THE ROLE OF THE MICROBIOME IN RECURRENT C. DIFF

FOLLOWING COMPLETION OF ANTIBIOTIC TREATMENT1,2

RECURRENCES CAN HAPPEN AS QUICKLY AS a few days

MOST RECURRENCES OCCUR WITHIN 1–2 WEEKS

While antibiotics are effective in treating C. diff, they inherently do not protect against recurrence

Recurrent C.Diff Gut Microbiome

Recurrent C. diff and microbiome health8

The gut microbiome has a profound effect on overall health such as protection against pathogens, including C. diff

In a healthy microbiome, there is an exceedingly diverse ecosystem that houses several trillion microbial cells

Recurrent C.Diff Gut Microbiome

Antibiotics disrupt the microbiome

The use of broad-spectrum antibiotics to treat a source infection disrupts the microbiome, creating conditions for primary C. diff infection to occur

Lack of microbial diversity is associated with both primary and recurrent C. diff infections

Recurrent C.Diff Gut Microbiome

Dormant C. diff spores linger

Although C. diff-targeted antibiotics kill vegetative toxin-producing bacteria, dormant C. diff spores remain—increasing the risk of recurrence

Dormant C. diff spores serve as a reservoir for recurrent infections

Recurrent C.Diff Gut Microbiome

A breeding ground for subsequent C. diff recurrences

C. diff-targeted antibiotics disrupt the microbiome, which can produce a favorable environment for the unaffected dormant C. diff spores to rapidly germinate and grow

A disrupted microbiome provides a "niche" for C. diff spores to switch from a dormant state to actively growing vegetative cells

Recurrent C.Diff Gut Microbiome

The cycle of recurrent
C. diff continues

Antibiotics that treat subsequent recurrences exacerbate an already-disrupted microbiome—contributing to a patient's cycle of recurrent C. diff

Following the first C. diff recurrence, a patient's risk of subsequent recurrence is >40%—after the second C. diff recurrence, a patient’s risk then increases to >60%

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Learn about recurrent C. diff and the microbiome

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TAKE THE C.Diff Challenge The Role of the Microbiome

Endless C. diff sequels? Can microbiome restoration change the ending of the same frightening plot? Answer 5 questions to put your knowledge to the test.

QUESTION 1 of 5

NEXT QUESTION

TRUE OR FALSE

The use of broad-spectrum antibiotics to treat a source infection may create conditions for a primary C. diff infection to occur.

Yipee! Oops!

The correct response is TRUE.

A healthy microbiome is diverse, but the use of broad-spectrum antibiotics depletes microbial diversity, creating conditions for primary (and recurrent) C. diff infections.

Did you know the Centers for Disease Control and Prevention (CDC) has characterized
C. diff as an Urgent Health Threat? With approximately 170,000 recurrent episodes in the US every year, recurrent C. diff is a serious condition that requires serious attention.

>40%

Following the first C. diff recurrence, a patient’s risk of subsequent recurrence is >40%— after the second C. diff recurrence, that risk then increases to >60%6

50%

Approximately half of all patients with recurrences have a C. diff-related hospital readmission7*

  • *196 of 413 patients were hospitalized within 6 weeks of completing their index C. diff antibiotic treatment or date of index hospitalization discharge, whichever occurred later.
NEXT QUESTION

1. Vincent C, Miller MA, Edens TJ, Mehrotra S, Dewar K, Manges AR. Microbiome. 2016;4(12):1-11. doi:10.1186/s40168-016-0156-3. 2. Chang JY, Antonopoulos DA, Kalra A, et al. J Infect Dis. 2008;197(3):435-438. doi:10.1086/525047. 3. Lynch SV, Pedersen O. N Engl J Med. 2016;375(24):2369-2379. doi:10.1056/NEJMra1600266. 4. CDC. Atlanta, GA: U.S. Department of Health and Human Services, 2019. doi: http://dx.doi.org/10.15620/cdc:82532. 5. Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. BMC Infect Dis. 2016;16(303):1-10. doi:10.1186/s12879-016-1610-3. 6. Kelly CP. Clin Microbiol Infect. 2012;18(suppl 6):21-27. doi:10.1111/1469-0691.12046. 7. Olsen MA, Yan Y, Reske KA, Zilberberg M, Dubberke ER. Am J Infect Control. 2015;43(4):318-322. doi:10.1016/j.ajic.2014.12.020.

QUESTION 2 of 5

TRUE OR FALSE

Following completion of C. diff-targeted antibiotic treatment, recurrences can happen as quickly as a few days.

Yay! Uh-Oh!

The correct response is TRUE.

Recurrences can happen as quickly as a few days following completion of antibiotic treatment, with most recurrences occurring within 1–2 weeks.

RECURRENCES CAN HAPPEN SCARY FAST: A FACT
THAT’S GROUNDED IN SCIENCE

A study published in The American Journal of Gastroenterology—examining cases of recurrent C. diff collected from two national, double blind, placebo-controlled trials—stated that the time between a prior C. diff infection and a subsequent recurrence is “relatively short.”

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It all came back and it’s worse than ever… it’s all I think about, it’s all I dwell on.

Quote from patient with recurrent C. diff

1. McFarland LV, Elmer GW, Surawicz CM. Am J Gastroenterol. 2002;97(7):1769-1775. doi:10.1111/j.1572-0241.2002.05839.x. 2. McFarland LV, Surawicz CM, Greenberg RN, et al. JAMA. 1994;271(24):1913-1918.

QUESTION 3 of 5

TRUE OR FALSE

C. diff-targeted antibiotics kill both vegetative toxin-producing bacteria and dormant C. diff spores—helping to protect patients against recurrence.

Bingo! Nope!

The correct response is FALSE.

While C. diff-targeted antibiotics are effective in treating an active infection, they inherently do not protect against recurrence. That’s because even though antibiotics are effective in treating C. diff vegetative growth, they do not affect dormant spores—leaving the patient with a disrupted microbiome vulnerable to recurrence.

WHEN C. DIFF KEEPS COMING BACK

From a patient perspective, recurrent C. diff takes a personal toll. The sheer nature of having up to 15 bowel movements a day can significantly impact quality of life and jeopardize one’s professional life. Many also report harmful psychological consequences, including fear and worsening anxiety/depression.

Anxiety icon Professional Icon Mental Health Icon

1. Budi N, Safdar N, Rose WE. FEMS Microbes. 2020;1(1):1-8. doi:10.1093/femsmc/xtaa001. 2. Lewis BB, Buffie CG, Carter RA, et al. J Infect Dis. 2015;212(10):1656-1665. doi:10.1093/infdis/jiv256. 3. Chilton CH, Pickering DS, Freeman J. Clin Microbiol Infect. 2018;24(5):476-482. doi:10.1016/j.cmi.2017.11.017. 4. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461. doi:10.1146/annurev-micro-091014-104115. 5. Chang JY, Antonopoulos DA, Kalra A, et al. J Infect Dis. 2008;197(3):435-438. doi:10.1086/525047. 6. Cole SA, Stahl TJ. Clin Colon Rectal Surg. 2015;28(2):65-69. doi:10.1055/s-0035-1547333. 7. Lurienne L, Bandinelli PA, Galvain T, Coursel CA, Oneto C, Feuerstadt P. J Patient Rep Outcomes. 2020;4(1):14. doi:10.1186/s41687-020-0179-1.

QUESTION 4 of 5

TRUE OR FALSE

Microbiome restoration following antibiotic treatment may help prevent C. diff spore germination.

Nice Job! Sorry!

The correct response is TRUE.

Research has shown that microbiome restoration following antibiotic treatment may help prevent C. diff spore germination—which may protect patients against recurrence.

RECURRENT C. DIFF IS A SERIOUS CONDITION

C. DIFF HAS BEEN CHARACTERIZED AS AN URGENT HEALTH THREAT BY THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC)

9 DAYS

On average, a patient with recurrent C. diff infection spends 9 cumulative days in the hospital10*

33% HIGHER

The risk of death for patients with recurrent C. diff is 33% higher compared to those who do not recur11†

  • *On average, approximately 2 of the 9 days were attributable to the recurrent C. diff episode.
    †As measured at 6 months after their initial C. diff episode.

1. Isaac S, Scher JU, Djukovic A, et al. J Antimicrob Chemother. 2017;72(1):128-136. doi:10.1093/jac/dkw383. 2. Haak BW, Lankelma JM, Hugenholtz F, Belzer C, de Vos WM, Wiersinga WJ. J Antimicrob Chemother. 2019;74(3):782-786. doi:10.1093/jac/dky471. 3. Chilton CH, Pickering DS, Freeman J. Clin Microbiol Infect. 2018;24(5):476-482. doi:10.1016/j.cmi.2017.11.017. 4. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461. doi:10.1146/annurev-micro-091014-104115. 5. Weingarden AR, Chen C, Bobr A, et al. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):G310-G319. doi:10.1152/ajpgi.00282.2013. 6. Crobach MJT, Vernon JJ, Loo VG, et al. Clin Microbiol Rev. 2018;31(2):e00021-17. doi:10.1128/CMR.00021-17. 7. Song Y, Garg S, Girotra M, et al. PLoS One. 2013;8(11):e81330. doi:10.1371/journal.pone.0081330. 8. Weingarden AR, Dosa PI, DeWinter E, et al. PLoS One. 2016;11(1):e0147210. doi:10.1371/journal.pone.0147210. 9. CDC. Atlanta, GA: U.S. Department of Health and Human Services, 2019. doi: http://dx.doi.org/10.15620/cdc:82532. 10. Zhang D, Prabhu VS, Marcella SW. Clin Infect Dis. 2018;66(9):1326-1332. doi:10.1093/cid/cix1021. 11. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Clin Microbiol Infect. 2015;21(2):164-170. doi:10.1016/j.cmi.2014.08.017.

QUESTION 5 of 5

TRUE OR FALSE

There are therapeutic options that may help restore the microbiome directly following antibiotic treatment.

Yay! Uh-Oh!

The correct response is TRUE.

While there are therapeutic options that may help restore the microbiome directly following antibiotic treatment, these options remain limited

QUOTES FROM PATIENTS WITH RECURRENT C. DIFF

Quote icon

I had no idea it would be dragging on for almost a year

Quote icon

I carry with me a change of clothes when I leave the house and even have a portable toilet in the car

Quote icon

I was scared to death it would come back

1. van Nood E, Vrieze A, Nieuwdorp M, et al. N Engl J Med. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037. 2. Suez J, Zmora N, Zilberman-Schapira G, et al. Cell. 2018;174(6):1406-1423.e16. doi:10.1016/j.cell.2018.08.047. 3. Tsigrelis C. Cleve Clin J Med. 2020;87(6):347-359. doi:10.3949/ccjm.87gr.20001. 4. Wang S, Xu M, Wang W, et al. PLoS ONE. 2016;11(8):e0161174. doi:10.1371/journal.pone.0161174. 5. Oksi J, Anttila VJ, Mattila E. Ann Med. 2020;52(1-2):12-20. doi:10.1080/07853890.2019.1701703. 6. Suez J, Zmora N, Segal E, Elinav E. Nat Med. 2019;25(5):716-729. doi:10.1038/s41591-019-0439-x.

/5 CORRECT

Score background Score background

Therapeutic options that restore the microbiome directly following antibiotic treatment remain limited

  • •Vancomycin followed by fecal microbiota transplantation (FMT) has been shown to help prevent subsequent C. diff recurrences14
  • •Although FMT can help prevent recurrent C. diff due to its ability to restore the microbiome, it may be met with resistance from patients14-17
  • •While probiotics are widely used, further research is needed in the prevention of recurrent C. diff12,18

Ongoing research is investigating microbiome restoration for the future

C. Diff Research

While today there is an unmet need in recurrent C. diff treatment for FDA-approved therapeutics with the ability to repopulate the microbiome, Aimmune and Seres are committed to furthering innovative microbiome-related research to understand its role in patients' health and quality of life.

LEARN MORE ABOUT THE MICROBIOME AND C. DIFF

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ADDITIONAL RESOURCES: Peggy Lillis Foundation | C. diff Foundation

Seres Therapeutics has provided financial support to the Peggy Lillis Foundation and the C. diff Foundation.

References: 1. McFarland LV, Elmer GW, Surawicz CM. Am J Gastroenterol. 2002;97(7):1769-1775. doi:10.1111/j.1572-0241.2002.05839.x. 2. McFarland LV, Surawicz CM, Greenberg RN, et al. JAMA. 1994;271(24):1913-1918. Budi N, Safdar N, Rose WE. FEMS Microbes. 2020;1(1):1-8. doi:10.1093/femsmc/xtaa001. 3. Budi N, Safdar N, Rose WE. FEMS Microbes. 2020;1(1):1-8. doi:10.1093/femsmc/xtaa001. 4. Lewis BB, Buffie CG, Carter RA, et al. J Infect Dis. 2015;212(10):1656-1665. doi:10.1093/infdis/jiv256. 5. Chang JY, Antonopoulos DA, Kalra A, et al. J Infect Dis. 2008;197(3):435-438. doi:10.1086/525047. 6. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461. doi:10.1146/annurev-micro-091014-104115. 7. Chilton CH, Pickering DS, Freeman J. Clin Microbiol Infect. 2018;24(5):476-482. doi:10.1016/j.cmi.2017.11.017. 8. Lynch SV, Pedersen O. N Engl J Med. 2016;375(24):2369-2379. doi:10.1056/NEJMra1600266. 9. Vincent C, Miller MA, Edens TJ, Mehrotra S, Dewar K, Manges AR. Microbiome. 2016;4(12):1-11. doi:10.1186/s40168-016-0156-3. 10. Theriot CM, Bowman AA, Young VB. mSphere. 2016;1(1):e00045-15. doi:10.1128/mSphere.00045-15. 11. Gerding DN, Kelly CP, Rahav G, et al. Clin Infect Dis. 2018;67(5):649-656. doi:10.1093/cid/ciy171. 12. Oksi J, Anttila VJ, Mattila E. Ann Med. 2020;52(1-2):12-20. doi:10.1080/07853890.2019.1701703. 13. Kelly CP. Clin Microbiol Infect. 2012;18(suppl 6):21-27. doi:10.1111/1469-0691.12046. 14. van Nood E, Vrieze A, Nieuwdorp M, et al. N Engl J Med. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037. 15. Suez J, Zmora N, Zilberman-Schapira G, et al. Cell. 2018;174(6):1406-1423.e16. doi:10.1016/j.cell.2018.08.047. 16. Tsigrelis C. Cleve Clin J Med. 2020;87(6):347-359. doi:10.3949/ccjm.87gr.20001. 17. Wang S, Xu M, Wang W, et al. PLoS ONE. 2016;11(8):e0161174. doi:10.1371/journal.pone.0161174. 18. Suez J, Zmora N, Segal E, Elinav E. Nat Med. 2019;25(5):716-729. doi:10.1038/s41591-019-0439-x.