VULNERABLE PATIENT GROUPS SLIDE RESOURCE SET FDX/13/0068/EUd | August 2013

Risk factors for a recurrence of Clostridium difficile infection (CDI) Immunocompromised state 1 Exposure to other antibacterial agents that disrupt the normal colonic microflora 2–5 Renal impairment 6,7 Aged 65 years or over 2,4,8 Impaired immune response to C. difficile toxin A 2 Severe underlying disease 2 Prolonged hospitalisation 8 Intensive care unit (ICU) stay 5 1.Cohen MB. J Pediatr Gastroenterol Nutr 2009;48(Suppl 2):S63–5; 2.Kyne L, et al. Lancet 2001;357:189–93; 3.Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; 4.Bauer MP, et al. Lancet 2011;377:63–73; 5.Hu MY, et al. Gastroenterology 2009;136:1206–14; 6.Do AN, et al. Clin Infect Dis 1998;26:954–9; 7.Bauer MP, et al. Clin Microbiol Infect 2011;17(Suppl 4):A1–4; 8.Pépin J, et al. Clin Infect Dis 2005;40:1591–7. FDX/12/0076/EUr | SJ204

Age-specific incidence of CDI and attributable mortality Loo VG, et al. N Engl J Med 2005;353:442–9. FDX/12/0076/EUb | SJ113

Risk factors among hematopoietic stem cell transplant (HSCT) recipients for CDI Multiple antibiotic courses (cephalosporins, quinolones) 1,2 Altered integrity of intestinal mucosa (chemotherapy/ total body irradiation) 1–3 Source of stem cells: cord blood 3 Vancomycin-resistant enterococci (VRE) colonisation 2 Renal impairment 2 Acute graft versus host disease (GvHD) 1–3 Immune suppression (pre-engraftment phase) 4,5 Diabetes mellitus 5 Prolonged and repeated hospital stays 1,4 1.Bobak D, et al. Bone Marrow Transplant 2008;42:705–13; 2.Alonso CD, et al. Clin Infect Dis 2012;54:1053–63; 3.Willems L, et al. Biol Blood Marrow Transplant 2012;18:1295–301; 4.Anathakrishnan AN. Nat Rev Gastroenterol Hepatol 2011;8:17–26; 5.Dubberke ER, et al. Clin Transplant 2010;24:192–8. AI/12/0055/EUg | DM110

Incidence of CDI in HSCT recipients Bobak D, et al. Bone Marrow Transplant 2008;42:705–13. AuthorTransplant typeNEpisodes of diarrhoea a CDI/episode of diarrhoea Mossad SB, et al Auto-HSCT21976 (34.7%) b 1 (1.3%) Yuen KY, et al NS c 15 (10.6%) Avery R, et al Auto-HSCT8061 (76.3%)3 (4.9%) Bilgrami S, et al Auto-HSCT200NS15 (7.5%) Barton T, et al Auto-HSCT127NS14 (11.0%) Gorschlueter M, et al NS371NS61 (6.9%) Tomblyn M, et al Both (91%)7 (6.4%) Jillella AP, et al Auto-HSCT5415 (27.8%) c 1 (6.7%) Arango JI, et al Auto-HSCT (64.8%)21 (15.5%) Cox GJ, et al Both (50.7%)6 (4.0%) van Kraaij MG, et al Both6048 (80%)2 (4.2%) Chakrabarti S, et al Allo-HSCT7549 (65.3%)10 (20.4%) a Episodes of diarrhoea per number of patients in the study population; b Total number of infectious complications; c Every patient had at least one episode of diarrhoea; HSCT, haematopoietic stem cell transplantation; NG, not given FDX/12/0076/EUo | CS201

Epidemiology and outcomes of CDI in HSCT recipients: USA, 2003 to year incidence of CDI by transplant type Alonso CD, et al. Clin Infect Dis 2012;54:1053–63. Overall CDI incidence did not vary significantly from 2003 to CDI incidence (%) Year Autologous (N=489) [overall incidence, 6.5%] Allogeneic (N=510) [overall incidence, 12.5%] All transplants (N=999) [overall incidence, 9.2%] AI/12/0055/EUg | DM112

Timing of CDI by HSCT type Alonso CD, et al. Clin Infect Dis 2012;54:1053–63. Median time of onset −7 Time to CDI (days) Day of transplant Number of cases − Autologous (n=30) Allogeneic (n=62) Graft type 6.5 days 33 days AI/12/0055/EUg | DM113

Acute GvHD among allogeneic HSCT recipients with and without CDI Alonso CD, et al. Clin Infect Dis 2012;54:1053–63. The 1-year probability of developing grade 2 or higher gastrointestinal GvHD was 25% in case patients and 4.6% in control patients (log-rank test; p= ) Time from stem cell transplant (days) Cumulative probability of acute GI GvHD (grade 2 or higher) CDI No CDI GI, gastrointestinal; GvHD, graft versus host disease FDX/12/0076/EUo | CS221

Kaplan–Meier graph of overall survival following allogeneic HSCT depending on the presence or absence of CDI Survival among allogeneic HSCT recipients with and without CDI Chakrabarti S, et al. Bone Marrow Transplant 2000;26:871–6. Median survival was 100 days in patients with CDI vs 41 months in patients without CDI (p=0.01) Cumulative survival Time (months) CDI (n=10) No CDI (n=65) AI/12/0055/EUg | DM115

Rates of CDI in patients with inflammatory bowel disease (IBD) Nguyen GC, et al. Am J Gastroenterol 2008;103:1443–50. Rates of CDI among hospitalised patients with IBD Patients with IBD, particularly those with ulcerative colitis, exhibited greater increases in rates of CDI vs other hospitalised subpopulations CDI cases per 1,000 admissions Year Ulcerative colitisNon-IBD GI patients Crohn’s diseaseAll hospital patients FDX/12/0076/EUd | DN126 GI, gastrointestinal

Liver transplant patients and CDI Adapted from Ali M, et al. Liver Transpl 2012;18:972–8. CDI was associated with higher mortality among liver transplant recipients vs non-transplant patients (5.5% vs 3.2%, p<0.001) p<0.001 Data from a US nationwide survey involving 193,174 hospital discharges from 2004 to 2008 FDX/13/0034/EU | ACE12

Solid organ transplant (SOT) patients and CDI Pant C, et al. Transpl Infect Dis 2012;14:540–7. SOTSOT + CDI Comparison: SOT vs SOT + CDI* Cases (unweighted)47,9051,293 Mortality2.4%7.4%p<0.001 Median length of stay, days (IQR) 4 (6)9 (15)p<0.001 Median costs (IQR)$31,488 (62,242)$53,808 (134,072)p<0.001 Organ complication33.9%38.1%p<0.001 Colectomy0.3%1.1%p<0.001 Outcomes of patients with SOT and CDI FDX/13/0034/EU | ACE13 *The data were evaluated using univariate regression analyses; IQR, interquartile range

Kidney transplant patients and CDI The overall rate of CDI among all KTRs was 6.1% (37 of 603) The rate of CDI among KTRs increased from 3.7% (6/161) in 2008 to 9.4% (19/201) in 2010 (p<0.05) Neofytos D, et al. Transpl Infect Dis 2013;15:134–41. Risk factors for CDIOdds ratio 95% confidence intervals p-value Prior VRE colonisation3.61.1– Administration of high-risk antibiotics – CDC high-risk donor5.91.7– Major predictors for CDI: results of multivariate analysis CDC, Centers for Disease Control and Prevention; KTR, kidney transplant recipient; VRE, vancomycin-resistant enterococci FDX/13/0034/EU | ACE14

Lung transplant patients and CDI CDI incidence rate was cases/100,000 patient-days for lung transplant patients (n=159) compared with 110 cases/100,000 patient-days (average rate for the entire hospital) Lee JT, et al. Clin Transplant 2013;27:303–10. p< FDX/13/0034/EU | ACE17

Clinical cure in patients with renal impairment Of 1,054 patients treated with fidaxomicin or vancomycin, 57.9% had abnormal renal function at baseline –27.4% had stage 2 chronic kidney disease (CKD) –21.3% had stage 3 CKD –9.1% had stage 4 or higher CKD Clinical cure rates (irrespective of treatment) were unaffected by mild renal impairment –91% in patients with normal renal function –92% in patients with stage 2 CKD –80% in patients with stage 3 CKD –75% in patients with stage 4 or higher CKD Cure rates were similar for fidaxomicin and vancomycin at each CKD level Mullane KM, et al. Am J Nephrol 2013;38:1–11. EPG10 Post hoc analysis; data from pooled analysis; Calculated creatinine clearance used to categorise patients as exhibiting no renal impairment (>90 mL/min/1.73 m 2 ) or stage 2 (60–89 mL/min/1.73 m 2 ), stage 3 (30–59 mL/min/1.73 m 2 ) or stage 4 (<30 mL/min/1.73 m 2 ) chronic kidney disease

Impact of cancer on response to treatment Cornely OA, et al. J Clin Oncol 2013;31:2493–9. p=0.693p<0.001 Rate (%) p=0.020 EPG11 Post hoc analysis of pooled data

Time to resolution of diarrhoea: patients with and without cancer Cornely OA, et al. J Clin Oncol 2013;31:2493–9. Post hoc analysis of pooled data p<0.001 EPG12