Page 37 – Practical Gastro

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #203

Metabolic Acidosis: Got Bicarbonate?

October 2020 • Volume XLIV, Issue 10

Acute or chronic metabolic acidosis is a condition that has serious complications. It develops from either increased acid production, increased enteric losses, or decreased renal acid secretion. Acutely, metabolic acidosis can cause serious cardiac and pulmonary complications; chronically, it can lead to alterations in protein catabolism, bone health, and hormonal changes. Correcting the metabolic acidosis is essential to minimizing these complications. Bicarbonate supplementation has been the mainstay for achieving acid-base balance; however, with ongoing medication shortages, clinicians must become creative with their treatment plan.

INTRODUCTION

The body’s ability to maintain acid-base balance is critical for health. The kidneys and lungs work harmoniously along with several buffering systems to maintain homeostasis. Acidemia occurs when arterial pH falls below 7.35, which can result in a metabolic, respiratory, or mixed acid-base disorder.¹ When the concentration of hydrogen ions in the body is increased reducing the bicarbonate concentration, metabolic acidosis ensues.² The three primary causes of metabolic acidosis are:³

Increased acid production

Loss of enteral bicarbonate in stool from pancreatic secretions

Decreased renal acid elimination or increased bicarbonate loss due to inability to “reclaim” filtered bicarbonate

Acute forms are most likely due to overproduction of acid; chronic forms are likely from the latter two causes.³

Acute metabolic acidosis can cause decreased cardiac output and arterial dilatation resulting in hypotension, decreased oxygenation, arrhythmias, and immune compromise.⁴ Chronic metabolic acidosis can lead to increased muscle degradation, increased osteoclastic activity, and alterations in endocrine function. Alterations in endocrine function include increased production of glucocorticoids and decreased production of thyroid hormones, insulin, and growth hormones.^5,6 While using bicarbonate to treat acute forms of metabolic acidosis is controversial as it has not always been shown to improve outcomes,⁷ it is the mainstay for chronic metabolic acidosis to help improve cellular function and prevent long term complications.³

Mechanism and Classification

Identifying the cause of metabolic acidosis is essential to guiding treatment and preventing adverse events. It can be classified based on the three major mechanisms as listed above. See Table 1A and B for more in-depth mechanisms. A useful tool is the measurement of the anion gap.^8,9 The anion gap is a value that represents the difference between the primary positively charged cation (Na+) and negatively charged anions (Cl- and HC03-) in the blood. Calculating the anion gap can also be helpful in classifying it as either elevated anion gap acidosis or normal (hyperchloremic) anion gap.¹⁰ Generally, excess acid production results in a high anion gap whereas excess base or decreased acid excretion by the kidneys results in hyperchloremic metabolic acidosis or normal metabolic acidosis.^8,9

Increased Acid Production

Increased acid accumulation that leads to metabolic acidosis can occur in a variety of clinical settings and leads to an anion gap metabolic acidosis. The main causes are due to lactic acidosis; ketoacidosis due to uncontrolled diabetes, excess alcohol or fasting; ingesting substances such as methanol, ethylene glycol, diethylene glycol, or propylene glycol; aspirin or acetaminophen poisoning, or rarely, toluene ingestion, and finally, D-lactic acidosis.^2,11

Loss of Bicarbonate

Metabolic acidosis related to loss of base or bicarbonate occurs due to several reasons. It can be due to diarrhea, ileostomy output, enterocutaneous fistulas, or short bowel syndrome where a significant amount of bicarbonate from pancreatic secretions can be lost in the stool. The kidney compensates by reabsorbing bicarbonate and increasing acid excretion rapidly. If volume depletion occurs, the kidney will also reabsorb increased NaCl to prevent intravascular loss.^12,13 Bicarbonate reabsorption can be impaired in the setting of proximal renal tubular acidosis in diseases such as multiple myeloma.¹⁴ Further, base can be lost if urine is exposed to the GI tract in the case of any neobladder reconstruction (ileo-conduit) and therefore urinary chloride is absorbed in the colon in exchange for bicarbonate and consequently increases bicarbonate GI losses.¹⁴

Decreased Renal Acid Elimination

One of the most common causes of metabolic acidosis is decreased renal acid secretion in chronic kidney disease. Usually metabolic acidosis does not ensue until patients have progressed to stage 4 chronic kidney disease (CKD) where acids from the metabolism of protein are not excreted, resulting in metabolic acidosis.^16,17 There are 2 mechanisms that responsible for the 3 types of renal tubular acidosis (RTA) that can cause metabolic acidosis:

Defects in secreting or transporting H+ ions from the distal convoluted tubules cause distal RTAs and low renin/low aldosterone level induced RTAs.

Increased bicarbonate losses from impaired reabsorption of bicarbonate causes, discussed earlier, results in a proximal RTA.¹⁵

Typical distal RTAs may cause severe acidosis, whereas low renin/low aldosterone secretion induced RTAs are often milder with hyperkalemia as the hallmark sign.¹⁸

Consequences

Bicarbonate is essential for health. Without it, serious consequences can result if untreated. Management of metabolic acidosis varies depending on acute or chronic status. In acute metabolic acidosis, symptoms usually do not develop unless pH falls to < 7.10, where patients can develop nausea, emesis, and an overall sense of malaise. In order to compensate, breathing often becomes more laborious resulting in longer, deeper breaths. Severe forms can have cardiac manifestations along with hypotension and shock, arrhythmias, and in the most extreme case, coma.^4-6

Treatment has only been demonstrated to be beneficial in non-anion gap acidosis and continues to be controversial in high anion gap metabolic acidosis.7 There are risks associated with treatment in the latter case as it can lead to hypernatremia and volume overload in addition to hypotension, decreased cardiac output, and an increase in mortality.¹⁹ Many studies have not associated treatment with decreased mortality; yet most sources continue to recommend administering bicarbonate in severe acidemia (pH <7.10) to correct the acidosis with the intention of reversing
organ failure.^7,20

Correction of chronic metabolic acidosis is essential. Symptomatically, patients experience less dyspnea due to decreased hypercapnic breathing.²¹Metabolic acidosis can also lead to decreased muscle function, decreased bone mineral density, and influence hormone levels.^5,22,23 In children, correction of the acidosis can result in improved skeletal growth.²⁴Patients with RTA can experience calcium containing kidney stones, which can be reversed with bicarbonate replacement.²⁵Progression to chronic kidney disease can be slowed down the when the acidosis is corrected.²⁶

Treatment

Correcting metabolic acidosis depends on many factors including the degree and chronicity of acidosis, ongoing acid production or bicarbonate losses, renal function, and whether oral/enteral vs. parenteral sources are needed. Once these factors have been evaluated and the level of bicarbonate has been determined, calculating the bicarbonate deficit can be helpful in estimating the amount of bicarbonate needed. The following formula can be used:

While this provides a rough estimate of the bicarbonate needed it should not replace serial measurements of HC03 (CO2 on a basic metabolic panel) and pH in order to determine if further supplementation is required. The clinician must also be mindful of the serum potassium as it can become depleted with ongoing GI losses, but often appears normal in the setting of acidosis. Once the acidosis is resolved, potassium levels should be monitored and replete as needed.

Methods of Supplementation

Bicarbonate can be administered in several ways including orally/enterally, intravenously, and via dialysate during hemodialysis. Administering sodium bicarbonate is the most common and fastest method to correct metabolic acidosis,⁷ however, other sources are available. If administered as another anion such as citrate or acetate, the liver will convert it to bicarbonate. In the acute care setting, tromethamine (THAM), had previously been used, which is a non-sodium-based buffer to correct the acidosis, however it has been discontinued by the manufacturer and is no longer available in the United States.²⁵Acetate or citrate can also be given via sodium or potassium salts depending on the type of deficiency and supplementation needed. Of note, the typical Western diet, which is high in animal protein, can contribute to acid production. Recommending a diet rich in fruits and vegetables can lead to an increase in base load and may help with minimizing chronic acidosis.²⁸ With the ever-increasing medication shortages, clinicians have become creative, using everyday sources of base such as baking soda as an alternative. Table 2 provides sources of bicarbonate supplementation.^29-31

Parenteral Nutrition Shortages

With patients on parenteral nutrition (PN) support, maximizing acetate, which is converted to bicarbonate in the body, will help restore metabolic balance. This has been difficult given recent PN shortages.³²Most recently, potassium and sodium acetate have been on the TPN shortage list making replacing bicarbonate difficult. When possible, replacing losses via the enteral route during shortages is recommended, however, some patients are unable to tolerate any source of enteral replacement. Other options might be to use premade PN mixtures and reserving custom PN for patients in which it is needed. Table 3 and 4 lists helpful websites and tips to help manage parenteral shortages.

CONCLUSION

Metabolic acidosis can occur due to several mechanisms. The first step is to identify the cause and determine if this is an acute or ongoing process. If left untreated, either in the acute or chronic setting it can have deleterious effects. Treatment traditionally has been with sodium bicarbonate drips or acetate in parenteral nutrition solutions. Given the recent shortages, clinicians must become creative in finding alternate ways to maintain acidbase balance.

References

^{Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol. 2010;6(5):274-285.}
^{Lim S. Metabolic acidosis. Acta Med Indones. 2007;39(3):145-150.}
^{Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.583.}
^{Kimmoun A, Novy E, Auchet T, et al. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. 2015; 19(1): 175. [published correction appears in Crit Care. 2017;21:40.}
^{Ballmer PE, McNurlan MA, Hulter HN, et al. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest, 1995;95:39-45.}
^{Soares SBM, de Menezes Silva LAW, de Carvalho Mrad FC, et al. Distal renal tubular acidosis: genetic causes and management. World J Pediatr. 2019;15(5):422-431.}
^{Velissaris D, Karamouzos V, Ktenopoulos N, et al. The Use of Sodium Bicarbonate in the Treatment of Acidosis in Sepsis: A Literature Update on a Long Term Debate. Crit Care Res Pract. 2015;2015:605830.}
^{Emmett M. Anion-gap interpretation: the old and the new. Nat Clin Pract Nephrol 2006; 2:4.}
^{Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore) 1977; 56:38.}
^{Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162-174.}
^{White L. D-Lactic Acidosis: More Prevalent Than We Think? Practical Gastroenterol. 2015; Sept (9):26-45.}
^{Wesson DE, Laski M. Hyperchloremic metabolic acidosis due to intestinal losses and other nonrenal causes. In: AcidBase Disorders and Their Treatment, edited by Gennari FJ, Adrogue HJ, Galla JH, Madias NE. Boca Raton, Taylor and Francis, 2005, 487-499.}
^{Gennari FJ, Weise WJ. Acid-base disturbances in gastrointestinal disease. Clin J Am Soc Nephrol, 2008;3:1861-1868.}
^{Van der Aa F, De Ridder D, Van Poppel H. When the Bowel Becomes The Bladder: Changes In Metabolism After Urinary Diversion. Practical Gastroenterology 2012;July(7):15-28.}
^{Alexander RT, Bitzan M. Renal Tubular Acidosis. Pediatr Clin North Am. 2019;66(1):135-157.}
^{Kraut JA, Madias NE. Metabolic Acidosis of CKD: An Update. Am J Kidney Dis. 2016;67(2):307-317.}
^{Raphael KL. Metabolic Acidosis in CKD: Core Curriculum 2019. Am J Kidney Dis. 2019;74(2):263-275.}
^{Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160.}
^{Kim HJ, Son YK, An WS. Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: a retrospective analysis. PLoS One. 2013;8(6):e65283.}
^{Mitchell JH, Wildenthal K, Johnson RL Jr. The effects of acid-base disturbances on cardiovascular and pulmonary function. Kidney Int 1972;1:375.}
^{Ordóñez FA, Santos F, Martínez V, et al. Resistance to growth hormone and insulin-like growth factor-I in acidotic rats. Pediatr Nephrol 2000;14:720.}
^{Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004;17:455.}
^{Bajpai A, Bagga A, Hari P, et al. Long-term outcome in children with primary distal renal tubular acidosis. Indian Pediatr. 2005;42(4):321-328.}
^{Wrong O. Nephrocalcinosis. In: Oxford Textbook of Clinical Nephrology, Davison AM, Cameron JS, Grünfeld J, et al (Eds), Oxford University Press, Oxford 2005. p.1375.}
^{Kallet RH, Jasmer RM, Luce JM, et al. The treatment of acidosis in acute lung injury with tris-hydroxymethyl aminomethane (THAM). Am J Respir Crit Care Med 2000;161:1149.}
^{Goraya N, Wesson DE. Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease. Curr Opin Nephrol Hypertens 2019;28:267–277.}
^{Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018;392:31.}
^{Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013;8(3):371-381.}
^{Sodium Bicarbonate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:// online.lexi.com.}
^{Potassium Bicarbonate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:// online.lexi.com.}
^{Penniston KL, Nakada SY, Holmes RP, et al. Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. J Endourol. 2008;22(3):567-570.}
^{American Society for Parenteral Nutrition Product shortages: https://www.nutritioncare.org/News/General_News/ Parenteral_Nutrition_Electrolyte_and_Mineral_Product_ Shortage_Considerations/.}

Download Tables, Images & References

FRONTIERS IN ENDOSCOPY, SERIES #66

Dilation Assisted Stone Extraction:Techniques and Outcomes

October 2020 • Volume XLIV, Issue 10

Taylor Frost,

Douglas G. Adler

Read Article

INTRODUCTION

Endoscopic retrograde cholangiopancreatography (ERCP), typically combined with endoscopic sphincterotomy (EST), has become the gold standard treatment for the management of common bile duct stones. Approximately 15-20% of patients who undergo EST will not achieve complete stone removal, necessitating either advanced endoscopic or surgical procedures.1 Factors that may predict difficult stone extraction include large stones (>12mm), multiple stones, stones above a stricture, and/or a small or tapered common bile duct.19 This review will focus on the indications, success rate, and adverse events of Dilation Assisted Stone Extraction (DASE) for difficult biliary stones.

Dilation Assisted Stone Extraction

Dilation Assisted Stone Extraction (DASE) was first introduced in 2003 by Ersoz, Tekesin, Ozutemiz and Gunsar to aid in the extraction of large or complex biliary stones.2 Since its initial description, DASE has been referred to by many names and now possess numerous synonyms which represent the same procedure. Dilation assisted stone extraction is often referenced as either full or limited endoscopic sphincterotomy plus endoscopic papillary large balloon dilation (EST+EPLBD) or biliary endoscopic sphincterotomy with biliary orifice balloon dilation (BES+BBD), or some combination thereof. Regardless, the procedure is performed in four stages; deep cannulation of the bile duct, endoscopic sphincterotomy of the papillary orifice, and balloon dilation of the biliary tree before finally extracting biliary stones. (Figure 1) In its first description, endoscopic sphincterotomy was performed at the papillary orifice and extended to the transverse fold. Dilation to 12-20mm, based on stone size, is then performed with a large diameter balloon (over the guidewire, esophageal/pyloric type balloons) immediately following sphincterotomy. Of note, balloon inflation is maintained until 20-45 seconds after the gradual disappearance of the waist of the balloon is observed as this is thought to indicate a progressive dilation of the orifice.

Endoscopic Papillary Balloon Dilation

Endoscopic Papillary Balloon Dilation (EPBD), also referred to as endoscopic sphincteroplasty, was first described in the early 1980s and has been advocated as an alternative to endoscopic sphincterotomy.3 The procedure is accomplished through pneumatic balloon dilation of the biliary orifice. It was postulated that EPBD preserved the function of the biliary sphincter (as opposed to biliary sphincterotomy, which permanently cuts the entire sphincter muscle) and thus may convey some advantage in regards to short and long term sequelae over endoscopic sphincterotomy. However, EPBD alone often did not produce a wide enough dilation for the retrieval of large biliary stones frequently resulting in a need for mechanical lithotripsy or other advanced procedures.4,5 After the advent of DASE, and the addition of balloon dilation to biliary sphincterotomy, endoscopists began to utilize larger esophageal/pyloric type balloons and in modern era the procedure is often referenced as Endoscopic Papillary Large Balloon Dilation (EPLBD) with or without sphincterotomy.

Comparison of Techniques
EST VS DASE

Endoscopic sphincterotomy with subsequent balloon catheter stone extraction is widely accepted as the standard therapy for common bile duct stones. However, sphincterotomy alone is often not effective in the removal of large common bile duct stones (>12mm).⁶In fact, in the sentinel study describing the DASE procedure was only implemented after sphincterotomy had failed and resulted in a 89-95% success rate depending the degree of dilation performed.¹ In regards to small bile duct stones (<12mm), EST alone and DASE have a similar success and complication rates although there may be a lower rate of stone reoccurrence with DASE.⁷

EST VS EPLBD

The use of endoscopic papillary large balloon dilation for the retrieval of large common bile duct stones has been heatedly debated throughout the literature and there are large differences in its utilization based on locoregional preferences.⁸ There are some studies, primarily performed in Asia, that suggest EPLBD is superior to or as effective as DASE or EST with similar complication rates.^9,10,11 However, it has been postulated that this may be related to population-based characteristics and operator experience with EST.7,10 A randomized, controlled, multicenter study from the United States comparing EPLBD to EST demonstrated significantly higher rates of pancreatitis (15.4% vs 0.8%) and subsequent death (6.8% vs 0%). In this study patients who received EPLBD underwent more invasive procedures, had longer hospital stays, and more time off from normal activities.12 This study was terminated early given the adverse outcomes in the EPLBD group. The remainder of this article will focus on DASE as it is the most commonly utilized advanced procedure for large common bile duct stones within the United States and Europe.

Indications, Success Rates, and Potential Adverse Events of Dilation Assisted Stone Extraction (DASE) Indications (periampullary diverticula, large stones)

The indications for the use of DASE have expanded since its initial description as a rescue procedure following failed EST. Often the endoscopist must determine the degree of difficulty anticipated with the extraction of the stone(s) based on their size, shape, and location. However, there is some evidence that DASE has a higher success rate than EST combined with balloon extraction alone when utilized on stones are greater than 12mm, with higher success rates seen with DASE in progressively larger stones.13 Other factors that may influence the decision to perform DASE over EST which include periampullary diverticula, a tapered distal bile duct, or a sigmoid shaped bile duct.

Success Rates

There is considerable variation between the definition of success seen within the literature on DASE. Some authors report overall stone clearance rates while others rely upon stone clearance on initial ERCP. Factors including differences in sphincterotomy/dilation size, operator experience, and average stone size are often present which may have impact on the overall stone clearance rate and make it difficult to compare studies. However, reported success rates on the initial ERCP of patients undergoing DASE have ranged from 72- 98% with the majority of studies reporting >85% success.1,14,15,16,17,18 Furthermore, a comparison of DASE vs EST alone found that DASE had a higher rate of stone clearance on the first attempt with reduced overall procedure time and a lower need for mechanical lithotripsy.19 In one retrospective review, it was found that DASE success rates were greatest when stones were >15mm in size but these authors also found a higher rate of failure, requiring multiple ERCP procedures, once stones were greater than 20mm in diameter.20 Furthermore, it has been suggested that patients with a single stone may have a higher success rate than those with a greater stone burden.16

Adverse Events

The most common adverse events of DASE are pancreatitis, bleeding, and perforation. There have been several well-designed retrospective studies which have described rates of pancreatitis ranging from 0-5.9% and bleeding of 0-2.9%.6,9,12,13,14,16,18,21 One retrospective study had a particularly high overall complication rate with pancreatitis occurring in 8.9% of patients and bleeding in 9.2%.17 However, the majority of DASE cases in this study were performed after failed EST stone extraction which may have influenced the overall complication rate. It has been postulated that sphincterotomy size and balloon dilation diameter/duration may have some effect on bleeding and perforation risk.22 Sphincterotomy size often varies considerably between studies and operators, and is subjectively measured by the endoscopists. However, when described as “full length”, complication rates have been similar to those with partial sphincterotomy.4

There is also considerable heterogeneity in regards to balloon dilation diameter and duration of actual dilation time. Balloon dilation diameter should primarily be chosen based on bile duct size and stone diameter. Balloon dilation size can vary between 8-20mm with the majority of studies utilizing 15mm.23 Theoretically, larger dilation diameters should carry more risk of perforation. However, a retrospective review of 101 patients who underwent DASE with balloon dilation to 12-20mm had a similar complication rate to other studies.24 In regards to balloon dilation times, a prospective randomized trial comparing dilation durations of 30 and 60 seconds found no difference in overall stone clearance or complications including pancreatitis, perforation, and bleeding.25 Overall, perforation appears to be relatively rare following DASE with rates of 0-1.4%.9,17 It is important to consider the complication rate of DASE within the context of endoscopic sphincterotomy as this is an integral part of the procedure. When comparing sphincterotomy alone to DASE, one prospective study of 121 patients found no difference in rates of pancreatitis, stone/basket impaction, bleeding or perforation.9 Furthermore, there is some data that suggests a lower rate of bleeding and recurrence of common bile duct stones in patients who underwent DASE compared EST alone.6

Altered Anatomy

There have been relatively few studies describing DASE use in patients with Billroth II anatomy however, two retrospective studies describe 100% successful stone extraction in a combined 37 patients without any procedural related complications.26,27 DASE has also been utilized in patients with Roux-en-Y anatomy and, while technically difficult, has had a high success rate although case numbers are low.28

CONCLUSION

DASE is a safe and effective advanced endoscopic procedure for the extraction of difficult biliary stones. Dilation diameter and duration of dilation time varies considerably between operators and should be dependent on stone and bile duct size. Furthermore, operator experience must be considered when choosing sphincterotomy and dilation size. The complication rate of DASE appears to be similar to that of endoscopic sphincterotomy while successful stone extraction appears to be greater than EST alone in stones greater than 12mm.

References

^{Samardzic J, Latic F, Kraljik D, et al. Treatment of common bile duct stones is the role of ERCP changed in era of minimally invasive surgery?. Med Arh. 2010;64(3):187-188.}
^{Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc. 2003;57(2):156-159. doi:10.1067/mge.2003.52}
^{Staritz M, Ewe K, Meyer zum Büschenfelde KH. Endoscopic papillary dilation (EPD) for the treatment of common bile duct stones and papillary stenosis. Endoscopy. 1983;15 Suppl 1:197-198. doi:10.1055/s-2007-1021507}
^{Mathuna PM, White P, Clarke E, Merriman R, Lennon JR, Crowe J. Endoscopic balloon sphincteroplasty (papillary dilation) for bile duct stones: efficacy, safety, and follow-up in 100 patients. Gastrointest Endosc. 1995;42(5):468-474. doi:10.1016/s0016-5107(95)70052-8}
^{Maydeo A, Bhandari S. Balloon sphincteroplasty for removing difficult bile duct stones. Endoscopy. 2007;39(11):958- 961. doi:10.1055/s-2007-966784}
^{Cipolletta L, Costamagna G, Bianco MA, et al. Endoscopic mechanical lithotripsy of difficult common bile duct stones. Br J Surg. 1997;84(10):1407-1409.}
^{Guo SB, Meng H, Duan ZJ, Li CY. Small sphincterotomy combined with endoscopic papillary large balloon dilation vs sphincterotomy alone for removal of common bile duct stones. World J Gastroenterol. 2014;20(47):17962-17969. doi:10.3748/wjg.v20.i47.17962}
^{Attam R, Freeman ML. Endoscopic papillary large balloon dilation for large common bile duct stones. J Hepatobiliary Pancreat Surg. 2009;16(5):618-623. doi:10.1007/s00534- 009-0134-2}
^{Feng Y, Zhu H, Chen X, et al. Comparison of endoscopic papillary large balloon dilation and endoscopic sphincterotomy for retrieval of choledocholithiasis: a meta-analysis of randomized controlled trials. J Gastroenterol. 2012;47(6):655- 663. doi:10.1007/s00535-012-0528-9}
^{Hwang JC, Kim JH, Lim SG, et al. Endoscopic large-balloon dilation alone versus endoscopic sphincterotomy plus largeballoon dilation for the treatment of large bile duct stones. BMC Gastroenterol. 2013;13:15. Published 2013 Jan 17. doi:10.1186/1471-230X-13-15}
^{Lai KH, Chan HH, Tsai TJ, Cheng JS, Hsu PI. Reappraisal of endoscopic papillary balloon dilation for the management of common bile duct stones. World J Gastrointest Endosc. 2015;7(2):77-86. doi:10.4253/wjge.v7.i2.77}
^{Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology. 2004;127(5):1291-1299. doi:10.1053/j.gastro.2004.07.017}
^{Li G, Pang Q, Zhang X, et al. Dilation-assisted stone extraction: an alternative method for removal of common bile duct stones. Dig Dis Sci. 2014;59(4):857-864. doi:10.1007/ s10620-013-2914-4}
^{Kuo CM, Chiu YC, Liang CM, et al. The efficacy of limited endoscopic sphincterotomy plus endoscopic papillary large balloon dilation for removal of large bile duct stones. BMC Gastroenterol. 2019;19(1):93. Published 2019 Jun 18. doi:10.1186/s12876-019-1017-x}
^{Kim HG, Cheon YK, Cho YD, et al. Small sphincterotomy combined with endoscopic papillary large balloon dilation versus sphincterotomy. World J Gastroenterol. 2009;15(34):4298-4304. doi:10.3748/wjg.15.4298}
^{Liu P, Lin H, Chen Y, Wu YS, Tang M, Lai L. Comparison of endoscopic papillary large balloon dilation with and without a prior endoscopic sphincterotomy for the treatment of patients with large and/or multiple common bile duct stones: a systematic review and meta-analysis. Ther Clin Risk Manag. 2019;15:91-101. Published 2019 Jan 9. doi:10.2147/TCRM. S182615}
^{Bang S, Kim MH, Park JY, Park SW, Song SY, Chung JB. Endoscopic papillary balloon dilation with large balloon after limited sphincterotomy for retrieval of choledocholithiasis. Yonsei Med J. 2006;47(6):805-810. doi:10.3349/ ymj.2006.47.6.805}
^{Di Mitri R, Mocciaro F, Pallio S, et al. Efficacy and safety of endoscopic papillary balloon dilation for the removal of bile duct stones: Data from a “real-life” multicenter study on Dilation-Assisted Stone Extraction. World J Gastrointest Endosc. 2016;8(18):646-652. doi:10.4253/wjge.v8.i18.646}
^{Tsuchida K, Iwasaki M, Tsubouchi M, et al. Comparison of the usefulness of endoscopic papillary large-balloon dilation with endoscopic sphincterotomy for large and multiple common bile duct stones. BMC Gastroenterol. 2015;15:59. Published 2015 May 16. doi:10.1186/s12876-015-0290-6}
^{Bisogni D, Manetti R, Talamucci L, et al. Efficacy and indications of dilation-assisted stone extraction for retrieval of “difficult common bile duct stones”: results and data analysis of a single Italian referral center for bilio-pancreatic disease treatment [published online ahead of print, 2019 Oct 14]. Minerva Med. 2019;10.23736/S0026-4806.19.06100-7. doi:10.23736/ S0026-4806.19.06100-7}
^{Ghazanfar S, Qureshi S, Leghari A, Taj MA, Niaz SK, Quraishy MS. Endoscopic balloon sphincteroplasty as an adjunct to endoscopic sphincterotomy in removing large and difficult bile duct stones. J Pak Med Assoc. 2010;60(12):1039- 1042.}
^{Park SJ, Kim JH, Hwang JC, et al. Factors predictive of adverse events following endoscopic papillary large balloon dilation: results from a multicenter series. Dig Dis Sci. 2013;58(4):1100-1109. doi:10.1007/s10620-012-2494-8}
^{Youn YH, Lim HC, Jahng JH, et al. The increase in balloon size to over 15 mm does not affect the development of pancreatitis after endoscopic papillary large balloon dilatation for bile duct stone removal. Dig Dis Sci. 2011;56(5):1572-1577. doi:10.1007/s10620-010-1438-4}
^{Heo JH, Kang DH, Jung HJ, et al. Endoscopic sphincterotomy plus large-balloon dilation versus endoscopic sphincterotomy for removal of bile-duct stones. Gastrointest Endosc. 2007;66(4):720-771. doi:10.1016/j.gie.2007.02.033}
^{Paspatis GA, Konstantinidis K, Tribonias G, et al. Sixtyversus thirty-seconds papillary balloon dilation after sphincterotomy for the treatment of large bile duct stones: a randomized controlled trial. Dig Liver Dis. 2013;45(4):301- 304. doi:10.1016/j.dld.2012.10.015}
^{Choi CW, Choi JS, Kang DH, et al. Endoscopic papillary large balloon dilation in Billroth II gastrectomy patients with bile duct stones. J Gastroenterol Hepatol. 2012;27(2):256-260. doi:10.1111/j.1440-1746.2011.06863.x}
^{Itoi T, Ishii K, Itokawa F, Kurihara T, Sofuni A. Large balloon papillary dilation for removal of bile duct stones in patients who have undergone a billroth ii gastrectomy. Dig Endosc. 2010;22 Suppl 1:S98-S102. doi:10.1111/j.1443- 1661.2010.00955.x}
^{Kim KH, Kim TN. Endoscopic papillary large balloon dilation for the retrieval of bile duct stones after prior Billroth II gastrectomy. Saudi J Gastroenterol. 2014;20(2):128-133. doi:10.4103/1319-3767.129478}

Download Tables, Images & References

A SPECIAL ARTICLE

Bezlotoxumab for Prevention of Recurrent C. difficile Infection in High-Risk Patients

October 2020 • Volume XLIV, Issue 10

Maheep Singh Sangha,

Colleen R. Kelly

Read Article

Recurrence of Clostridioides difficile infection (CDI) is a common occurrence and significantly increases hospitalizations, inpatient cost, morbidity, and mortality. While metronidazole, vancomycin, and fidaxomicin are approved for treatment, bezlotoxumab is the first drug approved by the FDA to prevent CDI recurrences. Results of phase 3 clinical trials from a pooled data set revealed that sustained cure from recurrence of CDI at 12 weeks was significantly higher in the bezlotoxumab group (63.5% [496/781]) in comparison to the placebo group (53.7% [415/773]). The number needed to treat in patients older than 65 years of age with recurrent CDI is six. Real-world data from a multicenter retrospective cohort study of 200 patients across 34 outpatient infusion centers in the United States revealed the overall CDI recurrence rate after a single infusion of bezlotoxumab was comparable to CDI recurrence reported for the overall population enrolled in the MODIFY I and II phase 3 clinical trials. Considering the high cost of bezlotoxumab, identifying a high-risk target population is essential to make this treatment cost-effective.

Clostridioides (formerly Clostridium) difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus which, in developed countries, is the leading cause of infectious diarrhea in hospitalized patients.^1,2 Disruption of healthy gastrointestinal tract flora by antibiotics leads to loss of colonization resistance and opportunistic infection with C. difficile.³ Over the last decade, there has been a rise in Clostridioides difficile infection (CDI) related hospitalizations, healthcare costs, morbidity, and mortality; furthermore, approximately 30% of patients develop recurrent CDI after completing initial antibiotic therapy. Those who have suffered a previous recurrence have an increased risk of further recurrences, up to 60% after a third CDI episode.^4,5 Other important risk factors for CDI recurrence are age > 65 years, immunosuppressive disease state or therapy, and antibiotic use.

Toxigenic strains of C. difficile produce two potent exotoxins: toxin A and toxin B, which are responsible for mucosal injury, acute inflammation (colitis), and diarrhea.^5-7 Toxin B is ten times more potent than toxin A and thus, strains that do not produce toxin A can be as virulent as strains producing both toxin A and B.⁸ A “hypervirulent” strain, NAP1/BI/027, produces an additional binary AB toxin called CDT. CDT toxin results in the breakdown of gut wall promoting adherence of bacteria and increased uptake of toxin A and toxin B. Additionally, loss of TcdC function in NAP1/ B1/027 leads to hyperproduction of toxin A 16 times and toxin B 23 times by down-regulating feedback inhibitor associated with halting toxin A and B production.⁹ Moreover, increased spread and survival of this strain have also been associated with increased sporulation, also called hypersporulation.¹⁰ Thus this strain has been associated with severe disease requiring intensive care unit admissions, colectomy, and significantly higher mortality rates.^5,6

Host immunity (passive or active) to C. difficile toxins may play an essential role in the severity of symptoms or risk of recurrence. Higher levels of anti-toxin A and anti-toxin B antibodies have been correlated with a protective effect against primary and recurrent Clostridioides difficile infection (rCDI).^11-13

Multiple medications, including metronidazole, vancomycin, and fidaxomicin, are used to treat primary disease, but these do little to prevent CDI recurrence.¹⁴Fidaxomicin may result in a lower incidence of rCDI when used early in patients with a non-NAP1/BI/027 strain; however, when compared to oral vancomycin, it does not appear to be more effective for the treatment of mild to moderate CDI.¹⁵Fecal microbiota transplantation (FMT) has demonstrated high cure rates for rCDI, but regulatory questions, lack of long-term safety data, and the absence of standardized techniques for delivery of fecal microbiota has limited widespread application of FMT.^16,17

With this in mind, a human monoclonal antibody against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab), were pursued as therapeutic agents to prevent rCDI in addition to the antibiotic therapy.¹⁸ After nine clinical trials, bezlotoxumab (BEZ; Zinplava), a novel agent, was approved by the FDA in 2016.^7,12,19-24

PHARMACOLOGY

Bezlotoxumab (BEZ) is an IgG1 immunoglobulin (human monoclonal antibody) that binds to toxin B and prevents it from entering the gastrointestinal cell layer preventing colonic cell damage (Figure 1,).^19,25,26 Bezlotoxumab does not bind to toxin A of Clostridioides difficile. There is a low potential for drug-drug interaction as bezlotoxumab is eliminated by catabolism. The long plasma half-life of 19 days allows the single-dose administration of bezlotoxumab to prevent rCDI. Ethnicity, gender, race, age, and comorbid conditions did not affect bezlotoxumab exposure. No dose adjustment is required in patients with renal or hepatic impairment.

There are no contraindications to bezlotoxumab, but caution is advised for use in patients with a history of congestive heart failure (CHF).^{27, 28} Per phase 3 clinical trials during the 12-week study period, a group of patients with a history of CHF treated with bezlotoxumab had a higher incidence of worsening CHF and adverse outcomes than the group of patients with a history of CHF treated with placebo.¹² Based on these studies, it is not clear whether congestive heart failure was well controlled in these patients before administering bezlotoxumab or not.

CLINICAL TRIALS
Phase 1 and 2

After five, phase 1 trials evaluated the safety and efficacy of bezlotoxumab, a single dose of 10 mg/ kg to be administered intravenously over 60 mins were recommended.^21,22,29

The first phase 2 trial was terminated early as animal data revealed that a combination of bezlotoxumab and actoxumab, a human monoclonal antibody that binds to toxin A, was more effective. Another phase 2, multicenter, randomized, doubleblind, placebo-controlled clinical trial with 200 patients, revealed lower recurrence rate and relative risk of recurrence of CDI associated with significantly longer time to CDI recurrence in the bezlotoxumab and actoxumab group compared to the placebo group.20 Data from the placebo-treated group showed no relationship between plasma antitoxin A antibodies and rCDI, whereas plasma antitoxin B antibodies were found to be protective against rCDI.

CLINICAL TRIALS
Phase 3 (MODIFY I and MODIFY II)

Two independent, multicenter, 12-week, doubleblind, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 patients (>= 18 years of age) evaluated the safety and efficacy of bezlotoxumab in patients receiving standardof-care antibiotics for primary or recurrent Clostridioides difficile. ¹²Efficacy was assessed in a modified intention-to-treat (mITT) group.

While both trials randomized patients to single-dose administration of bezlotoxumab alone, bezlotoxumab and actoxumab or placebo along with standard-of-care antibiotics; MODIFY I initially also included an actoxumab alone arm which was terminated early after being associated with significantly increased rates of death caused by sepsis and lack of efficacy compared to bezlotoxumab and actoxumab arm (p=0.02).^12,30Randomization was stratified based on the oral standard-of-care antibiotic and the location of the patient (inpatient vs. outpatient).

Clostridioides difficile infection (CDI) was confirmed by a positive stool test and >= 3 loose stools in >=24 hours. Standard-of-care antibiotics included oral metronidazole, vancomycin, or fidaxomicin. Patients on oral vancomycin or fidaxomicin could receive intravenous metronidazole. The choice of standard-of-care antibiotic therapy and the day of administration of the study infusion was the health care provider’s preference. In most patients (94%), bezlotoxumab was administered within the first six days of standard-of-care antibiotics, with day 3 being the median administration day.¹²

The primary endpoint was defined as a new episode of CDI recurrence after initial clinical cure during the 12 weeks of follow up period. The initial clinical cure was defined as no loose stools for two consecutive days after completing standard-of-care antibiotic therapy for <=16 days. A secondary endpoint, also called global cure or sustained clinical response, was the sustained cure rate, which meant initial clinical cure as defined above and no recurrence of CDI through 12 weeks.

Results of MODIFY I and MODIFY II

In the pooled data set from the MODIFY I and MODIFY II trials, the initial clinical cure rate was similar in the bezlotoxumab group (80% [625/781]) and the placebo group (80.3% [621/773]). However, sustained cure at 12 weeks was significantly higher in the bezlotoxumab group (63.5% [496/781]) in comparison to the placebo group (53.7% [415/773]).12 For sustained cure, the adjusted difference between bezlotoxumab and placebo group was 9.7 percentage points (95% CI 4.8 to 14.5; p<0.0001), and the pooled data set results were mostly driven by MODIFY II trial.12 Approximately 71% of recurrences of CDI occurred within the four weeks of study infusion.

Importantly, the subgroup analysis of the pooled data set, recurrent CDI rates were statistically significantly lower in the bezlotoxumab group in comparison to the placebo group for patients >=65 years of age, those suffering a recurrent episode of CDI, immunocompromised patients and in severe CDI,12 defined as a Zar score of 2 or higher.31 The determination of immunocompromised patients was based on medical history or the use of immunosuppressive therapy. The number needed to treat to prevent one episode of recurrent CDI with bezlotoxumab was ten; however, that number decreased to six for patients with age >=65 and previous CDI in the past six months.¹²

The initial cure rate for patients receiving actoxumab-bezlotoxumab was 73% (568/773) in the pooled data set. The rate of recurrent CDI was also similar in the actoxumab-bezlotoxumab group compared to the bezlotoxumab group, suggesting that the neutralization of toxin B by bezlotoxumab is adequate to reduce the risk of recurrent CDI.29 Interestingly, the rate of CDI recurrence was significantly lower for hypervirulent strain (NAP1/ BI/027) for patients who received a combination of actoxumab-bezlotoxumab (11.8% [9/76]) in comparison to bezlotoxumab alone (23.6% [21/89]) and the placebo group (34% [34/100]).12 This information suggests that the combination of actoxumab and bezlotoxumab might provide better results for the hypervirulent strain (NAP1/ BI/027); however, more future studies are required to confirm this.

REAL-WORLD DATA

A retrospective study of 46 patients was done in five university hospitals in Finland (in Helsinki, Kuopio, Oulu, Tampere, and Turku).³²These patients were the first 46 patients to receive bezlotoxumab in Finland in April – December 2017. Polymerase chain reaction (PCR) was the only test used to diagnose CDI. Patients received bezlotoxumab on 0 – 7 days after the initiation of the standardof-care antibiotics. Vancomycin was used alone or along with another antibiotic in 80% (37 of 46) of patients as a standard-of-care. Eighteen patients received metronidazole, fidaxomicin, and tigecycline. Patients had a mean age of 66 years, out of which 24 were men and 22 were women. 29 of the 46 patients received bezlotoxumab in inpatient and the other 17 in an outpatient setting. Twentyeight patients were immunocompromised due to immunosuppressive treatment or other medical comorbidities. 78% (36/46) of patients had three or more known risk factors for CDI’s recurrence.

Results revealed that 73% (32/44) patients did not have rCDI in 3 months of bezlotoxumab treatment.32 71% (20/28) of immunocompromised patients and 63% (10/16) of patients with severe CDI based on the Zar score did not have rCDI in the three months.32 Two severely ill patients died within three months of bezlotoxumab infusion at Turku University Hospital. One patient died five days after bezlotoxumab infusion due to end-stage cardiac disease, and the other died approximately 45 days after bezlotoxumab infusion due to graftversus-host disease.

Another study using whole-genome sequencing calculated the difference in the same-strain relapse versus new-strain reinfection in MODIFY I/ II trials.³³Two hundred fifty-nine patients were evaluated for rCDI, out of which 76% (198/259) of the patients in the study experienced relapse with the same strain, whereas only 19% (50/259) had reinfection with a new strain. Ribotype 027 was associated with higher proportions of relapses as compared to other ribotypes. This study also revealed that a cumulative incidence of CDI relapse with the same strain in high-risk patients was significantly lower for patients treated with bezlotoxumab than patients not treated with bezlotoxumab (p<0.0001).³³

One of the most extensive multicenter retrospective cohort study of 200 patients between April 2017 and December 2018 across 34 outpatient infusion centers in the United States was published recently.34 C. difficile was diagnosed using PCR (76.5%) and enzyme immunoassay (EIA) (23.5%). Patients received vancomycin (68.5%), fidaxomicin (30%), and metronidazole (1.5%) as a standardof-care antibiotics. The median time interval for bezlotoxumab infusion was 11 days from initiation of the standard-of-care antibiotics. Three patients were lost in follow up, and two chronically ill patients with multiple medical comorbidities died 40 days and 75 days post bezlotoxumab infusion. 86% of patients enrolled in the study had at least one CDI recurrence before bezlotoxumab infusion. 80% of patients had ≥2 risk factors for rCDI, most frequently age ≥65 years (67.7%), and ≥1 CDI episode in the past six months (61.5%). The study results revealed that the overall CDI recurrence rate after a single infusion of bezlotoxumab was 15.9%, which translates into 84.1% successful prevention of CDI recurrence in patients enrolled in the study.34 These results are comparable to 16.5% of CDI recurrence reported for the overall population enrolled in the MODIFY I and II phase 3 clinical trials.¹²

DISCUSSION

Data from MODIFY I and II phase 3 trials suggest that bezlotoxumab (15.7% [107/679]) decreases the recurrence rate of CDI when compared to placebo (25.6% [169/658]) in non-hypervirulent strains.¹²The only possible severe side-effect of bezlotoxumab infusion is worsening congestive heart failure in patients with a history of heart failure. It will be pertinent to develop cost-effective guidelines for targeting high-risk elderly patients, considering the high cost (approximately $4000 for a 1000mg/40ml vial) of bezlotoxumab.³⁵

FMT has also been effective for rCDI.^36,37 It is vital to recognize that it is typically administered after a course of antibiotic therapy rather than as a primary treatment modality; bezlotoxumab is also a preventive agent used in association with a standard-of-care treatment. Large head-to-head clinical trials will be required to determine the efficacy of FMT compared to bezlotoxumab to prevent a recurrence. It is crucial to keep in mind that neither fidaxomicin nor bezlotoxumab has shown significant efficacy in preventing recurrent CDI in patients infected with the hypervirulent strain (NAP1/BI/027).

A post hoc pooled analysis revealed that the CDI recurrence rate was further lower for the bezlotoxumab group when the diagnosis was made using toxin EIA 14.5% (54/372) compared to PCR 19.6% (70/357); while rates were similar for the placebo group.^38,39 Nucleic acid amplification tests (PCR) only identify the toxigenic DNA sequences but not the toxin protein, hence also detecting asymptomatic carriers of toxigenic strains of C. difficile. EIAs, which test directly for toxins A/B produced by the organism, are specific for active infection and predictive of poor outcomes compared to more sensitive nucleic acid amplification tests (NAAT), which detect toxigenic strains but not toxin protein.⁴⁰Thus, the number needed to treat (NNT) could be even lower for populations if EIA is used for diagnosis.³⁹

Currently, there is no data for the use of bezlotoxumab in the pediatric population or pregnant and lactating patients. Phase 4 clinical trials will provide further insight into the role of bezlotoxumab in these population subtypes.

CONCLUSION

The future for the treatment of recurrent CDI appears promising. While participants with ≥three risk factors had the most significant reduction of CDI recurrence with bezlotoxumab, those with 1 or 2 risk factors also significantly benefited. We recommend that bezlotoxumab be considered in treating high-risk patients, >= 65 years of age, with more than one risk factor to prevent further CDI recurrence. Patients with concomitant antibiotics use, inflammatory bowel disease, and those not responding to FMT may also benefit from bezlotoxumab treatment. As bezlotoxumab may be administered to patients at any point during a course of CDI treatment, outpatient infusion would avoid unnecessary inpatient cost and is an economical option. It will be intriguing to see more clinical trials to assess the combined effect of bezlotoxumab and FMT or bezlotoxumab and fidaxomicin for the treatment of recurrent C. difficile infection.

References

^{Rupnik, M., M.H. Wilcox, and D.N. Gerding, Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol, 2009. 7(7): p. 526-36.}
^{Magill, S.S., et al., Multistate point-prevalence survey of health care-associated infections. N Engl J Med, 2014. 370(13): p. 1198-208.}
^{Lagier, J.-C., Gut microbiota and Clostridium difficile infections. Human Microbiome Journal, 2016. 2: p. 10-14.}
^{McFarland, L.V., G.W. Elmer, and C.M. Surawicz, Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol, 2002. 97(7): p. 1769-75.}
^{Shields, K., et al., Recurrent Clostridium difficile infection: From colonization to cure. Anaerobe, 2015. 34: p. 59-73.}
^{Cohen, S.H., et al., Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol, 2010. 31(5): p. 431-55.}
^{Carter, G.P., J.I. Rood, and D. Lyras, The role of toxin A and toxin
B in Clostridium difficile-associated disease: Past and present perspectives. Gut Microbes, 2010. 1(1): p. 58-64.}
^{Steele, J., et al., Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridium difficile disease. J Infect Dis, 2013. 207(2): p. 323-30.}
^{Warny, M., et al., Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet, 2005. 366(9491): p. 1079-84.}
^{Akerlund, T., et al., Increased sporulation rate of epidemic Clostridium difficile Type 027/NAP1. J Clin Microbiol, 2008. 46(4): p. 1530-3.}
^{Leav, B.A., et al., Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine, 2010. 28(4): p. 965-9.}
^{Wilcox, M.H., et al., Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med, 2017. 376(4): p. 305-317.}
^{Gupta, S.B., et al., Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence. Clin Infect Dis, 2016. 63(6): p. 730-734.}
^{Linsky, A., K. Gupta, and J.A. Hermos, Fidaxomicin for Clostridium difficile infection. N Engl J Med, 2011. 364(19): p. 1875; author reply 1875-6.}
^{Louie, T.J., et al., Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med, 2011. 364(5): p. 422-31.}
^{Juul, F.E., et al., Fecal Microbiota Transplantation for Primary Clostridium difficile Infection. N Engl J Med, 2018. 378(26): p. 2535-2536.}
^{Bakken, J.S., et al., Treatment approaches including fecal microbiota transplantation for recurrent Clostridium difficile infection (RCDI) among infectious disease physicians. Anaerobe, 2013. 24: p. 20-4.}
^{Posteraro, B., et al., Actoxumab + bezlotoxumab combination: what promise for Clostridium difficile treatment? Expert Opin Biol Ther, 2018. 18(4): p. 469-476.}
^{Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium Difficile Infection. JAMA, 2017. 318(7): p. 659- 660.}
^{Lowy, I., et al., Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med, 2010. 362(3): p. 197-205.}
^{Taylor, C.P., et al., Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A. Vaccine, 2008. 26(27-28): p. 3404-9.}
^{ZINPLAVA (bezlotoxumab) injection, for intravenous use Initial U.S. Approval: 2016.}
^{Villafuerte Galvez, J.A. and C.P. Kelly, Bezlotoxumab: anti-toxin B monoclonal antibody to prevent recurrence of Clostridium difficile infection. Expert Rev Gastroenterol Hepatol, 2017. 11(7): p. 611-622.}
^{Traynor, K., Bezlotoxumab approved to prevent Clostridium difficile recurrence. Am J Health Syst Pharm, 2016. 73(23): p. 1902.}
^{Bartlett, J.G., Bezlotoxumab – A New Agent for Clostridium difficile Infection. N Engl J Med, 2017. 376(4): p. 381-382.}
^{Carter, G.P., et al., Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections. MBio, 2015. 6(3): p. e00551.}
^{Johnson, S. and D.N. Gerding, Bezlotoxumab. Clin Infect Dis, 2019. 68(4): p. 699-704.}
^{Chahine, E.B., J.C. Cho, and M.V. Worley, Bezlotoxumab for the Prevention of Clostridium difficile Recurrence. Consult Pharm, 2018. 33(2): p. 89-97.}
^{US Food and Drug Administration. BLA 761046: bezlotoxumab injection.}
^{Kuehne, S.A., et al., The role of toxin A and toxin B in Clostridium difficile infection. Nature, 2010. 467(7316): p. 711-3}
^{Zar, F.A., et al., A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis, 2007. 45(3): p. 302-7.}
^{Oksi, J., et al., Real-world efficacy of bezlotoxumab for prevention of recurrent Clostridium difficile infection: a retrospective study of 46 patients in five university hospitals in Finland. Eur J Clin Microbiol Infect Dis, 2019. 38(10): p. 1947-1952.}
^{Zeng, Z., et al., Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing. Anaerobe, 2019: p. 102137.}
^{Hengel, R.L., et al., Real-world Experience of Bezlotoxumab for Prevention of Clostridioides difficile Infection: A Retrospective Multicenter Cohort Study. Open Forum Infect Dis, 2020. 7(4): p. ofaa097.}
^{Zinplava Prices.}
^{Kelly, C.R., et al., Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology, 2015. 149(1): p. 223-37.}
^{Kelly, C.R., et al., Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol, 2014. 109(7): p. 1065-71.}
^{Wilcox, M., et al. Assessment of efficacy of bezlotoxumab for prevention of Clostridium difficile infection recurrence by diagnostic test method. in European Congress of Clinical Microbiology and Infectious Diseases, Amsterdam, the Netherlands. 2016.}
^{Wilcox, M.H., et al., Influence of Diagnostic Method on Outcomes in Phase 3 Clinical Trials of Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: A Post Hoc Analysis of MODIFY I/II. Open Forum Infect Dis, 2019. 6(8).}
^{Garvey, M.I., et al., Can a toxin gene NAAT be used to predict toxin EIA and the severity of Clostridium difficile infection? Antimicrob Resist Infect Control, 2017. 6: p. 127.}

Download Tables, Images & References

FROM THE PEDIATRIC LITERATURE

More Data on C. difficile and Pediatric IBD Outcomes

September 2020 • Volume XLIV, Issue 9

Read Article

Clostridioides difficile (C. diff), previously known as Clostridium difficile is a relatively common gastrointestinal tract infection and has a significant association with inflammatory bowel disease (IBD). C. diff infection and the C. diff carriage state may be difficult to differentiate in patients in IBD due to similar symptoms occurring with active IBD as well as with an active C. diff infection (diarrhea, abdominal pain, etc.). The authors of this study evaluated the progression to intestinal resection in pediatric patients with IBD diagnosed with C. diff carriage within one year of IBD diagnosis, and they evaluated fecal microbiome samples in such pediatric patients in relation to C. diff carriage state as well as in relation to a history of intestinal surgery.

Patients with Crohn disease (CD) from a single tertiary children’s hospital (age 21 years old or less) were retrospectively included in the study if they had stool samples as part of that institution’s IBD Biorepository and if they had C. diff testing within one year of the CD diagnosis. At the same time, a prospective study occurred for patients who were diagnosed with CD and who subsequently could provide stool sampling. Stool samples were analyzed for calprotectin levels and had C. diff polymerase chain reaction (PCR) testing as well as microbiome sampling performed by high throughput shotgun metagenomic sequencing (rapid parallel DNA sequencing). Metabolic pathways of bacteria were analyzed using nucleotide and peptide databases.

The retrospective aspect of the study demonstrated a C. diff positivity rate of 19% in the CD group with significantly more patients with C. diff having had antibiotic exposure within 30 days of testing. Most patients with CD were in the age range of 10 to 17 years, and the percentage of steroid exposure in the first year of life was not statistically different regardless of C. diff status. The rate of intestinal resection was significantly lower for patients with negative C. diff testing (21%) compared to patients with positive C. diff testing (67%). Additionally, patients with positive C. diff testing had a shorter mean time to intestinal resection (527 days) compared to patients with negative C. diff testing (1268 days). Univariate
analysis showed that steroid or anti-tumor necrosis factor (anti-TNF) medication exposure did not change results. Multivariate analysis demonstrated that only positive C. diff testing was associated with
the need for intestinal surgery in patients with CD

The subsequent prospective study demonstrated that 14% of patients with CD had positive C. diff testing, and 9% of patients with CD had a history of intestinal surgery. Similar to the retrospective cohort, patients with positive C. diff testing were significantly more likely to have had prior intestinal surgery. There was no difference in fecal calprotectin levels or reported IBD symptoms between groups. High throughput shotgun metagenomic sequencing demonstrated no overall difference in the fecal microbiome profile between patients with or without C. diff although there was a significant decrease in 123 taxa in patients with a positive C. diff infection. These taxa tended to be commensal organisms that had a potential mucosal protective effect. Metabolic profiles were not significantly different between patients regardless of C. diff status although patients that underwent intestinal surgery had 95 metabolic pathways that were altered compared to patients who had not had surgery (such as downregulated methionine biosynthesis pathways). Finally, patients with positive C. diff testing and a history of intestinal surgery had 47 bacterial species that were significantly reduced. These taxa were associated with protective gut function.

This study appears to show that young patients with CD and positive C. diff testing are at an increased risk of intestinal resection. These patients had microbiome changes noted as well suggesting the potential loss of a protective gut microbiome. The authors theorize that the early presence of C. diff in a young person with CD may be due to significant alterations in the microbiome leading to bowel inflammation and subsequent surgery.

^{Hellmann J, Andersen H, Fei L, Linn A, Bezold R, Lake K, Jackson K, Meyer D, Dirksing K, Bonkowski E, Ollberding N, Haslam D, Denson L. Microbial shifts and shorter time to bowel resection surgery associated with C. difficile in pediatric Crohn’s disease.}

Download Tables, Images & References

FROM THE PEDIATRIC LITERATURE

Degree of Villous Atrophy and Outcomes in Children

September 2020 • Volume XLIV, Issue 9

Read Article

Celiac disease (CD) is an immune-mediated disease typically associated with gastrointestinal inflammation in response to gluten exposure.
Esophagogastroduodenoscopy (EGD) with
duodenal biopsies has been considered “gold standard” for CD diagnosis; however, recent pediatric guidelines such as the European Society for Paediatric Gastroenterology Hepatology and Nutrition Guidelines for the Diagnosis of Coeliac Disease (https://journals.lww.com/jpgn/ Fulltext/2012/01000/European_Society_for_Pediatric_Gastroenterology,.28.aspx) suggest that serology screening may be an adequate substitute for EGD with duodenal biopsy. In particular, a tissue transglutaminase IgA antibody (TTG IgA) level greater than 10 times the upper limit of the measured laboratory value has a high association with CD. It is unclear if the degree of villi damage seen in CD corresponds well with TTG IgA antibody titer levels, and the authors of this study evaluated the effectiveness of determining intestinal villi length (disease severity) in pediatric patients with a new diagnosis of CD in regards to their long-term health outcomes as adults.

This study occurred at a single tertiary hospital in Finland, and retrospective data was obtained from a CD database containing the records of 906 pediatric patients from 1966 to 2014. Medical data at the time of CD diagnosis was reviewed such as the presence of gastrointestinal symptoms and other extra-intestinal disease manifestations, and duodenal biopsy results from these patients were divided into three groups: partial atrophy, subtotal atrophy, and total atrophy. Growth impairment was determined by decreased growth velocity noted on growth charts. TTG IgA and endomysial antibodies (EMA) were recorded from patients from 2000 onward when such serum testing had become available. Finally, pediatric patients with CD who were now adults completed three questionnaires including a questionnaire reviewing complications and co-morbidities associated with CD, the Gastrointestinal Symptom Rating Scale (GSRS) to evaluate the presence of gastrointestinal symptoms, and the Psychological General WellBeing questionnaire (PGWB) to evaluate quality of life.\

A total of 503 adult patients with CD diagnosed as children were asked to participate in this study, and 212 of these patients (42%) completed all questionnaires. The adult patients with partial and subtotal villous atrophy were significantly younger than the adult patients with total villous atrophy. However, all three villous atrophy groups had no difference as adults in regards to comorbid conditions, complications from celiac disease, selfreported symptoms, overall health, adherence to a gluten-free diet, GSRS score, and PGWB score even after adjusting for current age, sex, year of CD diagnosis, and median BMI.
This study demonstrates that pediatric patients with CD and more severe villous atrophy (and more health-related issues as children) appear to have similar long-term outcomes as adults when compared to pediatric patients with less severe villous damage. We can use this information to inform pediatric patients with CD and their families about the importance of continuing a gluten-free diet throughout their lives in order to have good health outcomes.

The duodenal biopsies of the 906 pediatric
patients demonstrated partial villous atrophy in 34%, subtotal villous atrophy in 40%, and total villous atrophy in 26% of patients. Children with total villous atrophy had significantly more extraintestinal manifestations, anemia, and impaired growth while patients with less severe atrophy had less abdominal pain and less CD detected by serum screening. Children with more advanced stages of villous atrophy were diagnosed during the earlier years of the study although there was no difference in patient age throughout the study at the time of CD diagnosis. More severe villous atrophy was identified in patients with significantly shorter height, lower body mass index (BMI), lower hemoglobin levels, and higher celiac
antibody levels (TTG IgA and EMA) at time of CD diagnosis.
A total of 503 adult patients with CD diagnosed as children were asked to participate in this study, and 212 of these patients (42%) completed all questionnaires. The adult patients with partial and subtotal villous atrophy were significantly younger than the adult patients with total villous atrophy. However, all three villous atrophy groups had no difference as adults in regards to comorbid conditions, complications from celiac disease, selfreported symptoms, overall health, adherence to a gluten-free diet, GSRS score, and PGWB score even after adjusting for current age, sex, year of CD diagnosis, and median BMI.

This study demonstrates that pediatric patients with CD and more severe villous atrophy (and more health-related issues as children) appear to have similar long-term outcomes as adults when compared to pediatric patients with less severe villous damage. We can use this information to inform pediatric patients with CD and their families about the importance of continuing a gluten-free diet throughout their lives in order to have good health outcomes.

^{Kroger S, Kurppa K, Repo M, Huhtala H, Kaukinen K, Lindfors K, Arvola T, Kivela L. Severity of villous atrophy at diagnosis in childhood does not predict long-term outcomes in celiac disease. Journal of Pediatric Gastroenterology and Nutrition 2020; 71: 71-77.}

Download Tables, Images & References

FROM THE LITERATURE

Impact of Serum ANA in Nonalcoholic Fatty Liver Disease

September 2020 • Volume XLIV, Issue 9

Read Article

To investigate the longitudinal impact of ANA on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD), antinuclear antibody (ANA), was found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH), or developed AIH after a mean followup of 106 months.

Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellular carcinoma, cardiovascular events, extrahepatic malignancy and overall survival was similar to ANAnegative cases.

Once AIH has been ruled out, the long-term outcomes and survival are not affected by the presence of ANA in patients with NAFLD.

^{Younes, R., Govare, O., Petta, S., et al. “Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease.” American Journal of Gastroenterology, 2020; Vol. 115, pp. 1289-1292.}

Download Tables, Images & References

FROM THE LITERATURE

Future High-Risk Adenomas After High-Risk Adenomas at Initial Screening

September 2020 • Volume XLIV, Issue 9

Read Article

To examine the risk of high-risk adenomas (HRA) at third colonoscopy stratified by findings on two previous examinations in a prospective screening colonoscopy cohort of US Veterans with a negative second examination, participants were identified who had three or more colonoscopies from CSP No. 380. The risk of HRA on the third examination, based on findings from the previous two examinations were evaluated. Multivariate logistic regression was used to adjust for multiple covariates. HRA was found at the third examination in 114 (12.8%) of 891 participants.

Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56 – 25%). Compared with those with no adenomas on both previous examinations, participants with HRA on first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (OR 3.41), 5 years (OR 3.14), and 7 years (OR 2.89).

In a screened population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination, supporting current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

^{Sullivan, B., Redding, T., Hauser, E., et al. “HighRisk Adenomas at Screening Colonoscopy Remain Predictive of Future High-Risk Adenomas, Despite an Intervening Negative Colonoscopy.” American Journal of Gastroenterology, 2020; Vol. 115, pp. 1275-1282.}

Download Tables, Images & References

FROM THE LITERATURE

Corticosteroids, TNF Antagonists and Outcomes from COVID-19 with IBD

September 2020 • Volume XLIV, Issue 9

Read Article

To characterize the clinical course of COVID-19 among patients with IBD and evaluate the association among demographics, clinical characteristics and immunosuppressant treatments on COVID-19 outcomes, study was carried out. Surveillance epidemiology of coronavirus under research exclusion for inflammatory bowel disease (SECURE-IBD), is a large international registry created to monitor outcomes of patients with IBD with confirmed COVID-19. Calculation of the age/standardized mortality ratios was carried out using multivariable logistic regression to identify factors associated with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.

A total of 525 cases from 33 countries were reported (median age 43 years, 53% men); 37 patients had severe COVID-19; 161 (31%) were hospitalized and 16 patients died (3% case fatality rate). Standardized mortality ratios for patients with IBD were 1.8, 1.5, and 1.7, relative to data from China, Italy and the United States, respectively. Risk factors for severe COVID-19 among patients with IBD included increased age (AOR 1.04), greater than 2 comorbidities (AOR 2.9), systemic corticosteroids (AOR 6.9), and sulfasalazine or 5-aminosalicylate use (AOR 3.1). Tumor necrosis factor antagonist treatment was not associated with severe COVID-19 (AOR 0.9).

It was concluded that increasing age, comorbidities and corticosteroids are associated with severe COVID-19 among patients with IBD, although a causal relationship cannot be definitively established. Notably, TNF antagonists do not appear to be associated with severe COVID-19.

^{Brenner, E., Ungaro, R., Gearry, R., et al. “Corticosteroids, But Not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Patients with Inflammatory Bowel Diseases: Results from an International Registry.” Gastroenterology 2020; Vol. 159, pp. 481-491.}

Download Tables, Images & References

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #33

Irritable Bowel Syndrome

September 2020 • Volume XLIV, Issue 9

Elizabeth J. Videlock,

Lin Chang

Read Article

Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder characterized by the presence of chronic or recurrent abdominal pain associated with altered bowel habits. It is a multifactorial condition that has been recently redefined as a disorder of gut-brain interaction. The diagnosis is based on symptom criteria and limited diagnostic testing. In recent years, there have been significant advances in developing efficacious dietary, pharmacologic and non-pharmacologic approaches in the treatment of IBS. Management should focus on a patient-centered approach, reducing cost, continuity of care, and improving patient satisfaction and health related quality of life. This review discusses the epidemiology, clinical symptoms, and evidence-based and practical approaches to diagnostic evaluation and treatment of IBS.

Irritable bowel syndrome (IBS) is a functional bowel disorder (FBD) that is characterized by abdominal pain associated with diarrhea and/or constipation. IBS is one of the most common gastrointestinal disorders diagnosed in primary care and gastroenterology practices.¹ In IBS, the gastrointestinal (GI) tract is grossly and histologically normal. For this reason, it has been referred to as a “functional” GI disorder. However, there is increasing evidence of distinct pathophysiologic mechanisms underlying IBS. Thus, IBS has now been redefined as a disorder of gut–brain interaction that is classified by GI symptoms related to any combination of the following: motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system (CNS) processing.²

EPIDEMIOLOGY

Prevalence and Impact

A recent population-based study found that 30% met criteria for ≥1 FBD and 4.6% met Rome IV criteria for IBS (Table 1).³Using the less stringent Rome III criteria (Table 1),4 the prevalence was 9%. IBS is subtyped by predominant bowel habit. Based on Rome IV subclassification criteria (Table 2), the prevalence of IBS with diarrhea (IBS-D), IBS with mixed symptoms (IBS-M), and IBS with constipation (IBS-C) are similar and < 5% are unsubtyped (IBS-U).^3,5 IBS is more prevalent in women and younger individuals.^1,6 Up to 50% individuals with IBS symptoms do not seek healthcare, and those who do have symptoms for an average of 7 years prior to being diagnosed with IBS.⁷ IBS is associated with a poorer health-related quality of life (HRQOL)8 and significant healthcare utilization and costs. It accounts for 10% to 15% of primary care visits and 25% to 50% of gastroenterology visits.⁹ The combined indirect and direct costs for IBS has been estimated to be $1.01 billion.¹⁰

Risk Factors

Post-infection IBS (PI-IBS) is defined as the onset of IBS symptoms following resolution of acute infectious gastroenteritis, characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture, in an individual without a history of IBS.¹¹ GI infection is associated with about a 4-fold increase in risk of IBS-symptoms at twelve months in comparison to uninfected individuals.¹² Risk factors for PIIBS include a preexisting GI condition, a history of more severe diarrheal illness, younger age, female gender, chronic stressful life events, or psychological disorders.¹³

There is an association between having IBS, including PI-IBS, and stressful life events in childhood and/or adulthood.^14,15 A history of early adverse life events (EALs) or traumatic experiences during childhood increases an individual’s risk for IBS by at least 2-fold. These EALs include, but are not limited to, maladjusted relationships with a parent or primary caregiver, severe illness or death of a parent, a mentally ill or incarcerated household member, and physical, sexual, or emotional abuse.¹⁶ Two survey studies found that the majority of IBS patients believe that stress causes and triggers their symptoms.^7,17

DIAGNOSIS

The differential diagnosis for the symptoms of IBS is shown in Table 3. The use of the Rome diagnostic algorithm (Figure 1)¹⁸which is comprised of a medical history and physical examination, evaluation of GI symptoms and alarm signs or symptoms, limited diagnostic testing and use of symptom-based Rome IV criteria (Table 1),¹which are sufficient to make the diagnosis of IBS. Alarm features include rectal bleeding, weight loss, iron deficiency anemia, nocturnal diarrhea, and a family history of colon cancer, inflammatory bowel disease (IBD) or celiac disease.¹⁹The presence of “red flags” or alarm features may indicate a need for further diagnostic tests but it should not exclude a patient from being diagnosed with IBS.¹⁹

The Rome IV criteria are currently the most widely used criteria for diagnosis of IBS and are accepted by regulatory agencies including the Food and Drug Administration (FDA). Symptom frequencies in the Rome IV criteria were based on US normative data. The purpose of the Rome criteria and the modifications in Rome IV are to improve the specificity (although this reduced the sensitivity) for the purposes of clinical research studies.²⁰However, in clinical practice, patients meeting Rome III or IV criteria can and should be diagnosed with IBS.

Recent AGA guidelines for the diagnostic evaluation of patients with IBS-D or chronic diarrhea recommend a fecal calprotectin or fecal lactoferrin to screen for IBD.²¹A normal level is associated with a <1% chance that symptoms are due to IBD. In individuals with IBS symptoms, it is cost-effective to obtain celiac serologies when the prevalence of celiac disease is at least 1%.²²Serum IgA tissue transglutaminase (tTG) and an IgA level should be ordered. Because IgA deficiency can lead to a false-negative result, a test for IgG deaminated gliadin peptides can be ordered in IgA-deficient patients.²¹While Giardia antigen and polymerase chain reaction (PCR) tests are recommended in patients with IBS-D symptoms, conventional ova and parasite stool testing is not recommended unless there is a history of recent travel to endemic areas.²¹In 25-30% of patients with IBS-D symptoms, there is evidence of bile acid diarrhea²³ and therefore, testing for bile acid diarrhea or an empiric trial of bile acid sequestrants is recommended.²¹A blood test measuring circulating antibodies to cytolethal distending toxin B and vinculin (anti-CdtB, antivinculin) have been shown to be increased in IBS-D and possibly IBS-M.²⁴However, this test has a low sensitivity (<50%), and the major societies did not issue recommendations for or against the use of these serologic tests.^21,25,26

Other routine blood tests, such as a metabolic panel and thyroid function tests, are rarely abnormal in patients with symptoms of IBS, and typically do not lead to an alternative diagnosis.²⁷Abdominal imaging such as a CT scan or ultrasound is not recommended in IBS patients without alarm signs or symptoms.

A colonoscopy should be performed according to the guidelines for colon cancer screening and surveillance in the general population in patients with IBS symptoms without alarm features.¹⁹There is a low pretest probability of IBD and colonic neoplasia in these patients. However, if a colonoscopy is performed in a patient with diarrheal symptoms, colon biopsies should be taken in the right and left colon to rule out microscopic colitis and collagenous colitis.

The association between small intestinal bacterial overgrowth (SIBO) and IBS remains controversial. With the possible exception of predicting response to rifaximin in patients with IBS-D,²⁸there is limited clinical utility of testing for SIBO (e.g., lactulose hydrogen breath test) in patients with IBS. Society guidelines currently do not recommend testing for evaluation of IBS.^19,25,26,29

Routine testing for carbohydrate malabsorption is generally not recommended in individuals with IBS symptoms.^19,25,26,29 However, lactose breath testing can be considered when lactose maldigestion remains a concern despite avoiding dairy products. Similarly, fructose breath testing can be considered in patients suspected of having fructose maldigestion. Adult Sucrase Isomaltase Deficiency has been recognized in a very small subgroup of IBS-D patients and can be considered especially if there is no response to a low fermentable oligosaccharides, di-saccharides, and mono-saccharides, and polyols (FODMAP) diet.^30,31

TREATMENT

Overall Approach

It is important to assess the severity and impact of symptoms on the patient’s HRQOL as they guide treatment. Patients with mild symptoms (i.e., do not impact daily activities) can be managed with providing a positive diagnosis of IBS, reassurance, education, and dietary guidance. Pharmacotherapy may not be required or can be used on an as needed basis. However, patients with moderate to severe symptoms (i.e., moderate to severe impact on daily activities) will benefit from the approaches used in patients with mild disease activity but also often require pharmacological and/or psychological therapies.

Understanding the biopsychosocial model of functional GI disorders which integrates clinical experience, pathogenesis with the bidirectional influence of psychologic and physiologic factors (brain-gut/mind-body interactions), and impact and clinical outcomes helps to guide management (Figure 2).² The biopsychosocial model provides a clinical framework for the physician to integrate the broad range of biomedical and psychosocial factors that explain the illness experience.²

A successful healthcare provider–patient relationship is the foundation of effective care of IBS patients. The quality of this relationship improves patient outcomes. Components of a therapeutic provider–patient relationship include a nonjudgmental patient-centered communication, a careful and cost-effective evaluation, inquiry into the patient’s understanding of the illness, patient education, and involvement of the patient in treatment decisions which can empower them.

As many treatments target normalization of bowel habits, treatment approaches can differ based on IBS bowel habit subtype. The Rome algorithms for IBS-C and IBS-D are shown in Figures 3 and 4, respectively. The individual treatments are described below. References to primary literature can be found in the American College of Gastroenterology (ACG) monograph32 unless cited directly.

Diet and Lifestyle Changes

The majority of IBS patients perceive that symptoms are exacerbated by meals and that they have food allergies or intolerances.33 There is more evidence that food intolerance rather than food allergies contributes to IBS symptoms. However, there is currently not strong evidence that food panels, which measure IgG levels to certain foods, predict food intolerance in IBS. A 1- to 2-week food and symptom diary can help determine consistent food triggers that can guide dietary modification and avoid eliminating more foods than necessary. Controlled trials have demonstrated that a low FODMAP diet is efficacious in reducing overall and individual symptoms of IBS. Although a low FODMAP diet was recommended by GI societies, the quality of evidence was considered very low. Although efficacy is thought to extend to all bowel habit subtypes, there appears to be more evidence to support its efficacy in patients with non-constipating IBS. Success of the low FODMAP diet is more likely if the patient works with a dietitian.

While there are studies that demonstrate a reduction in IBS symptoms with a gluten free diet, the evidence is of low quality and it is not recommended by GI societies.

Bulking agents, namely soluble fiber such as psyllium, have been shown to be efficacious in IBS. All studies were conducted in IBS, and not specifically IBS-C, and no study reported data by predominant bowel habit. However, anecdotal experience suggests that bulking agents are more effective in IBS-C than other subtypes.

Physical activity is beneficial in reducing IBS symptoms compared to usual activity.³⁴Improving sleep may also be helpful as poor sleep quality correlates with worse IBS-related abdominal pain, distress and HRQOL.³⁵

Pharmacological Therapies

Pharmacologic therapies and associated doses to treat IBS symptoms are listed in Table 5.

IBS-C

Laxatives

Osmotic laxatives, such as polyethylene glycol (PEG) or magnesium-containing products, are generally safe and well tolerated and can be considered in patients with mild IBS-C. In IBS-C, PEG has been shown to relieve constipation symptoms but not abdominal pain. Other osmotic laxatives, such as lactulose and sorbitol, are frequently associated with bloating and/or cramping in IBS patients. Stimulant laxatives (senna, bisacodyl) have been studied more in chronic (functional) constipation than IBS-C. They can be used if more effective than other therapies or on an as needed basis, but may cause abdominal cramping, urgency and loose stools.

Lubiprostone

Lubiprostone is a chloride channel (ClC-2) activator increases luminal chloride secretion. In randomized controlled trials (RCTs), lubiprostone improved stool consistency, straining, abdominal pain/discomfort and constipation severity. The most common side effects of lubiprostone are nausea and diarrhea. Taking lubiprostone with food helps to decrease nausea. Lubiprostone should be considered in patients with mild to moderate symptoms of IBS-C and when pain is not a predominant and persistent symptom.

Linaclotide and Plecanatide

Linaclotide is a minimally absorbed, guanylate cyclase C (GC-C) agonist that increases luminal secretion of chloride and bicarbonate via the cystic fibrosis transmembrane conductance regulator. In multiple clinical trials conducted in IBS-C patients, linaclotide at a dose of 290 μg per day has been associated with significant improvement of abdominal pain, bloating and constipation symptoms.

Plecanatide is a similar to uroguanylin, which is a natural ligand of the GC-C receptor that acts in a pH-dependent manner. Three RCTs showed that plecanatide significantly relieved abdominal pain and constipation symptoms compared to placebo. The main side effect of both GC-C agonists was diarrhea.

Based on their efficacy profile, these medications should be a mainstay in the treatment of IBS-C, particularly in patients with moderate to severe symptoms or when pain or bloating is a predominant symptom despite improvement in bowel habits.

Tenapanor

Tenapanor is a minimally absorbed, inhibitor of the GI sodium/hydrogen exchanger isoform 3 (NHE3) that increases excretion of sodium and water in stool. Tenapanor significantly improved abdominal pain and constipation symptoms and was approved by the FDA for IBS-C in 2019. It is not yet available.

Tegaserod

Several RCTs have demonstrated the efficacy of tegaserod, a selective 5-HT4 partial agonist, in improving symptoms of IBS-C and IBS-M compared to placebo.36 Tegaserod was suspended by the FDA in 2007 because of the higher incidence of cardiovascular ischemic events in patients compared to placebo (0.11% vs 0.01%). However, in 2019, the FDA approved the reintroduction of tegaserod for treatment of IBS-C in adult female patients <65 years of age with low cardiovascular risk. Tegaserod is contraindicated in patients with a history of myocardial infarction, stroke, transient ischemic attack, angina, ischemic colitis or other forms of intestinal ischemia.

IBS-D

Loperamide

Loperamide reduces diarrhea by acting directly on the intestinal smooth muscle via the µ-opioid receptor. Two small RCTs showed that it did not have a beneficial effect on global IBS symptoms or abdominal pain but reduced stool frequency. Although antidiarrheals can be used regularly, they are more commonly used on an as-needed basis (e.g., leaving the house, a long car trip, a meal, or a stressful event).

Eluxadoline

Eluxadoline is a mixed agonist of both µ- and a κ-opioid receptors and an antagonist of δ-opioid receptors and was approved by the FDA for IBS-D in 2015. RCTs demonstrated efficacy of both doses of eluxadoline in improving overall symptoms and stool consistency, frequency, urgency. The effect on abdominal pain was not as consistent. Due to an associated increased risk of pancreatitis, contraindications of using eluxadoline include lack of a gallbladder, known or suspected biliary duct obstruction, or sphincter of Oddi disease, alcohol intake of more than 3 drinks/day, a history of pancreatitis, structural diseases of the pancreas.

Rifaximin

Rifaximin is a broad-spectrum, minimally absorbed antibiotic that is approved to treat IBS-D. It has been shown to be superior to placebo in improving global symptoms, abdominal pain, diarrhea and bloating. Symptoms can return over time following treatment (e.g. within 3-6 months), but retreatment can be prescribed with up to two additional times for recurrent symptoms. Rifaximin is generally well tolerated.

Bile Acid Sequestrants

As previously mentioned, bile acid diarrhea is part of the evaluation of suspected IBS-D. Thus, an empiric trial of bile acid sequestrant therapy, such as cholestyramine (powder) or colesevelam (tablets) can be considered and may be effective in a subset of patients.

Alosetron and Ondansetron

5-HT3 receptor antagonists can slow gut transit and reduce visceral hypersensitivity and have been shown to be efficacious in treating IBS-D symptoms compared to placebo. RCTs demonstrated that alosetron significantly improved abdominal pain, diarrheal symptoms, and urgency in IBS-D. It is currently available under a risk evaluation and mitigation strategy for women with severe IBS-D who have failed traditional treatment. This restriction is due to the occurrence of rare GI-related serious adverse events including ischemic colitis and serious complications of constipation (rate of 1.1 and 0.66 per 1000 patient years, respectively).

The 5HT3 antagonist ondansetron is approved to relieve nausea and is currently being studied in IBS-D. A relatively smaller, placebo-controlled, crossover clinical trial with 3-week treatment periods demonstrated that ondansetron (4 mg tablets that could be titrated up to 8 mg three times daily) significantly reduced diarrhea but not abdominal pain.³⁷

Multiple Subtypes

Antispasmodics

Antispasmodics are smooth muscle relaxants and significantly improve IBS symptoms including abdominal pain compared to placebo. They are commonly used in IBS, particularly to relieve postprandial GI symptoms. Hyoscyamine and dicyclomine area most commonly prescribed for IBS in the US.

Compared to placebo, peppermint oil, a smooth muscle relaxant, overall reduces IBS symptoms. Peppermint oil is available in a small-intestinalrelease formulation, which can reduce abdominal pain, discomfort and severity of IBS symptoms.³⁸

Probiotics

There is considerable heterogeneity among probiotic RCTs in IBS. Many studies are small or of poor quality. In general, Bifidobacteria demonstrated some efficacy in reducing overall symptoms in IBS.¹⁹Bifidobacteria animalis subsp. lactis DN-173 010, Bifidobacterium bifidum MIMBb75 and Escherichia coli DSM17252 have been recommended for relief of bloating, distension, and overall symptoms in IBS.32

Central Neuromodulators

Centrally acting agents, such as antidepressants, have been relabeled as gut-brain neuromodulators as they work both in the brain and the gut.2 The rationale for using central neuromodulators in IBS is that they may reduce visceral perception and potentially treat coexistent psychological symptoms. Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and to a lesser extent serotonin–norepinephrine reuptake inhibitors (SNRIs) have been studied in IBS.

TCAs can be considered first-line treatment for IBS patients with predominant pain, especially if they have IBS-D since TCAs have anticholinergic effects and can reduce diarrhea. They can be started at 10-25 mg qhs and gradually increased to the lowest, most effective and tolerated dose (e.g., up to 75 or 100 mg). Because desipramine and nortriptyline have less anticholinergic and antihistaminic side effects compared with amitriptyline and imipramine, they are favored if constipation or sedation is a concern.

Most RCTs of SSRIs in IBS have been small. While SSRIs may improve global symptoms of IBS, they are not efficacious in relieving abdominal pain. They are generally tolerated better than TCAs. However, diarrhea may be a side effect and therefore they may be more useful in patients with constipation. They should be considered in patients with significant psychologic symptoms which can amplify IBS symptoms and/or negatively impact coping of symptoms.

SNRIs, such as duloxetine has only been assessed in a small IBS study,39 but there is substantial evidence of their pain inhibitory properties. Therefore, they may be efficacious in patients with chronic abdominal pain, particularly if TCAs are not effective or well tolerated. SNRIs have been approved to treat fibromyalgia and depression, which are often coexistent in IBS and thus may be an ideal agent in these overlap patients.

Psychological Therapies

The rationale of using psychological treatment for IBS is that symptoms can be triggered by stressful life events, there is a notable coexistence with psychiatric disorders, and central-acting therapies can reduce visceral perception. Cognitive behavioral therapy, relaxation therapy, multicomponent psychological therapy, hypnotherapy, and dynamic psychotherapy have been found to be effective in IBS. There are emerging studies demonstrating similar efficacy of internet based behavioral treatment, which may be more convenient and accessible than in-person treatments.

Fecal Microbiota Transplantation (FMT)

FMT has been assessed for the treatment of IBS. A recent meta-analysis of four studies showed no benefit of FMT for global IBS symptoms,40 but another meta-analysis found a beneficial effect for FMT from donor stool delivered via colonoscopy vs autologous stool based.41 Larger and higher quality studies are needed.

CONCLUSION

IBS is a common chronic GI disorder characterized by alterations in gut-brain interaction. It is a multifactorial, complex disorder that can be conceptualized using a biopsychosocial model. There are society guidelines for the diagnostic testing and treatment efficacy and safety in IBS which can help guide management, however, a patient-centered approach that considers multiple factors that affect treatment response are recommended. These factors include patient-related factors (comorbidities, treatment preferences, insurance, etc.), provider factors (past experience, knowledge and expertise, comfort and access to certain treatments, etc.) and system level factors (practice setting, location, reimbursement, etc.). Although beyond the scope of this review, we can look forward to emerging scientific data that will help enhance our understanding of IBS pathophysiology as well as advances in drug development for IBS.

References

^{Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology. 2016.}
^{Drossman DA, Chang L, Chey WD, et al. Rome IV Functional Gastrointestinal Disorders – Disorders of GutBrain Interaction. 4 ed. Raleigh, NC: Rome Foundation; 2016.}
^{Palsson OS, Whitehead W, Tornblom H, et al. Prevalence of Rome IV Functional Bowel Disorders Among Adults in the United States, Canada, and the United Kingdom. Gastroenterology. 2020.}
^{Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130(5):1480.}
^{Black CJ, Yiannakou Y, Houghton LA, Ford AC. Epidemiological, Clinical, and Psychological Characteristics of Individuals with Self-reported Irritable Bowel Syndrome Based on the Rome IV vs Rome III Criteria. Clin Gastroenterol Hepatol. 2019.}
^{Camilleri M. Sex as a biological variable in irritable bowel syndrome. Neurogastroenterol Motil. 2020:e13802.}
^{Sayuk GS, Wolf R, Chang L. Comparison of Symptoms, Healthcare Utilization, and Treatment in Diagnosed and Undiagnosed Individuals With Diarrhea-Predominant Irritable Bowel Syndrome. Am J Gastroenterol. 2017;112(6):892 El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther. 2002;16(6):1171.}
^{Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ, 3rd. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology. 1991;101(4):927.}
^{Everhart JE. Functional Intestinal Disorders. Washington, DC: US Government Printing Office: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.; 2008. Contract No.: NIH Publication No. 09-6443.}
^{Barbara G, Grover M, Bercik P, et al. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46.}
^{Klem F, Wadhwa A, Prokop LJ, et al. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Gastroenterology. 2017;152(5):1042.}
^{Ruigomez A, Garcia Rodriguez LA, Panes J. Risk of irritable bowel syndrome after an episode of bacterial gastroenteritis in general practice: influence of comorbidities. Clin Gastroenterol Hepatol. 2007;5(4):465.}
^{Whitehead WE, Crowell MD, Robinson JC, et al. Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction. Gut. 1992;33(6):825.}
^{Parker CH, Naliboff BD, Shih W, et al. Negative Events During Adulthood are Associated With Symptom Severity and Altered Stress Response in Patients With Irritable Bowel Syndrome. Clin Gastroenterol Hepatol. 2019.}
^{Bradford K, Shih W, Videlock EJ, et al. Association between early adverse life events and irritable bowel syndrome. Clin Gastroenterol Hepatol. 2012;10(4):385.}
^{Halpert A, Dalton CB, Palsson O, et al. What patients know about irritable bowel syndrome (IBS) and what they would like to know. National Survey on Patient Educational Needs in IBS and development and validation of the Patient Educational Needs Questionnaire (PEQ). Am J Gastroenterol. 2007;102(9):1972.}
^{Kellow JE, Guest Editor in Drossman DA, Chang L, Chey WD, Kellow JE, Tack J, Whitehead WE (Eds). Rome IV Diagnostic algorithms for common GI symptoms. 2nd ed. Raleigh, NC: Rome Foundation; 2016.}
^{Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidencebased position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 Suppl 1:S1.}
^{Lin L, Chang L. Benefits and Pitfalls of Change From Rome III to Rome IV Criteria for Irritable Bowel Syndrome and Fecal Incontinence. Clin Gastroenterol Hepatol. 2019.}
^{Smalley W, Falck-Ytter C, Carrasco-Labra A, et al. AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Gastroenterology. 2019;157(3):851.}
^{Spiegel BM, DeRosa VP, Gralnek IM, et al. Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a cost-effectiveness analysis. Gastroenterology. 2004;126(7):1721.}
^{Wedlake L, A’Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoeapredominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009;30(7):707.}
^{Pimentel M, Morales W, Rezaie A, et al. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS One.
2015;10(5):e0126438.}
^{Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019;2(1):6.}
^{Moayyedi P, Mearin F, Azpiroz F, et al. Irritable bowel syndrome diagnosis and management: A simplified algorithm for clinical practice. United European Gastroenterol J. 2017;5(6):773.}
^{Tolliver BA, Herrera JL, DiPalma JA. Evaluation of patients who meet clinical criteria for irritable bowel syndrome. Am J Gastroenterol. 1994;89(2):176.}
^{Rezaie A, Heimanson Z, McCallum R, Pimentel M. Lactulose Breath Testing as a Predictor of Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea. Am J Gastroenterol. 2019.}
^{The National Institute for Health and Care Excellence (NICE) Surveillance report 2017 – Irritable bowel syndrome (2008) NICE guideline CG61. London2017.}
^{Henstrom M, Diekmann L, Bonfiglio F, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67(2):263.}
^{Zheng T, Eswaran S, Photenhauer AL, et al. Reduced efficacy of low FODMAPs diet in patients with IBS-D carrying sucrase-isomaltase (SI) hypomorphic variants. Gut. 2019.}
^{Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1.}
^{Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40(1):141.}
^{Zhou C, Zhao E, Li Y, et al. Exercise therapy of patients with irritable bowel syndrome: A systematic review of randomized controlled trials. Neurogastroenterol Motil. 2019;31(2):e13461.}
^{Ballou S, Alhassan E, Hon E, et al. Sleep Disturbances Are Commonly Reported Among Patients Presenting to a Gastroenterology Clinic. Dig Dis Sci. 2018;63(11):2983.}
^{Chey WD, Pare P, Viegas A, et al. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am J Gastroenterol. 2008;103(5):1217.}
^{Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63(10):1617.}
^{Weerts Z, Masclee AAM, Witteman BJM, et al. Efficacy and Safety of Peppermint Oil in a Randomized, DoubleBlind Trial of Patients With Irritable Bowel Syndrome. Gastroenterology. 2020;158(1):123.}
^{Brennan BP, Fogarty KV, Roberts JL, et al. Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study. Hum Psychopharmacol. 2009;24(5):423.}
^{Xu D, Chen VL, Steiner CA, et al. Efficacy of Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2019;114(7):1043.}
^{Ianiro G, Eusebi LH, Black CJ, et al. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2019;50(3):240.}
^{Weinberg DS, Smalley W, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147(5):1146.}
^{The National Institute for Health and Care E. Surveillance report 2017 – Irritable bowel syndrome (2008) NICE guideline CG61. London2017.}

Download Tables, Images & References

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202

Clostridioides difficile Infection: Is There a Role for Diet and Probiotics?

September 2020 • Volume XLIV, Issue 9

Christopher Ward,

Colleen R. Kelly

Read Article

Clostridioides difficile is a spore forming bacterium leading to significant morbidity and mortality amongst hospitalized as well as non-hospitalized patients in the United States. While hospital acquired infections have reduced, in recent years we have seen an increase in community acquired infections. With the focus on antimicrobial therapies and fecal microbiota transplantation, it is important to understand the evidence behind probiotics and nutrition in the management of C. difficile infections. There is an abundance of new literature regarding the $40 billion a year probiotic industry, meanwhile patients require dietary advice following an infection. In this review, we aim to give the non-specialty clinician some clarity regarding these issues.

INTRODUCTION

Clostridioides difficile is an anaerobic, gram positive, spore forming bacterium that causes a spectrum of gastrointestinal symptoms ranging from mild diarrhea to colitis, toxic megacolon, intestinal perforation, and death. It is spread via the fecal-oral route and is frequently encountered in hospitals, affecting 1% of US hospital stays¹ and nursing homes where antibiotic use is common. Concerningly, community-acquired infections are common, and recent research suggests other undefined causes of CDI, as many cases occur without a history of antibiotic use.² There was a significant increase in CDI between 2000-2010, which has been attributed to increased detection with use of nucleic acid amplification testing, more virulent strains, and increased community antibiotic use. Since then, we have seen a reduction in healthcare associated CDI, though there are still almost half a million cases per year within the United States.³ Infection control measures, decreased fluroquinolone use, and improved antibiotic stewardship have been credited with these results.⁴

In recent years there has been an abundance of new literature on C. difficile with regards to management and prevention options. For the nonspecialty clinician, it is challenging to determine which data is high quality and what can be applied to their patients. With the spotlight on fecal microbiotatransplantation (FMT) and other non-antibiotic therapies for CDI, it is understandable that both clinicians and patients are seeking preventative options such as probiotics and nutrition. Here we evaluate the current evidence for these therapies in the prevention of CDI.

Probiotics

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.⁵ The literal translation is “for-life”, which conveys that they are good, natural, and beneficial to biological functions. Proposed mechanisms for beneficial effects include modification of the gut microbiota, competitive adherence to the mucosa and epithelium, strengthening of the gut epithelial barrier, and modulation of the immune system to convey an advantage to the host.⁶ Probiotics are marketed as dietary supplements with colourful labels and vague claims of “friendly bacteria” to “improve gut health.” This 40 billion dollar a year industry,⁷ while extremely appealing to patients and healthcare professionals, operates without the strict oversight by the U.S. Food and Drug Administration that is required of drugs. A quick internet search reveals a plethora of websites recommending various probiotics as a means to improve one’s health for various indications, including after CDI. A 2010 survey of gastroenterologists found that 98% of respondents believed probiotics have a role in treating gastrointestinal illnesses or symptoms, despite the paucity of data to support their use. Sixty percent believed that the literature supported the use of probiotics in the treatment of CDI.⁸ Due to the lack of regulation and freedom to make general health claims on product labels, there is little incentive for manufacturers to conduct clinical trials to support specific indications for their products.⁹

The trouble with many of the available products is that quality control is often sub-optimal with inconsistencies and deviations from the information provided on the product label including misidentified, misclassified or non-viable strains, contaminated products, or diminished functional properties.¹⁰ The belief that probiotics “can’t hurt” has been challenged by case reports of bloodstream infections with probiotic organisms in critically ill patients leading to the recommendation that they be used with caution in immunocompromised patients and those with structural heart disease or central venous catheters.¹¹ Microbiome analyses have shown that they may actually impede normal recolonization in the gut after a course of antibiotics.¹² Despite this, probiotics are widely recommended by physicians to prevent CDI in patients being treated with antibiotics (primary prevention) or in patients being treated for CDI to prevent recurrences (secondary prevention). Costs range from $30 to $100 per month for the most commonly recommended formulations, which are frequently taken for extended courses and typically not covered by insurance. Given these costs, the desire to provide reliable health information to our patients, and the potential for harm, it is important to critically appraise data supporting the use of probiotics in CDI.

Evidence to support probiotics in the management of CDI comes mainly from meta analyses, which pool data from smaller trials of variable probiotic formulations and methodologies. There is a paucity of high-quality clinical trial data of probiotics in CDI, and most studies are underpowered, with CDI as a secondary outcome in studies done to assess prevention of antibiotic associated diarrhea (AAD). A 2016 global review of guidelines, strategies, and recommendations for CDI prevention4 labelled probiotics as an area of research, but were unable to recommend their use. There is currently insufficient evidence to recommend any probiotic for the primary or secondary prevention of CDI.

The Literature

The PLACIDE trial is the largest double-blind clinical primary prevention randomized controlled trial (RCT) to date.¹³ This multicenter trial in the United Kingdom enrolled nearly 3000 elderly inpatients who were at high risk of contracting CDI. Patients >65 years old receiving antibiotics were randomized to treatment with a multi-strain preparation composed of bifidobacterium and Lactobacillus acidophillus strains or placebo for 21 days. AAD including CDI occurred in 10·8% of the microbial preparation group and 10·4% of those treated with placebo. CDI was an uncommon cause of AAD and occurred in just 0·8% of the microbial preparation group and 1·2% of the placebo group. The authors concluded that probiotics were of no benefit in prevention of AAD or CDI.

Many nutritional websites and magazines broadly claim “high quality evidence” for probiotics in CDI, most citing the Cochrane Review in 2017 by Golbenberg et al, which looked at probiotics for primary prevention of CDI in adults and children, enrolling 8672 participants.¹⁴ It is important to highlight that 27 of the 31 studies analysed were felt to be of unclear or high risk of bias and more than half had missing data. The incidence of CDI was 1.5% in the treatment group and 4% in the control groups, a 60% risk reduction. They concluded a modest benefit of probiotics (number needed to benefit=42). However, in posthoc subgroup analysis these benefits only held up in trials enrolling participants with baseline CDI risk >5%, which is higher than the average risk in American hospitals and therefore has questionable clinical application. The conclusions of this Cochrane review have been criticized as misleading, in that only 4/31 trials showed benefits and small, poorly controlled studies had too much influence.9 Results were heavily influenced by 5 studies with CDI baseline risk >15%, far above that seen in any hospital setting in the world, raising important questions of the external validity. Major limitations of this meta-analysis were that included studies used many differing probiotic combinations and dosages, multiple trials were small/underpowered, single center, missing data, participants lost to follow up, and in some cases, no fecal samples were obtained.

An earlier Cochrane review of probiotics for treatment of CDI, which included four studies, concluded that there is insufficient evidence to support their use.¹⁵ Published in 2017, the PICO trial randomized 33 patients with an initial mild to moderate CDI to 28 days of a four-strain probiotic or placebo in addition to anti-CDI therapy and showed no difference in rates of CDI recurrence.¹⁶

In light of all this evidence and despite what product labels and websites will claim, probiotic prophylaxis for CDI prevention is not recommended by the American College of Gastroenterology,¹⁷ the Association for Professionals in Infection Control and Epidemiology.¹⁸ or the European Society of Clinical Microbiology and Infectious Diseases.¹⁹

Saccharomyces Boulardii
Hope for Recurrent CDI?

There were several publications in the 1990s involving Saccharomyces boulardii that showed promise regarding CDI secondary prevention.²⁰ S. boulardii is a yeast that grows on lychee fruit. It was discovered by a French pharmacist who observed South-East Asian natives chewing the skins of the fruit to lessen the symptoms of cholera. It produces a protease that inactivates the receptor site for C. difficile toxin A, lending biologic plausibility to its use in CDI.²¹

A 1994 multicenter RCT showed decreased CDI recurrence in patients treated with S. boulardii in addition to either metronidazole or vancomycin in those who had already suffered a recurrence (34.6% with S. boulardii vs 64.7% with placebo).²² There was no benefit over placebo in patients with primary infection. A follow up study published in 2000 enrolled 168 recurrent CDI patients who were treated with a 28 day course of S. boulardii or placebo in addition to anti-CDI therapy.²³ The benefits in this study were limited to the subgroup who were treated with high-dose vancomycin and S. boulardii (16.7% recurrence vs. 50% with placebo). Those who received low dose vancomycin or metronidazole had similar rates of recurrence whether they were treated with the probiotic or placebo. The study was small, with n=32 in the high-dose vancomycin group, hence, no firm conclusions can be drawn. Unfortunately, a larger planned trial was never conducted and the benefits of S. boulardii for secondary prevention remain unknown.

Dietary Probiotics

Following a CDI, many patients seek dietary advice to prevent recurrence. This is another area without robust evidence to guide us. Dietary sources of probiotics include fermented milk products (such as yogurt, kefir, and buttermilk), fermented vegetables (such as kimchi and sauerkraut), and fermented soy products (such as miso and tempeh). There have been several studies looking into the use of yogurt in prevention of AAD, but not CDI. In 2003, one center randomized 202 elderly hospitalized patients receiving antibiotics to receive 16 ounces of yogurt per day for a week. The control group received no yogurt. The yogurt group reported less antibiotic associated diarrhea (12% vs 24%, p=0.04) and less diarrhea days (23 vs 60 days). The role of dietary probiotics in CDI is unclear and it is important to note that following CDI patients may have lactose intolerance and post-infectious irritable bowel syndrome,²⁴ so consumption of yogurt for that purpose may lead to worsening gastrointestinal (GI) upset.²⁵

Nutritional Tips Following CDI

In the immediate recovery period from CDI, patients are at increased risk for postinfectious irritable bowel syndrome (IBS) and ongoing diarrhea and therefore should consider following general advice that is given to other patients with IBS. There is however a lack of evidence for any of the following nutritional recommendations in the setting of CDI and further studies are required. Patients with post infectious IBS may have associated lactose intolerance; therefore, we advise avoiding high lactose containing foods, in particular milk and other high lactose containing milk products for 2-4 weeks.²⁴ Additionally, greasy foods, spicy foods,²⁶ and excessive caffeine intake²⁷ are often reported to cause GI distress and should be avoided at least in the short-term following CDI.

Microbiome

In recent years there has also been rapidly growing interest in the human gut microbiome in facilitating health benefits and its role in many diseases.²⁸No longer the “forgotten organ”²⁹, the function of the microbiome is now being extensively investigated. Encompassing 1014 microorganisms, including bacteria, viruses, fungi, and protozoa;³⁰both human and animal models have shown the importance of the microbiome in resistance against CDI.³¹Disruption of the microbiome is at the core of the pathogenesis,³²though we have yet to identify which specific microbes are responsible. Given the importance of the microbiome in the development of CDI, there are select diets that may improve or diversify the microbiome and alter one’s chance of developing an infection.

Select Diets

Several studies have shown the consumption of a Western diet, consisting of high animal protein and fat with low fiber has resulted in reduced diversity overall and specifically lower amounts of Bifidobacterium and Eubacterium.^33-34 Consumption of a gluten free diet may lead to reduced diversity and increased pathogenic bacteria.^35-36 A vegan or plant-based diet appears to promote microbiome diversity.^37-38 From this it might be inferred that a Western or gluten free diet may be associated with increased CDI, meanwhile vegan or plant-based diets may be protective against the development of CDI. Further studies are needed before making recommendations on this.

Fiber

Dietary fiber is found in beans, grains, vegetables, and fruits. Most fiber is not absorbed, remaining in the gut where it improves the consistency of the stool.39 There are no human studies relating fiber intake to CDI, however animal studies have shown that a diet high in soluble fiber can help eliminate CDI quicker than diets high in insoluble fiber.^40-42 The recommended amount of dietary fiber is 25g per day for moderately active Americans.⁴³ Most individuals are unable to obtain this goal with diet alone. Fiber supplements may be recommended to meet this goal and there is evidence to support benefits in various GI conditions, including IBS,39 constipation,⁴⁴and post infectious GI symptoms,⁴⁵such as after CDI. We recommend products containing psyllium, a plant-based fiber, which absorbs liquid and provides bulk to the stool for our CDI patients. We suggest starting with 1 sachet in the evening to avoid side effects such as daytime gassiness that may occur when taken in the morning. Dose can be titrated to effect.

Sugar Alcohols

Sugar alcohols or polyols such as mannitol and sorbitol are found naturally in many foods such as pineapples, sweet potatoes, and carrots, but are also found in many processed foods and liquid medications. While some mouse studies have suggested that an increase in gut polyols is associated with increased susceptibility to CDI,⁴⁶there is no evidence in humans that increased dietary sugar alcohol intake is associated with CDI.

Food Additives

Research is well underway regarding artificial sweeteners and their alteration of the gut microbiome. Saccharin and sucralose have been shown to shift populations of microbiota.⁴⁷One study in Nature by Collins et al found that the hypervirulent strain ribotype 027 is able to grow on low concentrations of trehalose, a naturally occurring sugar that the food industry began using to improve texture and stability of products in the early 21st century, around the time that CDI rates skyrocketed.48 Trehalose is found naturally in small amounts in mushrooms and shrimp, however significantly higher amounts are added by the food industry to dried and frozen foods including ice cream and frozen vegetables as well as instant noodles, soups, and many baked goods. People who do not tolerate mushrooms may lack the enzyme trehalase and suffer GI symptoms with other trehalose containing foods.⁴⁹Any possible link between this and CDI is unclear. See Table 1 for summary of the evidence for probiotics or diet.

CONCLUSIONS

The treatment and recovery from CDI is multifaceted. There is currently no evidence that probiotics reduce the incidence or recurrence of CDI. They are an enormously lucrative market with little regulation or incentive for drug companies to perform the trials that could potentially lead to progress in this area. Disruption of the microbiome is at the core of the pathogenesis of this disease. Increasing the diversity of one’s microbiome can be achieved through consuming a plant-based diet with increased dietary fiber, however the link between these interventions and a reduction in CDI is yet to be made. There is much hope that altering the microbiome, through diet and/or use of probiotics will become frontline in the treatment and recovery from Clostridioides difficile infection, however further research is required.

References

^{Lucado J, Gould C, Elixhauser A. Clostridium Difficile Infections (CDI) in Hospital Stays, 2009: Statistical Brief #124. 2012 Jan. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Feb-. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK92613/}
^{Khanna S, Pardi DS, Aronson SL et al. Outcomes in community-acquired Clostridium difficile infection. Aliment Pharmacol Ther. 2012;35(5):613-618}
^{Tabak YP, et al “Trend of Clostridium difficile Infections by Onset Settings: A Multicenter Study” ASM Microbe 2016; Abstract Friday-290.}
^{Balsells E, Filipescu T, Kyaw MH et al. Infection prevention and control of Clostridium difficile: a global review of guidelines, strategies, and recommendations. J Glob Health. 2016;6(2):020410.}
^{Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506-14}
^{Bermudez-Brito M, Plaza-Díaz J, Muñoz-Quezada S et al. Probiotic mechanisms of action. Ann Nutr Metab. 2012;61(2):160-174.}
^{Research ZM. Probiotics Market: Size, Share & Trends Analysis Report by Ingredient Type (Bacteria and Yeast), by Form (Liquid Probiotic and Dry Probiotic), by Application (Food & Beverages, Dietary Supplements, and Animal Feed), By End User (Human Probiotics and Animal Probiotics): Global Industry Perspective, Comprehensive Analysis, and Forecast, 2019 – 2026. 2020.}
^{Williams MD, Ha CY, Ciorba MA. Probiotics as therapy in gastroenterology: a study of physician opinions and recommendations. J Clin Gastroenterol. 2010;44(9):631-636.}
^{Freedman SB, Schnadower D, Tarr PI. The Probiotic Conundrum: Regulatory Confusion, Conflicting Studies, and Safety Concerns. Jama 2020;323:823-824.}
^{Kolaček S, Hojsak I, Berni Canani R, et al. Commercial Probiotic Products: A Call for Improved Quality Control. A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 2017;65:117-124.}
^{Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis 2015;60 Suppl 2:S129-34.}
^{Suez J, Zmora N, Zilberman-Schapira G, et al. PostAntibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell 2018;174:1406-1423.e16.}
^{Allen SJ, Wareham K, Wang D, et al. A high-dose preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated and Clostridium difficile diarrhoea in older people admitted to hospital: a multicentre, randomised, double-blind, placebo-controlled, parallel arm trial (PLACIDE). Health Technol Assess 2013;17:1-140.}
^{Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2017;12:Cd006095}
^{Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008:Cd004611.}
^{Barker AK, Duster M, Valentine S, et al. A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO). J Antimicrob Chemother 2017;72:3177- 3180.}
^{Surawicz CM, Brandt LJ, Binion DJ, et al. Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498.}
^{Dubberke ER, Carling P, Carrico R, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 Update. Infect Control Hosp Epidemiol. 2014;35(6):628-645.}
^{Debast SB, Bauer MP, Kuijper EJ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20 Suppl 2:1-26.}
^{Starr J. Clostridium difficile associated diarrhoea: diagnosis and treatment. BMJ. 2005;331(7515):498-501.}
^{Na X, Kelly C. Probiotics in clostridium difficile Infection. J Clin Gastroenterol. 2011;45 Suppl(Suppl):S154-S158.}
^{McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. Jama 1994;271:1913-8.}
^{Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31:1012-7.}
^{Bridges M. Got Lactase? A Clinician’s Guide to Lactose Intolerance Practical Gastroenterology. 2018;July(7):50.}
^{Beniwal RS, Arena VC, Thomas L, et al. A randomized trial of yogurt for prevention of antibiotic-associated diarrhea. Dig Dis Sci. 2003;48(10):2077-2082.}
^{Esmaillzadeh A, Keshteli AH, Hajishafiee M et al. Consumption of spicy foods and the prevalence of irritable bowel syndrome. World J Gastroenterol. 2013;19(38):6465- 6471.}
^{Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40(1):141–162}
^{Bull MJ, Plummer NT. Part 1: The human gut microbiome in health and disease. Integr Med Clin J. (2014) 13:17–22.}
^{O’Hara A.M., Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7:688–693.}
^{Gill SR, Pop M, DeBoy RT et al. Metagenomic Analysis of the human distal gut microbiome. Science. 2006;312:1355– 9.}
^{Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest. 2014;124(10):4182-4189.}
^{Britton RA, Young VB. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 2012;20(7):313–319.}
^{Wu GD, Chen J, Hofmann C et al. Linking long-term dietary patterns with gut microbial enterotypes. Sci ence. 2011;334:105–8.}
^{Singh RK, Chang HW, Yan D, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017;15(1):73. Published 2017 Apr 8.}
^{Sanz Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans. Gut Microbes. 1:135–7.}
^{Bonder MJ, Tigchelaar EF, Cai X et al. The infuence of a short-term gluten-free diet on the human gut micro biome. Genome Med. 2016;8:45.}
^{Tomova A, Bukovsky I, Rembert E, et al. The Effects of Vegetarian and Vegan Diets on Gut Microbiota. Front Nutr. 2019;6:47. Published 2019 Apr 17. 38. Wong MW, Yi CH, Liu TT et al. . Impact of vegan diets on gut microbiota: an update on the clinical implications. Tzu Chi Med J. (2018) 30:200–3. 10.4103/tcmj.tcmj_21_18}
^{Yang J, Wang HP, Zhou et al. Effect of dietary fiber on constipation: a meta analysis. World J Gastroenterol. 2012;18(48):7378-7383.}
^{Ward PB, Young GP. Dynamics of Clostridium difficile infection. Control using diet. Adv Exp Med Biol. 1997;412:63-75}
^{May T, Mackie RI, Fahey GC et al. Effect of fiber source on short-chain fatty acid production and on the growth and toxin production by Clostridium difficile. Scand J Gastroenterol. 1994;29(10):916-922.}
^{Frankel WL, Choi DM, Zhang W, et al. Soy fiber delays disease onset and prolongs survival in experimental Clostridium difficile ileocecitis. JPEN J Parenter Enteral Nutr. 1994;18(1):55-61..}
^{U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015.}
^{El-Salhy M, Ystad SO, Mazzawi T et al. Dietary fiber in irritable bowel syndrome (Review). Int J Mol Med. 2017;40(3):607-613.}
^{Iacob T, Ţăţulescu DF, Dumitraşcu DL. Therapy of the postinfectious irritable bowel syndrome: an update. Clujul Med. 2017;90(2):133-138.}
^{Theriot CM, Koenigsknecht MJ, Carlson PE Jr, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114}
^{Ruiz-Ojeda FJ, Plaza-Díaz J, Sáez-Lara MJ et al. Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials [published correction appears in Adv Nutr. 2020 Mar 1;11(2):468]. Adv Nutr. 2019;10(suppl_1):S31-S48.}
^{Collins, J., Robinson, C., Danhof, H. et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature 553, 291–294 (2018).}
^{Arola H, Koivula T, Karvonen AL et al.Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms. Scand J Gastroenterol. 1999;34(9):898-903.}

Download Tables, Images & References

INTRODUCTION

Mechanism and Classification

Increased Acid Production

Loss of Bicarbonate

Decreased Renal Acid Elimination

Consequences

Treatment

Methods of Supplementation

Parenteral Nutrition Shortages

CONCLUSION

References

INTRODUCTION

Dilation Assisted Stone Extraction

Endoscopic Papillary Balloon Dilation

Comparison of TechniquesEST VS DASE

EST VS EPLBD

Indications, Success Rates, and Potential Adverse Events of Dilation Assisted Stone Extraction (DASE) Indications (periampullary diverticula, large stones)

Success Rates

Adverse Events

Altered Anatomy

CONCLUSION

References

PHARMACOLOGY

CLINICAL TRIALSPhase 1 and 2

CLINICAL TRIALSPhase 3 (MODIFY I and MODIFY II)

Results of MODIFY I and MODIFY II

REAL-WORLD DATA

DISCUSSION

CONCLUSION

References

EPIDEMIOLOGY

Prevalence and Impact

Risk Factors

DIAGNOSIS

TREATMENT

Overall Approach

Diet and Lifestyle Changes

Pharmacological Therapies

IBS-C

Laxatives

Lubiprostone

Linaclotide and Plecanatide

Tenapanor

Tegaserod

IBS-D

Loperamide

Eluxadoline

Rifaximin

Bile Acid Sequestrants

Alosetron and Ondansetron

Multiple Subtypes

Antispasmodics

Probiotics

Central Neuromodulators

Psychological Therapies

Fecal Microbiota Transplantation (FMT)

CONCLUSION

References

INTRODUCTION

Probiotics

The Literature

Saccharomyces BoulardiiHope for Recurrent CDI?

Dietary Probiotics

Nutritional Tips Following CDI

Microbiome

Select Diets

Fiber

Sugar Alcohols

Food Additives

CONCLUSIONS

References

Comparison of Techniques
EST VS DASE

CLINICAL TRIALS
Phase 1 and 2

CLINICAL TRIALS
Phase 3 (MODIFY I and MODIFY II)

Saccharomyces Boulardii
Hope for Recurrent CDI?