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Clostridioides difficile Management in the High Risk

Patient

Gianni Scappaticci, PharmD, BCOP

Clinical Specialist, BMT and Cellular Immunotherapies

University of Michigan Health System

Ann Arbor, MI

Disclosures

• The speaker has nothing to disclose regarding the content of this presentation

• Kathy Edwards, PharmD, BCPS, BCOP (mentor) has served as a consultant for Genzyme Corporation

• This presentation actively discusses off label use of oral vancomycin and fidaxomicin

2

Objectives

• Describe the microbiology, epidemiology, risk factors, and economic burden of Clostridioides difficile infections (CDI)

• Summarize management of CDI in high risk patients

3

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Clostridioides difficile (CDI)

• Anaerobic, gram-positive, spore forming bacillus

• Infection—Asymptomatic colonization

—Toxic megacolon, bowel perforation, sepsis, shock and death

• Toxins—TcdA/B and CDT

Rupnik M, et al. Nature 2009;7(7):526-536.

Cohen SH, et al. Infect Control Hosp Epidemiol 2010;31(5):431-455

4

Clostridioides difficile (CDI) Burden

• Leading cause of nosocomial diarrhea and infection—250K new infections annually (US only)

• Occurs in ~33% of all allogeneic hematopoietic cell transplantations (HCT)

—CDI > methicillin-resistant Staphylococcus aureus (MRSA)

• Increased length of stay (LOS) —2.8-5.5 days

• Increased cost —~$5 billion/year

• Mortality—14-20,000 people/year

• Identified as an independent risk factor for increased mortality in HCT patients

5

Ng, SC, et al. Gastroenterol. 2013;145(e2):158-165 Dubberke ER, et al. Infect Control Hosp Epidemiol. 2014;35(6):628-645.

Banaei N, et al. N Engl J Med. 2015;372(24):2368-2369. Gu SL, et al. J Med Microbiol. 2015;64(Pt 3):209-216.

Schuster MG, et al. Open Forum Infect Dis. 2017;4:1-7 Dubberke ER, et al. Transpl Infect Dis. 2018;20:e12855

CDI Changing Epidemiology

• 2002-2006—Increased outbreaks of CDI

—Unusually severe

—Mortality increased from 2% to 7%

• NAP1/B1/027 Strain—NAP: gel electrophoresis pattern

—B1: Restriction endonuclease analysis pattern

—027: PCR ribotype designation

6

Cohen SH, et al. Infect Control Hosp Epidemiol 2010;31(5):431-455

Freeman J, et al. Clin Microbiol Rev. 2010;23(3): 529-549

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CDI Changing Epidemiology

7Warny M, et al. Lancet 2005; 366:1079-84

500

250

NAP1/B1/027Control

0

1250

1000

750

Toxi

n A

Co

nce

ntr

atio

n (

µg

/L)

24 48 72

Time (h)

250

Toxi

n B

Co

nce

ntr

atio

n (

µg

/L)

Time (h)

NAP1/B1/027Control

200

150

100

50

0

0 24 48 72

NAP1/B1/027

PaLoc

tcdD tcdB tcdE tcdA tcdC

Cohen SH, et al. Infect Control Hosp Epidemiol 2010;31(5):431-455Freeman J, et al. Clin Microbiology 2010;23(3): 529-549

McDonald LC, et al. NEJM 2005; 353(23): 2433-2441

CDI Changing Epidemiology

Rupnik M, et al. Nature 2009;7(7):526-536

Pathogenesis

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Mulherin DW, et al. Infection. 2014;42(6):999-1005.

Dubberke ER, et al. Infect Control Hosp Epidemiol. 2014;35(6):628-645

CDIAge

Hospitalization Antibiotics

PPI/H2RA

Traditional Risk Factors

PPI: Proton Pump Inhibitor H2RA: Histamine 2 Receptor Antagonist

Modifiable Risk Factors for CDI (Antibiotics)

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FQs: Fluoroquinolones Clinda: Clindamycin Abx: Antibiotics

MLS: Macrolide-Lincosamide-Streptogramin

Author/YearCephalosporins

FQs Clinda Macrolides β-Lactam Comments

1 2 3

Loo et al, 2015 + + + +

Muto et al, 2005 + + +

Pepin et al, 2005 + ++ + + + PPIs no ↑

Hensgens et al, 2012 + + + + +7-10 fold ↑ in CDI 1 month

post exposure to Abx

Johnson et al, 1999 ++ ↑ MLS Resistance in CDI

Thibault et al, 1991 +Metronidazole also increased

risk of CDI

Loo VG, et al. N Engl J Med. 2015;353:2442-2449

Muto CA, et al. Infect Control Hosp Epidemiol. 2005; 26:273-280

Pepin J, et al. Clin Infect Dis. 2005; 41:1254-1260

Hensgens MP, et al. J Antimicrob Chemother 2012; 67:742-748

Johnson S, et al. N Engl J Med 1999; 341:1645-1651

Thibault A, et al. Infect Control Hosp Epidemiol. 1991;12:345-348

Modifiable Risk Factors for CDI (Acid Suppression)

12CI: Confidence Interval

Author/Year PPIs H2RA Comments

Dial et al, 2005 ++ +

Adjusted rate ratio of CDIPPI = 2.9 (95% CI 2.4 – 3.4)H2RA = 2 (95% CI 1.6 – 2.7)

Stevens et al, 2011 ++

Adjusted hazard ratio of CDIPPI = 4.5 (95% CI 2.3 – 9)

PPI + Abx = 15.7 (95% CI 6.4 – 38.8)

Howell et al, 2010 ++ +

Risk of CDI increased from 0.3% (95% CI .21 – 0.31%)H2RA = 0.6% (95% CI 0.49 – 0.79%)

PPI = 0.9% (95% CI 0.8 – 0.98%)

PPI 2x/day = 1.4% (95% CI (1.15 – 1.71%)

Dial et al, 2004 ++Adjusted odds ratio

PPI = 2.1 (95% CI 1.2 – 3.5)

Dial S, et al. JAMA. 2005;294:2989-2995

Stevens V, et al. Pharmacoepidemiol Drug Saf. 2011;20:1035-1042

Howell MD, et al. Arch Intern Med. 2010;170:784-790

Dial S, et al. CMAJ. 2004; 171:33-38

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Audience Response Question #1

Which of the following agents is no longer recommended for the treatment of CDI in adult patients by the IDSA and SHEA?

A) Metronidazole

B) Vancomycin

C) Fidaxomicin

D) Tolevamer

IDSA: Infectious Diseases Society of America

SHEA: Society for Healthcare Epidemiology of America13

Metronidazole Under Fire

14Musher DM, et al. Clin Infect Dis. 2005; 40:1586-1590

Metronidazole Under Fire

15Pepin J, et al. Clin Infect Dis. 2005; 40:1591-1597

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Vancomycin (VAN) vs. Metronidazole (MTZ)

16Zar FA, et al., Clin Infect Dis. 2007 45:302-307

Study Design:

Prospective, Randomized, double blindPrimary Outcomes:

Cure, treatment failure, and relapse

Vancomycin 125

mg Q6H x 10 days N = 266

Metronidazole 250

mg Q6H x 10 days N = 289

Mild

N = 40

Mild

N = 41

Severe

N = 38

Severe

N = 31

Severity

Number Cured/Number Treated (%)

P ValueMTZ VAN Total

Mild 37/41 (90) 39/40 (98) 76/81 (94) 0.36

Severe 29/38 (76) 30/31 (97) 59/69 (86) 0.02

All 66/79 (84) 69/71 (97) 135/150 (90) 0.01

Severity

Number Relapse/Number Cured (%)

P ValueMTZ VAN Total

Mild 3/37 (8) 2/39 (5) 5/76 (7) 0.67

Severe 6/29 (21) 3/30 (10) 9/59 (15) 0.30

All 9/66 (14) 5/69 (7) 14/135 (10) 0.27

Severity Scoring (2 points)

• Pseudomembranous colitis

• Admission to ICU

Severity Scoring (1 point)

• >60 years

• Temp >38.3°C

• Albumin <2.5 mg/dL

• WBC >15K cells/mm3

Severe CDI ≥ 2 Points

WBC: white blood cell ICU: intensive care unit

Vancomycin (VAN) vs. Metronidazole (MTZ)

17Johnson S, et al., Clin Infect Dis 2014;59:345-354

Study Design:

Prospective, multicenter, randomized, double blindPrimary Outcomes:

Clinical success (resolution of diarrhea)

N = 1118 pts

Tolevamer

N = 563

VAN 125 mg Q6H

x 10 days N = 266

MTZ 375 mg Q6H

x 10 days N = 289

Mild Moderate Severe

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

(%)

Overall

Success of Therapy for CDI

Metronidazole Vancomycin

Recurrence

72.7%

81.1%78.7%

82.7%

73.9%

82.2%

78.5%

66.3%

23.0%20.6%

P=0.02 P<0.001 P<0.001P<0.001

P<0.001

Vancomycin (VAN) vs. Metronidazole (MTZ)

SCr: serum creatinine IQR: Interquartile Range OR: Overall Response18

Siegfried J, et al., Infect Dis Clin Pract. 2016;24:210-216

Study Design:

Single center, retrospectivePrimary Outcomes:

Rate of treatment response to initial therapy

VAN 125 mg Q6H

X 14 daysN = 77

MTZ 250 mg Q6H

X 14 daysN = 91

Outcome MTZ VAN P Value

Response 82% 97% 0.002

Time to Resolution

(days)5 (3 – 9) 6 (4 – 11) 0.250

Recurrence 9% 13% 0.440

• WBC ≤15 cells/µL

• SCr <1.5x baseline

Mild-Mod CDI

(N=168)

• 16 patients switched to vancomycin (median 5

days, IQR 4-7 days)

• 14/16 = persistence of diarrhea

• 2/16 = progression to severe diarrhea

• Metronidazole independent predictor of treatment

failure [OR = 8.5; 95% CI = 1.8-40.8]

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Vancomycin vs. Metronidazole (Summary)

• Increasing amount of data illustrating concerns with efficacy of metronidazole for CDI in general

—Zar et al- vancomycin is superior for severe CDI

—Johnson et al- vancomycin is superior for initial treatment of CDI (mild, moderate, and severe), also decreased rCDI

—Siegfried et al- metronidazole may not be optimal for mild-moderate CDI

rCDI: recurrent CDI19

Zar FA, et al., Clin Infect Dis. 2007 45:302-307

Johnson S, et al., Clin Infect Dis 2014;59:345-354

Siegfried J, et al., Infect Dis Clin Pract. 2016;24:210-216

Definition of Severe CDI

20Bauer MP, et al., Clin Infect Dis. 2012;55(Suppl 2):S149-153

Study Design:

Review of 2 Randomized Controlled Trials (RCTs)Primary Outcomes:

Impact of fever, leukocytosis, and renal failure on CDI

• Fever ≥ 38.5°C

• WBC ≥ 15 cells/µL

• SCr ≥ 1.5 mg/dL

Database from 2

RCTs (N=1105)

Recurrence of CDI

(N = 194; 20%)

Failed Initial

Therapy (N = 143; 13%)

Treatment Failure

Risk Factor Incidence Risk Ratio

Fever 1.2% 2.45 (95% CI 1.07 – 5.61)

Leukocytosis 13.9% 2.29 (95% CI 1.63 – 3.21)

Renal Failure 14.5% 2.52 (95% CI 1.82 – 3.50)

Recurrence

Risk Factor Incidence Risk Ratio

Fever 0.8% 0.55 (95% CI 0.09 – 3.51)

Leukocytosis 10.4% 1.00 (95% CI 0.67 – 1.50)

Renal Failure 10.8% 1.45 (95% CI 1.05 – 2.02)

Definition of Severe CDI –ATLAS Criteria

Nc: Number cured Nt: Number Treated 21Miller MA, et al. BMC Infect Dis 2013;13:148

Study Design:

Review of 2 RCTsPrimary Outcomes:

Identify variables and test predictive cure rate

Parameter 0 Points 1 Point 2 Points

A Age <60 years 60-79 ≥80

T Systemic Abx No ---- Yes

L Leukocyte Count <16K 16-25K >25K

A Albumin >35 g/L 26-35 g/L ≤25 g/L

S SCr ≤120 µmol/L 121-179 µmol/L ≥180 µmol/L

ATLAS ScorePredicted cure rate

(%)(Nc/Nt)

Actual Cure Rate

(%)(Nc/Nt)

0 100 (161/161) 96.3 (155/161)

1 94.9 (160/169) 93.5 (158/169)

2 89.8 (144/160) 93.1 (149/160)

3 84.8 (146/172) 87.2 (150/172)

4 79.7 (99/124) 78.2 (97/124)

5 74.6 (68/91) 81.3 (74/91)

6 69.5 (40/58) 74.1 (43/59)

7 64.4 (10/16) 62.5 (10/16)

8 59.4 (7/11) 54.6 (6/11)

9 54.3 (3/5) 40 (2/5)

10 49.2 (N/A) NA

Overall 86.7 (838/967) 87.3 (844/967)

Predicted cure rate = 100 – [5.08 x (ATLAS score)]

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Audience Response Question #2

Which of the following agents have/has the highest clinical cure rates for patients with CDI?

A) Metronidazole

B) Vancomycin

C) Fidaxomicin

D) Tolevamer

E) B and C

22References

Vancomycin versus Fidaxomicin

Fidaxomicin versus Vancomycin

mITT: modified intention to treat

ITT: intention to treat24

Louie TJ, et al. N Engl J Med 2011; 364:422-431

Study Design:

Phase III, prospective, multicenter, double-blind, RCTPrimary Outcomes:

Rate of clinical cure in ITT and per-protocol population

Fidaxomicin - Background

• Macrolide antibiotic

• 8x more active than vancomycin

in vitro against C. difficile

• Low systemic absorption

• High fecal concentrations

• Less collateral damage

Inclusion Criteria

• ≥16 years old

• CDI+ w/ >3 loose BM/24 hours

Exclusion Criteria

• Toxic megacolon

• Ulcerative colitis or Crohn’s

disease

• CDI+ <3 months ago

Vancomycin 125 mg

Q6H X 10 daysN = 327

Fidaxomicin 200 mg

Q12H X 10 daysN = 302

Received ≥3 doses (w/failure)

or ≥8 doses (w/cure)

Per

Protocol

Randomized and received 1

dose of study drugmITT

≤3 unformed stools for 2

consecutive days

Clinical

Cure

Persistent diarrhea +/- the need

for additional therapy

Clinical

Failure

Resolution of diarrhea without

recurrence

Global

Cure

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Fidaxomicin versus Vancomycin

25Louie TJ, et al. N Engl J Med 2011; 364:422-431

Study Design:

Phase III, prospective, multicenter, double-blind, RCTPrimary Outcomes:

Rate of clinical cure in ITT and per-protocol population

Vancomycin 125 mg

Q6H X 10 daysN = 327

Fidaxomicin 200 mg

Q12H X 10 daysN = 302

N = 287mITT

N = 283Per

Protocol

N = 309mITT

N = 283Per

Protocol

mITT

Recurrence

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

(%)

Clinical Cure

Fidaxomicin versus Vancomycin Outcomes

Fidaxomicin Vancomycin

Global Cure

88.2%85.8%

92.1%

89.8%

15.4%

25.3%24.0%

13.3%

77.7%

67.1%

P=0.005

P=0.006

PP mITT PP mITT PP

74.6%

64.1%

P=0.004

P=0.006

Fidaxomicin versus Vancomycin – European study

26Cornely OA, et al. Lancet Infect Dis 2012;12:281-289

Study Design:

Prospective, multicenter, double-blind, RCTPrimary Outcomes:

Rate of clinical cure in ITT and per-protocol population

Vancomycin 125 mg

Q6H X 10 daysN = 257

Fidaxomicin 200 mg

Q12HX 10 days N = 252

N = 221mITT

N = 216Per

Protocol

N = 223mITT

N = 235Per

Protocol

mITT

Recurrence

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

(%)

Clinical Cure

Fidaxomicin versus Vancomycin Outcomes

Fidaxomicin Vancomycin

Global Cure

87.7% 86.8%

91.7% 90.6%

12.7%

26.9%

25.3%

12.8%

79.6%

65.5%

P=0.0002

P=0.001

PP mITT PP mITT PP

76.6%

63.4%

P=0.002

P=0.008

Fidaxomicin versus Vancomycin – Pooled Data

Prev: Previous27

Cornely OA, et al. Lancet Infect Dis 2012;12:281-289

Louie TJ, et al. N Engl J Med 2011; 364:422-431

Clinical Cure Rates (mITT)

Variable Fidaxomicin Vancomycin P Value

No Prev CDI 86.8% 86.4% NA

1 Prev CDI 92.5% 88.9% NA

Not Severe 91.5% 91.8% 0.914

Severe 76.2% 70.5% 0.473

Recurrence Rates (mITT)

Variable Fidaxomicin Vancomycin P Value

No Prev CDI 11.4% 25.7% 0.0004

1 Prev CDI 18.9% 34.4% 0.145

Not Severe 13.9% 25.6% NA

Severe 8.3% 32.6% NA

Sustained Response Rates (mITT)

Variable Fidaxomicin Vancomycin P Value

No Prev CDI 76.9% 64.3% NA

1 Prev CDI 75.0% 58.3% NA

Not Severe 78.8% 68.4% 0.020

Severe 69.8% 47.5% 0.012

Summary

• Fidaxomicin is noninferior to vancomycin

for clinical cure of CDI

• Fidaxomicin significantly reduced the rate

of rCDI in most patients compared to

vancomycin

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Prevention of CDI (Primary and Secondary)

Vancomycin for Primary Prevention

VRE BSI: Vancomycin resistant enterococcus blood stream infection29

Ganetsky A, et al. Clin Inf Dis. 2019;68(12):2003-2009

Study Design:

Retrospective Cohort StudyPrimary Outcomes:

Vancomycin prophylaxis and impact of CDI

Total Patients

Assessed N = 145

No Prophylaxis

(historical controls) N = 55

Vancomycin 125 mg

2x/day on admission until discharge

N = 90

N = 0

(0%)

CDI

Cases

N = 11

(20%)

CDI

Cases

P <0.001

N = 1

(1.1%)

VRE

BSI

N = 2

(3.6%)

VRE

BSI

P <0.557

N = 4

(4.4%)

CDI 90

days

Vancomycin for Primary Prevention

sHR: Subhazard Ratio aGVHD: acute graft versus host disease

aGVHD GI: acute GVHD gastrointestinal tract30

Ganetsky A, et al. Clin Inf Dis. 2019;68(12):2003-2009

Study Design:

Retrospective Cohort StudyPrimary Outcomes:

Vancomycin prophylaxis and impact of CDI

Total Patients

Assessed N = 145

Vancomycin 125 mg

2x/day on admission until discharge

N = 90

sHR 1.59 (0.88, 2.89); P=0.12aGVHD

(G2-4)

sHR 0.65 (0.25, 1.66); P=0.36aGVHD

(G3-4)

sHR 1.95 (0.93, 4.07); P=0.08aGVHD

GI (G2-4)

sHR 1.26 (0.63, 2.53); P=0.53aGVHD

(G2-4)

sHR 0.27 (0.08, 0.94); P=0.04aGVHD

(G3-4)

Day 1

80

Day 1

00

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Fidaxomicin for Primary Prevention – DEFLECT-1 Protocol

31Mullane KM, et al. CID 2019:68 (15 January)

Study Design:

Randomized, double-blind, placebo controlled studyPrimary Outcomes:

Incidence of CDI at 30 days (failure)

Fidaxomicin 200 mg

once daily N = 305

Matching Placebo

N = 306

Patients ≥18 years old

undergoing HSCT and receiving FQ prophylaxis

Starting within 2 days of

conditioning or FQ initiation (whichever is

first)

• Neutrophil

Engraftment

• Completion of FQ

prophylaxis

• Completion of

systemic antibiotics

7 days

after

Fidaxomicin for Primary Prevention – DEFLECT-1 Protocol

aHCT: autologous hematopoietic cell transplant alloHCT: allogeneic hematopoietic cell transplant 32Mullane KM, et al. CID 2019:68 (15 January)

Study Design:

Randomized, double-blind, placebo controlled studyPrimary Outcomes:

Incidence of CDI at 30 days (failure)

Fidaxomicin 200 mg

once daily N = 305

aHCT: 58.5%

Matching Placebo

N = 306aHCT: 58.9%

• Treatment Completed

[N = 227; 75.4%]• Duration of treatment

22 ± 8.6 days

• Treatment Completed

[N = 218; 72.9%]• Duration of treatment

22.7 ± 8.99 days

Fidaxomicin Placebo P Value

Failure (30 days) 28.6% 30.8% 0.2778

Confirmed CDI 4.3% 10.7% 0.0014

Confirmed CDI aHCT 2.8% 8% 0.0163

Confirmed CDI

alloHCT6.4% 14.6% 0.0166

Failure (60 days) 35.2% 35.8% 0.4420

Confirmed CDI 5.6% 10.7% 0.0117

Confirmed CDI aHCT 3.4% 8% 0.0321

Confirmed CDI

alloHCT8.8% 14.6% 0.0759

Failure (70 days) 29.2% 31.1% 0.3091

Confirmed CDI 4.7% 10.7% 0.0026

Vancomycin Prophylaxis as Secondary Prevention of CDI

HM: Hematological Malignancy dUCB: Double Umbilical Cord Blood 33Morrisette T, et al. Biol Blood Marrow Transplant 2019;25: 2091-2097

Study Design:

RetrospectivePrimary Outcomes:

CDI Recurrence at 60 days post vancomycin

NOVP = No Prophylaxis

(Postprotocol group) N = 29

OVP = Vancomycin 125

mg 2x/dayN = 21

Continue prophylactic

vancomycin x 7 days post broad

spectrum antibiotics

Duration

• ≥18 years with a

history of HCT or diagnosis of HM

• Initial CDI treated with

vancomycin and must be receiving

concurrent broad

spectrum antibiotics

Baseline VAN None P Value

Age (years) 56 (43.5-61.5) 62 (54-70.5) 0.034

Weight (kg) 85.5 (80.1-100.1) 72.8 (61.1-79.8) 0.001

HSCT 57% 62% 0.776

Auto/Allo 8%/92% 33%/67% 0.776/0.193

dUCB 50% 56% >0.999

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Vancomycin Prophylaxis as Secondary Prevention of CDI

BSA: Broad Spectrum Antibiotics34

Morrisette T, et al. Biol Blood Marrow Transplant 2019;25: 2091-2097

Study Design:

RetrospectivePrimary Outcomes:

CDI Recurrence at 60 days post vancomycin

VAN None P Value

Outpatient

Diagnosis10% 35% 0.051

Hospital LOS

(days)26 (21-34) 14 (4-21) 0.012

BSA Duration

(days)17.5 (14.8-31.3) 11 (9-17) 0.034

Community

CDI10% 41% 0.024

Hospital CDI 71% 31% 0.009

Outcome VAN None P Value

Recurrent CDI 5% 35% 0.016

VRE (infections) 14% 10% 0.686

Mortality (60 days) 10% 7% >0.999

Treatment Failure 43% 35% 0.570

Add Metronidazole 29% 14% 0.286

>14 days Vancomycin 14% 21% 0.716

Increase vancomycin dose 10% 10% >0.999

Switch to alternative agent 0% 7% 0.503

Recommended References

• L Clifford McDonald, Dale N Gerding, Stuart Johnson, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), Clinical Infectious Diseases, Volume 66, Issue 7, 1 April 2018, Pages e1–e48, https://doi.org/10.1093/cid/cix1085

• Rupnik M, et al. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nature 2009;7(7):526-536

• Miller MA, et al. Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection which predicts response to therapy. BMC Infect Dis 2013;13:148

• Cornely OA, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double blind, non-inferiority, randomized controlled trial. Lancet Infect Dis 2012;12:281-289

• Louie TJ, et al. Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J Med 2011; 364:422-431

35

Clostridioides difficile Management in the High Risk

Patient

Gianni Scappaticci, PharmD, BCOP

Clinical Specialist, BMT and Cellular Immunotherapies

University of Michigan Health System

Ann Arbor, MI