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

Abstract

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.

Dose escalation studies with caspofungin against Candida glabrata

“…However, in RPMI 1640, caspofungin killing activity decreased at 16-32 mg l 21 when compared with the killing at 0.25-1 mg l 21 (Table 3). This paradoxically decreased activity of caspofungin at higher caspofungin concentrations is part of the stress response of cells characterized by increased chitin content (Ben-Ami et al, 2011;Perlin, 2014). Theoretically, this stress adaptation allows the development of a more profound resistance mechanism over time for surviving fungi (Perlin, 2014).…”

“…This paradoxically decreased activity of caspofungin at higher caspofungin concentrations is part of the stress response of cells characterized by increased chitin content (Ben-Ami et al, 2011;Perlin, 2014). Theoretically, this stress adaptation allows the development of a more profound resistance mechanism over time for surviving fungi (Perlin, 2014). In accordance with previous experiments (Szilágyi et al, 2012), adding 50% serum eliminated the paradoxically decreased activity of caspofungin at 16-32 mg l 21 noted in RPMI 1640 for isolates 11900, 9098 and 18910, as indicated by the high k values (Fig.…”

“…and thus higher doses may hypothetically produce better outcomes (Andes et al, 2010;Chen et al, 2011;Howard et al, 2011;Perlin, 2014;Wiederhold et al, 2011). Based on findings with the echinocandin-susceptible C. glabrata ATCC 2001 strain, Howard et al (2011) suggested that echinocandin dose escalation combined with early treatment [5 h post-infection (p.i.)]…”

“…A potential explanation may lie in the activity of echinocandins; i.e. the slower growth in tissues may lead to slower cell wall synthesis, which may, in turn, weaken the in vivo killing activity of caspofungin, similarly to what is seen with antibacterial agents inhibiting cell wall synthesis (Chen et al, 2011;Perlin, 2014). Certainly, other factors (e.g.…”

“…to echinocandins is low worldwide (Perlin, 2014), secondary resistance to caspofungin at some medical centres is more substantial (Alexander et al, 2013;Beyda et al, 2014;Pappas et al, 2007;Perlin, 2014;Pfaller et al, 2012;Shields et al, 2013). In a tertiary-care cancer centre in the USA, caspofungin resistance rates of C. glabrata among patients suffering from cancer (Farmakiotis et al, 2014) and acute leukaemia (Wang et al, 2015) were 10.3% (15 out of 146 isolates) and 58.3% (7 out of 12 isolates), respectively.…”