Oops… I C-Diffed again. Primary Prophylaxis for Clostridioides Difficile Infections in Hematopoietic Stem Cell

Transplant Patients

Andrew Y. Rubio, Pharm.D. PGY-1 Pharmacy Resident

Methodist Hospital and Methodist Children’s Hospital The University of Texas at Austin College of Pharmacy & UT Health San Antonio

Pharmacotherapy Education and Research Center

November 15th, 2019

Learning Objectives: 1. Review the importance and pathophysiology of Clostridioides difficile infections (CDI)2. Understand the background, process, and risks of hematopoietic stem cell transplantations

(HSCT)3. Recognize the relevance and consequences of CDI in the HSCT setting4. Evaluate the literature supporting primary prophylaxis of CDI in HSCT patients5. Formulate an evidence-based recommendation for prevention of CDI in HSCT patients

RUBIO 2

1. Clostridioides difficile infection (CDI) a. Background1-4

i. Formerly known as Clostridium difficile ii. CDI is identified by the Centers for Disease Control and Prevention (CDC)

as an urgent health threat 1. 500,000 infections annually 2. 15,000 deaths annually

iii. Contributes to roughly $6.3 billion in healthcare costs annually3 iv. All antibiotics have a warning for increased risk of CDI, with clindamycin

having a boxed warning b. Pathophysiology (Figure 1)1,4-7

i. The gastrointestinal (GI) tract contains more than 1,000 species of organisms as part of the normal flora

ii. The GI microbiota provides colonization resistance against pathogenic organisms

iii. Antibiotics kill normal GI flora along with the targeted pathogens iv. Disruption of normal GI flora leads to a loss in colonization resistance

allowing for an overgrowth of organisms resistant to the antibiotics v. C. difficile exposure and colonization

1. C. difficile is present in normal GI flora a. Gram positive, spore-forming, obligate anaerobic organism

2. Gut microbiome offers protection against CDI 3. C. difficile is resistant to many antibiotics and spores become activated

and infectious vi. C. difficile secretes toxins (toxin A and toxin B)

1. Compromise intestinal epithelium leading to loss of barrier integrity 2. Increases inflammatory response causing fluid secretion and mucosal

injury

Figure 1. Pathophysiology of CDI7

RUBIO 3

Table 1. Risk Factors for Developing CDI8

• Recent antibiotic exposure • Hematopoietic stem cell transplantation • Extended duration of antibiotic use • Recent hospitalization • Age > 65 years • Severe comorbid illness • Cancer chemotherapy • Acid-suppressing medication use • GI surgery • Long term care facility residency

c. Clinical presentation1,9-10 i. Asymptomatic colonization can occur in 10-30% of hospitalized patients ii. It is important to differentiate between colonization and CDI iii. CDI can range from mild to severe and can be potentially fatal

1. Severe infections include leukocytosis with a WBC count >15,000 cells/mL or SCr >1.5 mg/dL

Table 2. CDI Symptoms and Complications8

Symptoms Complications • Watery profuse diarrhea • Fever • Abdominal cramping • Nausea • Anorexia • Leukocytosis

• Toxic megacolon • Bowel perforation • Peritonitis • Sepsis • Death

d. Diagnosis1, 9, 11-12 i. Testing should be performed in patients with new unexplained diarrhea

1. ≥3 unformed stools in 24 hours ii. Multistep testing should include symptoms and laboratory findings,

radiographic evidence, or endoscopy 1. Positive toxin production 2. Endoscopy confirming pseudomembranous colitis

a. Estimated to only be seen in about half of patients iii. Toxin must also be present with active diarrhea

1. Can be detected up to 30 days after treatment13 2. Test for cure not recommended

RUBIO 4

Table 3. Testing Recommendations for CDI1,12-13

Detection Test Sensitivity Specificity Notes

Clostridiojdes difficile

presence

Laboratory stool test High Low • Takes 2-3 days

• Gold standard

Glutamate dehydrogenase (GDH) antigen

High Low

• Must be combined with toxin test

• Quick turnaround • ~$10

Toxin presence

Enzyme immunoassay

(EIA) Low Moderate

• Simple • Quick turnaround • Inexpensive

Nucleic acid amplification test

(NAAT) High Low

• Should be followed by EIA detecting toxin A and B or toxin B

• Expensive • Rapid

Polymerase chain reaction (PCR) High High • Quick turnaround

• ~$22

Toxigenic cultures High Low

• Not frequently performed (labor intensive)

• Long turnaround times

e. Differential diagnosis1,14 i. Osmotic diarrhea ii. Inflammatory bowel disease iii. Infection with another pathogen iv. Chemotherapy induced diarrhea v. Graft vs. host disease (GvHD)

f. Prevention15-17 i. Hand hygiene

1. Spores are not killed by alcohol 2. Use soap and water

ii. Antibiotic stewardship 1. De-escalation whenever appropriate 2. Proper duration of antibiotic therapies

iii. Contact precautions 1. Signs for contact precautions 2. Use of gowns and gloves during patient encounters 3. Cleaning of patient rooms and equipment 4. Chlorhexidine bathing 5. Private room and dedicated toilet

iv. Avoid gastric acid suppression g. Treatment1

i. Discontinuation of offending antibiotics when possible

RUBIO 5

Table 4. Recommendations for the Treatment of CDI in Adults Based on IDSA 2017 Guidelines1

Initial episode non-severe

• Vancomycin 125 mg PO four times daily for 10 days • Fidaxomicin 200 mg PO twice daily for 10 days • Alternative: metronidazole 500 mg PO three times daily for 10 days

Initial episode severe

• Vancomycin 125 mg PO four times daily for 10 days • Fidaxomicin 200 mg PO twice daily for 10 days

Initial episode fulminant

• Vancomycin 500 mg PO/NG tube four times daily AND metronidazole 500 mg IV three times daily

• Consider rectal instillation of vancomycin

Second or subsequent episode

• Vancomycin 125 mg PO four times daily for 10 days • Vancomycin prolonged tapered therapy • Vancomycin 125 mg PO four times daily followed by rifaximin • Fidaxomicin 200 mg PO twice daily for 10 days • Fecal microbiota transplantation

Cost of Full Course of First Line CDI Treatments Based on Average Wholesale Price18

Vancomycin liquid (IV formulation compounded as oral liquid) $52 Vancomycin capsules $1,273 Fidaxomicin tablets $3,360

2. Hematopoietic Stem Cell Transplantation (HSCT)

a. Background19-20 i. Process by which normal hematopoiesis and/or lymphopoiesis is established

by the infusion of ex vivo pluripotent stem cells ii. Infusion of stem cells typically occurs following administration of

chemotherapy and/or radiation to the recipient iii. The most severe toxicity with chemotherapy regimens used in myeloablative

therapy is myelosuppression 1. HSCT allows dose intensification of chemotherapy by 3 to 10 fold

over standard dose iv. Donor source can be autologous or allogeneic dependent upon the

malignancy treated and patient characteristics v. Autologous

1. Infusion of patient’s own stem cells 2. Serves to rescue the patient from myelosuppressive effects 3. Faster immune reconstitution 4. Lower infection risk and no graft-versus-host disease (GvHD)

vi. Allogeneic 1. Infusion of donor stem cells 2. Replaces a missing or abnormal hematopoietic or lymphoid

component in non-malignant disorders 3. Rescues recipient from myeloablative therapy given for treatment of

malignant disease

RUBIO 6

4. Establishes graft-versus-leukemia (tumor) effect mediated by donor cell recognition and destruction or inhibition of residual host malignant cells

5. Increased risk of infections due to prolonged immunosuppression 6. High risk of GvHD

Table 5. Indications for HSCT21

• Acute myeloid leukemia (AML) • Acute lymphoblastic leukemia • Myelodysplastic syndromes • Myeloproliferative neoplasms • Chronic myeloid leukemia • Peripheral T-cell lymphoma

• Follicular lymphoma • Diffuse large B-cell lymphoma • Neuroblastoma • Nonmalignant inherited and acquired

marrow disorders • Autoimmune diseases

b. HSCT process20,22-25

Figure 3. HSCT Process22

i. Mobilization

1. Movement of stem cells from the bone marrow into the blood through use of granulocyte-colony stimulating factors

ii. HSCT collection 1. Bone marrow harvest

a. Procured through multiple needle aspirations

RUBIO 7

2. Peripheral blood stem cell harvest a. Apheresis machine is used, which separates stem cells from

other blood parts 3. Umbilical cord harvesting 4. Agents are then cryopreserved for processing and storage

iii. Conditioning20

1. Myeloablative a. Causes irreversible cytopenia b. Stem cell support is mandatory c. Standard of care for AML patients d. Lower rates of relapse

2. Non-myeloablative a. Causes minimal cytopenia b. Given with or without stem cell support c. Involves minimization of anti-tumor intensity and

maximization of immunosuppression 3. Reduced-intensity regimens

a. Can cause cytopenia of variable durations b. Should be given with stem cell support

4. Non-myeloablative and reduced-intensity regimens aim to exploit the premise of allogeneic HSCT, providing graft-versus-leukemia or graft-versus-tumor effects while also reducing toxicity

a. Higher rates of relapse and transplant rejection 5. Intensity is dependent on type of malignancy, transplant, and patient

risk factors iv. Immunosuppression

1. Required only for allogeneic HSCT 2. Prevention of graft rejection

a. Eradicates host immune system to allow acceptance of donor cells

3. GvHD prevention a. Calcineurin inhibitors with short course methotrexate b. Post-transplant cyclophosphamide in select regimens

i. Often utilized leading to more prolonged immunosuppression

v. Infusion of stem cells 1. Day of infusion is referred to as Day 0

vi. Recovery/engraftment 1. Transplanted stem cells begin production of platelets, red blood cells,

and white blood cells 2. Sustained ANC >0.5 x 109/L for three consecutive days and a

platelet count >20 x 109/L c. Complications of HSCT20-25

i. Nausea and vomiting 1. Managed with NK-1-receptor antagonists, 5-HT3 receptor

antagonists, and corticosteroids

RUBIO 8

ii. Mucositis 1. Painful inflammation and ulceration of the mucous membranes lining

the digestive tract 2. Managed with good oral hygiene, cryotherapy, and palifermin 3. Increased risk of mucosal barrier breakdown leading to translocation

of gastrointestinal flora into the blood iii. GvHD26-27

1. Condition that may develop in allogeneic HSCT where graft views recipient’s tissue as foreign and “attacks” the recipient’s tissues

2. Clinical features determine whether classification is acute or chronic 3. Approximately 35-50% of recipients develop acute GvHD 4. Leading cause of non-relapse mortality in allogeneic HSCT patients 5. Benefits include graft-versus-tumor and graft-versus-leukemia effects

(refer to Figure 4) 6. Characterized by erythema, maculopapular rash, nausea, vomiting,

profuse diarrhea, ileus, or anorexia 7. Risk factors

a. Degree of mismatch between donor and recipient b. Intensity of conditioning regimen c. Stem cell source d. Age of patient/donor e. Prophylaxis regimen f. CMV Status

8. Managed with immunosuppression, steroids, and monoclonal antibodies

Figure 4. Prognosis of Patients that Develop GvHD28

RUBIO 9

9. GI microbiome plays an important role in GvHD29-30 a. Intestinal bacteria contribute to health of host through a

variety of functions b. Multiple studies have demonstrated that decreased microbiota

diversity leads to reduced overall survival c. Allogeneic HSCT recipients have a disruption in their

microbiome due to many infectious and inflammatory processes

d. Neutropenic fever treatment with anaerobic coverage is associated with increased risk for GvHD29

e. Presence of anaerobic species Blautia, is associated with reduced GvHD-related mortality and improved overall survival30

f. When combined with other risk factors, allogeneic patients are often at higher risk of GvHD

iv. Infection20,25,31 1. Risk mainly related to time since transplant and presence/absence of

GvHD 2. Patients may experience a period of profound pancytopenia spanning

days to weeks depending on the stem cell dose, donor source, and conditioning regimen intensity

Figure 5. Timing of Immune Reconstitution in HSCT25

3. Risk factors for infection

a. Immunosuppression b. GvHD c. Age d. Comorbidities e. Pathogen exposure/colonization

4. Recommended prophylaxis should include antibacterial, antiviral, and antifungal agents

RUBIO 10

5. Antibacterial prophylaxis is recommended to be continued until recovery from neutropenia

a. Length of prophylaxis varies b. Agents should be broad spectrum c. American Society of Blood and Bone Marrow

Transplantation Guidelines strongly recommend broad spectrum agents in adult HSCT patients with anticipated neutropenic period of 7 days or more32

d. Prophylaxis with fluoroquinolones has been shown in large meta-analyses to decrease gram-negative infections, infection-related complications, and mortality in neutropenic patients31

6. Oncology patients are at higher risk for vancomycin resistant enterococcus (VRE) bloodstream infections34-35

a. Colonization with VRE and antibiotic use lead to domination of the GI flora

b. Mucosal lining damaged from chemotherapy allows for translocation of VRE into the bloodstream

3. CDI and HSCT patients a. Background33-38

i. Infection remains a major cause of morbidity and mortality in HSCT patients ii. CDI rates in HSCT patients are as high as 33%

1. Recurrence rates up to 41% in HSCT population37 2. Compared to ~1% of overall U.S. population 3. Identified as an independent risk factor for increased mortality

iii. Most risk factors for allogeneic HSCT patients are not modifiable 1. Patients must maintain antibiotic prophylaxis during neutropenia

iv. No specific recommendations for CDI treatment in HSCT patients due to scarcity of data

v. Mortality rate of CDI patients in HSCT is similar to non-HSCT population 1. Complications of CDI are often devastating in this patient population

b. Why are CDI rates higher in HSCT patients?39-42 i. Chemotherapy damages mucosal lining

1. Grade ≥2 mucositis ii. Reactivation of Cytomegalovirus iii. Reactivation of Herpesviridae iv. Chemotherapeutics may have antimicrobial properties v. Ubiquitous use of fluoroquinolone prophylaxis vi. Prolonged neutropenia vii. Prolonged broad-spectrum antibiotic use for treatment of febrile neutropenia viii. Prolonged hospitalizations

c. Importance37,42 i. Immunosuppressed patients are often excluded in clinical trials, which makes

treatment guideline recommendations difficult to use 1. Typically treat CDI in immunosuppressed patients similarly to non-

immunosuppressed patients ii. CDI rates in allogeneic HSCT are double that of autologous HSCT42

RUBIO 11

iii. Studies have shown no difference in all-cause mortality when comparing patients with CDI versus uninfected allogeneic HSCT patients42

iv. Early CDI during allogeneic HSCT is correlated with increased risk of GI GvHD by more than 3-fold42

1. Preparative regimens cause damage to the tissues 2. Proinflammatory cytokines promote antigen-presenting cells to

activate donor T cells, which causes a cascade of cytotoxicity 3. Theorized that local infection of the gut may further destroy

epithelial integrity augmenting responses during a cycle of inflammation

Figure 6. Rates of GvHD in allogeneic HSCT patients with and without CDI42

4. Higher rates of GvHD grade II or higher in patients with CDI

a. Unable to associate higher GvHD rates due to infection itself or treatment with vancomycin leading to disruption of gut microbiome

Figure 7. Effects of antibiotic exposure on increased 5-year GvHD-related mortality43

RUBIO 12

5. Oral vancomycin does not have an increased risk of GvHD related mortality in allogeneic patients

d. Colonization37,44-45 i. Transmission is likely spread from person to person via the fecal-oral route ii. Asymptomatic colonization with toxigenic C. difficile has been found

predictive of CDI in HSCT patients 1. Develop CDI within 2 weeks of hospital admission

iii. Prevalence of asymptomatic colonization among HSCT adults is estimated between 3-26%43

iv. Colonization with non-toxigenic C. difficile has appeared protective44 v. Studies suggest avoiding broad spectrum antibiotics that alter GI microbiome

due to risks leading to GvHD46-47 4. Secondary prophylaxis for CDI (Table 6)48-53

a. Due to high morbidity and costs associated with CDI, studies have assessed the efficacy of oral vancomycin as secondary prophylaxis in high-risk populations

b. Oral vancomycin 125 mg once daily for the duration of antimicrobial treatment may be considered if secondary prophylaxis is implemented1

i. Optimal dosing strategy has not been defined- studies currently ongoing46

Table 6. Studies Assessing Oral Vancomycin as Secondary Prophylaxis Study Design Methods Findings Limitations Carignan et al. (2016)49

N=551

Multi-center retrospective cohort study

Vancomycin 125 mg PO QID vs. no prophylaxis

Vancomycin is an effective strategy for secondary prevention for those re-exposed to antibiotics

• Non-heterogeneity among patient population

• Lack of standardized follow-up for recurrence in days off vancomycin

• Patients on metronidazole for non-CDI indications

• Unclear medication review + treatment doses

Van Hise et al. (2016)50

N=223

Retrospective single-center cohort study

Vancomycin 125-250 mg PO BID vs. no prophylaxis

Vancomycin may be effective at preventing CDI recurrence in patients who require antibiotic therapy

• Surveillance duration only 4 weeks

• Did not study changes in fecal flora

Splinter et al. (2018)51

N=29

Retrospective cohort study assessing use in renal transplant patients

Vancomycin 125 mg PO BID vs. no prophylaxis

No instances of CDI in the treatment group vs. 2 in control group

• Difference not statistically significant

• No follow-up after vancomycin discontinuation

• Small sample size • Lack of randomization

RUBIO 13

Knight et al. (2019)52

N=91

Retrospective single-center cohort study

Vancomycin 125-250 mg PO QID vs. no prophylaxis

Vancomycin as secondary prophylaxis appears to reduce the risk of recurrent CDI for up to 12 months without increasing VRE infections

• Variable antibiotic exposure within groups

• Unmatched prophylaxis strategies

• Used treatment doses for prophylaxis

Morrisette et al. (2019)53

N=50

Retrospective cohort study assessing use in HSCT patients

Vancomycin 125 mg PO BID continuing 7 days after antibiotic discontinuation vs. no prophylaxis

Decreased incidence of recurrent CDI with no increase in VRE infections

• Lengthy duration of prophylaxis

• Concurrent major prevention strategies may have skewed CDI to decrease

c. Studies had similar limitations

i. Lacked consistent and defined patient follow up 1. No detection of late-recurrences 2. May have been detected in Carignan study

ii. Potentially missed patients who were treated at different hospital systems iii. Earlier studies did not investigate the impact of resistant organism acquisition iv. Adverse effects not reported

d. All five studies demonstrate that oral vancomycin appears to be effective at reducing the risk of CDI recurrence in high-risk patients

5. Abstract (Table 7) a. Secondary prophylaxis studies have led to preliminary investigation questioning the

safety and efficacy of primary CDI prophylaxis in HSCT patients Table 7. Does Oral Vancomycin Prophylaxis for Clostridium Difficile Infection Improve Allogeneic Hematopoietic Stem Cell Transplant Outcomes54

Background • Allogeneic HSCT patients are at high risk for CDI • No guideline recommendations utilizing antimicrobial prophylaxis for CDI in

allogeneic HSCT patients • Hackensack University Medical Center used oral vancomycin prophylaxis in

this population Methods • Retrospective medical record review of HSCT patients between January 2013

and December 2014 with at least one readmission within one year • Collected data on allogeneic HSCT related information, prophylactic oral

vancomycin usage, antimicrobial exposures, GvHD development, VRE bacteremia, mortality, and occurrence of CDI during hospital stay

• Primary objective: evaluate the development of CDI • Secondary objectives: occurrence of GvHD, VRE bacteremia, and death

RUBIO 14

• Group A: patients with documented CDI history who received vancomycin prophylaxis

• Group B: patients with documented CDI history who did not receive vancomycin prophylaxis

• Group C: patients without documented CDI history who did not receive prophylactic vancomycin

Results CDI VRE bacteremia

GvHD Death within 1 year

Group A (n=12) 2 (17%) 3 (25%) 12 (100%) 6 (50%) Group B (n=7) 1 (14%) 0 (0%) 4 (57%) 1 (14%) Group C (n=161) 17 (11%) 15 (9%) 120 (75%) 55 (34%)

Conclusion • “The possible influence of oral vancomycin prophylaxis on outcomes in allogeneic HSCT patients remains unknown”

• Missing group for patients without documented CDI history who received vancomycin prophylaxis

• 109 patients were excluded due to not being readmitted within one year • Hypothesis generating

Clinical Questions: Should HSCT patients receive primary prophylaxis for CDI? If so, which agent should they receive?

Table 8. Ganetsky A, Han JH, Hughes ME, et al. Oral vancomycin prophylaxis is highly effective in preventing Clostridium difficile infection in allogeneic hematopoietic cell transplant recipients. Clin Infect Dis. 2019;68(12):2003-2009.35

Objective To evaluate the use of prophylactic oral vancomycin and incidence of CDI in allogeneic HSCT patients

Methods Retrospective, single center, cohort study between April 2015 and November 2016 at the Hospital of the University of Pennsylvania

Patient Population Inclusion Patients receiving allogeneic HSCT

Exclusion Allergy or intolerance to vancomycin

Intervention Vancomycin 125 mg twice daily starting on the day of inpatient admission and continuing until the day of discharge compared to a cohort of unexposed patients between April 2015 and December 2015

Outcomes Evaluated Primary • Association between oral vancomycin prophylaxis and CDI diagnosis from time of

inpatient admission to hospital discharge

RUBIO 15

Secondary • Acute and chronic GvHD • Relapse, non-relapse mortality, overall survival • Incidence of VRE bloodstream infections

Statistics • Utilized X2 or Fisher’s exact test for categorical variables • Wilcoxon rank-sum was used for continuous variables • Calculations were performed using Stata v15.1 • A 2-tailed P value <0.05 was considered to be significant

Results • Total of 145 patients were included in the study • No cases of CDI in patients that received prophylaxis (0/90) • CDI occurred in 11/55 (20%) patients that did not receive prophylaxis (P<0.001) • Oral vancomycin prophylaxis was not associated with a higher risk of acute grades 2-4

GvHD Author’s Conclusions

Prophylaxis with oral vancomycin is highly effective in preventing CDI in allogeneic HSCT patients without increasing the risk of GvHD, VRE bloodstream infections, or disease relapse.

Reviewer’s Critique Strengths • Targets a population often not included

in studies • No significant baseline differences • Reported the days of broad spectrum

gram-negative antibiotic exposure • Followed patients for incidence of CDI

and GvHD after discharge

Limitations • Retrospective, single cohort • Small sample size for rare outcomes • Additional preventative measures

unspecified • No analysis on changes in the gut

microbiota • No routine screening for VRE • Time periods for comparator groups were

not aligned • Lack of difference in length of

hospitalization, GvHD rates, and survival outcomes

• Lengthy prophylaxis period Take-home Points

• Demonstrated vancomycin as a viable option for prophylaxis against CDI in allogeneic HSCT patients

• Vancomycin use did not increase GvHD rates, VRE bloodstream infections, or relapse • Risks for GvHD and VRE still unclear within small study population size • GvHD rates were also not lowered as would be expected with decrease in CDI • Lack of differences between groups raises question if early identification and treatment of

CDI is just as effective as prophylaxis • Further studies needed to assess the efficacy and safety of vancomycin prophylaxis

RUBIO 16

Table 8. Mullane KM, Winston DJ, Nooka A, et al. A randomized, placebo-controlled trial of fidaxomicin for prophylaxis of Clostridium difficile-associated diarrhea in adults undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2019; 68(2):196–203.55

Objective To examine the efficacy and safety of fidaxomicin as prophylaxis against CDI in patients undergoing autologous or allogeneic HSCT and receiving fluoroquinolone prophylaxis during neutropenia

Methods Randomized, double-blind, placebo-controlled study at 42 centers in North America

Patient Population Inclusion Criteria • ≥18 years old • Undergoing HSCT • Planned fluoroquinolone prophylaxis

during neutropenia

Exclusion Criteria • Active CDI • Fulminant colitis • Toxic megacolon, or ileus • Receipt of a cord blood transplant • History of inflammatory bowel disease • Pregnant or breast-feeding • Current use of any drugs potentially

useful in the treatment of CDI Intervention

Randomized to receive daily fidaxomicin or matching placebo within two days of starting conditioning or at fluoroquinolone initiation until seven days after neutrophil engraftment or completion of fluoroquinolone prophylaxis

Outcomes Evaluated Primary

• Prophylactic failure of fidaxomicin vs. placebo through 30 days o Confirmed CDI o Use of antibiotics potentially effective against CDI (metronidazole) o Missing CDI assessments (due to death, AE, or any other reason)

Secondary • CDI incidence 30, 60, and 70 days after study medication discontinuation • Time to onset CDI • Treatment-emergent adverse effects • All-cause mortality • Gastrointestinal hemorrhagic events • Time to neutrophil engraftment • Acute GvHD

Statistics • Used modified intention-to-treat analysis • 1-sided Wald test for a difference in proportions

RUBIO 17

Results • 611 patients enrolled, 600 patients received at least 1 dose of a study drug • Study completed by 227 fidaxomicin recipients and 218 placebo recipients • Prophylactic failure through 30 days occurred in 28.6% of fidaxomicin-treated patients

and 30.8% of placebo (P=0.278) • Incidence of confirmed CDI for both autologous and allogeneic HSCT patients was

lower in the prophylaxis group than placebo at 30 days post treatment (6.4 vs 14.6% allogeneic and 2.8 vs 8.0% in autologous)

• The incidence of confirmed CDI was lower in the placebo group through 60 days after the study treatment ended (5.6 vs 10.7%; P=0.0014)

Author’s Conclusions Prophylaxis of CDI with fidaxomicin can reduce the incidence of confirmed CDI in the HSCT population

Reviewer’s Critique Strengths

• Randomized, double-blind, placebo controlled

• Clear on methods used for prophylaxis

• Appropriate diagnosis of CDI • Baseline characteristics matched

between two groups • Included autologous and allogeneic

patients • Sensitivity analysis determined a priori

Limitations • Primary analysis not met • Stringent failure qualifications may

have led to lack of difference • Microbiota changes were not assessed • Only 64% of patients completed

study treatment and follow-up • Lower than expected incidence of

confirmed CDI

Take-home Points • Prophylactic failure was similar in fidaxomicin and placebo groups • Fidaxomicin was shown to be a reasonable option for CDI after a priori analysis was

performed • The sensitivity analysis showed a significant decrease of confirmed CDI in the

fidaxomicin group, but the overall incidence was much lower than expected • Questionable utility due to high cost and unmet primarily analysis of this study • Further studies assessing the safety and efficacy of fidaxomicin are warranted

6. Future Directions

a. ID Week abstracts i. Many hospitals have implemented vancomycin 125 mg PO once or twice

daily as secondary prophylaxis in high risk patients with favorable results b. Current studies ongoing to determine best practices for CDI prophylaxis46

7. Summary of Evidence a. Pros to primary prophylaxis for CDI

i. Protective for CDI and improvement in morbidity and mortality ii. CDI is associated with increased rates of GvHD

1. GvHD is the leading non-relapse cause of death

RUBIO 18

2. However, unable to distinguish occurrence of CDI or CDI treatment as cause for GvHD

3. Vancomycin use is not associated with increased rates of GvHD-related mortality

iii. Leads to decrease in relapse of malignancy b. Cons to prophylaxis for CDI

i. Unclear long-term effects 1. VRE infections 2. Increased rates of GvHD due to disruption of microbiome

8. Recommendations a. Who, if any, should get primary prophylaxis?

i. Due to the unknown consequences of prophylaxis, I limit the utility to only allogeneic HSCT patients who are colonized with C. difficile due to their increased risk of GvHD with CDI

1. Routine screening for allogeneic patients a. GDH testing performed with admission labs b. Weekly screening thereafter

ii. I do not recommend primary prophylaxis in autologous HSCT patients 1. Rates of CDI are much lower in autologous patients 2. Virtually no GvHD in autologous patients

b. If primary prophylaxis is given, vancomycin should be preferred over fidaxomicin due to:

i. Higher cost associated with fidaxomicin ii. Apparent risk reduction with vancomycin

1. ARR 20% with vancomycin use 2. ARR 8.4% with fidaxomicin use 3. It would be ideal to conduct a head-to-head comparison of efficacy

with vancomycin or fidaxomicin in HSCT patients to better determine preferred agent

iii. Reserving fidaxomicin as an option to patients that develop CDI with vancomycin prophylaxis or vancomycin-resistant CDI

c. When and how to administer: i. Dose of vancomycin 125 mg PO BID starting at time of antibiotic initiation

until discontinuation of antibiotic therapy d. Maintain high-level antimicrobial stewardship techniques

i. Minimizing antibiotic exposure (particularly fluoroquinolones in our HSCT patients)

ii. Improve prevention practices e. More studies are warranted to determine the safety and efficacy of primary

prophylaxis of CDI before it is routinely incorporated into the transplant setting for all donor types

RUBIO 19

References 1. McDonald LC, Gerding DN, Johnson S, 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). Clin Infect Dis. 2018;66(7):987-994.

2. CDC Press Releases. Center for Disease Control and Prevention (CDC). 2015. Available at: http://www.cdc.gov/media/releases/2015/p0225-Clostridium-difficile.html. Accessed October 18, 2019.

3. Zhang S, Palazuelos-Munoz S, Balsells EM, et al. Cost of hospital management of Clostridium difficile infection in United States—a meta-analysis and modelling study. BMC Infect Dis. 2016;16:447.

4. Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defense. Nat Rev Microbiol. 2016;14(10):609-620.

5. Cergind DN YV. Clostridium difficile infection. In: Bennett JE, Dolin R BM, ed. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Saunders Elsevier; 2015:2744-2756.e3.

6. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7(7):526-536.

7. Rao K, Safdar N. Fecal microbiota transplantation for the treatment of Clostridium difficile infection. J Hosp Med. 2016;11(1):56-61.

8. Gerding D, Young V. Clostridium difficile Infection. In: Bennett J, Dolin R, Blaser M, ed. Mandell, Douglas, And Bennett's Principles And Practice Of Infection Diseases. 8th ed. Philadelphia: Elsevier Saunders; 2015:2744-56.

9. Burnham C-AD, Carroll KC. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013;26(3):604-630.

10. Rivera EV, Woods S. Prevalence of asymptomatic Clostridium difficile colonization in a nursing home population: a cross-sectional study. J Gend Specif Med. 2003;6(2):27-30.

11. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-98.

12. Crobach MJ, Planche T, Eckert C, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2016;22 Suppl 4:S63-81.

13. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22(5):813-8.

14. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015; 313:398.

15. Gerding DN, Muto CA, Owens RC. Measures to control and prevent Clostridium difficile infection. Clin Infect Dis. 2008;46 Suppl 1:S43-9.

16. Revolinski, Sara L., and L. Silva Munoz-Price. Clostridioides difficile in transplant patients: early diagnosis, treatment, and prevention. Current opinion in infectious diseases 32.4 (2019): 307-313.

17. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107(7):1001-10.

18. Drekonja D, Butler M, MacDonald R, et al. Comparative effectiveness of Clostridium difficile treatments: a systematic review. Annals of internal medicine 155.12 (2011): 839-847.

19. Copelan EA. Hematopoietic stem-cell transplantation. The New England journal of medicine. 2006; 354(17): 1813-26. 20. Bacigalupo A, Ballen K, Rizzo D et al. Defining the intensity of conditioning regimens: Working definitions. Biol Blood

Marrow Transplant. 2009; 15(12): 1628-33. 21. Majhail NS, Farnia SH, Carpenter PA et al. Indications for autologous and allogeneic hematopoietic cell transplantation:

Guidelines from the american society for blood and marrow transplantation. Biol Blood Marrow Transplant. 2015; 21(11): 1863-9.

22. Mancardi G, Sormani MP, Murano PA et al. Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. Mult Scler. 2018;24(3):245-255.

23. Bensinger W, Dipersio JF, Mccarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant. 2009;43(3):181-195.

24. Hequet O. Hematopoietic stem and progenitor cell harvesting: technical advances and clinical utility. J Blood Med. 2015;6:55-67.

25. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238.

26. Jacobsohn DA,Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis.2007;2:35. 27. Przepiorka D,Smith TL,Folloder J,et al.Risk factors for acute graft-versus-host disease after allogeneic blood stem cell

transplantation. Blood. 1999;94(4):1465-1470. 28. Cahn JY, Klein JP, Lee SJ, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint

Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106(4):1495-500.

29. Shono Y, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Science translational medicine 8.339 (2016): 339ra71-339ra71.

RUBIO 20

30. Horton L, Haste N,Taplitz R, et al. Rethinking antimicrobial prophylaxis in the transplant patient in the world of emerging resistant organisms—where are we today? Current hematologic malignancy reports 13.1 (2018): 59-67.

31. Leather HL WJBIIAF, Forman SJ, Negrin RS, eds. Thomas' Hematopoietic Cell Transplantation. Hoboken: Wiley-Blackwell; 2009: 1325-1345.

32. Tomblyn M, Chiller T, Einsele H, et al.; Center for International Blood and Marrow Research; National Marrow Donor program; European Blood and MarrowTransplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Disease Canada; Centers for Disease Control and Prevention. Guidelines for preventing infectious complica- tions among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15:1143–238.

33. Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a metaanalysis. Clin Infect Dis 1996; 23:795–805.

34. Webb B, Healy R, Majers J, et al. Prediction of bloodstream infection due to vancomycin-resistant enterococcus in patients with hematological malignancy undergoing induction therapy or hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2016; S54-S55.

35. Ganetsky A, Han JH, Hughes ME, et al. Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients. Clin Infect Dis. 2019;68(12):2003-2009.

36. Schuster MG, Cleveland AA, Dubberke ER, et al. Infections in hematopoietic cell transplant recipients: results from the organ transplant infection project, a multicenter, prospective, cohort study. Open Forum Infect Dis 2017; 4:1–7.

37. Revolinski SL, Munoz-price LS. Clostridium difficile in Immunocompromised Hosts: A Review of Epidemiology, Risk Factors, Treatment, and Prevention. Clin Infect Dis. 2019;68(12):2144-2153.

38. Dubberke ER, Reske KA, Olsen MA, et al. Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients. Transpl Infect Dis. 2018; 20:e12855.

39. Alonso CD, Dufresne SF, Hanna DB, et al. Clostridium difficile infection after adult autologous stem cell transplantation: a multicenter study of epidemiology and risk factors. Biol Blood Marrow Transplant 2013 ; 19:1502–8.

40. Lavallee C, Labbe AC, Talbot JD, et al. Risk factors for the development of Clostridium difficile infection in adult allogeneic hematopoietic stem cell trans- plant recipients: a single-center study in Quebec, Canada. Transpl Infect Dis. 2016; 19. doi:10.1111/tid.12648.

41. Alonso CD, Braun DA, Patel I, et al. A multicenter, retrospective, case-cohort study of the epidemiology and risk factors for Clostridium difficile infection among cord blood transplant recipients. Transpl Infect Dis. 2017 ; 19. doi:10.1111/ tid.12728.

42. Alonso CD, Treadway SB, Hanna DB, et al. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2012;54(8):1053-63.

43. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra71.

44. Jain T, Croswell C, Urday-cornejo V, et al. Clostridium Difficile Colonization in Hematopoietic Stem Cell Transplant Recipients: A Prospective Study of the Epidemiology and Outcomes Involving Toxigenic and Nontoxigenic Strains. Biol Blood Marrow Transplant. 2016;22(1):157-63.

45. Furuya-kanamori L, Marquess J, Yakob L, et al. Asymptomatic Clostridium difficile colonization: epidemiology and clinical implications. BMC Infect Dis. 2015;15:516.

46. Shallis RM, Terry CM, Lim SH. Changes in intestinal microbiota and their effects on allogeneic stem cell transplantation. Am J Hematol 2018; 93:122–8.

47. Weber D, Jeng R, Peled J, et al. Microbiota Disruption Induced by Early Use of Broad Spectrum Antibiotics is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation, Biology of Blood and Marrow Transplantation (2017).

48. Brown C, Manis M, Bohm N, et al. Oral vancomycin for secondary prophylaxis of clostridium difficile infection. Annals of Pharmacotherapy 53.4 (2019): 396-401.

49. Carignan A, Poulin S, Martin P, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol. 2016;111:1834-1840.

50. Van Hise NW, Bryant AM, Hennessey EK, et al. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis. 2016;63:651-653.

51. Splinter LE, Kerstenetzky L, Jorgenson MR, et al. Vancomycin prophylaxis for prevention of Clostridium difficile infection recurrence in renal transplant patients. Ann Pharmacother. 2018;52:113-119.

52. Knight EM, Schiller DS, Fulman MK, Rastogi R. Long-Term Efficacy of Oral Vancomycin Prophylaxis for the Prevention of Clostridium difficile Recurrence. J Pharm Pract. 2019;:897190019825994.

53. Morrisette T, Van matre AG, Miller MA, et al. Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population. Biol Blood Marrow Transplant. 2019;25(10):2091-2097.

54. Pereiras MA, Urnoski E, Wynd M, et al. Does oral vancomycin prophylaxis for Clostridium difficile infection improve allogeneic hematopoietic stem cell transplant outcomes? Biol Blood Marrow Transplant. 2017; 23:S395.

55. Mullane KM, Winston DJ, Nooka A, et al. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019;68(2):196-203.