Susceptibility of Candida albicans biofilms to azithromycin, tigecycline and vancomycin and the interaction between tigecycline and antifungals
Introduction
Catheter-related bloodstream infections (CR-BSIs) result in significant morbidity and mortality, increased length of stay and increased cost of care in patients requiring intravascular devices. The incidence of CR-BSI has paralleled the increased use of intravascular devices such as central venous catheters and those used in haemodialysis over the past 2 decades [1]. Candida albicans has emerged as a significant pathogen causing CR-BSI, especially amongst immunosuppressed and hospitalised patients. Although Gram-positive bacteria such as Staphylococcus epidermidis and Staphylococcus aureus have been found to be the most common pathogens associated with CR-BSI, epidemiological studies have indicated that Candida spp. are the fourth leading cause [1], [2].
Biofilm formation by pathogenic microorganisms, including C. albicans, plays a key role in infection of intravascular devices and contributes to the difficulty in the management of these device-related infections [3], [4], [5], [6], [7], [8], [9]. By the mid 1980s it had been established that bacteria embedded in biofilms (sessile form) were particularly resistant to conventional antibiotics compared with their planktonic (free culture) form [9]. Candida albicans biofilms were also found to have greater resistance to the majority of the antifungal agents used in the mid 1990s [10]. Thus, current clinical guidelines recommend removal of these devices as part of the management of CR-BSI caused by Candida spp. whenever feasible [11].
Prior to the availability of echinocandins and azoles, the polyene antifungal agent amphotericin B (AmB) was the major antifungal agent used in the management of invasive Candida infections. The high incidence of nephrotoxicity of AmB led to the evaluation of combination therapies in the hope of decreasing the amount of AmB required to treat fungal infections thus minimising the risk of nephrotoxicity. These studies performed in the 1970s and 1980s revealed that antibiotics such as rifampicin and tetracyclines enhanced the effect of AmB against various pathogenic yeasts in their planktonic form in vitro [12], [13], [14], [15], [16], [17].
Since then, it has been determined that echinocandins and lipid formulations of AmB have activity against C. albicans biofilms [18], [19]. El-Azizi [20] showed that rifampicin and doxycycline (DOX) enhanced the activity of AmB against non-albicansCandida spp. biofilms in vitro. Recently, our laboratory has shown that DOX enhances the activity of certain antifungal agents and has intrinsic activity against C. albicans biofilms [21].
Thus, we screened several standard Gram-positive antibacterial agents, including azithromycin (AZM), tigecycline (TIG) and vancomycin (VAN), against C. albicans biofilms. Of these antibiotics, it was found that TIG had the greatest antifungal activity against mature C. albicans biofilms. Therefore, we chose to study TIG in detail and to characterise its activity alone and in combination with AmB, caspofungin (CAS) and fluconazole (FLC) against C. albicans biofilms.
Section snippets
Materials
The clinically derived wild-type SC5314 strain of C. albicans was used for this study [22]. AZM and VAN were obtained from Sigma Chemical Co. (St Louis, MO). TIG (Wyeth Pharmaceuticals Inc., Philadelphia, PA) was purchased from the hospital pharmacy (Raymond G. Murphy VA Medical Center, Albuquerque, NM). The antifungal agents FLC and AMB were from Sigma Chemical Co., and CAS (Merck, Whitehouse Station, NJ) was purchased from the hospital pharmacy. Stock solutions of TIG (10 mg/mL) and AZM (100
Results
Of the antibacterial agents screened for antifungal activity against mature C. albicans biofilms, AZM had modest activity against mature C. albicans biofilms starting at a concentration of 1024 μg/mL as well as reduction in the metabolic activity of the biofilms by 16.9% at 2048 μg/mL. VAN had no antifungal activity at any concentration tested.
In contrast, high concentrations of TIG had substantial activity against mature C. albicans biofilms. The antifungal effect was first apparent at a
Discussion
The presence of biofilms on intravascular devices makes the treatment of CR-BSI difficult. Although the current recommendation suggesting the removal of these devices in the management of CR-BSI may be ideal, clinicians frequently find this option to be difficult because of the patient's underlying conditions (i.e. critically ill status, coagulopathy, thrombocytopenia) or lack of another appropriate intravascular access site. Until recently, the Infectious Diseases Society of America (IDSA)
Acknowledgment
The authors thank William Fonzi (Georgetown University, Washington, DC) for providing strain SC5314.
Funding: This work was supported in part by grants from the Department of Veterans’ Affairs (MERIT Award to SAL) and the Biomedical Research Institute of New Mexico (SAL).
Competing interests: SAL: speaker's bureau for Pfizer and Astellas. All other authors declare no competing interests.
Ethical approval: Not required.
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