Toxigenic diphtheria rarely detected amid rising cases of nontoxigenic <i>Corynebacterium diphtheriae</i> infections in Ontario, Canada, 2011–2023

Diphtheria remains a major public health threat in areas of the world where diphtheria toxoid-containing vaccine programs are not successfully implemented or maintained. In countries with high vaccine coverage, diphtheria is well-controlled with occasional travel-related cases eliciting a robust public health response to limit transmission. While classic diphtheria is caused by toxigenic <i>Corynebacterium diphtheriae</i> and rarely by other species, such as <i>Corynebacterium ulcerans</i>, infections due to nontoxigenic <i>C. diphtheriae</i> (not covered by the vaccine) are increasingly being reported. We describe the genomic epidemiology of toxigenic and nontoxigenic <i>C. diphtheriae</i> in Ontario, Canada, based on isolates submitted to the Public Health Ontario Laboratory. Of 146 cases, four cases (2.7%) involved toxigenic <i>C. diphtheriae</i>, three of which were associated with travel from endemic countries. Most isolates were nontoxigenic (97.2%) and from cutaneous sources (84.9%), with an increase in submission of nontoxigenic <i>C. diphtheriae</i> isolates from one in 2016 to 65 in 2023. Based on whole-genome sequencing and BIGSdb-Pasteur core genome multi-locus strain typing, most nontoxigenic isolates were categorized into three highly related genetic clusters from sublineages 32 and 76, suggesting epidemiologically linked cases indicative of local transmission. Apart from intermediate susceptibility to penicillin in 98.0% of isolates, antimicrobial resistance was rarely detected. Because infections with nontoxigenic <i>C. diphtheriae</i> are not prevented by vaccination and do not cause classic diphtheria, healthcare professionals should be aware of these trends, given the clinical, public health, and infection control implications when <i>C. diphtheriae</i> is identified in the microbiology laboratory prior to knowledge of toxigenicity.IMPORTANCEInfections by toxigenic and nontoxigenic <i>Corynebacterium diphtheriae</i> cause vastly different diseases requiring different treatment and public health responses. Healthcare practitioners should be aware of the complexities of diphtheria from a global perspective. Toxigenic <i>C. diphtheriae</i> remains prevalent in regions that do not have well-established vaccination programs, while vaccine hesitancy and compliance issues challenge countries that do require childhood vaccination. These factors, coupled with the propensity for human travel and migration, heighten the risk of cases and outbreaks in non-endemic countries and designate diphtheria as a relevant re-emerging threat. Further complicating public health decisions is the increasing incidence of nontoxigenic <i>C. diphtheriae</i> infections identified among highly vaccinated populations. An excessive public health response in these cases would be burdensome and expensive. Our findings will aid public health departments and hospitals with local risk assessments of the likelihood that a laboratory identification of <i>C. diphtheriae</i> represents a case of toxigenic diphtheria by raising awareness of the disproportionately small number of toxigenic <i>C. diphtheriae</i> recovered from clinical specimens compared to the vast majority of nontoxigenic isolates. Genomic analysis suggests local transmission of nontoxigenic strains, while isolation of toxigenic <i>C. diphtheriae</i> from among a highly vaccinated population remains associated with travel to endemic regions.