Development of echinocandin‐resistant <i><scp>C</scp>andida albicans</i> candidemia following brief prophylactic exposure to micafungin therapy

Ruggero, Michael; Topal, Jeffrey

doi:10.1111/tid.12230

Cited by 24 publications

(15 citation statements)

References 21 publications

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“…In the post-echinocandin era, there have been increasing reports of echinocandin treatment failures in most clinically-relevant species, especially in C. glabrata [7, 21–24]. Fortunately, resistance rates remained rare in the local context.…”

Section: Discussionmentioning

confidence: 99%

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

Teo

Candra

Lee

et al. 2017

Antimicrob Resist Infect Control

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BackgroundCandidemia is a common cause of nosocomial bloodstream infections, resulting in high morbidity and mortality. This study was conducted to describe the epidemiology, species distribution, antifungal susceptibility patterns and outcomes of candidemia in a large regional tertiary referral hospital.MethodsA retrospective surveillance study of patients with candidemia was conducted at Singapore General Hospital between July 2012 and December 2015. In addition, incidence densities and species distribution of candidemia episodes were analysed from 2008 to 2015.ResultsIn the period of 2012 to 2015, 261 candidemia episodes were identified. The overall incidence was 0.14/1000 inpatient-days. C. glabrata (31.4%), C. tropicalis (29.9%), and C. albicans (23.8%) were most commonly isolated. The incidence of C. glabrata significantly increased from 2008 to 2015 (Coefficient 0.004, confidence interval 0–0.007, p = 0.04). Fluconazole resistance was detected primarily in C. tropicalis (16.7%) and C. glabrata (7.2%). fks mutations were identified in one C. albicans and one C. tropicalis. Candidemia episodes caused by C. tropicalis were more commonly encountered in patients with haematological malignancies (p = 0.01), neutropenia (p < 0.001) and higher SAPS II scores (p = 0.02), while prior exposure to echinocandins was associated with isolation of C. parapsilosis (p = 0.001). Echinocandins (73.3%) were most commonly prescribed as initial treatment. The median (range) time to initial treatment was 1 (0–9) days. The 30-day in-hospital mortality rate was 49.8%. High SAPS II score (Odds ratio, OR 1.08; 95% confidence interval, CI 1.05–1.11) and renal replacement therapy (OR 5.54; CI 2.80–10.97) were independent predictors of mortality, while drain placement (OR 0.44; CI 0.19–0.99) was protective.ConclusionsDecreasing azole susceptibilities to C. tropicalis and the emergence of echinocandin resistance suggest that susceptibility patterns may no longer be sufficiently predicted by speciation in our institution. Candidemia is associated with poor outcomes. Strategies optimising antifungal therapy, especially in the critically-ill population, should be explored.

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Section: Discussionmentioning

confidence: 99%

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

Teo

Candra

Lee

et al. 2017

Antimicrob Resist Infect Control

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“…The co-evolution of azole and echinocandin multidrug resistance among C. glabrata is an alarming trend [59]. Similarly, breakthrough infections involving C. albicans are also being reported in patients with graft-versus-host disease following a stem cell transplant who received micafungin prophylaxis [130]. Most recently, a disturbing report from a retrospective observational study involving echinocandin-based anti- Aspergillus prophylaxis for 152 patients with acute myeloid leukemia during remission-induction chemotherapy showed a higher risk of breakthrough IFI [131].…”

Section: Prophylaxis: Benefits With a Potential Resistance Costmentioning

confidence: 99%

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Perlin

2014

Drugs

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This article addresses the emergence of echinocandin resistance among Candida species, mechanisms of resistance, factors that promote resistance and confounding issues surrounding standard susceptibility testing. Fungal infections remain a significant cause of global morbidity and mortality, especially among patients with underlying immunosupression. Antifungal therapy is a critical component of patient management for acute and chronic diseases. Yet, therapeutic choices are limited due to only a few drug classes available to treat systemic disease. Moreover, the problem is exacerbated by the emergence of antifungal resistance, which has resulted in difficult to manage multidrug resistant strains. Echinocandin drugs are now the preferred choice to treat a range of candidiasis. These drugs target and inhibit the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a key cell wall polymer. Therapeutic failures involving acquisition of resistance among susceptible organisms like Candida albicans is largely a rare event. However, in recent years, there is an alarming trend of increased resistance among strains of Candida glabrata, which in many cases are also resistant to azole drugs. Echinocandin resistance is always acquired during therapy and the mechanism of resistance is well established to involve amino acid changes in “hot-spot regions of the Fks subunits carrying the catalytic portion of glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values. A range of drug responses, from complete to partial refractory response, is observed depending on the nature of the amino acid substitution, and clinical responses are recapitulated in pharmacodynamic models of infection. The cellular processes promoting the formation of resistant Fks strains involve complex stress response pathways, which yield a variety of adaptive compensatory genetic responses. Stress-adapted cells become drug tolerant and can form stable drug resistant FKS mutations with continued drug exposure. A major concern for resistance detection is that classical broth microdilution techniques show significant variability among clinical microbiology laboratories for certain echinocandin drugs and Candida species. The consequence is that susceptible strains are misclassified according to established clinical breakpoints, and this has led to confusion in the field. Clinical factors that appear to promote echinocandin resistance include the expanding use of antifungal agents for empiric therapy and prophylaxis. Furthermore, host reservoirs such as biofilms in the gastrointestinal tract or intra-abdominal infections can seed development of resistant organisms during therapy. A fundamental understanding of the primary molecular resistance mechanism, along with cellular and clinical factors that promote resistance emergence, is critical to develop better diagnostic tools and therapeutic strategies to overcome and prevent echinocandin resistance.

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“…The expanding use of echinocandins for prophylaxis has increased patient exposure to echinocandin drugs. This has implications for drug resistance as breakthrough infections have been reported [77]. It is not surprising that broadening patient exposure to echinocandin drugs may inadvertently promote the emergence of resistance.…”

Section: Risk Factors For Resistance Emergencementioning

confidence: 99%

Echinocandin Resistance in Candida

Perlin

2015

Clinical Infectious Diseases

267

218

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Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKSencoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.

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Development of echinocandin‐resistant Candida albicans candidemia following brief prophylactic exposure to micafungin therapy

Cited by 24 publications

References 21 publications

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Echinocandin Resistance in Candida

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