Changing Epidemiology of Clostridium difficile and Emergence of New Virulent Strains

The epidemiology of Clostridium difficile infection (CDI) is constantly changing and is influenced by antibiotic usage patterns, healthcare patient environment, and emergence of new strains. Between 1982 and 1991, 4 outbreak periods were noted in 1 hospital in Minnesota, each marked by clusters of specific strains, designated by restriction endonuclease typing (REA) as groups B and K (both type 053 by polymerase chain reaction [PCR] ribotyping) [1]. In addition to these outbreaks, there was a background incidence of CDI due to a wide variety of C. difficile strains including 6 isolations of a REA group BI (ribotype 027) strain, a strain that would dramatically impact North America and Europe 2 decades later. In the 1990s, there were hospital CDI outbreaks in the United States due to a highly clindamycin-resistant strain (REA group J, ribotype 001) that was specifically associated with clindamycin use and which responded in several instances to restriction of that drug [2]. The strain with the most profound impact on CDI epidemiology, strain BI/027 (also designated NAP1 by pulsed-field gel electrophoresis typing), emerged in North America in 2000 and in Europe a few years later [3–5]. Whole-genome sequencing and phylogenetic analysis has shown that BI/027 strains compose 2 distinct lineages that emerged in North America in the early to mid-1990s shortly after acquisition of a fluoroquinolone resistance–conferring mutation and a related conjugative transposon [6]. Hospital and institutional outbreaks due to fluoroquinolone-resistant BI/027 strains were notable for unprecedented incidence and severity of the associated CDI cases. In this issue of Clinical Infectious Diseases, Lim et al have documented a new outbreak strain in a multihospital setting in Melbourne, Australia, that, although not associated with a large number of cases, was associated with increased severity and higher mortality among those infected compared with other circulating strains in these hospitals [7]. This strain was initially thought to be the BI/027 strain based on results of the Xpert C. difficile PCR assay (Cepheid, Sunnyvale, California) used as a diagnostic test on submitted stool specimens by the clinical laboratory. The Xpert C. difficile assay identifies presumptive 027 strains based on detection of the genes for toxin B (tcdB), binary toxin CDT (cdt), and a single base-pair (bp) deletion at position 117 in the gene coding for the anti-sigma factor TcdC (tcdC) [8]. When these stool specimens were cultured, and the recovered C. difficile isolates subjected to formal ribotype analysis, they turned out to be ribotype 244, not 027. Wholegenome sequencing analysis of strain 244 showed >10 000 single-nucleotide polymorphisms between this strain and a 027 strain, but placed 244 in the same clade as 027 and in agreement with results obtained earlier by microarray analysis [9]. Although the Xpert C. difficile PCR assay incorrectly identified this strain, it did identify a related strain and was associated with severe disease. All 3 of the targets for the Xpert assay are postulated to be virulence factors for the BI/027 strain, although none is conclusively demonstrated to be the factor responsible for the increased virulence associated with this strain. The single bp deletion at position 117 in tcdC results in a nonsense mutation and a premature stop codon and ultimately a truncated, nonfunctional TcdC protein. TcdC is a negative regulator of toxin A and toxin B production, and the lack of a functional TcdC in the BI/027 strains was postulated to be responsible for the increased production Received 28 February 2014; accepted 12 March 2014; electronically published 4 April 2014. Correspondence: Stuart Johnson, MD, FIDSA, Research Service, Hines VA Hospital, 5000 S Fifth Ave, Bldg 1, Room C344, Hines, IL 60141 ([email protected]). Clinical Infectious Diseases 2014;58(12):1731–3 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciu205