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Delayed Antimicrobial Hypersensitivity: Immunology and Diagnostics

Oral challenge is performed to confirm an immune-mediated ADR in the event of negative delayed-IDT or negative patch testing, the authors said. However, they emphasized that this method should never be used in patients with SJS, TEN, or DRESS.
The antibiotic lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro. However, this test is unvalidated and is associated with both false-positive and false-negative results; it is currently only used in research settings.
According to the authors, use of ex-vivo diagnostic techniques—specifically ELISpot, which analyzes antigen-specific, cytokine-producing cells in peripheral blood after a patient is exposed to a drug—holds potential as a new approach to assigning causality in antimicrobial-associated T cell-mediated ADRs; it also has higher sensitivity in detecting drug-specific T cell responses than LTT has. However, ELISpot is also currently used only within research settings.
An understanding of key cytokine mediators involved in the different form of T cell-mediated ADRs will help to further development of these tools, the
authors noted.
Cross Reactivity in T Cell-Mediated Reactions
The authors also highlight the need for clinicians to understand the concept of cross-reactivity based on shared chemical structure among antimicrobial agents—specifically if in-vivo and ex-vivo diagnostics are unavailable. “A knowledge of side chain cross-reactivity aids empirical antibiotic choice in the setting of immune-mediated ADRs,” they emphasized.
Current data indicate that most cross-reactivity in the beta-lactam class of antibiotics occurs because of similarities between agents in their side chain structures. Cross-reactivity and tolerance have also been reported for aminoglycosides, in which ADRs occur more commonly with topical agents than systemic ones, due to contact sensitization. For quinolone antibiotics, delayed immune-mediated ADRs occur less commonly than immediate ADRs occur, and cross-reactivity occurs more frequently between first- and second-generation quinolones than between third- and fourth-generation quinolones. Cross-reactivity also occurs between antibiotic sulfonamides, particularly between sulfasalazine and sulfamethoxazole, the authors noted.
In contrast, however, cross-reactivity between carbapenems or between macrolides seems to be rare. The authors added that cross-reactivity between most classes of antiretrovirals also seems to be very uncommon because these drugs lack structural similarities. Nevertheless, they stressed that patients with a history of severe hypersensitivity to a nonnucleoside reverse transcriptase inhibitor (NNRTI) should be carefully monitored if new NNRTI therapy is started.
The process by which an antibiotic label is assigned, acted on, and maintained remains imprecise, the authors said. As a consequence, “[p]redicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines,” they concluded.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.
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