Fatal respiratory diphtheria caused by Beta-lactam-resistant toxigenic Corynebacterium diphtheriae. Corynebacterium diphtheriae strain:BQ11

Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Diphtheria is rare in developed countries but remains endemic in parts of Asia, the South Pacific, the Middle East, Eastern Europe and the Caribbean. Although resistance to erythromycin has been recognised, Penicillin and beta -lactam resistance in toxigenic diphtheria has not yet been described. Here we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and other beta-lactam antibiotics. Toxigenic C. diphtheriae strain BQ11 was isolated from an unvaccinated adult female in April 2011 in Australia. Using long-read whole genome sequencing we assembled the genome sequence of C. dipththeriae BQ11 to determine the genetic mechanisms of resistance. We found a 6,682 bp beta-lactam resistance gene cassette that is not found in the genomes of beta-lactam susceptible C. diphtheriae. Surprisingly, this element has been mobilised into the genome of BQ11 as a novel transposon. Remarkably, we found that transposon copy number was highly dynamic. When cultured with exposure to meropenem, selective pressure drives a rapid increase in transposon copy number and a corresponding change from a carbapenem susceptible to a carbapenem resistant phenotype. This case of fatal respiratory toxigenic diphtheria caused by beta-lactam resistant C. diphtheriae highlights the ongoing threat posed by the potential introduction of diphtheria from endemic regions to non-immune or partially immune individuals and demonstrates threat of emergent antimicrobial resistance within this species.

白喉是一种由产毒白喉棒杆菌（Corynebacterium diphtheriae）引起的潜在致死性呼吸道传染病。白喉在发达国家已极为罕见，但在亚洲部分区域、南太平洋、中东、东欧及加勒比地区仍呈地方性流行态势。尽管已报道过白喉杆菌对红霉素的耐药性，但产毒白喉棒杆菌对青霉素及β-内酰胺类（beta-lactam）抗生素的耐药性此前尚未见诸报道。本文报告1例由产毒白喉棒杆菌引发的致死性呼吸道白喉病例，该分离菌株对青霉素及其他β-内酰胺类抗生素均表现出耐药性。产毒白喉棒杆菌菌株BQ11于2011年4月在澳大利亚从一名未接种白喉疫苗的成年女性体内分离获得。本研究采用长读长全基因组测序（long-read whole genome sequencing）技术组装了该菌株的基因组序列，以解析其耐药性的遗传机制。研究发现一段长度为6682 bp的β-内酰胺类耐药基因盒，该序列在对β-内酰胺类敏感的白喉棒杆菌基因组中从未被检出。令人意外的是，该元件以一种新型转座子（transposon）的形式被整合进入BQ11的基因组。值得注意的是，该转座子的拷贝数具有高度动态性。当菌株在美罗培南（meropenem）暴露的培养条件下生长时，抗生素选择压力会驱动转座子拷贝数快速增加，同时使菌株从碳青霉烯类（carbapenem）敏感表型转变为耐药表型。这例由β-内酰胺类耐药产毒白喉棒杆菌引发的致死性呼吸道白喉病例，既凸显了白喉从地方性流行区域传入非免疫或部分免疫人群所带来的持续威胁，也揭示了该菌种中新发抗菌药物耐药性的潜在风险。