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Pharmacological Management of Pediatric Clostridioides difficile Infection: Clarifying the Controversies

Published:August 17, 2021DOI:https://doi.org/10.1016/j.pedhc.2021.06.005
      Clostridioides difficile infection (CDI) is a major public health concern for pediatric and adult patients. The management of pediatric CDI poses a challenge to healthcare providers due to lack of strong randomized controlled trials to guide pharmacological management. Additionally, recent updates to CDI guidelines recommend oral vancomycin over metronidazole for the management of CDI in adults, leaving questions regarding how to best manage pediatric patients. This continuing education pharmacotherapy review describes available evidence for the safety and efficacy of medications used in the treatment and management of pediatric CDI and aims to clarify discrepancies between pediatric and adult recommendations.

      KEY WORDS

      INSTRUCTIONS

      To obtain continuing education credit:
      • 1.
        Read the article carefully.
      • 2.
        Read each question and determine the correct answer.
      • 3.
        Visit PedsCESM, ce.napnap.org, to complete the online Posttest and evaluation.
      • 4.
        You must receive 70% correct responses to receive the certificate.
      • 5.
        Tests will be accepted until April 30th, 2023.

      OBJECTIVES

      • 1.
        Describe the prevalence, pathogenesis, and diagnosis of Clostridioides difficile infection (CDI) in pediatric patients.
      • 2.
        Identify modifiable and nonmodifiable risk factors for CDI in pediatric patients.
      • 3.
        Recognize available medications and therapies used in the treatment and management of CDI infection in pediatric patients.
      • 4.
        Evaluate new evidence supporting the safety and efficacy of various pharmacological agents used in the management of pediatric CDI.
      Posttest Questions
      Contact hours: 1.25 (1.25 Pharmacology)
      Passing score: 70%
      This continuing education activity is administered by the National Association of Pediatric Nurse Practitioners (NAPNAP) as an Agency providing continuing education credit. Individuals who complete this program and earn a 70% or higher score on the Posttest will be awarded 1.25 contact hours (1.25 Pharmacology).
      Earn FREE CE Contact Hours Online
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      • 1.
        To take the Posttest for this article and earn contact hours, please go to PedsCESM at ce.napnap.org.
      • 2.
        In the Course Catalog, search for the name of the CE article.
      • 3.
        If you already have an account with PedsCESM, log in using your username and password. If you are a NAPNAP member, log in with your username and password. If you are a first-time user and NAPNAP nonmember, click on “New Customer? Click Here.”
      • 4.
        Once you have successfully passed the Posttest and completed the evaluation form, you will be able to print out your certificate immediately.

      INTRODUCTION

      Clostridioides difficile (C. difficile), formerly Clostridium difficile, is a gram-positive, spore-forming organism normally colonized in the gut microbiota (
      • Shim J.O.
      Clostridium difficile in children: To treat or not to treat?.
      ;
      • Tamma P.D.
      • Sandora T.J.
      Clostridium difficile infection in children: Current state and unanswered questions.
      ). Over the last two decades, CDI has become a major public health concern for both adult and pediatric patients (
      • Gupta A.
      • Khanna S.
      Community-acquired Clostridium difficile infection: An increasing public health threat.
      ). There has also been a notable rise in pediatric CDI hospitalizations, with an estimated increased incidence from 3,565 patients in 1997 to 7,779 patients in 2006 (p <.001) (
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ). Overall, the estimated incidence in pediatrics remains lower than that estimated in all age groups, with a report in 2015 stating the incidence in pediatrics to be 24.2 per 100,000 pediatric patients, compared with 147.2 per 100,000 in all age groups (
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
      • Dunn J.R.
      • McDonald L.C.
      Burden of Clostridium difficile infection in the United States.
      ). It is likely, this rise in incidence can be attributed to increased use of antibiotics, particularly cephalosporins and fluoroquinolones, as well as hypervirulent strains (
      • Warny M.
      • Pepin J.
      • Fang A.
      • Killgore G.
      • Thompson A.
      • Brazier J.
      • McDonald L.C.
      Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe.
      ). However, despite the increased incidence of infection, the severity of disease in children has remained stable over time (
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ). Significant efforts have been taken by the Centers for Disease Control and Prevention to reduce the incidence of CDI and prevent the development of antibiotic resistance, including educating on appropriate facility cleaning, supporting antimicrobial stewardship programs, and emphasizing prompt recognition and treatment (
      • Kadri S.S.
      Key takeaways from the US CDC's 2019 antibiotic resistance threats report for frontline providers.
      ).
      The management of pediatric patients with CDI poses a challenge to health care providers because of the lack of randomized controlled trials to guide pharmacological management. Robust data exists to guide therapies for the management of CDI in the adult population; however, specific data to guide the management of CDI in the pediatric population is not well-defined or readily available. In 2018, the Infectious Diseases Society of America (IDSA) published updated C. difficile guidelines; these guidelines only briefly touch on the pediatric population (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Throughout the guidelines, adult treatment recommendations carry strong recommendations with high quality of evidence; on the contrary, the pediatric treatment recommendations are made on the basis of low quality of evidence and are rated as weak, leading practitioners to rely on extrapolation from the adult population and clinical experience.
      Additional reviews have been published to clarify appropriate pharmacological management of pediatric patients with CDI (
      • Alvarez A.M.
      • Rathore M.H.
      Clostridium difficile infection in children.
      ;
      • Borali E.
      • De Giacomo C.
      Clostridium difficile infection in children: A review.
      ;
      • Campbell C.T.
      • Poisson M.O.
      • Hand E.O.
      An updated review of Clostridium difficile treatment in pediatrics.
      ). However, several questions remain with respect to pediatric patients. For example, the IDSA recommendations support oral vancomycin over metronidazole for the pharmacological management in adult patients; should this be the practice in children (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      )? The Food and Drug Administration (FDA) issued recent warnings regarding transmission of multidrug-resistant organisms (MDRO) with fecal microbiota transplant (FMT); how does this impact pediatric patients (
      Food and Drug Administration
      Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms.
      )? With IDSA guideline updates, this warning and newly available literature warrant an updated evaluation of pharmacological options for pediatric patients with CDI. The pathogenesis of CDI and other topics and unique aspects of CDI in the pediatric population through a question-and-answer format is addressed.

      Review of Pathogenesis

      C. difficile is normally found in the gastrointestinal tract. Alterations in the microbiota because of antibiotics or other environmental changes can lead to the overgrowth of C. difficile and the development of CDI. The pathogenicity of CDI can be attributed to the production of toxins A and B: toxin A is an enterotoxin and toxin B is a cytotoxin. These toxins enter the cells in the colon and bind to receptors within the lumen. Cellular apoptosis is then triggered, resulting in an inflammatory cascade that leads to the typical symptoms of diarrhea and colitis. Although there is no standardized consensus definition of each severity, the most common signs and symptoms on the basis of disease severity are described in Table 1. Despite good diagnostic testing, morbidity remains high because of the high rate of recurrence after initial infection (
      • Antonara S.
      • Leber A.L.
      Diagnosis of Clostridium difficile infections in children.
      ). As many as 20% of pediatric patients will experience a recurrence of CDI (
      • Aldrich A.M.
      • Argo T.
      • Koehler T.J.
      • Olivero R.
      Analysis of treatment outcomes for recurrent Clostridium difficile infections and fecal microbiota transplantation in a pediatric hospital.
      ).
      TABLE 1Characteristics of Clostridioides difficile infection by disease severity
      Sources. Cohen et al., 2010; Gomez-Simmonds, Kubin, & Furuya, 2014;
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      Disease SeverityIDSA CriteriaSigns and Symptoms
      Mild to moderateWBC count < 15,000 cells/mm3 and serum creatinine < 1.5 × baselineAcute-onset, frequent, malodorous diarrhea accompanied by abdominal pain
      SevereWBC count ≥ 15,000 cells/mm3 or serum creatinine ≥ 1.5 × baselineLeukocytosis, elevated serum creatinine, high diarrheal output, fever, as well as hypotension and shock in cases of fulminant disease
      Note. IDSA, Infectious Diseases Society of America; WBC, white blood cell.

      When to Test

      There is no standardized frequency of diarrheal episodes to definitively determine when to test for CDI in children (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Several studies have cited a range of at least 3–6 loose, watery stools for 24–72 hr, but this range is highly variable (
      • Fekety R.
      • Silva J.
      • Kauffman C.
      • Buggy B.
      • Deery H.G.
      Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: Comparison of two dosage regimens.
      ;
      • Teasley D.G.
      • Gerding D.N.
      • Olson M.M.
      • Peterson L.R.
      • Gebhard R.L.
      • Schwartz M.J.
      • Lee Jr, J.T.
      Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis.
      ;
      • Tedesco F.J.
      • Barton R.W.
      • Alpers D.H.
      Clindamycin-associated colitis. A prospective study.
      ). Determining an appropriate frequency of stools ultimately depends on a variety of patient factors, including underlying disease states, surgical interventions, and concomitant medications (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). IDSA guidelines currently recommend C. difficile testing be considered in those with unexplained and new-onset unformed stools at a frequency of at least three in a 24-hr period, although this recommendation is based on low-quality evidence.
      Another important consideration in pediatric patients is the rate of asymptomatic colonization (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Compared to adults with reported colonization rates ranging from 3% to 20%, pediatric patients have reportedly much higher colonization rates ranging from 2% to 50% (
      • Tamma P.D.
      • Sandora T.J.
      Clostridium difficile infection in children: Current state and unanswered questions.
      ). Colonization rates have been reported as high as 37% in infants less than 1 month of age, 30% in less than 6 months of age, and 14% in less than 1 year of age (
      • Jangi S.
      • Lamont J.T.
      Asymptomatic colonization by Clostridium difficile in infants: Implications for disease in later life.
      ). Despite these high colonization rates, clinical CDI in neonates and infants is rare, likely because of lack of toxin receptors in early life and thus the inability of toxins to bind and cause clinical disease (
      • Pothoulakis C.
      • Lamont J.T.
      Microbes and microbial toxins: Paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins.
      ;
      • Tamma P.D.
      • Sandora T.J.
      Clostridium difficile infection in children: Current state and unanswered questions.
      ). Colonization rates decrease with increasing age, and similar rates to adults are seen by approximately 2 years of age (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ;
      • Tamma P.D.
      • Sandora T.J.
      Clostridium difficile infection in children: Current state and unanswered questions.
      ). Although colonization rates typically decline over the first year of life, detection may still occur, leading to higher rates of positives when tested in the absence of clinical disease (
      • Tamma P.D.
      • Sandora T.J.
      Clostridium difficile infection in children: Current state and unanswered questions.
      ). IDSA guidelines recommend against testing for C. difficile in neonates and infants because of high rates of asymptomatic carriage (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). In addition, these guidelines recommend against routine testing in patients up to 2 years of age until other etiologies are excluded. Only in patients aged at least 2 years or older is testing recommended if the patient has prolonged diarrhea combined with risk factors or a close exposure.

      WHAT RISK FACTORS HAVE BEEN IDENTIFIED FOR PEDIATRIC PATIENTS?

      Risk factors for CDI are well-defined in the adult population, including a variety of pharmacological, host-specific, and clinical intervention-related factors (
      • Eze P.
      • Balsells E.
      • Kyaw M.H.
      • Nair H.
      Risk factors for Clostridium difficile infections—An overview of the evidence base and challenges in data synthesis.
      ). Few studies have evaluated risk factors in pediatric patients (
      • Kim J.
      • Shaklee J.F.
      • Smathers S.
      • Prasad P.
      • Asti L.
      • Zoltanski J.
      • Zaoutis T.
      Risk factors and outcomes associated with severe clostridium difficile infection in children.
      ;
      • Samady W.
      • Pong A.
      • Fisher E.
      Risk factors for the development of Clostridium difficile infection in hospitalized children.
      ). In general, risk factors can be separated into two major categories: modifiable and nonmodifiable (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ).
      The most prominent modifiable risk factor defined in the pediatric population is exposure to antibiotic agents (
      • Borali E.
      • De Giacomo C.
      Clostridium difficile infection in children: A review.
      ). Exposure to antibiotic agents induces changes in the intestinal flora, leading to the development of CDI (
      • Borali E.
      • De Giacomo C.
      Clostridium difficile infection in children: A review.
      ;
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Although all antibiotics carry some inherent risk, the third- and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and clindamycin carry the highest risk of CDI (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). A recent study of pediatric patients in the inpatient and outpatient settings identified cephalosporins and clindamycin to be the most common antibiotics received within the 30 days before CDI diagnosis (
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ). In addition, patients exposed to at least two classes of antibiotics are more likely to develop CDI than those who only receive one class of antibiotics (
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ). These antibiotics are hypothesized to eradicate normal bowel microbiota, which allows for the proliferation of C. difficile bacteria and the development of clinical disease.
      Proton pump inhibitors and other suppressors of gastric acid have been documented to increase risk of CDI because of the alterations in gastric pH that allow for bacterial survival (
      • Mezoff E.A.
      • Cohen M.B.
      Acid suppression and the risk of Clostridium difficile infection.
      ). A recent study found that the odds of developing community-acquired CDI were the same for proton pump inhibitors and antibiotics (odds ratio, 8.17; 95% CI;
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ). Another retrospective case-control study in pediatric patients found that the risk of CDI was 4.5 times higher in those patients receiving histamine-2 receptor antagonists (
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ). Judicious use of acid suppression therapy should be considered in the pediatric population.
      Nonmodifiable risk factors of importance include comorbid conditions such as transplant (solid organ and hematopoietic stem cell), pancreatitis, inflammatory bowel disease (IBD), HIV, malignancy, and cystic fibrosis (
      • Borali E.
      • De Giacomo C.
      Clostridium difficile infection in children: A review.
      ;
      • Pant C.
      • Deshpande A.
      • Gilroy R.
      • Olyaee M.
      • Donskey C.J.
      Rising incidence of Clostridium difficile related discharges among hospitalized children in the United States.
      ). The most common nonmodifiable risk factors in pediatric patients include IBD, solid organ transplant, and malignancy (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Hospitalization has also been reported as a major risk factor for pediatric CDI across several studies, with nearly 50% of patients in some studies presenting with a history of hospitalization within the last month (
      • Dulęba K.
      • Pawłowska M.
      • Wietlicka-Piszcz M.
      Clostridium difficile infection in children hospitalized due to diarrhea.
      ;
      • Morinville V.
      • McDonald J.
      Clostridium difficile-associated diarrhea in 200 Canadian children.
      ). A retrospective cohort study evaluated risk factors for CDI and recurrence within 60 days among hospitalized pediatric patients over 7 years (
      • Schwab E.M.
      • Wilkes J.
      • Korgenski K.
      • Hersh A.L.
      • Pavia A.T.
      • Stevens V.W.
      Risk factors for recurrent Clostridium difficile infection in pediatric inpatients.
      ). Patients with malignancy, complex chronic conditions, and antibiotic use were more likely to have recurrence after initial CDI than other risk factors.
      Severe disease is less common in children, only occurring in approximately 2% of patients (
      • Samady W.
      • Pong A.
      • Fisher E.
      Risk factors for the development of Clostridium difficile infection in hospitalized children.
      ). Regardless of the low incidence, several studies have aimed to define risk factors for severe disease (
      • Kim J.
      • Shaklee J.F.
      • Smathers S.
      • Prasad P.
      • Asti L.
      • Zoltanski J.
      • Zaoutis T.
      Risk factors and outcomes associated with severe clostridium difficile infection in children.
      ;
      • Price V.
      • Portwine C.
      • Zelcer S.
      • Ethier M.C.
      • Gillmeister B.
      • Silva M.
      • Sung L.
      Clostridium difficile infection in pediatric acute myeloid leukemia: From the Canadian Infections in Acute Myeloid Leukemia Research Group.
      ). Severe disease has been defined as CDI with one complication or at least two laboratory or clinical indicators consistent with severe disease in adults (
      • Kim J.
      • Shaklee J.F.
      • Smathers S.
      • Prasad P.
      • Asti L.
      • Zoltanski J.
      • Zaoutis T.
      Risk factors and outcomes associated with severe clostridium difficile infection in children.
      ). Although many studies have looked at a variety of risk factors, including prior treatment failure and malignancy, the only risk factor identified for severe disease in children is exposure to three antibiotic classes within 30 days before infection (
      • Kim J.
      • Shaklee J.F.
      • Smathers S.
      • Prasad P.
      • Asti L.
      • Zoltanski J.
      • Zaoutis T.
      Risk factors and outcomes associated with severe clostridium difficile infection in children.
      ;
      • Price V.
      • Portwine C.
      • Zelcer S.
      • Ethier M.C.
      • Gillmeister B.
      • Silva M.
      • Sung L.
      Clostridium difficile infection in pediatric acute myeloid leukemia: From the Canadian Infections in Acute Myeloid Leukemia Research Group.
      ).
      Although many risk factors present in children mirror those in adults, it is important to note the differences between pediatric and adult risk factors for CDI. A retrospective review of children with CDI in the inpatient and outpatient settings identified a unique risk factor regarding antibiotic exposure compared with adults (
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ). In this study, children who received antibiotics within 30 days of illness more commonly had CDI than controls (40.6% vs. 27.5%), though this difference was not statistically significant (p =.06). In comparison, the risk of CDI in adults exposed to antibiotics may persist up to 90 days after antibiotic use (
      • Hopkins R.J.
      • Wilson R.B.
      Treatment of recurrent Clostridium difficile colitis: A narrative review.
      ). It is essential that these modifiable and nonmodifiable risk factors are considered when caring for pediatric patients to mitigate risk.

      Which Agent Should Be First-Line: Metronidazole or Oral Vancomycin?

      The IDSA CDI guidelines published in 2018 drastically changed pharmacological management in adult patients with the recommendation of oral vancomycin over metronidazole (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). The role of vancomycin in the management of pediatric patients with CDI remains unclear as either metronidazole or oral vancomycin are recommended for pediatric patients with an initial episode or first recurrence (Table 2).
      TABLE 2Comparison of pediatric and adult Infectious Diseases Society of America's recommendations
      Source.
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      .
      Clinical DefinitionPediatric RecommendationAdult Recommendation
      Initial episode, nonsevere
      • Metronidazole
      • Oral vancomycin
      • Oral vancomycin
      • Fidaxomicin
      • Metronidazole only if other agents unavailable
      Initial episode, severe
      • Oral vancomycin with or without intravenous metronidazole
      • Oral vancomycin
      • Fidaxomicin
      Initial episode, fulminant
      • Oral or rectal vancomycin and intravenous metronidazole
      First recurrence
      • Metronidazole
      • Oral vancomycin
      • Oral vancomycin
      • Fidaxomicin
      Second or subsequent recurrences
      • Oral vancomycin followed by rifaximin taper
      • Fecal microbiota transplant
      • Oral vancomycin followed by rifaximin
      • Fidaxomicin
      • Fecal microbiota transplant
      Metronidazole forms a toxic metabolite that is thought to disrupt the deoxyribonucleic acid of microbial cells (). Before the release of this guideline, metronidazole was the favored agent for mild disease in an immunocompetent host in both adult and pediatric patients (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). It is still a common agent in pediatric patients because of its lower cost and ease of access compared to oral vancomycin.
      A prospective study evaluated 82 pediatric patients with CDI, 56 of whom received metronidazole (
      • Kim J.
      • Shaklee J.F.
      • Smathers S.
      • Prasad P.
      • Asti L.
      • Zoltanski J.
      • Zaoutis T.
      Risk factors and outcomes associated with severe clostridium difficile infection in children.
      ). Of the patients who received metronidazole, 6 (11%) patients experienced treatment failure. However, in a subset analysis, half of those patients were classified to have severe disease. Similarly, a population-based cohort study assessed treatment failure rates in 69 pediatric patients with CDI treated with metronidazole versus oral vancomycin (
      • Khanna S.
      • Baddour L.M.
      • Huskins W.C.
      • Kammer P.P.
      • Faubion W.A.
      • Zinsmeister A.R.
      • Pardi D.S.
      The epidemiology of Clostridium difficile infection in children: A population-based study.
      ). Although not statistically significant, 18% of those treated with metronidazole experienced treatment failure compared with no treatment failures in the vancomycin group. These data suggest that metronidazole should not be used as the first-line for an initial episode of severe CDI in pediatric patients. Because of limited evidence and scarcity of well-designed studies demonstrating a statistically significant higher rate of relapse with metronidazole, the IDSA CDI guideline continues to recommend metronidazole except in cases of severe disease (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Additional well-designed pediatric studies are needed to confirm this finding.
      Vancomycin inhibits cell wall synthesis through blockade of glycopeptide polymerization (
      • Aldrich A.M.
      • Argo T.
      • Koehler T.J.
      • Olivero R.
      Analysis of treatment outcomes for recurrent Clostridium difficile infections and fecal microbiota transplantation in a pediatric hospital.
      ; ). When given orally, vancomycin is poorly absorbed systemically and is delivered directly to the site of action. Changes to the IDSA guidelines published in 2018 resulting in favoring oral vancomycin over metronidazole were in response to several recent randomized controlled trials in adults demonstrating statistically significant improvements in resolution of diarrhea at the end of treatment and no recurrence of CDI 1 month after treatment in patients treated with oral vancomycin compared with metronidazole (
      • Johnson S.
      • Louie T.J.
      • Gerding D.N.
      • Cornely O.A.
      • Chasan-Taber S.
      Polymer Alternative for CDI Treatment (PACT) investigators
      Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: Results from two multinational, randomized, controlled trials.
      ;
      • Zar F.A.
      • Bakkanagari S.R.
      • Moorthi K.M.
      • Davis M.B.
      A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity.
      ). Recommendations reflect the results of these trials, in which oral vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of nonsevere or severe CDI as well as the first or subsequent occurrences in adult patients (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Metronidazole is only recommended for an initial, nonsevere episode if other agents are not available.
      Unfortunately, there are no similar studies in pediatrics, leaving disparities between adult and pediatric recommendations. In pediatric patients, oral vancomycin or metronidazole is recommended for an initial episode or first recurrent of nonsevere CDI in pediatric patients (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Large randomized controlled trials are needed in the pediatric population to further clarify the preferred agent for an initial, nonsevere episode or first recurrence. Table 3 summarizes the differences between oral vancomycin and metronidazole.
      TABLE 3Anti-infective agents used in the treatment and management of Clostridioides difficile infection in pediatrics
      AgentMechanism(s)DosageMaximum Single DoseAdverse EventsMedication Cost
      Average wholesale Price scale (generic): $, $0–50; $$, $51–100; $$$, $101–150; $$$$ 151–200; $$$$$ > $200. Prices expressed per milliliter or per tablet/capsule.
      Vancomycin (oral)Inhibits bacterial cell wall synthesis directly at the site of action with no systemic absorption10 mg/kg/dose four times daily

      Pulsed Taper

      10 mg/kg/dose four times daily for 10–14 days then

      10 mg/kg/dose twice daily for 7 days then

      10 mg/kg/dose once daily for 7 days then

      10 mg/kg/dose every 2 or 3 days for 2–8 weeks
      125 mg
      Higher doses of up to 500 mg per dose have been used in severe infections.
      Abdominal pain

      Fatigue

      Fever
      Capsule: $-$$

      Oral solution: $
      Vancomycin (enema—severe disease with ileus)10 mg/kg/dose rectally every 6 hr500 mg
      MetronidazoleInteracts with DNA to cause strand breaks

      Inhibits protein synthesis and induces cell death
      7.5 mg/kg/dose three to four times daily500 mgDisulfiram reaction

      Abdominal pain

      Rash
      Capsule, tablet: $

      intravenous solution: $
      FidaxomicinInhibits RNA polymerase resulting in protein synthesis inhibition and cell death of Clostridioides difficilePatients < 12.5 kg: 16 mg/kg/dose twice daily

      Patients > 12.5 kg: 200 mg twice daily
      200 mgNausea

      Fever
      Oral suspension: $

      Tablet: $$$$$
      RifaximinAntibiotic derivative that inhibits bacterial RNA15 to 30 mg/kg/day in three divided dosses400 mgNausea

      Dizziness

      Fatigue
      Tablet: $-$$
      IVIGAntitoxin A antibodies within IVIG bind and neutralize toxin A400 mg/kg/dose once every 3 weeksNot describedAseptic meningitis

      Hypotension

      Infusion reactions
      Intravenous solution: $-$$
      Note. IVIG, Intravenous immunoglobulin; DNA, deoxyribonucleic acid; RNA, ribonucleic acid.
      a Average wholesale Price scale (generic): $, $0–50; $$, $51–100; $$$, $101–150; $$$$ 151–200; $$$$$ > $200. Prices expressed per milliliter or per tablet/capsule.
      b Higher doses of up to 500 mg per dose have been used in severe infections.
      On the basis of the available evidence, it is reasonable to consider the use of oral vancomycin over metronidazole first-line in pediatric patients with an initial, nonsevere episode, initial severe episode, and recurrent CDI. However, the increased cost of oral vancomycin compared with metronidazole may be a limitation in some patients and should be considered when selecting a medication.

      What Is the Preferred Dosing Regimen of Oral Vancomycin?

      Various dosing regimens for oral vancomycin have been recommended in the pediatric population. Current guideline dosing recommendations depend on the severity of the disease (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). In patients with an initial episode or first recurrence of nonsevere disease, a dosage of 10 mg/kg/dose four times daily with a maximum of 125 mg per dose is recommended. In patients with an initial severe episode or second/subsequent recurrence, a dosage of 10 mg/kg/dose four times daily with a maximum of 500 mg per dose is recommended (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ).
      Lower doses of oral vancomycin, less than or equal to 500 mg day−1 have been suggested to be as effective as higher doses of oral vancomycin, greater than 500 mg day−1 (
      • Simone A.
      Low-dose antibiotics effective in treating C. difficile. Pharmacy Times.
      ). Clinical improvement was seen in 86% of patients receiving high dose therapy and 85% of patients receiving low dose therapy at 72 hr in a small study of adult patients (
      • Simone A.
      Low-dose antibiotics effective in treating C. difficile. Pharmacy Times.
      ). At discharge, 96% of high dose therapy patients and 93% of low dose therapy patients had clinical improvement. In addition, there were no statistically significant differences in mortality, retreatment, or 30-day readmission for CDI or any cause. The fecal pharmacokinetic properties of oral vancomycin may provide further explanation as to why lower doses are as effective as higher doses. Another small study of 15 adult patients, nine of whom had confirmed CDI, compared three dosing regimens of oral vancomycin (125 mg every 6 hr, 250 mg every 6 hr, and 500 mg every 6 hr) to determine fecal concentrations of oral vancomycin (
      • Gonzales M.
      • Pepin J.
      • Frost E.H.
      • Carrier J.C.
      • Sirard S.
      • Fortier L.C.
      • Valiquette L.
      Faecal pharmacokinetics of orally administered vancomycin in patients with suspected Clostridium difficile infection.
      ). All three dosing regimens achieved approximately 100 times greater concentrations than the minimum inhibitory concentration 90, supporting the suggestion that lower doses are as effective as higher doses. Antimicrobial stewardship programs around the country have since encouraged the use of lower doses of oral vancomycin. The efficacy of a lower dose of oral vancomycin in pediatrics has not been well elucidated, but many pediatric centers have adopted the lower maximum of 125 mg per dose in patients with nonsevere CDI. On the basis of available clinical data, it is reasonable to consider a dosing regimen of oral vancomycin, 10 mg kg−1/dose four times daily to a maximum of either 125 mg in nonsevere cases or 500 mg in severe cases of CDI. Prolonged tapers have also been recommended in pediatric patients for a second or subsequent occurrence (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Vancomycin enemas may also be considered in cases of fulminant disease, though data to support this route of administration is weak. Recommended dosing for prolonged tapers and enemas is described in Table 3.

      What Is the Role Of Fidaxomicin in Pediatric Patients?

      Clinical trials have recently been published describing the safety and efficacy of fidaxomicin in pediatric patients, which was previously only recommended in adults. An open-label pharmacokinetic study was completed in pediatric patients to measure the safety and efficacy of fidaxomicin (
      • O'Gorman M.A.
      • Michaels M.G.
      • Kaplan S.L.
      • Otley A.
      • Kociolek L.K.
      • Hoffenberg E.J.
      • Sears P.
      Safety and pharmacokinetic study of fidaxomicin in children with Clostridium difficile-associated diarrhea: A phase 2a multicenter clinical trial.
      ). Patients with C. difficile associated diarrhea were given oral fidaxomicin 16 mg/kg/day divided twice daily with a maximum dosage of 200 mg for 10 days (
      • O'Gorman M.A.
      • Michaels M.G.
      • Kaplan S.L.
      • Otley A.
      • Kociolek L.K.
      • Hoffenberg E.J.
      • Sears P.
      Safety and pharmacokinetic study of fidaxomicin in children with Clostridium difficile-associated diarrhea: A phase 2a multicenter clinical trial.
      ). A total of 40 pediatric patients with underlying comorbidities, including gastrointestinal disorders (most commonly reported as nausea, vomiting, abdominal pain, constipation, salivary hypersecretion, gastroesophageal reflux disease, and diarrhea), malignancy, and history of CDI, were included in the study. Overall, researchers found that 92% of patients had an early clinical response rate, and the sustained clinical response at 30 days was 66%. Adverse events were reported in 74% of patients, with the majority classified as mild (45%), including nausea, vomiting, urticaria, and abdominal pain, and only 16% being attributed to treatment. The authors concluded that fidaxomicin was well-tolerated in pediatric patients, and the pharmacokinetic profile was very similar to that seen in adults with a high clinical response rate.
      A phase 3, multicenter, investigator-blind, randomized, parallel-group trial was recently published that investigated the safety and efficacy of fidaxomicin and oral vancomycin in children and adolescents with CDI (
      • Wolf J.
      • Kalocsai K.
      • Fortuny C.
      • Lazar S.
      • Bosis S.
      • Korczowski B.
      • van Maanen R.
      Safety and efficacy of fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: A phase 3, multicenter, randomized, single-blind clinical trial (Sunshine).
      ). Pediatric patients with confirmed CDI were randomized to either fidaxomicin (32 mg/kg/day) divided twice daily with a maximum of 400 mg/day for children < 6 years of age; 200 mg two times daily for children ≥ 6 years of age for 10 days) or oral vancomycin (standard dosing, maximum: 125 mg/dos;
      • Wolf J.
      • Kalocsai K.
      • Fortuny C.
      • Lazar S.
      • Bosis S.
      • Korczowski B.
      • van Maanen R.
      Safety and efficacy of fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: A phase 3, multicenter, randomized, single-blind clinical trial (Sunshine).
      . The primary outcome was the percentage of patients with a confirmed clinical response 2 days after treatment. In the fidaxomicin group, approximately 78% of patients met the primary outcome. The rate of confirmed clinical response 2 days after the end of treatment was 77% in the fidaxomicin group and 71% in the oral vancomycin group. Global cure rates, defined as confirmed clinical response without recurrence of CDI, were significantly higher with fidaxomicin than oral vancomycin, 68% versus 50%. Stool concentrations of fidaxomicin were noted to be high and systemic absorption negligible. The authors concluded that fidaxomicin was well-tolerated and demonstrated higher rates of global cure than vancomycin in children and adolescents with CDI.
      This study demonstrates promising results that may aid to further align the adult and pediatric guidelines, eliminating the previously described discrepancies. The dosage of fidaxomicin formally approved by the FDA includes 16 mg/kg/dose twice daily for 10 days in patients greater than 6 months of age and less than 12.5 kg (maximum 200 mg per dose) and 200 mg twice daily for 10 days in patients weighing at least 12.5 kg (
      • Wolf J.
      • Kalocsai K.
      • Fortuny C.
      • Lazar S.
      • Bosis S.
      • Korczowski B.
      • van Maanen R.
      Safety and efficacy of fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: A phase 3, multicenter, randomized, single-blind clinical trial (Sunshine).
      ). These data suggest that oral vancomycin or fidaxomicin may be considered in pediatric patients with confirmed CDI in alignment with adult guideline recommendations. However, the higher cost of fidaxomicin may limit its clinical use compared with oral vancomycin and metronidazole.

      When Should FMT Be Considered in Pediatric Patients?

      FMT was first used in the fourth century by Chinese doctors who administered stool to patients with severe diarrhea or food poisoning with reported excellent outcomes (
      • Zhang F.
      • Luo W.
      • Shi Y.
      • Fan Z.
      • Ji G.
      Should we standardize the, 1, 700. year-old fecal microbiota transplantation?.
      ). FMT is used when a patient is assumed to have an altered microbiome resulting in disease caused by CDI (
      • Vindigni S.M.
      • Surawicz C.M.
      Fecal microbiota transplantation.
      ). The primary goal is to restore the normal microbiome and replace the pathogenic flora (
      • Gupta A.
      • Khanna S.
      Community-acquired Clostridium difficile infection: An increasing public health threat.
      ). Potential routes of administration include colonoscopy, feeding tube, rectal enema, and oral capsule (
      • Postigo R.
      • Kim J.H.
      Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: A review and pooled analysis.
      ). Although the best route of administration has been debated, previous uncontrolled studies in adults have cited colonoscopy as the most effective route of FMT, with reported efficacy of 90% after single treatment compared with 80% when administered via nasogastric tube (
      • Postigo R.
      • Kim J.H.
      Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: A review and pooled analysis.
      ).
      The pediatric population requires special caution for FMT. There is less evidence for use, more concern for adverse effects, and fear of long-term outcomes when the microbiome is manipulated (
      • Vindigni S.M.
      • Surawicz C.M.
      Fecal microbiota transplantation.
      ). Adverse effects most commonly are mild and include abdominal pain, nausea, bloating, and flatulence. The efficacy of FMT in pediatrics has been described in a large retrospective study of 335 patients between the ages of 11 months and 23 years at 18 pediatric centers over 13 years (
      • Nicholson M.R.
      • Mitchell P.D.
      • Alexander E.
      • Ballal S.
      • Bartlett M.
      • Becker P.
      • Kahn S.A.
      Efficacy of fecal microbiota transplantation for Clostridium difficile infection in children.
      ). Success was defined as no recurrence within 2 months following FMT. Successful outcomes following a single FMT were seen in 81% of patients, and 87% of patients had a successful outcome following the first or repeated FMT. Another retrospective cohort study was conducted in children over a 1-year period who had recurrent CDI defined as greater than two episodes of CDI or having failed at least one course of therapy with oral vancomycin to assess safety, efficacy, and cost of a nurse-led FMT program for recurrent CDI (
      • Brumbaugh D.E.
      • De Zoeten E.F.
      • Pyo-Twist A.
      • Fidanza S.
      • Hughes S.
      • Dolan S.A.
      • Dominguez S.R.
      An intragastric fecal microbiota transplantation program for treatment of recurrent Clostridium difficile in children is efficacious, safe, and inexpensive.
      ). Patients who were previously healthy had a success rate of 94%, whereas medically complex children had a lower success rate of 75%. Authors also found that intragastric administration had lower facility and professional charges compared with colonoscopy and nasoduodenal tube. Stool collected from a stool bank was also lower cost than related-donor stool. The authors concluded that intragastric FMT using stool bank products was an inexpensive and efficacious treatment for recurrent CDI in pediatrics.
      The FDA released a safety alert on June 13, 2019 warning both providers and patients of the risks associated with FMT after two patients developed MDROs posttransplant, resulting in the death of one patient (
      Food and Drug Administration
      Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms.
      ). The patients with adverse outcomes were adult immunocompromised patients who developed invasive infections caused by extended-spectrum β-lactamase positive Escherichia coli (E. coli). The stool sample had not been tested for MDROs, and both patients received stool from the same donor. This safety alert is not the first caution issued by the FDA (
      Food and Drug Administration
      Guidance for industry: Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies.
      ). These recent events prompted the FDA to recommend additional protections regarding investigational FMT. The FDA now recommends providing a donor questionnaire to screen for MDRO risk factors so that these potential donors may be excluded and MDRO testing of stool to exclude those who test positive for MDRO (
      Food and Drug Administration
      Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms.
      ).
      Although concerns remain regarding alterations of the microbiome, adverse effects, and uncertain long-term effects, current data suggest that FMT may be considered in pediatric patients with recurrent CDI or therapeutic failure after at least one course of vancomycin. Intragastric administration may be less costly institutionally compared with the administration via colonoscopy or nasoduodenal tube. Special caution should be taken in immunocompromised patients.

      What Is the Role Of Alternative Therapies in Pediatric Patients?

      Bezlotoxumab

      Bezlotoxumab is a monoclonal antibody that binds to and neutralizes C. difficile toxin B to prevent toxic effects (). This agent was approved in October of 2016 as adjunctive therapy to reduce the recurrence of CDI in adult patients receiving antibacterial medication treatment of CDI and who are at high risk for recurrence. It is not indicated for the treatment of CDI. Although pediatric-specific data regarding the newer toxin-binding agents are not yet available, adult data will be presented here for completeness. Bezlotoxumab is a human monoclonal antibody used to reduce the recurrence of CDI in adult patients (
      • Wilcox M.H.
      • Gerding D.N.
      • Poxton I.R.
      • Kelly C.
      • Nathan R.
      • Birch T.
      MODIFY I and MODIFY II Investigators
      Bezlotoxumab for prevention of recurrent Clostridium difficile infection.
      ). Although this agent is not indicated for use in the treatment of CDI, it can be used in combination with an antibacterial treatment for CDI. A double-blind, randomized, placebo-controlled, Phase 3 trial of 2,655 adults received standard of care antibiotics and were then divided to either receive bezlotoxumab (10 mg/kg), actoxumab plus bezlotoxumab (10 mg/kg each), or placebo (
      • Wilcox M.H.
      • Gerding D.N.
      • Poxton I.R.
      • Kelly C.
      • Nathan R.
      • Birch T.
      MODIFY I and MODIFY II Investigators
      Bezlotoxumab for prevention of recurrent Clostridium difficile infection.
      ). The recurrent CDI rate was significantly lower in the group who received bezlotoxumab alone (p <.0001). The most common adverse events reported were gastrointestinal upset, which was similar among treatment groups. Overall, the authors concluded from this study that bezlotoxumab had a significantly lower rate of recurrence compared with placebo with a safe adverse effect profile. Currently, bezlotoxumab is not used in pediatric patients for the prevention of recurrence and cannot be recommended routinely for use because of the lack of available evidence. Further studies are needed to clarify the role of toxin-binding agents in pediatric patients before clear recommendations can be made.

      Rifaximin

      Rifaximin is an antibiotic derivative that exerts its mechanism through inhibition of bacterial ribonucleic acid in both gram-positive and gram-negative aerobic and anaerobic bacteria (
      • Berman A.L.
      Efficacy of rifaximin and vancomycin combination therapy in a patient with refractory Clostridium difficile-associated diarrhea.
      ;
      • Major G.
      • Bradshaw L.
      • Boota N.
      • Sprange K.
      • Diggle M.
      • Montgomery A.
      RAPID Collaboration Group
      Follow-on rifAximin for the prevention of recurrence following standard treatment of infection with Clostridium difficile (RAPID): A randomised placebo controlled trial.
      ). Rifaximin was initially approved in May 2004 and is indicated for hepatic encephalopathy and irritable bowel syndrome in adults and traveler's diarrhea in adult and pediatric patients aged at least 12 years (). Treatment of second or subsequent recurrence of CDI in adult patients is considered an off-label indication. A dosing regimen of 15–30 mg/kg/day in three divided doses (maximum 400 mg per dose) for 20 days is recommended for pediatric patients with CDI (
      • Gawronska A.
      • Banasiuk M.
      • Lachowicz D.
      • Pituch H.
      • Albrecht P.
      • Banaszkiewicz A.
      Metronidazole or rifaximin for treatment of Clostridium difficile in pediatric patients with inflammatory bowel disease: A randomized clinical trial.
      ;
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). Small clinical trials and case reports have been published, primarily in adults, to assess the efficacy and safety of rifaximin in patients with CDI. The main concern with rifaximin is that while it has seemed good in vitro activity against C. difficile, resistance develops quickly (
      • Major G.
      • Bradshaw L.
      • Boota N.
      • Sprange K.
      • Diggle M.
      • Montgomery A.
      RAPID Collaboration Group
      Follow-on rifAximin for the prevention of recurrence following standard treatment of infection with Clostridium difficile (RAPID): A randomised placebo controlled trial.
      ). In addition, rifaximin is only commercially available in tablet form, which may present challenges for pediatric patients unable to take solid dosage forms. An oral suspension formulation of rifaximin would require additional extemporaneous compounding and likely increase cost (
      • Cober M.P.
      • Johnson C.E.
      • Lee J.
      • Currie K.
      Stability of extemporaneously prepared rifaximin oral suspensions.
      ).
      Rifaximin was directly compared with metronidazole in a prospective, single-blind, randomized clinical trial conducted in pediatric patients with irritable bowel disease (
      • Gawronska A.
      • Banasiuk M.
      • Lachowicz D.
      • Pituch H.
      • Albrecht P.
      • Banaszkiewicz A.
      Metronidazole or rifaximin for treatment of Clostridium difficile in pediatric patients with inflammatory bowel disease: A randomized clinical trial.
      ). Patients were randomly assigned to receive either oral metronidazole or rifaximin for 14 days. Seventeen patients were randomized to receive metronidazole, and 14 patients were randomized to receive rifaximin. No statistically significant differences were found in cure rate between groups or recurrence. Overall, the authors concluded that both metronidazole and rifaximin were comparably effective treatments for pediatric patients with CDI, specifically those with IBD. Although small clinical trials have demonstrated no difference in cure rate or recurrence between rifaximin and metronidazole, rifaximin remains an alternative option for a second or subsequent recurrence after oral vancomycin, metronidazole, and FMT. Pediatric data suggest there may be some benefit specifically in patients with a second or subsequent recurrence or IBD, but larger randomized clinical trials are needed before its use can be routinely recommended in pediatric patients. It is pertinent to note that rifaximin is not currently recommended by any guideline, including IDSA, because of concerns for resistance (
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • Wilcox M.H.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ).

      Intravenous Immunoglobulin

      Intravenous immunoglobulin (IVIG) is an immune globulin with a variety of proposed mechanisms depending on the indication for use, including as a replacement for immunodeficiency, providing immunoglobulin G (IgG) antibodies against bacteria, and providing passive immunity through increasing antibody titers (). IVIG was initially used in 1952 for use in primary immunodeficiency disorders and was not used for the management of CDI until 1991 (
      • Leung D.Y.
      • Kelly C.P.
      • Boguniewicz M.
      • Pothoulakis C.
      • LaMont J.T.
      • Flores A.
      Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.
      ). Since then, there have been several different formulations developed and approved for a variety of neuropathies, immunodeficiencies, and infectious diseases. Management of severe, refractory, or recurrent CDI is considered an off-label indication in adults. For chronic colitis because of CDI in pediatric patients, a dosing regimen of 400 mg/kg/dose once every 3 weeks has been suggested (
      • Abougergi M.S.
      • Kwon J.H.
      Intravenous immunoglobulin for the treatment of Clostridium difficile infection: A review.
      ). Minimal data exist for the use of IVIG in pediatric patients with CDI (
      • Leung D.Y.
      • Kelly C.P.
      • Boguniewicz M.
      • Pothoulakis C.
      • LaMont J.T.
      • Flores A.
      Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.
      ). The manufacturing of IVIG includes collection of immunoglobulins from a pool of donors who often express antitoxin A and B antibody titers.
      The proposed mechanism is that the antitoxin A antibodies within IVIG bind toxin A with further neutralization. A study was conducted to evaluate the utility of treatment with IVIG in pediatric patients with chronic relapsing colitis caused by the C. difficile toxin. It is hypothesized that immunoglobulin A (IgA) provides mucosal immunity, and low IgG antitoxin antibody titer may predispose pediatric patients to recurrent CDI. During the study, six pediatric patients who had chronic relapsing C. difficile colitis were tested for levels of IgG and IgA to C. difficile toxin A before intervention. Levels of IgG were found to be significantly lower in these patients than in the healthy population (p =.026). Five of the patients were then treated with 400 mg kg−1 of IVIG every 3 weeks. After IVIG administration, significant increases in IgG were seen but not in IgA antitoxin A levels (p =.01 and p =.406, respectively). All five children who received IVIG had resolution of symptoms. In addition, these patients cleared toxin B from their stool. Authors used these results to suggest that IgG antitoxin A deficiency could predispose pediatric patients to chronic relapsing CDI and may have a place in therapy for inducing remission. However, IgA antitoxin A levels did not significantly increase despite patients experiencing symptom relief, which challenges the hypothesis that IgA may be associated with mucosal protection. In addition, measurement of IgG to antitoxin A is not routinely conducted in clinical practice, leaving many questions about the clinical applicability of this small study. There is currently not enough information to recommend the routine use of IVIG in pediatric CDI. In addition, the frequent, intermittent shortages of IVIG further complicate its use for this indication. IVIG may be considered in patients with chronic, relapsing CDI who have low levels of IgG if readily available.

      Conclusion

      CDI is a serious infection associated with significant morbidity in pediatric patients. Public health organizations continue to prioritize prevention and prompt recognition and treatment of CDI as the incidence continues to rise in both adult and pediatric patients. Recent guideline changes in the adult literature have challenged pediatric practitioners to determine the most appropriate pharmacological management of pediatric CDI on the basis of extrapolated recommendations from adult literature. Oral vancomycin or metronidazole continue to be the mainstay of treatment in pediatric patients, likely because of experience, available dosage forms, and cost, despite adult recommendations favoring oral vancomycin or fidaxomicin over metronidazole. Additional randomized controlled trials are needed to standardize appropriate first-line therapy for pediatric patients with CDI, but recent literature is promising to support the safety and efficacy of oral vancomycin or fidaxomicin in pediatric patients. FMT may be considered in the setting of recurrent CDI or therapeutic failure with oral vancomycin. Intragastric administration may be less costly institutionally compared with the administration via colonoscopy or nasoduodenal tube. Other alternative therapies, such as toxin-binding agents, rifaximin, and IVIG cannot be routinely recommended and should be considered on a case-by-case basis. Additional randomized controlled studies are needed to strengthen evidence and align adult and pediatric recommendations for the management of pediatric CDI. Until further guideline clarification is available, the best pediatric evidence should be used in combination with patient-specific factors and consideration of the cost and availability of each pharmacological agent.

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      Biography

      Mackenzie N. DeVine, Pediatric Clinical Pharmacist, Department of Pharmacy, Children's Hospital Colorado, Aurora, CO.
      Christine E. MacBrayne, Antimicrobial Stewardship and Infectious Diseases Clinical Pharmacist Specialist, Department of Pharmacy, Children's Hospital Colorado, Aurora, CO.
      Jason Child, HIV/Infectious Diseases and Antimicrobial Stewardship Clinical Specialist, Children's Hospital Colorado, Aurora, CO.
      Allison B. Blackmer, Director, Clinical Practice, Quality and Advocacy; American Society for Parenteral and Enteral Nutrition and Adjunct Associate Professor of Pharmacy; University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO.