Fatal Respiratory Diphtheria Caused by ß-Lactam–Resistant Corynebacterium diphtheriae

Abstract

Background Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognised, β-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other β-lactam antibiotics and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element. Methods Long-read whole genome sequencing was performed using Pacific Biosciences SMRT sequencing to determine the genome sequence of C. diphtheriae BQ11 and mechanism of β-lactam resistance. To investigate phenotypic inducibility of meropenem resistance, short read sequencing was performed using an Illumina NextSeq500 sequencer on the strain with and without exposure to meropenem. Results BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin MIC ≥ 256 μg/ml), β-lactam/β-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 μg/mL; ceftriaxone MIC ≥ 8 μg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin binding protein Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low level to high level meropenem resistant phenotype. Conclusions We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for treatment of C. diphtheriae infection and may lead to clinical failure.

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

“…PBP2m is a putative low-affinity PBP, which would explain why it is less affected by beta-lactam antibiotics. Very recently, Forde et al [80] have reported high-level penicillin resistance (MIC > 256 g/L) in C. diphtheriae strain BQ11 and have attributed this phenotype to a penicillin-binding protein located on transposon Tn3503. We found that the pbp2m-containing unit is 99.92% similar to Tn3503, which additionally harbors a helicase (Additional file 4: Fig.…”

“…S14). Besides, PBP2m is 100% identical to the PBP from BQ11 and therefore also possesses the V361A alteration (using C. jeikeium as reference) that was hypothesized to confer high-level penicillin resistance [80]. Further studies on the expression of pbp2m in its variable genetic backgrounds are required to understand the observed difference in penicillin resistance levels.…”

Interactions between the Re-Emerging Pathogen Corynebacterium diphtheriae and Host Cells

“…It can be expected that the global SARS-CoV-2 pandemic, which overwhelmed public health systems in many countries, will result in a further increase of diphtheria due to neglected vaccination programs, and also recent military conflicts such as in Yemen, Ethiopia, or Ukraine may interfere with vaccination. Furthermore, antibiotic-resistant strains of C. diphtheriae are increasingly observed [ 28 , 29 ]. Consequently, not only surveillance of cases, but also continuing research focusing on the re-emerging pathogen is crucial.…”

Endemic erythromycin resistant Corynebacterium diphtheriae in Vietnam in the 1990s

“…Penicillin and erythromycin have long been the primary treatments for diphtheria, but recent reports describe an increase in resistance against these antimicrobials, potentially posing a problem for diphtheria treatment [17–20]. Several studies have descibed resistance mechanisms against antimicrobials used for the treatment of diphtheria [21–23]. Specifically, erythromycin resistance in C.…”

“…Several studies have descibed resistance mechanisms against antimicrobials used for the treatment of diphtheria [21][22][23]. Specifically, erythromycin resistance in C. diphtheriae is commonly encoded by the plasmid mediated erm(X) gene [24].…”