Research Abstract
Catheter-related infections due to Candida albicans biofilms are a leading cause of fungal nosocomial bloodstream infection. In this paper, we describe the development of a model of catheter-associated infection with C. albicans biofilms and show that antifungal lock therapy with liposomal amphotericin B is an effective treatment strategy for these infections. Silicone catheters surgically placed in New Zealand White rabbits were infected with C. albicans, and the rabbits were randomized into three groups: (i) untreated controls, (ii) liposomal amphotericin B lock, and (iii) fluconazole lock. Upon completion of therapy, blood cultures were obtained and the catheters were removed for quantitative culture and scanning electron microscopic analyses. Quantitative cultures revealed that catheters treated with liposomal amphotericin B yielded 0 CFU, which was significant compared to the untreated controls (P < 0.001) and the fluconazole-treated group (P = 0.0079). Although fluconazole treatment tended to have lower CFU compared to untreated controls, there was no difference in mean colony counts between these two groups (1.128 ± 0.764 and 1.841 ± 1.141 log10 CFU/catheter segment, respectively; P = 0.297). Scanning electron microscopy revealed abundant biofilm in the control and fluconazole groups, while the liposomal amphotericin B group was virtually cleared. These findings suggest a possible treatment strategy for the successful salvage of catheters infected with C. albicans biofilms and describe an animal model that may play an important role in the further study of C. albicans biofilm pathogenesis and evaluation of potential antibiofilm agents.
Nosocomial bloodstream infections are a significant cause of morbidity and mortality among hospitalized patients, with Candida species representing the fourth most common cause of such infections (9). Central venous catheters (CVCs) are responsible for many of these infections, and up to 40% of patients with Candida isolated from their CVCs have underlying fungemia (1). Despite the introduction of new antifungal therapies, the attributable mortality of patients with candidemia remains unacceptably high, ranging from 39 to 49% (10, 26).
Adherence of microorganisms and biofilm formation on catheter surfaces is a common mechanism for catheter-associated bloodstream infection (20). These biofilms are characterized by the production of a thick extracellular matrix and an altered resistance phenotype (8). Electron microscopic evaluation of catheters removed from patients has demonstrated widespread biofilm colonization, confirming the importance of biofilms in catheter-associated infections (20). CVCs infected with Candida biofilms are especially problematic since Candida species adhere avidly to catheter material and antifungal therapy alone is insufficient for cure (6). This explains the rationale behind the recent national guidelines recommending the removal of catheters infected with Candida in order to eradicate a potential nidus of bloodstream infection (17, 19). However, catheter removal is not always feasible for patients with coagulopathy or limited vascular access and is associated with increased healthcare expenses as well as complications related to catheter replacement (18).
Data from several laboratories have demonstrated the near-total resistance of in vitro Candida albicans biofilms to common antifungal agents (6, 7, 13, 15). More recently, our group and others have observed that in vitro C. albicans biofilms show susceptibility to the lipid formulations of amphotericin B and the echinocandins (3, 16). Although these data suggest a possible strategy for the salvage of CVCs infected with C. albicans biofilms, the clinical significance of these observations remains unknown. There has been no in vivo validation of these findings because (i) no animal model of catheter-related C. albicans biofilm infection is available and (ii) no prospective, randomized clinical trials have been performed. In this study, we describe the development of the first clinically relevant animal model of C. albicans biofilm-associated catheter infection and evaluate the effectiveness of liposomal amphotericin B antifungal lock therapy.
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