Examining An Emergence of Multi-drug Resistance Among Candida Species
Despite having emerged as either the third or fourth leading cause of blood stream infections in the United States, the threat of multi-drug resistant Candida species remains an underappreciated concern.
Antimicrobial resistance is a well-recognized phenomenon, with terms such as methicillin-resistant Staphylococcus aureus, carbapenemase producing enterobacteraciae, and multi-drug resistant Acinetobacter permeating media reports and medical literature. However, despite Candida having emerged as either the third or fourth leading cause of blood stream infections (BSIs) in the United States, the threat of multi-drug resistant Candida species remains an underappreciated concern.
During the past 2 decades, there has been a marked shift in the distribution of Candida species causing invasive disease. Although C. albicans remains the single most commonly isolated species, non-albicans Candida, as a group, now account for the majority of the infections. Moreover, within the non-albicans group, C. glabrata is the most commonly isolated pathogen, followed by C. parapsilosis, C. tropicalis, and C. krusei.1,2
The observed shift in epidemiology is significant because although antifungal resistance remains rare among C. albicans isolates, the non-albicans species, particularly C. glabrata and C. krusei, are associated with decreased susceptibility to commonly used antifungal agents. For instance, C. krusei is well known to be intrinsically resistant to fluconazole. Furthermore, in many medical centers, up to 30% of C. glabrata isolates are fluconazole-resistant.3
The emergence of echinocandin resistance represents a new and additional concern. In a recent population-based surveillance study of 4 metropolitan regions in the United States, approximately 6% of C. glabrata bloodstream isolates were determined to be nonsusceptible to echinocandins and 1.7% were multi-drug resistant.4 In 2012, Pfaller et al reported that 11% of fluconazole-resistant C. glabrata were also resistant to one or more of the echinocandins.5 In a separate survey of C. glabrata isolates recovered between 2008 and 2013, 36% of C. glabrata isolates that were found to be resistant to at least one echinocandin were also determined to be resistant to fluconazole.6
Multi-drug resistance is occurring despite the fact that resistance to azoles and echinocandins occurs through very different mechanisms. For example, azole (fluconazole) resistance is frequently attributed to efflux pumps in the Candida cell membrane, whereas echinocandin resistance generally occurs via mutations at “hot-spot” regions of the genes (FKS1 and FKS2) that encode for 1, 3 beta d-glucan synthase, the enzyme target of echinocandins that is located on the fungal cell wall.3
The increased use of antifungal agents has been postulated to be a strong driving force behind the growing rates of antifungal resistance that are being seen worldwide. Decreased fluconazole susceptibility among clinically relevant Candida spp, the fungicidal activity of echinocandins, and their favorable side-effect profile have contributed to an increased and more widespread echinocandin utilization profiles.
At Duke University Medical Center in the United States, they reported that echinocandins accounted for 68% of their directed antifungal therapy for C. glabrata BSI from 2001 to 2010. During that same time period, the medical center witnessed a nearly 3-fold rise in echinocandin resistance among clinical isolates of C. glabrata.3 Prior exposure to echinocandins was found to be independently associated with echinocandin resistance. Although that only reflects a single center’s experience, it does bring into stark relief a potential threat facing clinicians who manage patients at risk for developing invasive candidiasis. This phenomenon is particularly concerning, considering that echinocandin usage is likely to become even more prevalent in the near future now that these agents have emerged as the preferred therapy for the primary treatment of candidemia and invasive candidiasis.
Earlier this year, the Infectious Diseases Society of America (IDSA) published updated guidelines for the management of candidemia and invasive candidiasis. Whereas the previous guidelines recommended a stratified approach that accounted for severity of illness and likelihood of azole resistance when deciding which antifungal to use as primary therapy for candidemia, the new guidelines recommend an echinocandin as the preferred agent. Fluconazole is now categorized as an acceptable alternative for initial therapy of candidemia only in a select group of patients.7 The new update more closely aligns the IDSA recommendations with those of the European Society for Clinical Microbiology and Infectious Diseases; the organization has recommended echinocandins as first-line therapy for invasive candidiasis since 2012.8 This paradigm shift takes into account growing evidence suggesting that echinocandins are more efficacious than other antifungals, including fluconazole, as initial treatment of candidemia and invasive candidiasis, even in infections caused by C. albicans.9-13
Even though there is sound evidence to support this broader use of echinocandins as first-line antifungal therapy, it is not without its potential hazards. Specifically, these hazards include the rising rates of echinocandin resistance and the concomitant development of multi-drug resistance worldwide. These are very concerning prospects given the limited options currently available for treatment of not only candidemia/candidiasis, but other invasive fungal infections.
Amazingly enough, similar to how we have had to return to the “old drugs,” such as polymyxins, for the management of multi-drug—resistant gram negative bacterial infections, we now face the possibility of once again having to turn to the “polyenes” for treatment of serious candidal infections. Do we need to start to clean off the cobwebs from amphotericin B preparations?
Invasive fungal infections, especially candidemia and invasive candidiasis, are likely to continue to emerge as prominent health care issues as advances in medicine lead to increased populations of high-risk patients. Thus, careful consideration must be given to identifying methods to minimize the risk of perpetuating the development of multi-drug resistant Candida spp. Simply avoiding echinocandin use is not a reasonable option given the potential benefits of these agents. However, avoiding unnecessary use and the mitigating factors that contribute to antifungal failure hold significant appeal. One of the main challenges in avoiding unnecessary antifungal use is the difficulty in making an early diagnosis of invasive candidiasis. Current diagnostic modalities do not have adequate sensitivity or specificities to allow for a reliable and early detection of invasive candidiasis. Continuous emphasis on the development and implementation of new, effective diagnostic technology will be dramatically important.
Furthermore, with regard to minimizing the risk of antifungal failure, a few specific factors must be taken into account. The first relates to ensuring that adequate source control is obtained. Persistent administration of an antifungal without adequately addressing the source of the infection, whether an infected vascular catheter or an intra-abdominal abscess, sets up a situation favoring the development of in vivo resistance. Another factor to consider is whether the isolated Candida spp is intrinsically susceptible to the selected antifungal agent. The recent IDSA guidelines recommend performing susceptibility assays on all Candida blood stream isolates. However, although significant strides have been made with regard to Candida susceptibility testing in the past decade, some issues remain with interpretation, inter-laboratory variability, and, more importantly, the availability of susceptibility testing in many medical centers.14
Ensuring high-quality susceptibility testing that is readily available and affordable in the clinical setting has the potential to allow for earlier recognition of antifungal resistance that would require modification of therapy, as well as to promote appropriate step-down de-escalation therapy to further minimize unnecessary echinocandin and antifungal utilization. In addition, the creation of antifungal stewardship programs would also assist in the appropriate and adequate utilization of all antifungals.
The emergence of multi-drug resistance in Candida species represents a significant health-care threat. There is a pressing need for the development of novel antifungals to address this problem. In the meantime, we are faced with the real possibility of needing to revive “old” antifungals such as amphotericin B or consider initiating combination antifungal therapy for the management of candidiasis. Thus, the initiation and appropriate utilization of an antifungal stewardship program is an essential and important task now facing medical centers, especially those with a high prevalence of invasive fungal infections and significant utilization of antifungals.
Rhonda Colombo, MD, is an assistant professor of medicine in the Division of Infectious Diseases at the Medical College of Georgia/Augusta University in Augusta, Georgia. Jose A. Vazquez, MD, is division chief and professor in the Division of Infectious Diseases at the Medical College of Georgia/Augusta University.
- Diekema D, Arbefeville S, Boyken L, Kroeger J, Pfaller M. The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbiol Infect Dis. 2012 May; 73(1):45-48. doi: 10.1016/j.diagmicrobio.2012.02.001.
- Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008—2009. Antimicrob Agents Chemother. 2011;55(2):561-566. doi: 10.1128/AAC.01079-10.
- Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724-1732. doi: 10.1093/cid/cit136.
- Vallabhaneni S, Cleveland A, Farley M, et al. Epidemiology and risk factors for echinocandin nonsusceptible candida glabrata bloodstream infections: data from a large multisite population-based candidemia surveillance program, 2008-2014. Open Forum Infect Dis. 2015;2(4):ofv163. doi: 10.1093/ofid/ofv163.
- Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Micro. 2012;50(4):1199-1203. doi: 10.1128/JCM.06112-11.
- Pham CD, Iqbal N, Bolden CB et al. Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance. Antimicrob Agents Chemother. 2014;58(8):4690-4696. doi: 10.1128/AAC.03255-14.
- Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50. doi: 10.1093/cid/civ933.
- Cornely OA, Bassetti M, Calandra T, et al; ESCMID Fungal Infection Study Group. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012;18(suppl 7):19-37. doi: 10.1111/1469-0691.12039.
- Reboli AC, Rotstein C, Pappas PG, et al; Anidulafungin Study Grokup. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24): 2472-2482.
- Kett DH, Shorr AF, Reboli AC, Reisman AL, Biswas P, Schlamm HT. Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: support for the 2009 idsa treatment guidelines for candidiasis. Crit Care. 2011;15(5):R253. doi: 10.1186/cc10514.
- Reboli AC, Shorr AF, Rotstein C, et al. Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome. BMC Infect Dis. 2011;11:261. doi: 10.1186/1471-2334-11-261.
- Eschenauer GA, Carver PL, Lin SW, et al. Fluconazole versus an echinocandin for C. glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother. 2013;68(4):922-926. doi: 10.1093/jac/dks482.
- Andes DR, Safdar N, Baddley JW, et al; Mycoses Study Group. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8): 110-1122. doi: 10.1093/cid/cis021.
- Eschenauer GA, Nguyen MH, Shoham S, Vazquez JA, et al. Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of blood stream isolates. Antimicrob Agents Chemother. 2014;58(4):1897-1906. doi: 10.1128/AAC.02163-13.