Fecal microbiota transplantation for recurrent

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Published by John Wiley & Sons Ltd ...... United European Gastroenterol J. 2017;5:868-879. 40. Brandt LJ, Aroniadis OC ... Schneider KM, Wirtz TH, Kroy D, et al.
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Received: 20 February 2018    Revised: 19 June 2018    Accepted: 12 July 2018 DOI: 10.1111/tid.12967

CASE REPORT

Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with solid organ transplants: an institutional experience and review of the literature Steven C. Lin1

 | Carolyn D. Alonso2

1 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 2

Division of Infectious Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Correspondence: Steven C. Lin, Division of Gastroenterology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. Email: [email protected]

 | Alan C. Moss1

Abstract Clostridium difficile, an anaerobic gram-­positive, spore-­forming bacillus, has become the most common cause of nosocomial infectious diarrhea, and is associated with increased mortality in all populations. Patients who have received solid organ transplants (SOT) are at increased risk of Clostridium difficile infection (CDI) and CDI recurrence (rCDI). This may be related to chronic immunosuppression, frequent antibiotic exposure, and increased or prolonged hospitalizations. Increased morbidity and mortality from CDI is well-­described in SOT patients. Conventional treatments for index and recurrent CDI include vancomycin and fidaxomicin. Fecal microbiota transplantation has emerged as an effective and safe alternative for treating rCDI in the general population. Reports of its safety in certain immunocompromised populations, such as those with inflammatory bowel disease, appear reassuring, but outcomes among SOT patients are less well known. Here, we summarize the experiences published to date on the treatment of rCDI with FMT in SOT patient, and also describe our detailed FMT protocol and experience in treating a series of SOT patients with rCDI. In addition to reporting the safety and efficacy of our FMT experience, we also discuss the diagnostic challenges and considerations in this population of solid organ transplant recipients. KEYWORDS

efficacy, fecal microbiota transplantation, immunocompromised, recurrent Clostridium difficile infection, safety, solid organ transplant

1 |  I NTRO D U C TI O N

over the past few decades.1 The Centers for Disease Control and Prevention (CDC) attributed nearly 500 000 cases in the

Clostridium difficile, an anaerobic gram-­ p ositive, spore-­ forming, toxin-­p roducing bacillus, has emerged as a major enteric pathogen

United States annually and over 14 000 deaths to C. difficile.2,3 Hospitalizations for CDI doubled between 2000 and 2010.4

Abbreviations: AZA, azathioprine; CDI, Clostridium difficile infection; CSA, cyclosporine; CTA, cytotoxicity assay; FMT, fecal microbiota transplantation; HIV/AIDs, human immunodeficiency virus/acquired immunodeficiency syndrome; HSCT, hematopoietic stem cell transplantation; IBD, inflammatory bowel disease; NAAT, nucleic acid amplification test; PCKD, polypcystic kidney disease; rCDI, recurrent Clostridium difficile infection; SLE, systemic lupus erythematosus; SOT, solid organ transplant; T1DM and T2DM, Type 1 and 2 Diabetes Mellitus, respectively; TC, toxigenic culture. Alonso and Moss equally contributed to this study.

Transpl Infect Dis. 2018;e12967. https://doi.org/10.1111/tid.12967

wileyonlinelibrary.com/journal/tid

© 2018 John Wiley & Sons A/S.  |  1 of 9 Published by John Wiley & Sons Ltd

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TA B L E   1   Baseline characteristics of patients receiving FMT for recurrent CDI after solid organ transplantation Patient 1 Age (years)

64

Patient 2 63

Patient 3 34

Patient 4 58

Patient 5 62

Gender

F

M

F

F

F

Smoker

No

No

No

Prior

No

BMI (kg/m2)

34.5

30.7

21.3

18.5

23.6

WBC (k/μL)

10.5

11.1

4.3

6.8

14.5

Hgb (g/dL) Plt (K/μL) Albumin (g/dL)

11.6 374

12 371

9.8 181

11.3 223 4.1

11.5 303

4.6

4.2

4.5

Solid organ transplant(s)

Kidney

Pancreas

Kidney

Kidney (prior pancreas)

Kidney

4.0

Transplant Indication

PCKD

T1DM, hypoglycemia unawareness

Reflux nephropathy

T1DM nephropathy

SLE Nephritis

Year of most recent transplant

2002

2008

2013

2008

2000

Other comorbidities

HTN, PCKD, Sarcoidosis

HTN, HLD, T2DM

HTN

CAD, CHF, COPD, T1DM

Atrial fibrillation, ILD, HBV, SLE

CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; HBV, hepatitis B virus; HLD, hyperlipidemia; HTN, hypertension; ILD, interstitial lung disease; PCKD, polypcystic kidney disease; SLE, systemic lupus erythematosus; T1DM and T2DM, Type 1 and 2 Diabetes Mellitus respectively.

Factors behind increasing CDI incidence and mortality include in-

2 | C A S E S

creased antibiotic use, an aging population, and the emergence of virulent strains such as the BI/NAP1/027/toxinotype III strain. 5,6

In Table 1, we describe a series of SOT recipients at our academic,

Among patients receiving solid organ transplantation (SOT) and

tertiary-­care hospital. Each patient presented with rCDI and under-

hematopoietic stem cell transplantation, CDI rates also increased.7

went treatment with FMT (Table 1). We also summarize the clinical

Factors contributing to increased pathogenicity of C. difficile in

course of one of these patients in detail. Table 2 outlines the out-

this population include iatrogenic immunosuppression, antibi-

comes in these patients after FMT.

otic use, and prolonged or frequent hospitalizations. 8 CDI among transplant receipts is associated with significant morbidity and mortality.9,10

Patient 1 is a 64 year-­old woman with a history polycystic kidney disease complicated by renal failure requiring a living, unrelated donor kidney transplant (2002). Her post-­ transplant course was

As per the recent guidelines published by the Infectious

complicated by severe hemorrhagic E. coli enterocolitis, and throm-

Diseases Society of America (IDSA) and the Society for Healthcare

botic thrombocytopenic purpura and hemolytic-­uremic syndrome.

Epidemiology of America (SHEA), treatment options for initial and

She had complications including acute renal failure requiring dialysis

recurrent episodes of CDI include vancomycin or fidaxomicin, either

and ischemic colitis requiring a right hemi-­colectomy. Her first ep-

as a 10 day course or as a taper in recurrent cases.11-13 Recurrence is

isode of CDI was 8 years after her kidney transplant (2010), after

common in transplant receipts because of ongoing immunosuppres-

receiving cephalexin for cellulitis. She subsequently developed five

sion and frequent antibiotic exposure. The concept and application

recurrences of CDI—these were treated with oral vancomycin (twice

of fecal microbiota transplantation (FMT) emerged after it was dis-

with tapers).

covered that patients with recurrent or refractory CDI (rCDI) had

At the time of initial evaluation, she had just completed a 10-­

markedly decreased fecal bacterial diversity using 16S r-­RNA gene

day course of fidaxomicin but continued to have 3-­4 loose stools a

sequencing.14 Thus, FMT has been developed as a safe, effective option for rCDI.15-17 However, the safety and efficacy of FMT in SOT

day. She was on azathioprine 50 mg daily, cyclosporine 125 mg twice daily, famotidine 20 mg daily and Saccharomyces boulardii 250 mg

recipients is not well-­established. Currently, no guidelines for the

daily (Florastor ®). We performed FMT using donor stool obtained

treatment of rCDI with FMT exist in this population. Few case re-

from OpenBiome (Somerville, Massachusetts), delivered to the

ports have demonstrated the short-­term safety and efficacy of FMT

cecum during a colonoscopy.

in SOT recipients. We describe a case series of patients with SOT

One week following FMT, the patient developed abdominal

and rCDI. We report long-­term efficacy and safety data, and sum-

cramping without fevers or chills. She was prescribed hyoscyamine

marize the current available literature on the epidemiology, role, and

(anti-­spasmodic) after a reassuring abdominal X-­ray. She continued

experience of FMT for treating rCDI in SOT patients.

to have abdominal pain and loose stools, and tested positive again

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TA B L E   2   Prior CDI and peri-­FMT characteristics, risk factors, and outcomes Patient 1 # of Prior CDI episodes

Patient 2

Patient 3

Patient 4

Patient 5

6

5

6

3

4

Prior CDI due to antibiotics

Yes

Yes

Yes

Yes

Antibiotic indication

Cellulitis

Cellulitis; PPx

Pneumonia/UTI

Bronchitis

Time SOT-­1st CDI (years)

11.1

4.6

0.7

9.2

15.4

Time 1st CDI-­FMT (years)

2.5

4.0

1.8

0.5

2.1

No -­

Severity of most recent CDI (IDSA criteria)

Mild-­Moderate

Mild-­Moderate

Mild-­Moderate

Mild-­Moderate

Mild-­Moderate

Pre-­FMT probiotic

Yes

No

No

No

Yes

Pre-­FMT PPI/H2B

Yes

No

No

Yes

Yes

Immunosuppression

AZA, CSA

Tacro, MMF

AZA, Tacro, Prednisone

Tacro, MMF, Prednisone

Tacro, Prednisone

Transplant-­specific complications

No

No

No

No

No

Previous acute rejection

No

No

No

No

No

Chronic antimicrobials at time of FMT

No

No

No

No

No

Formed stools before FMT

No

Yes

Yes

Yes

Yes

Inpatient FMT

No

No

No

No

No

FMT delivery

Colonoscopy

Colonoscopy

Colonoscopy

Colonoscopy

Colonoscopy

Post-­FMT follow-­up (months)

27.7

Post-­FMT CDI recurrence (days to recurrence)

Yes (12)

Received 2nd FMT FMT-­related adverse events

Y Cramping

8.4

21.9

2.5

1.2

No

No

No

No

No

No

No

No

No

No

Cramping; Constipation

No

AZA, azathioprine; CDI, C. difficile infection; CKD, chronic kidney disease; CSA, cyclosporine; FMT, fecal microbiota transplantation; H2B, H2 receptor blocker; HELLP, hemolysis, elevated liver enzymes, low platelets; MMF, mycophenolate mofetile; PPI, proton-­pump inhibitor; PPx, prophylaxis; Tacro, tacrolimus; TTP-­HUS, thrombotic thrombocytopenic purpura-­hemolytic uremic syndrome; UTI, urinary tract infection.

for C. difficile by C. difficile toxin A/B gene PCR. She was placed on

vancomycin, fidaxomicin, and finally with a vancomycin taper over

an oral vancomycin course by her primary care provider (without

2 months. At the time of FMT, he had just completed his vancomy-

improvement) and then on fidaxomicin for 14 days, with resolution

cin taper and was having formed stools. Following a well-­tolerated

of diarrheal symptoms. After her diarrhea resolved, she underwent

FMT, he did not have another recurrence during his nearly 9 month

a second FMT via colonoscopy. After this, she had no further CDI

follow-­up period.

recurrence over 10 months of follow-­up.

Patient 3 is a 34 year-­old woman with a history of reflux ne-

Patient 2 is a 63 year-­old man with a history of type 1 diabe-

phropathy complicated by stage 5 chronic kidney disease. She un-

tes mellitus with severe hypoglycemic unawareness. He received

derwent a living related donor kidney transplant in 2013. Her initial

a pancreas transplant in 2008. Postoperatively, he was placed on

immunosuppressive regimen included MMF and tacrolimus, and

mycophenolate mofetil (MMF) and tacrolimus, as well as sulfame-

she was placed on Bactrim and Valcyte for prophylaxis. Her MMF

thoxazole/trimethoprim (Bactrim) and valganciclovir (Valcyte) for

was eventually replaced with azathioprine. Her first CDI occurred

antimicrobial prophylaxis. His first episode of CDI occurred approx-

approximately 9 months after her transplantation, after being ad-

imately 1 week after a 2-­week course of cephalexin for cellulitis of

mitted for a urinary tract infection (UTI) and possible pneumonia,

his right index finger. During this infection, his Bactrim was also in-

during which time she received intravenous ceftriaxone. This index

creased to twice a day. His index CDI was treated with a 2-­week

CDI was treated with a 3-­week course of oral vancomycin (overlap-

course of metronidazole. His prophylactic Bactrim was then dis-

ping a 1 week course of levofloxacin for UTI and pneumonia). She

continued. However, he subsequently developed 4 more episodes

subsequently developed 5 more course of CDI, treated with either

of CDI. One of these episodes of CDI followed a course of oral

vancomycin tapers or fidaxomicin. In early 2016, she developed

doxycycline for an upper respiratory infection. His episodes of CDI

thrombotic microangiopathy thought related to tacrolimus; thus,

recurrence were treated with metronidazole (for first recurrence),

her tacrolimus was briefly switched to cyclosporine for 2-­3 months.

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She ultimately received FMT, which was well-­tolerated. She remains

pylori stool antigen, stool bacterial cultures, stool ova & parasite

without diarrheal symptoms now for a 22-­month follow-­up period.

testing, and stool C. difficile toxin.18 The constituents of the FMT

Patient 4 is a 58 year-­old woman with a history of type 1 diabetes

preparation include human feces filtered to 330 microns, sodium

mellitus complicated by nephropathy. She received a pancreas trans-

chloride (0.9%), glycerol (12.5%), and water. These preparations are

plant in 1996, which failed, followed by a deceased donor kidney

packaged in plastic bottles and kept in a locked freezer in the en-

transplant in 2008. Her immunosuppressive medications included

doscopy center, maintained at −20°C. The thawing process starts

MMF and tacrolimus. Her index CDI occurred after a bout of bron-

approximately one hour prior to FMT. A preparation is thawed in a

chitis for which she was treated with a 5-­day course of azithromycin.

warm water bath at 30°C. Alternative thawing methods include leav-

She was off of all prophylactic antimicrobials at the time of her index

ing the preparation at room temperature or in a refrigerator. Once

CDI. She subsequently developed two CDI recurrences. After she

thawed, a preparation can sit at room temperature for 4 hours or

received her FMT, she experienced mild cramping and constipation.

in the refrigerator for 8 hours. If unused, thawed preparations are

However, at 2.5 months follow-­up, she was noted to be asymptom-

discarded.

atic without evidence of CDI recurrence.

For patients undergoing treatment for an episode of CDI or who

Patient 5 is a 62 year-­old woman with a history of interstitial lung

are on chronic CDI antibiotic suppression, CDI treatment courses

disease and lupus nephritis. She received a living donor kidney trans-

must be completed prior to FMT. Our policy recommends discon-

plant in 2000. She was on a stable regimen of tacrolimus and pred-

tinuation of oral vancomycin 24 hours or oral fidaxomicin 48 hours

nisone when she developed abdominal cramping, diarrhea, and was

prior to FMT. During the treatment procedure, the thawed prepa-

diagnosed with her index CDI. She completed a 2-­week oral vanco-

ration is loaded into four 60 cc Luer-­slip syringes. A colonoscopy is

mycin course, but 3 months later had a bout of diverticulitis compli-

performed and upon reaching the cecum, the preparation is injected

cated by perforated sigmoid, requiring partial left-­sided colectomy

consecutively into the right colon. If the cecum cannot be reached,

with colostomy. During this peri-­operative time and subsequently,

or if patients are high-­risk for the procedure or anesthesia, a flexible

she developed three more episodes of CDI, treated with vancomycin

sigmoidoscopy may be performed with delivery of the preparation

tapers. After her most recent episode and upon completion of her

into the descending or sigmoid colon. Routine postprocedure mon-

taper, she received FMT without adverse events.

itoring applies, and patients are encouraged to avoid unnecessary

Overall, the cases we present include a series of four patients

antibiotics. Patients are also counseled about possible associated

with kidney transplantation and one patient with a pancreas trans-

post-­FMT symptoms, such as change in bowel habits, abdominal

plant who developed rCDI treated with FMT. The number of years

pain, cramping, or bloating. They are advised to contact us immedi-

from transplantation to FMT ranged from 5 to 18 years. The time

ately if these symptoms occur.

between organ transplantation to index CDI range from 0.7 to 15.4 years. Patient 1 had six episodes of CDI and required two FMT procedures, whereas patients 2-­5 had a mean of 4.5 CDI episodes and each underwent a single FMT. Patients 2 and 3 developed their index CDI episodes while receiving prophylactic Bactrim. Patient 2 had Bactrim discontinued for rCDI. Four of the five cases had their index CDI following a course of antibiotics. Two patients had CDI following cephalexin for soft tissue infections; one developed CDI

4 | REVIEW OF LITERATURE ON THE EPIDEMIOLOGY OF CDI IN PATIENTS WITH SOLID ORGAN TRANSPLANTATION AND THE APPLICATION OF FMT IN THIS POPULATION 4.1 | Epidemiology of CDI in SOT patients

following a course of IV ceftriaxone for a urinary tract infection and

CDI is an established major infectious complication following SOT.

pneumonia; and one developed CDI following a course of azithromy-

More than 34 700 patients in the United States received a SOT in

cin for bronchitis. FMT was well tolerated by our patients. The most

2017—this number continues to grow.19 In SOT recipients, it is es-

common adverse event was cramping; patient 4 also developed con-

timated that the risk of CDI is up to five times higher than the gen-

stipation after FMT.

eral population. 20 The estimated annual incidence of CDI after SOT ranges from 2.5% to 22.9%.7 In one meta-­analysis, the estimated

3 |  FEC A L M I C RO B I OTA TR A N S PL A NTATI O N PROTO CO L

prevalence was 7.4%, varying based on type of organ transplant.8 Higher prevalence was noted in those receiving more than one organ (12.7%), and those receiving lung (10.8%), liver (9.1%), and intestinal transplants (8%). Lower prevalence of CDI was noted in heart (5.2%),

Our fecal microbiota preparations are obtained from OpenBiome

kidney (4.7%), and pancreas (3.2%) transplants.8 The incidence of

(Somerville, Massachusetts; www.openbiome.org). The donor

CDI in SOT patients is highest within the first 3 months of trans-

screening process is rigorous and includes a 200-­point clinical ques-

plantation (early onset CDI), likely due to new immunosuppression,

tionnaire and an extensive array of blood and stool tests performed

antimicrobial exposure, and prolonged hospitalization. 21 Late onset

by the company. Screening includes complete blood count with

CDI (>6 months post-­ transplant) may be associated with antimi-

differential, hepatitis panel (A, B, and C), liver function tests, HIV,

crobial exposure or intensified immunosuppression to treat graft

human T-­cell lymphotropic virus, and syphilis testing, Helicobacter

rejection.9,21,22

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The increased morbidity and mortality of CDI in SOT patients 9,10,20

is well-­described.

unknown, particularly in the symptomatic patient. Furthermore,

CDI in SOT patients is also associated with

up to 25% of patients may have some component of postinfec-

more hospital readmissions, admissions to intensive care units,

tious irritable bowel syndrome, which many further confound the

longer hospital length-­of-­stay, higher costs, and poorer transplant

clinical picture. 27 Among asymptomatic patients, the colonization

outcomes.

23

In a retrospective cohort of patients who underwent

rates of C. difficile following FMT are known to be low. In one

kidney or pancreas transplant (N = 998), 28 recipients (2.8%) devel-

prospective cohort of non-­SOT patients that underwent FMT fol-

oped CDI. Compared to controls, patients who developed CDI were

lowed for 8 weeks, asymptomatic C. difficile carriage rates (NAAT)

more likely to be males, have received deceased-­donor organs, be

were noted to be 2.1%. 28

leukopenic, and have undergone a gastrointestinal procedure within 3 months preceding CDI diagnosis. 24

4.2 | Risk factors for CDI recurrence in SOT patients

4.4 | Treatment considerations and the role of CDI prophylaxis Treatment of first CDI recurrence typically involves oral vancomy-

In the general population, risk factors for rCDI include advanced age,

cin or fidaxomicin.12,13,29 Guidelines differ for second recurrences

multiple medical comorbidities, increased hospital length-­of-­stay,

and beyond, but most suggest vancomycin with a taper. 21,30 In the

previous gastrointestinal surgery or manipulation, inflammatory

2017 guidelines published by the Infectious Diseases Society of

bowel disease (IBD), chemotherapy, tube-­feeding, acid-­suppressive

America (IDSA) and the Society for Healthcare Epidemiology of

1,24

medications, and prolonged antibiotic use.

Among SOT patients,

America (SHEA), a strong recommendation was made based on mod-

post-­transplant specific risk factors for developing rCDI have also

erate quality of evidence to consider FMT as treatment for second

been established and include chronic immunosuppression, antibiotic

or subsequent rCDI.13 Selection of treatment should be based off

exposure for infection prophylaxis, and frequent hospitalizations. In

of disease severity, risk of recurrence, and presence of complica-

heart and lung transplant recipients, the reported rates of recurrent

tions.11,12,21 Prophylaxis against rCDI in SOT patients has been stud-

7,10,21

CDI in this population are noted to be between 29% and 50%.

ied using metronidazole and vancomycin.31 A small study (N = 36)

Increased immunosuppression related to graft rejection also in-

showed that renal transplant patients with a history of CDI who

creases the risk for CDI recurrence.9,21,22

were receiving broad-­spectrum antibiotics had 0% CDI recurrence on prophylaxis with oral vancomycin (125 mg twice daily), vs 8% among those without vancomycin (P = 0.54).32 Larger well-­powered,

4.3 | Diagnostic considerations

prospective studies are required to investigate the effects of these

The diagnosis of CDI and rCDI can be made using numerous assays, 11,12

whose availability vary across institutions.

The gold standard

for detecting toxins A/B or a toxigenic C. difficile strain is stool cytotoxicity assay (CTA) and toxigenic culture (TC), respectively.6,12 However, the time to result for these tests are 48-­72 hours to 7 days

4.5 | Role of fecal microbiota transplantation The treatment of rCDI with fecal microbiota transplantation has

Most clinical settings now use the rapid and highly

gained significant traction over the past decade.16 The mechanism

sensitive nucleic acid amplification test (NAAT) to detect tcdA/tcdB

of action of FMT is assumed to be the reconstitution of the intesti-

or tcdC gene as a marker of the presence of toxigenic C. difficile. One

nal microbiotic flora by diminishing the metabolic niche that C. dif-

challenge in interpreting a positive NAAT test is its clinical speci-

ficile has acquired in an affected patients’ colonic ecology. 33 The

respectively.

25

preventive measures.

ficity. The testing can also be positive in asymptomatic carriers.12

microbial ecology of a patient’s colon post-­FMT shows increased

The introduction of widespread NAAT testing for CDI has led to an

diversity and reconstitution of phyla that promote colonic health,

increase in incidence, with occasional inappropriate treatment of

including Firmicutes, Bacteroidetes, and Faecalibacterium. 34,35 It is

6

CDI in carriers whose diarrhea is not caused by C. difficile. For this

an effective therapy for rCDI, with reported efficacy between

12

reason, CDI testing is only recommended in symptomatic patients.

60% and 90% after one treatment. 33,36,37 Some studies cite pri-

In populations with co-­morbid conditions that cause diarrhea—such

mary and secondary cure rates of 91% and 98%, respectively. 37,38

as IBD, antibiotic or medication-­associated diarrhea—testing for CDI

Various formulations and route of administration have been stud-

is a challenge.5 The reported indices for classifying CDI severity are

ied: nasoduodenal tube, 39 oral capsules, 36 or most typically, in

based on many parameters that are also impacted by these comorbid

liquid form during a colonoscopy. 37,40 Higher efficacy rates are

conditions, so determining CDI severity in the setting of other pro-

reported with lower gastrointestinal delivery modalities,15 though

cesses may be difficult.

20,24,26

a recent trial proved oral capsules to be noninferior. 36 In a system-

Following FMT, many patients report altered stool pattern

atic review and meta-­analysis, FMT was generally safe; mortality

for days to weeks. Unlike antimicrobial agents, FMT is not bac-

occurred mostly in the critically ill or elderly with severe comor-

teriostatic and requires time for the transplanted microbiome to

bidities.15 Common mild adverse events include diarrhea, cramp-

integrate and provide metabolic competition to C. difficile. The

ing, belching, nausea, abdominal pain, bloating, and transient

utility and timing of repeat NAAT testing after FMT is currently

fever.16,41

N = 1 (heart) N = 2 (renal, lung)

Case report

Case report

Multicenter, retrospective

Case report

Retrospective

Case report

Case report

Ehlermann et al. (2014) 42

Friedman-­Moraco et al. (2014) 43

Kelly et al. (2014) 46

Bilal et al. (2015) 44

Alrabaa et al. (2017)18

Flannigan et al. (2017)35

Schneider et al. (2018) 45

Flexible Sigmoidoscopy (proximal rectum), then oral capsules

Enema

Naso-­duodenal tube

Colonoscopy

Colonoscopy

Renal SOT: Naso-­jejunal tube (NJT), then colonoscopy Lung SOT: Colonoscopy, then NJT

Endoscopy (duodenum)

FMT delivery route

FMT, fecal microbiota transplantation; NJT, naso-­jejunal tube; SOT, solid organ transplantation.

N = 1 (liver)

N = 1 Pediatric (5 years-­old; heart)

N = 13 (6 with SOT: lung, liver, kidney)

N = 1 (dual SOT: liver, kidney)

N = 80 immuno-­ compromised patients (n = 19 with SOT)

# of Patients and organ transplanted

Study design

References

Severe, complicated CDI without response to PO vancomycin; received FMT via flexible sigmoidoscopy (brother as donor) Slight increase in stool frequency 6 d after 1st FMT; 2nd FMT via oral capsules

1st FMT – normalized diarrhea within 1 wk; recurrence after antibiotics for cervical adenitis 3 mo later 2nd FMT – remained well for >2 y

CDI recurrence in 3 of 6 patient with SOT (recurrence of diarrhea within 8 wk and positive CDI testing); 2 of these 3 received 2nd FMT; 1 patient had cure after 2nd FMT

Diarrhea resolved 2 d after 1st FMT

Primary outcome: CDI cure rate (absence of diarrhea within 12 wk post-­FMT) and adverse events CDI cure rate 79% after 1st FMT 12 patients repeated FMT Overall cure rate 89% (including those with 2 FMTs)

Renal SOT: CDI recurrence 2 wk after FMT via NJT. After 2nd FMT via colonoscopy, no recurrence at 1 y Lung SOT: CDI recurrence 3 wk after FMT via colonoscopy; expired in hospice 5 d after 2nd FMT via NJT

Diarrhea improved after 3 d (daughter as donor); no recurrence at end of follow-­up period

Summary

TA B L E   3   Prior case reports and studies on the use and outcomes of FMT in patients with SOT

None

None

Cramping, diarrhea

None

Diarrhea, bloating, discomfort

None

None

Most common adverse Events

8 wk

2.5 y

Unclear

6 mo (expired from cardiac arrest)

11 mo (mean); range 3-­46  mo

1 y (renal); 1 mo (lung)

4 mo

Length of follow-­up

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4.6 | Previously described cases and studies on the use of FMT in SOT patients

studies, suggesting durability of FMT for maintaining remission in these patients. Overall, our series demonstrate the safety and efficacy of FMT

Currently, there are only a handful of studies on the utility and

in patients with SOT using a uniform, well-­defined protocol, and are

outcome of FMT in the SOT population specifically, and most are

able to achieve a cure rate of 80%-­100% after one or more FMT. It

with limited follow-­up intervals

35,42-45

(see Table 3). Early case

is important to note that Patient 1 was determined to have relapsed

reports demonstrated the safety and feasibility of FMT in this

within 2 weeks of FMT, and this determination was based off of

population. One case report described a pediatric heart transplant

NAAT testing, which is the primary test available at our institution.

patient with rCDI who required two FMTs (delivered by rectal en-

Thus, it can be debated whether this patient truly relapsed (and if

emas) to adequately reconstitute colonic microbial diversity with

a positive NAAT test this close to an index FMT represents a true

the phylas Firmicutes, Bacteroidetes and families Lachnospiraceae

positive) or if she would have improved with time (ie become as-

and Ruminococcaceae.35 Other case reports vary by the route of

ymptomatic at 1 month after FMT) without requiring a second FMT.

FMT delivery—endoscopically into the duodenum,42 through a

Nonetheless, our cure rate was achieved using the most efficacious

naso-­jejunal tube,

43

during colonoscopy,

44

and via flexible sigmoi-

modality—through colonoscopy—whereas previously published

doscopy or with oral capsules.45 Cure rates range from 50% to

series vary in preparation delivery modality and thus may reflect

100% depending on the length of follow-­up (ranging from 8 weeks

a wider range of cure rates (50%-­100%). It is notable that most of

to 2.5 years).18,35,42-45

our patients considered for FMT for rCDI were late (>6 months) fol-

In recent years, two larger cohorts of patients with SOT receiv-

lowing SOT and were on stable immunosuppression at time of FMT.

ing FMT have been published, further demonstrating the safety and

Thus, one limitation of our experience is that we cannot comment

efficacy of FMT in this group. Alrabaa et al. described a single-­center

specifically regarding the safety or efficacy of FMT in patients early

series of 13 patients with rCDI who received FMT through a naso-­

after SOT or in whom there has been recent augmentation of im-

duodenal tube. Six of the thirteen were SOT recipients (1 lung, 1

munosuppression. However, our data complement and add to the

kidney/lung, 4 kidney).18 After the 1st FMT, 3 of 6 (50% cure rate)

limited published experience using FMT in immunocompromised pa-

of SOT patients recurred; 2 of the 3 received a second FMT, one

tient populations, specifically amongst SOT recipients.

of whom achieved cure. Limitations of the study include unclear follow-­up intervals. The largest, multicentered cohort to date documents 80 immunocompromised patients.46 The cure rate after a

6 | CO N C LU S I O N S

single FMT was 78%. Among the 19 SOT patients in this cohort, there was one death due to pneumonia from aspiration.46 The SOT

Fecal microbiota transplantation is a safe and efficacious treatment

patients in this cohort, however, were not well-­characterized; mean

modality for rCDI. In our experience and in review of the litera-

follow-­up time for all patients was 11 months. Twelve patients in the

ture, it appears safe in SOT patients and may act as an alternative

entire cohort required a second FMT for cure, though 1 patient died

to conventional therapies. However, the literature regarding safety

during the procedure to administer FMT.

and efficacy in this population is limited and predominately based upon small, single-­center, retrospective reviews. Larger prospective

5 | D I S CU S S I O N

studies are needed before treatment guidelines for CDI pertaining to FMT are changed to include patients with SOT. In our experience treating five SOT recipients with FMT for rCDI,

Our series of five SOT patients with rCDI had a cure rate of 80%

we also found the procedure to be effective with an 80% primary

after one FMT, and 100% cure rate after two FMTs. Four of the five

cure rate after one FMT, with few mild FMT-­related AEs and no

patients had their initial CDI following a course of antibiotics, ei-

transplant-­related AEs. Most of our patients had antibiotic exposure

ther for soft tissue infections, urinary tract infection, or pneumonia.

as the primary driver for CDI, with cephalosporins being a common

Cephalosporins were the most commonly implicated antibiotic. FMT

trigger. Prophylactic Bactrim may have also contributed to the CDI

was well tolerated by our patients, with cramping being the most

risk in several of our patients. Thus, the risk versus benefit of antimi-

common adverse event. This is similar to the safety profile of FMT in

crobial use and prophylaxis should be weighed in those with CDI risk

SOT patients published to date, with case reports and series docu-

factors, especially post FMT to minimize relapse. Thus, candidates

menting diarrhea, bloating, mild discomfort, or cramping as the most

for FMT should be selected carefully, keeping in mind major comor-

common adverse events. In our series of SOT patients, the demo-

bidities, risk factors for recurrence after FMT, severity of CDI, and

graphic, baseline, and CDI-­related histories are well-­characterized

the risks involved with certain delivery modalities.

in comparison to prior case reports or series, including the number of prior episodes of CDI, time from SOT to first CDI, time from first CDI to FMT, and the type of immunosuppression they were on at

C O N FL I C T O F I N T E R E S T

time of FMT. We have a significantly longer follow-­up period in two

Dr. Carolyn Alonso has acted as a scientific advisor to Merck and

of our patients (over 21 months) compared to prior aforementioned

Roche Diagnostics. Dr. Alonso has received research funding from

|

LIN et al.

8 of 9      

Merck. Dr. Alonso has NIH Loan Repayment Funding through the National Institute of Allergy and Infectious Diseases (NIAID). Dr. Alan Moss has acted as a consultant to Seres Therapeutics. There

14.

are no conflicts of interest. 15.

AU T H O R S C O N T R I B U T I O N S Steven C. Lin: Drafting of the manuscript, analysis and interpretation of data, critical revision of the manuscript, approved final sub-

16. 17.

mission. Carolyn D. Alonso: Drafting of the manuscript, analysis and interpretation of data, critical revision of the manuscript, approved final submission. Alan C. Moss: Drafting of the manuscript, analysis

18.

and interpretation of data, critical revision of the manuscript, approved final submission.

20.

ORCID Steven C. Lin 

19.

http://orcid.org/0000-0003-4620-1505

Carolyn D. Alonso 

21.

http://orcid.org/0000-0002-3140-1128 22.

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How to cite this article: Lin SC, Alonso CD, Moss AC. Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with solid organ transplants: an institutional experience and review of the literature. Transpl Infect Dis. 2018;e12967. https://doi.org/10.1111/tid.12967