ICU Patients' Antibiotic Exposure and Triazole-Resistance in Invasive Candidiasis: Parallel Analysis of Aggregated and Individual Data

Abstract

Background: The relationship between antibiotic use and the incidence of triazole-resistant phenotypes of invasive candidiasis (IC) in critically ill patients is unclear. Different methodologies on determining this relationship may yield different results. Methods: A retrospective multicenter observational analysis was conducted to investigate exposure to antibiotics and the incidence of non-duplicate clinical isolates of Candida spp. resistant to fluconazole, voriconazole, or both during November 2013 to April 2018, using two different methodologies: group-level (time-series analysis) and individual-patient-level (regression analysis and propensity-score adjusting). Results: Of 393 identified Candida spp. from 388 critically ill patients, there were three phenotypes of IC identified: fluconazole-resistance (FR, 63, 16.0%); voriconazole-resistance (VR, 46, 11.7%); and cross-resistance between fluconazole and voriconazole (CR, 32, 8.1%). Exposure to several antibacterial agents with activity against the anaerobic gastrointestinal flora, especially third-generation cefalosporins (mainly cefoperazone/sulbactam and ceftriaxone), but not triazoles, have an immediate effect (time lag = 0) on subsequent ICU-acquired triazole-resistant IC in the group-level (p < 0.05). When the same patient database was analyzed at the individual-patient-level, we found that exposure to many antifungal agents was significantly associated with triazole-resistance (fluconazole [adjusted odds ratio (aOR) = 2.73] or caspofungin [aOR = 11.32] on FR, voriconazole [aOR = 2.87] on CR). Compared to the mono-triazole-resistant phenotype, CR IC has worse clinical outcomes (14-days mortality) and a higher level of resistance. Conclusion: Group-level and individual-patient-level analyses of antibiotic-use-versus-resistance relations yielded distinct but valuable results. Antibacterials with antianaerobic activity and antifungals might have "indirect" and "direct" effect on triazole-resistant IC, respectively.

Keywords: critical illness; drug resistance; fungal; invasive candidiasis; regression analysis; time series analysis.

FIGURE 1

Monthly incidence of non-duplicate triazole-resistant isolates and antibiotic consumption per 100 patient-days (A) Fluconazole-resistant invasive candidiasis (B) Voriconazole-resistant invasive candidiasis (C) Cross-resistant invasive candidiasis. The number on the x-axis are months (from November 2013 to April 2018).

FIGURE 2

Cumulative survival in patients with cross-resistant, mono-triazole-resistant, and non-resistant invasive candidiasis using Kaplan-Meier curves. The dashed line indicates the 95% confidence interval: yellow for non-resistant; green for mono-triazole-resistant; red for cross-resistant invasive candidiasis.