Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined by BMD method according to CLSI (M27 Ed4). Disconnected growth (PG plus TE) was most frequent with caspofungin (49.6%), followed by anidulafungin (33.7%), micafungin (25.7%), while it was least frequent with rezafungin (16.9%). PG was relatively common in the case of caspofungin (30.1%) but was rare in the case of rezafungin (3.0%). C. tropicalis, C. albicans, C. orthopsilosis and C. inconspicua exhibited PG most frequently with caspofungin, micafungin or anidulafungin. PG never occurred in the case of C. krusei isolates. Against C. tropicalis and C. albicans, echinocandins frequently showed PG after 24 h followed by TE after 48 h. All four echinocandins exhibited TE for the majority of C. auris and C. dubliniensis isolates. Disconnected growth was common among Candida species and was echinocandin- and species-dependent. In contrast to earlier echinocandins, PG was infrequently found with rezafungin.

We compared the efficacy of single six mg/kg and 2x3 mg/kg caspofungin doses to the traditional one mg/kg daily against C. albicans in a neutropenic murine model. In lethality experiments, all regimens improved survival (p<0.0014 for all three isolates); differences among the treated groups were not statistically significant. We calculated kidney fungal burdens on each study day for six days postinfection using two isolates in two experiments. In the first three days, only the six mg/kg dose produced significant decrease on all study days (p<0.05-0.001), but differences between the three treatment arms disappeared by 4-6 days postinfection (p<0.05 for all isolates on all days).

Candida auris is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences the killing activities of echinocandins against C. auris is currently lacking. We determined the killing activities of anidulafungin and micafungin (0.25, 1, 8, 16 and 32 mg/L each) with and without nikkomycin Z (8 mg/L) against 15 isolates representing four C. auris clades (South Asian n = 5; East Asian n = 3; South African n = 3; South American n = 4, two of which were of environmental origin). Two and one isolates from the South Asian clade harbored mutations in the hot-spot 1 (S639Y and S639P) and 2 (R1354H) regions of the FKS1 gene, respectively. The anidulafungin, micafungin and nikkomycin Z MIC ranges were 0.015-4, 0.03-4 and 2->16 mg/L, respectively. Anidulafungin and micafungin alone exerted weak fungistatic activity against wild-type isolates and the isolate with a mutation in the hot-spot 2 region of FKS1 but was ineffective against the isolates with a mutation in the hot-spot 1 region. The nikkomycin Z killing curves were always similar to their respective controls. Twenty-two of sixty (36.7%) anidulafungin plus nikkomycin Z and twenty-four of sixty (40%) micafungin plus nikkomycin Z combinations produced at least 100-fold decreases in the CFUs (synergy), with a 41.7% and 20% fungicidal effect, respectively, against wild-type isolates. Antagonism was never observed. Similar results were found with the isolate with a mutation in hot-spot 2 of FKS1, but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of FKS1. The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type C. auris isolates produced significantly greater killing rates than either drug alone. Further studies are warranted to verify the clinical efficacy of echinocandin plus nikkomycin Z combinations against echinocandin susceptible C. auris isolates.