Clostridium difficile Infection Caused by the Epidemic BI/NAP1/027 Strain  Jennifer R. O'Connor, Stuart Johnson, Dale N. Gerding  Gastroenterology  Volume 136, Issue 6, Pages 1913-1924 (May 2009) DOI: 10.1053/j.gastro.2009.02.073 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 Extent of BI/NAP1/027 distribution. (A) States in the United States that have had ≥1 hospital that has reported CDI caused by the BI/NAP1/027 epidemic strain as of October 2008 (red).116 (B) Percentage of C difficile isolates in Canadian provinces (no data are available for territories) with the BI/NAP1/027 strain in the 2005 Canadian Nosocomial Infection Surveillance Program (CNISP) survey.97 (C) Hospitals in Europe reporting outbreaks (stars) and sporadic cases (circles) of CDI caused by the BI/NAP1/027 strain.89 Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 Frequency and mortality of CDI. (A) National estimates of US short-stay hospital discharges with C difficile infection as any listed diagnosis or the primary hospitalization diagnosis, based on the national inpatient sample117and unpublished data, 2008). (B) C difficile–related mortality based on listings on US death certificates from 1999 to 2004, with age-adjusted mortality rates per million people for the same years (shown in box).118 Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions

Figure 3 Model of regulation of toxin gene expression in C difficile. (A) Logarithmic growth phase. In logarithmic growth phase a single transcript encompassing tcdR, tcdB, and tcdA is expressed at a low level, most likely from a TcdR-independent promoter.25 In the presence of GTP and BCAAs, CodY binds to the TcdR-dependent tcdR promoter, PtcdR,21 which represses high-level expression of TcdR (required for high-level toxin expression22); thus, the toxin genes, tcdA and tcdB, are not optimally expressed. At this time the negative regulator gene, tcdC, is also maximally expressed.25 TcdC is a membrane-associated protein30 that most likely sequesters any small amount of TcdR that is expressed from the longer transcript,24 which further prevents expression of the toxin genes. (B) Stationary growth phase. Under nutrient limiting conditions or stress, such as in stationary phase, the toxin genes are highly expressed. In the absence of GTP and BCAA, CodY is unable to bind the TcdR-dependent tcdR promoter21; thus, it cannot repress tcdR expression. In addition, tcdC expression is minimal.25 TcdR is expressed and is free to interact with the RNA polymerase holoenzyme (RNAP).22,25 This complex can then bind to the tcdR promoter as well as to PtcdB and PtcdA to facilitate maximal expression of the tcdR, tcdA, and tcdB genes, resulting in production of toxins A and B.22 TcdE, a holin-like protein, is thought to facilitate release of toxins A and B from the C difficile cell.20 Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions

Jennifer R. O'Connor Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions

Stuart Johnson Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions

Dale N. Gerding Gastroenterology 2009 136, 1913-1924DOI: (10.1053/j.gastro.2009.02.073) Copyright © 2009 AGA Institute Terms and Conditions