Discussion
Drug-induced SSLR represent a major problem – along with other
idiosyncratic hypersensitivity reactions – to management of infectious
diseases due to the difficulty in timely confirmation the diagnosis and
accurate identification of the culprit drug. Approximately 10% of the
general population report an allergy to β-lactam antibiotics; however,
90% of reported allergies to β-lactam antibiotic cannot be confirmed
immunologically 16. Such false labeling of patients
puts them at greater risk of adverse reaction due to the use of less
safe alternatives to treat their infection which increases length of
hospital stay and likelihood of bad outcomes. Furthermore, resorting to
non-beta-lactam antibiotics increases the cost burden of healthcare and
contributes to worsening the bacterial resistance problem.
The pathophysiology of SSLR to β-lactam antibiotics is unclear (Figure
2). However, many cases of drug-induced delayed hypersensitivity appear
to evolve due to increased toxicity of reactive drug metabolites
followed by a mis-directed immune response. We have demonstrated that
there is a difference in cellular capacity with respect to defense with
reactive drug metabolites between patients who have sustained a SSLR to
β-lactam antibiotics versus the cells of healthy volunteers. This
implies that dealing with reactive drug metabolite burden may be a
critical first step in the pathogenesis of SSLR to β-lactam antibiotics.
We have previously demonstrated this with respect to cefaclor and these
findings suggest that this may be a common element in the pathogenesis
of serious delayed adverse drug reactions to β-lactam antibiotics,
supporting the importance of initial bioactivation of the drug leading
to a misdirected immune response resulting in delayed drug
hypersensitivity manifested as a SSLR5.
In addition to informing pathogenesis this has implications for
diagnostic assessments. All the available diagnostic aids including skin
testing and oral re-challenge have their risks and shortcomings and are
not always feasible to perform either due to lack of expertise or fear
of inducing a severe reaction in the patient. The LTA has the advantage
of being safe as an in vitro test and can be used both as a diagnostic
test and an investigative tool for the pathophysiology of SSLRs. Kearns
et al.5 tested 19 patients (10 male and 9 females)
suspected of developing SSLR to cefaclor and found that subjects with
SSLR exhibited an increase in cell death of 50% to 167% above
baseline. The effect was specific to cefaclor and was not produced by
incubation of isolated cells with another cephalosporin (cephalexin)
along with metabolic activation system 5. In another
study, the same group also tested 10 patients with SSLR to cefaclor
using the LTA test. The degree of cell death in the patient pollution
was highly positive and ranged from 40% to 140% increase above
baseline 17. In a validation study for the LTA test
using systemic re-exposure as a gold standard to determine the
predictive value of the test for diagnosis of hypersensitivity reactions
(HSRs) to different groups of drugs, we tested 11 patients with HSRs to
beta-lactam antibiotics (6 to amoxicillin and 5 to cefaclor)14. When the results of the re-exposure were compared
to the LTA results, all except one patient had complete agreement.
Data presented here points to the value of the LTA to explore
mechanism(s) of drug hypersensitivity and potentially as a diagnostic
tool for beta-lactam-induced SSLRs. Further research with larger numbers
of patients is needed to further explore the pathophysiology and biology
of SSLR to to β-lactam antibiotics.