Cross-reactivity between vancomycin, teicoplanin, and telavancin in patients with HLA-A∗32:01-positive vancomycin-induced DRESS sharing an HLA class II haplotype

Abstract

All fifteen patients with HLA-A*32:01 restricted vancomycin-induced DRESS, showed negative ex vivo responses to dalbavancin however two showed cross-reactivity to teicoplanin and telavancin. Adjunctive diagnostic testing should be considered to detect potential cross-reactivity amongst glycopeptides.

Figure 1.

IFN-γ release ELISpot results using PBMCs from 15 potential vancomycin DRESS patients after 20 hours of incubation with vancomycin, teicoplanin, dalbavancin, and telavancin (Telavancin stimulation was tested on 11 cases). Means of the triplicates are plotted. Error bars indicate interquartile range of the median ELISpot results from all cases after background subtraction. A positive response was defined as >50 SFU/million cells after background removal. Two patients (Patient ID 8 and 15) showed cross-reactivity between vancomycin, teicoplanin and telavancin and one patient (Patient ID 7) showed potential cross-reactivity between vancomycin and telavancin at 500 μg/mL (see Supplemental Table E3 for details).

Figure 2.. Prediction of binding interactions between vancomycin, teicoplanin, telavancin and HLA-DQ.

A model of HLA-DQ (DQA1*01:01 in green, DQB1*05:03 in beige) is shown. AutoDock Vina was used for molecular docking with vancomycin (red), teicoplanin (cyan), telavancin (yellow). Molecular docking of vancomycin, teicoplanin and telavancin with class II HLA molecules, HLA-DR, -DQ and -DP sequences were obtained from the HLA/IMGT database (http://www.ebi.ac.uk/ipd/imgt/hla/allele.html). Atomic homology models were generated with SWISS-MODELLER based on the most closely related crystal structures. The class II HLA complex models were then geometry minimized by using PHENIX. Vancomycin, teicoplanin and telavancin were docked into the HLA-A*32:01 model with AutoDock Vina. The scoring grid dimensions were 40 × 40 × 40 Å centered on a site corresponding to the Ca of the fifth peptide amino acid position (P5). Vancomycin was docked, with exhaustiveness set to 40. The top 9 scoring orientations were determined and compared. PyMOL was used to generate molecular graphics (PyMOL Molecular Graphics System, version 1.8; Schrödinger, Cambridge, Mass).