Breakthrough Invasive Candida glabrata in Patients on Micafungin: a Novel FKS Gene Conversion Correlated with Sequential Elevation of MIC

Abstract

c Candida glabrata strains sequentially isolated from blood developed resistance to micafungin (MICs from <0.015 to 4 g/ml). A novel mutation identified in micafungin-resistant strains at bp 262 of FKS2 (containing a deletion of F659 [F659del]) was inserted into the homologous region in FKS1. CASE REPORTA 93-year-old man was admitted to our hospital with a diagnosis of pulmonary tuberculosis (day 1). The patient had been receiving treatment for essential hypertension with chronic renal failure for a decade. On admission, the patient's vital signs were normal; however, serum laboratory data showed a marked elevation of creatinine (Cr) (4.7 mg/dl) and blood urea nitrogen (BUN) (74.5 mg/dl). After initiation of antituberculous therapy with oral isoniazid (300 mg/day) plus rifampin (450 mg/day), renal failure progressed (Cr, 7.0 mg/dl) due to drug-induced myoglobinemia (1,000 ng/ml) with uremic symptoms. Although an urgent flexible double lumen (FDL) catheter was introduced into the internal jugular vein, readministration of isoniazid (day 18) caused severe rhabdomyolysis (myoglobinemia, 25,650 ng/ml), with a recurrence of the uremic symptoms.On day 27, the patient suddenly went into a state of shock with high fever and was empirically treated with intravenous meropenem (0.5 g/day), vancomycin (0.5 g, every 48 h [q48h]), and fluconazole (200 mg/day) based on a tentative diagnosis of aspiration pneumonia or catheter-related bloodstream infection complicated by sepsis. On the same day, two sets of blood cultures and serum endotoxin antigen were negative except for an elevation of ␤-D-glucan (133 pg/ml). On day 32, the patient's serum value of ␤-D-glucan rose to 530 pg/ml, and he had a positive result for serum galactomannan (Aspergillus antigen) of 4.5, thrombocytopenia (6.4 ϫ 10 3 platelets/l), and leukocytopenia (2.0 ϫ 10 3 leukocytes/l). Therefore, the fluconazole was changed to voriconazole (6 mg/kg of body weight/day, q12h) with the intent of targeting Aspergillus spp. However, on day 35, a blood culture collected on day 32 (strain NO1) was identified as Candida glabrata; therefore, voriconazole was changed to intravenous micafungin (100 mg/day) according to the Infectious Diseases Society of America (IDSA) 2009 guidelines (1). A blood culture taken on day 34 (NO2) also was positive for C. glabrata; however, after initiation of treatment with micafungin, the persistent fever subsided, and a blood culture taken at day 37 was negative for the yeast. Both strain NO1 and strain NO2 were susceptible to micafungin (MIC, Ͻ0.015 g/ml) but susceptible-dose dependent to fluconazole (MIC Ͻ8 g/ml) by Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) methods (CLSI document M27-S4). With regard to voriconazole, no breakpoint was determined for C. glabrata. In spite of two rounds of replacement of the FDL catheter, the serum value of ␤-D-glucan remained high (Ͼ600 pg/ml), and blood cultures taken on day 48 (NO3) and day 51 (NO4) again yielded C. glabrata. Based on the suspicion of a micafungin-resista...

Clinical and Microbiological Characteristics of Breakthrough Candidemia in Allogeneic Hematopoietic Stem Cell Transplant Recipients in a Japanese Hospital

“…In general, in current treatment guidelines, a lower dose of micafungin (50 mg/day) has been approved for use for prophylactic administration (11,12). This is probably why there are only a few studies on the development of BC when a sufficient dose of micafungin (Ն100 mg/day) is provided (9,17). Among the 13 strains that caused BC during micafungin treatment and for which a breakpoint was established and antifungal susceptibility testing was performed, 11 strains were susceptible to micafungin in vitro (85%).…”

“…The rate of BC among all patients with hematological malignancies and candidemia was previously found to range from 19% to 72% (3)(4)(5). According to the findings of some previous studies focused on BC, risk factors for BC are severe neutropenia, the use of corticosteroids, the presence of a central venous catheter (CVC), and resistance to antifungal agents (6)(7)(8)(9)(10). Furthermore, a recent multicenter study found that the causes of BC, particularly in patients with BC receiving azole or liposomal amphotericin B, might be associated with microbiological factors, such as resistance to antifungal agents, and/or host factors, such as neutropenia or the presence of a CVC (7).…”

Antifungal drug susceptibility, molecular basis of resistance to echinocandins and molecular epidemiology of fluconazole resistance among clinical Candida glabrata isolates in Kuwait

“…However, resistance to echinocandins in Candida spp. has also appeared in recent years with the highest rate occurring among C. glabrata and breakthrough invasive C. glabrata infections have been reported in patients on micafungin therapy [14][15][16][21][22][23][24] . Resistance to polyenes is also being reported with increasing frequency in clinical C. glabrata isolates [25][26][27][28][29] and a multidrug-resistant phenotype (resistant to azoles and echinocandins) occurring in ICU and non-ICU settings has also been described in recent years 30,31 .…”

Development of Echinocandin Resistance in Candida tropicalis following Short-Term Exposure to Caspofungin for Empiric Therapy

“…Acquired resistance to echinocandins has been reported in C. albicans, with some isolates containing the same S645P mutation in HS-1 of the FKS1 gene (30,32,33). Echinocandin resistance is particularly alarming in C. glabrata because nearly one-third of clinical isolates of this haploid species are also intrinsically resistant to azoles (38)(39)(40). Mutations in HS-1 and HS-2 of both FKS1 and FKS2 genes confer resistance to echinocandins in C. glabrata (12,13,40).…”