Cross-resistance (CR) between
voriconazole and
fluconazole for non-albicans Candida (NAC) species is not uncommon, but little is known about the risk factors and clinical consequences associated with this resistance phenotype. A case-case-control study was performed at a university-affiliated hospital in China between November 2012 and April 2016. The two case groups respectively comprised patients with a mono-resistance (MR) NAC
infection (
fluconazole or
voriconazole resistance) and patients with a
CR NAC infection (
fluconazole and
voriconazole resistance). Patients with a no-resistance (NR) NAC
infection were included as the control group. Models were adjusted for demographic and clinical risk factors, and the risk of resistance associated with exposure to specific
antibiotics or non-
antibiotics were assessed. Of 259 episodes, 33 (12.7%) and 27 (10.4%) were identified as MR and
CR NAC infections, respectively. The broad use of
azoles was strongly associated with the emergence of MR and
CR NAC infections (adjusted odds ratio [95% confidence interval] = 2.69 [1.10-6.58] and 2.53 [1.02-6.28], respectively). The time at risk (1.02 [1.00-1.03]) with 12 days as a breakpoint was also an independent risk factor for
CR NAC infection. The number of species associated with a high minimum inhibitory concentration (≥128 μg/mL) of
fluconazole was higher for
CR NAC infections than for MR NAC
infections. Different resistance phenotypes (CR vs. MR vs. NR) were associated with all-cause mortality rates. These findings indicate a worrisome propensity of
CR NAC infections and emphasize the need for strict antifungal stewardship.