Creation and Internal Validation of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection

Abstract

Background IDSA guidelines on candidemia recommend fluconazole as first-line therapy when the risk of fluconazole-resistance (fluc-R) is low. There is no method to estimate risk of resistance resulting in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial use of fluconazole or early step-down would be appropriate. Methods We performed a retrospective analysis of all hospitalized adult patients with positive blood culture for Candida spp. from 2013 to 2019. We performed a multivariable logistic regression model to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals. We used receiver operator curves to assess performance across the probability spectrum. Results 539 adults with candidemia were identified. 13.4% (72/539) of Candida isolates were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (2.02 [1.13, 3.63]), myelodysplastic syndrome (3.09 [1.13, 8.44]) and receipt of azole therapy (5.42 [2.90, 10.1]) within 1 year prior to index blood culture, as well as history of bone marrow or stem cell transplant (2.81 [1.41, 5.63]). The model had good discrimination (optimism corrected c-statistic 0.771) and all the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cut-off of 90.3%. Conclusions This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive fluconazole as initial therapy or early stepdown.

The Risk Factors and Mechanisms of Azole Resistance of Candida tropicalis Blood Isolates in Thailand: A Retrospective Cohort Study

“…Environmental spreading of resistant C. tropicalis strains was possible, according to previous reports on C. tropicalis and C. parapsilosis [ 6 , 28 ]. However, we have no direct evidence of patient-to-patient transmission, although the history of azole exposure was still a strong independent risk factor as in previous studies [ 12 , 13 ].…”

“…Similarly, in China, fluconazole-resistant isolates increased from less than 10% in 2010–2012 to more than 30% in 2016–2017 [ 7 ]. Several studies reported the relationship between azole-resistant Candida infection and identified multiple risk factors including previous exposure to fluconazole and a history of bacterial bloodstream infection [ 12 , 13 ]. The description of C. tropicalis azole resistance was attributed to the four major mechanisms related to ERG11 mutations, ERG11 overexpression, alteration of membrane sterol composition, and increased expression of the efflux pump genes [ 14 ].…”

Treatment of invasive candidiasis in the era of Candida resistance

“…The SENTRY Antifungal Surveillance Program reported a steady emergence of fluconazole-resistant species, with the highest rates of fluconazole-resistant in C. glabrata [11]. Regardless of Candida species, the risk of fluconazole resistance increases with suboptimal doses and up to 3-fold higher risk has been described with prolonged use [12]. The Centers for Disease Control and Prevention (CDC) listed fluconazole-resistant Candida species among the pathogens posing a serious threat to human health in its 2013 landmark report on antimicrobial resistance [13].…”

Validation Study of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection

“…To the Editor —We read with interest the article by Rauseo et al [ 1 ] regarding the derivation and internal validation of a clinical predictive model for fluconazole resistance in patients hospitalized with candidemia. Their model consisted of 5 clinical parameters associated with fluconazole-resistant candidemia: older age, hematopoietic stem cell transplant (HSCT), myelodysplastic syndrome (MDS), azole exposure, and recent bacteremia.…”

“…External validation of this model in an international cohort is desirable before its clinical implementation, especially considering previous difficulties validating similar risk models in invasive candidiasis [ 2 ]. We aimed to assess the generalizability of Rauseo et al's [ 1 ] model to an Australian context and explore clinical factors predictive of fluconazole resistance in an Australian setting.…”