The rate of antimicrobial associated anaphylaxis in the two large healthcare facilities included in this study was 18.6 (95% CI: 11.8 − 29.5) cases per 100 000 exposures. Compared to a large national study from the UK which reported an overall incidence of reported antibiotic-induced anaphylaxis was 4.0 per 100 000 exposures, where the highest incidence was seen with teicoplanin (16.4 per 100 000 exposures) then co-amoxiclav (8.7 per 100 000 exposures), our incident seems higher and involves different antibiotics [10].
In a US population-based study utilizing EHRs of patients with active healthcare plans over a period of 9 years, out of 7,449,076 patients assessed; they found only 1 of 1543 (0.065%) oral and 1 of 1030 (0.097%) parenteral confirmed penicillin-associated anaphylaxis [15]. Although different in design, compared to our study this incidence seems much less than that reported in our study.
Epidemiological data from different countries have reported a drug anaphylaxis fatality rate of between 0.05–0.51 per million/year, with antimicrobials being the leading causal drug [16]. In our study period, there was one drug anaphylaxis related mortality; this is in line with reports from other countries where fatalities in hospitalized anaphylaxis cases are very uncommon [17, 18, 19].
Low mortality rates could be explained by the easily identifiable anaphylaxis symptoms, which are rapid in onset and classic. In addition to the availability of anaphylactic kits in almost all areas within the hospital and familiarity of staff in managing anaphylaxis events.
Interestingly the majority of antimicrobial anaphylaxis documented in the EHRs which were excluded from our study, were patient self-reported. This may have implications on antimicrobial choices and infection outcomes; as the accuracy of patient-reported antimicrobial allergy history has been brought to question [20]. This finding raises the need for better tools to identify, document, and classify patient’s allergies, in order to facilitate the decision process should the patient have a forthcoming need for an antimicrobial. De-labeling patients that may not be truly allergic to antimicrobials has been of interest lately, with successful experiences reported [21, 22].
Our study is the first in the region to explore the epidemiology and outcomes of antimicrobial anaphylaxis. A key finding was that unlike other studies where penicillins/aminopenicillins have been reported to be the most frequently implicated antimicrobial class in antimicrobial anaphylaxis; in our setting cephalosporins were the top implicated antimicrobials, driven mainly by anaphylaxis associated with ceftriaxone.
The International Collaborative Study of Severe Anaphylaxis reports an incidence of parenteral cephalosporin-associated anaphylaxis of 5.7 cases per 100 000 exposures [23]. While the real‐world frequency of anaphylaxis from 12 California hospitals reports a lower incidence of 0.6 cases per 100 000 exposures with oral cephalosporins and 1.6 per 100 000 exposures with parenteral cephalosporin [24].
The rate of ceftriaxone-induced anaphylaxis was higher in our study 48.9 (95% CI: 19.0 − 125.6) cases per 100000 exposures. Such high incidence has been reported in a Korean study of 76 cephalosporin-induced anaphylaxis where the highest incidence was reported with ceftriaxone (9.2 per 100 000 exposures) [25], this difference in incidence may suggest a genetic predisposition to this reaction to ceftriaxone in these two populations.
Ceftriaxone is a third-generation parenteral cephalosporin and an essential antibiotic that is listed as a first-line agent for multiple susceptible organisms including N. gonorrhea, N. meningitides, and H.influenzae [26]. It is generally considered well tolerated with no dose adjustments required in patients with renal or hepatic impairment. Therefore, besides the high incidence of ceftriaxone anaphylaxis and implications of managing an episode, poor infection-related outcomes should be expected in cases where ceftriaxone were to be replaced by a second line agent.
In our study in 26.2% of the cases, the patient’s antimicrobial was discontinued after the anaphylaxis event with no further orders for any other antimicrobial; out of which, the majority were initiated empirically, and none were associated with mortality. Although assessing antimicrobial appropriateness was out of the scope of this study, it is startling to say that in almost a quarter of the cases antimicrobials may have been prescribed unnecessarily.
A switch to a more toxic antimicrobial, and/or a broader spectrum antimicrobial were predictors of prolonged hospitalization in our study. As a severe allergic reaction drives prescribers away from their first empiric choice this outcome is foreseen and expected. Prolonged hospitalization has both morbidity and economic consequences and was significantly high in the population studied here > 50%. However, interpretation should be made cautiously since we did not control confounders such as disease severity due to the small sample size.
In the five infection-related mortality cases, one patient’s culture grew carbapenem-resistant Klebsiella pneumoniae with the OXA48 gene detected while the other four patient’s cultures did not grow any resistant organisms. Possibly indicating that mortality was driven by adverse drug toxicity rather than a drug-bug mismatch.
In none of the cases was desensitization attempted, although desensitization is an effective approach to patients with a clear IgE type reaction. There are multiple published desensitization protocols [27, 28, 29], prescribers may need to more frequently weigh the benefit of a desensitization approach vs switching to a less favorable antimicrobial.