The antibiotic vancomycin is invaluable within combination drug regimens used around the world to treat severe, antibiotic-resistant, Gram-positive infections. However, vancomycin is also the most common cause globally of DRESS (drug reaction with eosinophilia and systemic symptoms), a severe hypersensitivity syndrome with significant mortality and long-term morbidity.
“While the true incidence of DRESS isn’t known, vancomycin has long been known to be a common antibiotic trigger,” said Elizabeth J. Phillips, M.D., the John A. Oates Chair in Clinical Research and a professor of medicine and pharmacology at Vanderbilt University Medical Center.
In new research published in the Journal of Allergy and Clinical Immunology, Phillips and an international research team have identified the gene variation that predisposes patients to vancomycin-induced DRESS. In a follow-up study published in The Journal of Molecular Diagnostics, her group has developed and validated a simple, inexpensive test to identify the specific gene associated with vancomycin-induced DRESS in at-risk patients.
The HLA-DRESS Connection
In the Journal of Allergy and Clinical Immunology, the researchers showed that vancomycin-associated DRESS predominantly occurs in patients with a specific variation in their human leukocyte antigen (HLA) genes, HLA-A*32:01, which is carried in just over 6% of the U.S. population. HLA variants have previously been associated with severe drug reactions and other immune disorders, but their full impact is only emerging.
The team identified the gene variation using BioVU, Vanderbilt’s expansive database of genome and phenome data connected via deidentified patient records. Their analysis revealed a strong signal of a potential association between HLA-A*32:01 and vancomycin-induced DRESS.
They confirmed the HLA-DRESS connection through a prospective study that included 23 patients diagnosed with DRESS after receiving vancomycin. Nineteen (86 percent) of the patients had the HLA-A*32:01 variant. In a control group of vancomycin-tolerant patients, none had the gene variation.
A Clinical Test
Next, Phillips and team sought a practical assay to help medical providers identify the HLA-A*32:01 allele in the field. The test needed to return results within two days and be cost-effective to support widespread use globally, Phillips said.
Allele-specific PCR (AS-PCR) offered an effective HLA typing mechanism. The approach outlined in The Journal of Molecular Diagnostics provides an accurate shortcut to sequence-based typing methods that is significantly less expensive and could be set up in most research laboratories using standard PCR equipment.
Testing 458 DNA samples from BioVU that had previously undergone sequence-based HLA typing, the researchers pinpointed the HLA-A*32:01 allele with 100 percent specificity.
Vancomycin is destined to remain an important drug globally for treating serious bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus). For the approximately 20% of those carrying HLA-A*32:01 that are at risk of vancomycin-induced DRESS, according to this new research, AS-PCR appears to offer a practical means of screening.
“Routine testing could detect hundreds of thousands of patients at risk each year in the U.S. alone.”
“AS-PCR is fast, reliable and can be set up in routine diagnostic laboratories without highly specialized requirements. Routine testing could detect hundreds of thousands of patients at risk each year in the U.S. alone. This represents a huge advance for precision medicine,” Phillips said.