Patients with Long-Term Oral Carriage Harbor High-Persister Mutants of Candida albicans

Abstract

Fungal biofilms produce a small number of persister cells which can tolerate high concentrations of fungicidal agents. Persisters form upon attachment to a surface, an important step in the pathogenesis of Candida strains. The periodic application of antimicrobial agents may select for strains with increased levels of persister cells. In order to test this possibility, 150 isolates of Candida albicans and C. glabrata were obtained from cancer patients who were at high risk for the development of oral candidiasis and who had been treated with topical chlorhexidine once a day. Persister levels were measured by exposing biofilms growing in the wells of microtiter plates to high concentrations of amphotericin B and plating for survivors. The persister levels of the isolates varied from 0.2 to 9%, and strains isolated from patients with long-term carriage had high levels of persisters. High-persister strains were isolated from every patient with Candida carriage of more than 8 consecutive weeks but from no patients with transient carriage. All of the high-persister isolates had an amphotericin B MIC that was the same as that for the wild type, indicating that these strains were drugtolerant rather than drug-resistant mutants. Biofilms of the majority of high-persister strains also showed an increased tolerance to chlorhexidine and had the same MIC for this antimicrobial as the wild type. This study suggests that persister cells are clinically relevant, and antimicrobial therapy selects for high-persister strains in vivo. The drug tolerance of persisters may be a critical but overlooked component responsible for antimicrobial drug failure and relapsing infections.

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

“…The persister levels in the patient group with chronic carriage (.8 weeks) were significantly higher than the persister levels in the group that displayed transient carriage (,8 weeks) of Candida species. The results clearly established a link between persistence and chronic C. albicans infections (LaFleur et al, 2010).…”

“…Contrary to bacterial populations, planktonic Candida populations do not produce persister cells refractory to the lethal action of antibiotics. Similarly to the in vivo selection of P. aeruginosa hip mutants in CF lungs (Mulcahy et al, 2010), LaFleur et al (2010) were able to demonstrate that in vivo selection for Candida hip mutants occurs in patients with oral candidiasis. For this study, the persistence phenotype of 150 clinical isolates obtained from cancer patients, who were at high risk for candidiasis because of chemotherapy treatment, was determined.…”

“…A more general role in chronic infections, beyond the involvement in biofilm tolerance, was subsequently put forward for persisters (Lewis, 2007), explaining why important chronic infections such as tuberculosis and pneumonia often recur despite the application of antibiotics and the absence of detectable antibiotic resistance through laboratory testing of the causative agents. Only recently, a direct link was provided between the recalcitrance of chronic infections and persistence (LaFleur et al, 2010;Mulcahy et al, 2010), a major breakthrough in this research area.…”

The toxin-antitoxin systemtisB-istR1

“…They are causing major health problems since they are recalcitrant to antibiotics. 7,25,[53][54][55] It is well-known that treatment with bacteriocidal antibiotics kills the vast majority of susceptible bacteria. However, dependent on genotype, physiological status, and other less well-defined conditions, some cells stochastically enter a state of very low metabolic activity or even complete dormancy.…”

Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance

“…P. aeruginosa is a source of nosocomial infection outbreaks and causes life-threatening infections in people suffering from cystic fibrosis (Lyczak et al, 2002). In addition to the intrinsic resistance to antibiotics and genetically acquired resistance mechanisms of P. aeruginosa, it is now believed that persister cells contribute significantly to treatment failure by their presence in infection-related biofilm populations (Brooun et al, 2000;LaFleur et al, 2010;Mulcahy et al, 2010;Spoering & Lewis, 2001). …”