Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS -Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

Abstract

We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

Pan-Echinocandin-Resistant Candida glabrata Bloodstream Infection Complicating COVID-19: A Fatal Case Report

“…In our case, taking advantage of morphologically different C. glabrata colonies [51] from the patient's blood culture that yielded isolate 2, we were able to detect echinocandin resistance by testing more than one colony. Consistent with recent studies [16,26], we found that isolate 2 harbored the FKS2 HS1 F659Y. In a two-year antifungal resistance surveillance study [16], 8 (15.7%) of 51 C. glabrata isolates with FKS HS alterations harbored the FKS2 HS1 F659S/V/Y [25,52], which was the second found after the FKS2 HS1 S663P (16 isolates).…”

“…We provided the evidence of an in vivo development of FKS-associated echinocandin resistance during the patient's treatment with caspofungin, consistent with previous case reports [26,39,40]. In two of them, echinocandin-resistant isolates were recovered from blood cultures of patients who had recurrent or persistent C. glabrata infections, thus implying micafungin treatments for 86 days in one case [26] and 30 days in the other case [39]. In another one [40], echinocandin resistance emerged within 8 days of the patient's treatment with micafungin, and surprisingly, the patient had no previous or prolonged echinocandin exposure [41], but only uncontrolled diabetes, as a potential risk factor for microbiological failure.…”

“…Ultimately, the appearance of echinocandin resistance in our patient's C. glabrata isolate aggravated the feared adverse prognosis of candidemia [38]. We provided the evidence of an in vivo development of FKS-associated echinocandin resistance during the patient's treatment with caspofungin, consistent with previous case reports [26,39,40]. In two of them, echinocandin-resistant isolates were recovered from blood cultures of patients who had recurrent or persistent C. glabrata infections, thus implying micafungin treatments for 86 days in one case [26] and 30 days in the other case [39].…”

“…Interestingly, both the isolates showed an intermediate susceptibility to fluconazole (MIC, 8 mg/L) and, according to the epidemiological cutoff values established by the CLSI [23], a wild-type susceptibility to amphotericin B, and the other azole (itraconazole, posaconazole and voriconazole) antifungal agents tested. A sequence analysis of the FKS1/FKS2 genes [24] allowed us to identify T1976A (hot spot 1) and A3997T (hot spot 2) mutations in the FKS2 gene, which resulted in an F659Y or I1333F amino acid change, respectively, with the former being already known [16,25,26] and the latter probably responsible for the observed echinocandin resistance. Furthermore, the MALDI-TOF MS-based analysis of profiles from C. glabrata isolates 1 and 2 allowed for comparing them with each other and with profiles from a clinical collection of C. glabrata isolates, which had been cultured from sterile or mucosal site samples (UCSC1-12, UCSC17-21).…”

Low level of antifungal resistance of Candida glabrata blood isolates in Turkey: Fluconazole minimum inhibitory concentration and FKS mutations can predict therapeutic failure

“…Candida glabrata is the second leading cause of candidaemia in USA, 1 Canada, 2 Australia 3 and some Scandinavian countries 4‐9 and the first cause of candidaemia in intensive care units and patients with haematological malignancies and solid tumours 10,11 . Compared to the other Candida species, C glabrata is much more tolerant to antifungals, 12 which allows it to rapidly develop antifungal resistance during the course of antifungal therapy 13‐22 . Indeed, C glabrata isolates resistant to azoles or echinocandins and even those demonstrating multidrug resistance are increasingly being identified in clinical settings 6,8,23 .…”