VULNERABLE PATIENT GROUPSSLIDE RESOURCE SET

FDX/13/0068/EUd | August 2013

Risk factors for a recurrence of Clostridium difficile infection (CDI)

• Immunocompromised state1

• Exposure to other antibacterial agents that disrupt the normal colonic microflora2–5

• Renal impairment6,7

• Aged 65 years or over2,4,8

• Impaired immune response to C. difficile toxin A2

• Severe underlying disease2

• Prolonged hospitalisation8

• Intensive care unit (ICU) stay5

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.

<40 41–50 51–60 61–70 71–80 81–90 >900

10

20

30

40

50

60

70

80CDI rate per 1,000 ad-missions

Attributable 30-day mortal-ity rate

Age (years)

Ra

te (

%)

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 blood3

• Vancomycin-resistant enterococci (VRE) colonisation2

• Renal impairment2

• Acute graft versus host disease (GvHD)1–3

• Immune suppression (pre-engraftment phase)4,5

• Diabetes mellitus5

• Prolonged and repeated hospital stays1,4

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.

Author Transplant type N Episodes of diarrhoeaa CDI/episode of diarrhoea

Mossad SB, et al. 1996. Auto-HSCT 219 76 (34.7%)b 1 (1.3%)

Yuen KY, et al. 1998. NS 120 141c 15 (10.6%)

Avery R, et al. 2000. Auto-HSCT 80 61 (76.3%) 3 (4.9%)

Bilgrami S, et al. 1999. Auto-HSCT 200 NS 15 (7.5%)

Barton T, et al. 2001. Auto-HSCT 127 NS 14 (11.0%)

Gorschlueter M, et al. 2001.

NS 371 NS 61 (6.9%)

Tomblyn M, et al. 2002. Both 119 109 (91%) 7 (6.4%)

Jillella AP, et al. 2003. Auto-HSCT 54 15 (27.8%)c 1 (6.7%)

Arango JI, et al. 2006. Auto-HSCT 242 157 (64.8%) 21 (15.5%)

Cox GJ, et al. 1994. Both 296 150 (50.7%) 6 (4.0%)

van Kraaij MG, et al. 2000. Both 60 48 (80%) 2 (4.2%)

Chakrabarti S, et al. 2000. Allo-HSCT 75 49 (65.3%) 10 (20.4%)aEpisodes of diarrhoea per number of patients in the study population;

bTotal number of infectious complications; cEvery 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 2008

1-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 2008

0

4

8

12

16

20

CD

I inc

iden

ce (

%)

2003 2004 2005 2006 2007 2008Year

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)

0 7 14 21 28 35 42 49 56 63 70 77 84024

68

1012

Day of transplant

Num

ber

of

case

s

−30 0 30 60 90 120 150 180 210 240 270 300 330 360

Autologous(n=30)

Allogeneic(n=62)G

raft

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=0.0001)

0.28

0.24

0.20

0.16

0.12

0.08

0.04

0.000 25 50 75 100 125 150 175 200 225 250 275 300 325 350 375

Time from stem cell transplant (days)

Cum

ulat

ive

prob

abili

ty o

f acu

te

GI G

vHD

(gr

ade

2 or

hig

her)

CDINo 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)

Cum

ulat

ive

surv

ival

Time (months)

0 10 20 30 40 50 600.0

0.2

0.4

0.6

0.8

1.0

1.2

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

60

40

20

10

0

CD

I cas

es p

er

1,00

0 ad

mis

sion

s

30

1998

50

1999 2000 2001 2002 2003 2004Year

Ulcerative colitis Non-IBD GI patients

Crohn’s disease All hospital patients

FDX/12/0076/EUd | DN126GI, 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)

Non-transplantpatients

Liver transplantrecipients

Liver and kidney transplant recipients

0

1

2

3

4

0.9%

2.7%2.3%

Pre

vale

nce

(%

)

p<0.001

Data from a US nationwide survey involving193,174 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.

SOT SOT + CDI Comparison: SOT vs SOT + CDI*

Cases (unweighted) 47,905 1,293

Mortality 2.4% 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 complication 33.9% 38.1% p<0.001

Colectomy 0.3% 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 CDI Odds ratio 95% confidence intervals p-value

Prior VRE colonisation 3.6 1.1–11.3 0.03

Administration of high-risk antibiotics 6.6 2.1–21.0 0.001

CDC high-risk donor 5.9 1.7–20.8 0.006

Major predictors for CDI: results of multivariate analysis

CDC, Centers for Disease Control and Prevention;KTR, kidney transplant recipient;

VRE, vancomycin-resistant enterococciFDX/13/0034/EU | ACE14

Lung transplant patients and CDI

• CDI incidence rate was 224.6 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.

Lung transplant patients Non-lung transplant patients0

50

100

150

200

250

Inci

de

nce

pe

r 1

00

,00

0 p

atie

nt

da

ys

p<0.0001

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 m2) or stage 2 (60–89 mL/min/1.73 m2), stage 3 (30–59 mL/min/1.73 m2) or stage 4 (<30 mL/min/1.73 m2) chronic kidney disease

Clinical cure Recurrence Sustainedclinical cure

0

20

40

60

80

10088.6

20.0

70.979.2

21.4

62.3

Patients without cancer

All patientswith cancer

Impact of cancer on response to treatment

Cornely OA, et al. J Clin Oncol 2013;31:2493–9.

p=0.693p<0.001

Rat

e (%

)

p=0.020

EPG11Post hoc analysis of pooled data

All patients0

20

40

60

80

100

120

55 hoursn=922

100 hoursn=183

No cancer

Cancer

Me

dia

n t

ime

to

re

solu

tion

of

dia

rrh

oe

a (

ho

urs

)

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