6G assays suggested alterations in efflux activity after TRC and CHX exposure, whereas EtOH impaired efflux. Most changes decreased after drug-free passages, indicating adaptive rather than fixed resistance.

Conclusion

C. auris demonstrates dynamic and mostly reversible tolerance patterns affecting both antifungals and biocides. R6G assays provided indirect functional observations consistent with altered membrane transport dynamics following biocidal exposure, which may have contributed to the observed adaptive susceptibility shifts. The observed susceptibility shifts highlights the adaptive potential of this pathogen under disinfection stress and underscores the need to consider cross-tolerance when designing infection control strategies in healthcare settings.

Graphic abstract of the study