Keywords

antacids, antibiotics,

 

Authors

  1. Nang, Catherine PharmD

Abstract

Abstract: The purpose of this article is to discuss the pharmacological causes of pediatric Clostridioides difficile infection (CDI) and the treatment options available to clinicians. The authors identify antibiotic classes and antacids and how they interfere with normal gastrointestinal processes to cause CDI. In addition, the treatment algorithm for pediatric patients, which differs slightly from adults, is presented. Choosing the appropriate medication is imperative in reducing symptoms, recurrence, and optimizing treatment of CDI. This article will discuss the medications that contribute to CDI and not cover infectious causes or structural causes.

 

Article Content

RISK FACTORS FOR CLOSTRIDIOIDES DIFFICILE INFECTION

Patient-specific risk factors for Clostridioides difficile infection (CDI) in adults include antibiotic use, severe comorbid illness, obesity, cancer chemotherapy, hematopoietic stem cell transplantation, inflammatory bowel disease, cirrhosis, and gastric acid suppression (Bartlett, 2006). Inflammatory bowel disease involving structural causes includes those with a history of inflammatory bowel diseases like Crohn's disease or ulcerative colitis where inflammatory processes in the intestinal tract have made it susceptible for CDI bacterial colonization.

 

Previously, pediatric patients were not considered to be a high-risk population for contracting CDI, hence the minimal studies and identification on risk factors. However, recent cohort studies revealed that the CDI numbers are increasing for pediatric patients. The focus of these studies has been on whether the risk factors for adults also apply to children. The most significant findings of risk factors for pediatrics were prior antibiotic usage, antacid usage, and history of gastrointestinal surgery (Tschudin-Sutter et al., 2014). The aim of this article is to identify antibiotic classes and antacids and how they interfere with normal gastrointestinal processes to cause CDI. In addition, the treatment algorithm for pediatric patients differs slightly from adults, and choosing the appropriate medication is imperative in reducing symptoms and recurrence and in optimizing treatment of CDI.

 

CATEGORIZATIONS OF CDI

From the Recommendations for Surveillance of Clostridium difficile-associated disease, CDI is categorized according to when and where patients may have been potentially exposed to precipitating factors (Johnson et al., 2021). The four categories patients can be classified in are healthcare-facility-onset, healthcare facility associated; community-onset, healthcare facility associated; indeterminant; or community-associated CDI-associated disease. The categorizations with descriptors and onset are outlined in the Supplemental Material in Table 1, available at http://links.lww.com/JPSN/A53.

 

Categorizing CDI can help in identifying any new medications patients may have been exposed to and if they contribute to causing diseases. In addition, reporting cases benefits public health on the prevalence and future prevention of CDI in pediatric patients where knowledge of risk factors is still limited.

 

MEDICATIONS THAT CAUSE CDI

The most common precipitating agents that cause normal intestinal bacterial disruption and facilitate CDI are antibiotics. Antibiotics disrupt the barrier function of the normal colonic microbiota, providing a niche for CDI to multiply and spread toxins (Britton & Young, 2014). With the spread of CDI toxins, patients become symptomatic.

 

Although extensive studies on pediatric CDI are not well known, a cohort study of 200 patients reported that penicillins and cephalosporins were the largest culprits of CDI (Tschudin-Sutter, 2014). Other antibiotic classes also caused CDI but at lower numbers, but because studies have involved only small cohorts of participants, all offending antibacterial agents identified in Supplemental Material in Table 2, available at http://links.lww.com/JPSN/A54 are also suggested to be discontinued.

 

The second most common drug class that causes CDI are antacids. Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) are two classifications of antacids, with PPIs causing higher rates of CDI than H2RAs in pediatric patients (Tschudin-Sutter, 2014). PPIs are indicated for the treatment of gastroesophageal reflux disease, peptic ulcer disease, and hypersecretory conditions like Zollinger-Ellison syndrome and are part of a combination therapy for Helicobacter pylori ulcers. Medical personnel could also see PPIs used for indications that may be off-label or non-Food and Drug Administration approved. These indications include aspiration prophylaxis in patients undergoing anesthesia, Barrett's esophagus, functional dyspepsia, and nonsteroidal anti-inflammatory drug-induced ulcers. The suffix -azole allows for easy identification of this class of medications compared with other gastric-acid-lowering therapies like H2RAs, which end in -itidine. Table 3 in Supplemental Materials available at http://links.lww.com/JPSN/A55 includes currently available PPIs and H2RAs.

 

The exact mechanism of how PPIs and H2RAs cause CDIs is not well understood. However, the proposed mechanism is that antacids decrease gastric acid levels allowing for opportunistic bacterial growth. The reduced stomach acid allows for the vegetative bacteria to pass into the small intestine. Another theory is that PPIs impair white blood cells and the body's immunity toward bacterial pathogens (Patil & Blankenship, 2013). Regardless of how mechanistically antacids may cause CDI, their use should be discontinued for children suspected of having CDI.

 

INITIAL TREATMENT OF CDI

Before initial treatment begins for CDI, discontinuation of the inciting antibiotic or antacid is crucial (McDonald et al., 2007). Fluid rehydration is also important for children experiencing water loss through diarrheal episodes. Treatment should not be initiated for asymptomatic colonization with CDI. Once diarrhea is confirmed for CDI, clinicians can select between oral vancomycin and metronidazole for initial treatment (See Table 4 in Supplemental Materials, available at http://links.lww.com/JPSN/A56). Vancomycin is a bactericidal agent that alters bacterial cell walls and its replication. Metronidazole is also a bactericidal agent that disrupts bacterial replication, leading to bacterial cell death.

 

For pediatric patients, vancomycin is preferred over metronidazole because it is associated with a lower risk of recurrence and alleviates symptoms quicker. In a study by Khanna et al. (2013), 18% of people experienced treatment failure with metronidazole whereas none experienced treatments failure with vancomycin. If at all possible, vancomycin should be administered orally for CDI because of its ability to remain in the gastrointestinal tract where the infection is located. The systemic absorption of vancomycin is limited, which is ideal for avoiding any potential toxicities associated with vancomycin such as ototoxicity or nephrotoxicity (Rao et al., 2011).

 

Vancomycin is also preferred for patients who have more severe, fulminant CDI for these reasons. The Infectious Diseases Society of America defines fulminant CDI as having signs of hypotension, shock, ileus, or megacolon. Clinicians can also consider rectal instillation of vancomycin for severe or fulminant disease.

 

Metronidazole is given orally or intravenously. Adolescent patients should be told not to partake in any alcoholic drinks during treatment with metronidazole. Researchers have found that the combination of alcohol and metronidazole may possibly cause a disulfiram-like reaction of flushing and rapid heartbeat (Steel & Wharton, 2020). There has also been some association of seizures and metronidazole. If patients are unable to tolerate oral medications, intravenous metronidazole can be administered. Metronidazole intravenously is dosed at 30 mg/kg per day in three divided doses with a maximum dose of 500 mg/dose.

 

TREATMENT FAILURE AND RECURRENCE

The initial recommendation is to discontinue any concomitant antibiotics not treating CDI because of its risk for recurrence in our pediatric population (Tschudin-Sutter et al., 2014). If recurrence does occur, symptoms can begin within 8 weeks of symptom resolution in the first episode of CDI (McDonald et al., 2007). For the first recurrence, a second course of vancomycin or metronidazole is recommended. For second or subsequent recurrences, metronidazole is not recommended by the American Academy of Pediatrics. Instead, a fidaxomicin or a pulsed-tapered regimen of vancomycin can be used. The dosing recommendations are outlined in Table 5 in Supplemental Materials, available at http://links.lww.com/JPSN/A57.

 

The current studies support that fidaxomicin is the preferred treatment with the lowest risk of recurrence for adult patients. However, studies on fidaxomicin and pediatric patients are limited and are only currently recommended for persistent diseases.

 

Although limited studies are available for pediatric CDI, extended periods of antibiotic and antacid usage have shown to be risk factors for children who have contracted CDI. Identifying the medications that may perpetuate CDI is important for halting this opportunistic bacterium. In addition, diagnosing and treating CDI is crucial for our pediatric population as severe diarrhea could be potentially life-threatening. For further information on pediatric epidemiology and diagnostic tests for CDI, readers are directed to article by Pasaron (2022) in this issue, Journal of Pediatric Surgical Nursing, 11(2) pages 49-57.

 

Acknowledgments

I thank Raquel Pasaron, DNP, ARNP, FNP-BC; Omid Afshari, PharmD, Area Pharmacy Director; Jenny Liang, PharmD, Inpatient Pharmacy Director-Vallejo; Maybellene Fernandez, PharmD, Inpatient Pharmacy Supervisor-Vallejo; Wesley Mortensen, PharmD, MBA, Clinical Operations Manager and Residency Program Director; Virginia Hon, PharmD, CDCES, Ambulatory Care Pharmacist and Residency Program Coordinator; and Hisham Awadalla, PharmD, Ambulatory Care Supervisor and Residency Program Coordinator.

 

References

 

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Johnson S., Lavergne V., Skinner A. M., Gonzales-Luna A. J., Garey K. W., Kelly C. P., Wilcox M. H. (2021). Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused update guidelines on management of Clostridioides difficile infection in adults. Clinical Infectious Diseases, 73, e1044-e1029.

 

Khanna S., Baddour L. M., Huskins W. C., Kammer P. P., Faubion W. A., Zinsmeister A. R., Harmsen W. S., Pardi D. S. (2013). The epidemiology of Clostridium difficile infection in children: A population-based study. Clinical Infectious Diseases, 56(10), 1401-1406. [Context Link]

 

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Pascaron R. in this issue add[horizontal ellipsis].

 

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