Pediatric ASP Toolkit

• A study of 1,488 adult inpatients admitted between 2013-2014 found that twenty percent of patients experienced at least 1 antibiotic-associated adverse drug event. Twenty percent of non-clinically indicated antibiotic regimens were associated with an adverse drug event. (Tamma PD, et al. Association of Adverse Events with Antibiotic Use in Hospitalized Patients. JAMA Intern Med. 2017 Sep 1; 177(9):1308-1315)
• A multicenter cohort study of adults hospitalized with pneumonia found that two thirds (67.8% [4391 of 6481]) of patients received excess antibiotic therapy. Antibiotics prescribed at discharge accounted for 93.2% of excess duration. Each excess day of treatment was associated with a 5% increase in the odds of antibiotic-associated adverse events reported by patients after discharge. (Vaughn VM, et al. Excess Antibiotic Treatment Duration and Adverse Events in Patients Hospitalized With Pneumonia: A Multihospital Cohort Study. Ann Intern Med. 2019;171(3):153-163.)
• A retrospective review of 400 antibiotic courses prescribed to hospitalized children found (Same RG et al. Antibiotic-Associated Adverse Events in Hospitalized Children. JPIDS. Jan 2021): 
  • 21% of antibiotic courses administered to hospitalized children resulted in at least 1 AE
  • 66% of children who developed an AE required further interventions
  • Each additional day of antibiotic therapy associated with 7% increased odds of developing an AE
  • 30% of AEs occurred after hospital discharge
  • 15% of AEs were associated with antibiotics that were unnecessary

• A study using national surveillance system found antibiotics were implicated in 19% of all ED visits for drug-related adverse events from 2004-2006. It was estimated that antibiotic-related adverse events led to nearly 150,000 ED visits per year. Most ED visits for antibiotic-associated adverse events were for allergic reactions (79% of visits). (Shehab N, et al. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008 Sep 15;47(6):735-743.)
• A follow up study using the national surveillance system from 2013-2014 found that 16% of all ED visits were for systemic antibiotic-related adverse events out of over 42,500 cases. Among children 5 years and younger, antibiotics were the most common drug class implicated in ED visits for adverse drug events (56.5%). For children aged 6-19 years old, antibiotics were implicated in 31.8% of ED visits. (Shehab N, et al. US Emergency Department Visits for Outpatient Adverse Drug Events, 2013-2014. JAMA 2016; 316 (20): 2115-2125). 
• Specifically for children, a study using national surveillance data found that between 2011-2015, an estimated 69,464 ED visits per year were made among children with adverse drug events. Almost half of all ED visits for adverse drug events in children 19 years and younger are due to antibiotics. Forty percent of ED visits for adverse drug events occur in children 2 years and less. (Lovegrove MC et al. US Emergency Department Visits for Adverse Drug Events from Antibiotics in Children, 2011–2015. J Pediatric Infect Dis Soc. 2018 Aug 23.)

• At a single institution, Goldman et al found that the incidence in children of adverse drug reactions due to TMP-SMX was 13 cases/100,000 admissions in 2005-2006. This was an increase from 5 cases/100,000 admissions in the 2000-2004 time period. The majority of these patients were prescribed TMP-SMX for a skin and soft tissue infection. (Goldman JL, Jackson MA, Herigon JC, Hersh AL, Shapiro DJ, Leeder JS. Trends in adverse reactions to trimethoprim-sulfamethoxazole. Pediatrics. 2013 Jan;131(1):e103-8.)
• A case series reported 5 cases of healthy adolescents who developed severe acute respiratory failure while taking TMP-SMX. 2 of the adolescents died. The TMP-SMX was prescribed for treatment of acne vulgaris. https://pediatrics.aappublications.org/content/143/6/e20183242.long
• A review of the literature found 41 patient cases of aseptic meningitis associated with use of TMP-SMX. 9 cases (22%) were pediatric patients younger than 20 years of age. The mechanism for this adverse event is unclear. Overall, 11 cases (27%) held a diagnosis of an autoimmune disease and 6 (15%) had a diagnosis of HIV. https://doi.org/10.1016/j.anai.2014.08.006 

Antibiotic Exposure Increases the Risk of CDI

Previous antibiotic exposure is recognized as the single most important risk factor for CDI in adults and children, and nearly all antibiotics have been associated with C difficile disease (Owens RC Jr, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antibiotic-associated risk factors for Clostridium difficile infection. Clin Infect Dis. 2008;46:(suppl 1 S19-S31)

Antibiotics associated with the highest incidence rates of pediatric community-acquired CDI development relative to their frequency of prescription include clindamycin, cefdinir and amoxicillin/clavulanate. (Dang R, Alabaster A, Miranda-Katz M, Parmar D, Greenhow TL. Impact of Antecedent Antibiotic Usage on Community-associated Clostridioides difficile Infection in Pediatrics. Pediatr Infect Dis J. 2021 Feb 12. doi: 10.1097/INF.0000000000002991. Published online ahead of print.)

Current Incidence of CDI in Children

Lesse et al (NEJM 2015) used active population and laboratory-based surveillance across 10 geographic areas in 2011 to identify the burden of CDI in the United States. Among children 1-17 years, the incidence of CDI was 24.2 per 100,000 persons; with community-associated CDI incidence of 17.9 per 100,000 persons and healthcare associated CDI incidence of 6.3 per 100,000 persons. (Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Feb 26;372(9):825-34)

Increasing Incidence of CDI in Children

Several studies have noted a rise in CDI-related hospitalizations.

• A national study from the US military health system database of 1,331 children with community-acquired CDI demonstrated a significantly increasing trend from 2001 to 2013 with an average annual increase of 48% (P < .001). (Adams DJ, Eberly MD, Rajnik M, Nylund CM. Risk Factors for Community-Associated Clostridium difficile Infection in Children. The Journal of Pediatrics. 2017 Jul; 186:105-109.)
• A study using the Kids’ Inpatient Database which looked at data from 2003-2012 found that the incidence of CDI among hospitalized children increased by 145% during that time period – from 24.0 to 58.0 per 10,000 hospital discharges per year. (Pant C, Deshpande A, Gilroy R, Olyaee M, Donskey CJ. Rising Incidence of Clostridium difficile Related Discharges among Hospitalized Children in the United States. Infect Control Hosp Epidemiol. 2016; 37(1): 104-106)

CDI Associated with Increased Mortality, Prolonged Hospitalization, Increased Hospital Costs

• Sammons et al (CID 2013) found that when matched to children without CDI, children with CDI had increased mortality (OR 6.73, 95% CI 3.77-12.02), longer length of hospital stay, and higher hospital costs. (Sammons JS, Localio R, Xiao R, Coffin SE, Zaoutis T. Clostridium difficile infection is associated with increased risk of death and prolonged hospitalization in children. Clin Infect Dis. 2013 Jul;57(1):1-8.)
• Through use of a large nationally representative dataset of pediatric hospital discharge data, Mehrotra et al determined that the attributable cost of hospitalization for a child with CDI was nearly $2,000 greater than for a child without CDI after adjusting for length of hospital stay. (Mehrotra P, Jang J, Gidengil C, Sandora TJ. Attributable Cost of Clostridium difficile Infection in Pediatric Patients. Infect Control Hosp Epidemiol. 2017; 38(12): 1472-1477)

Role of Antimicrobial Stewardship in Controlling CDI Rates

CDI Clinical Practice Guideline

• To reduce the risk of CDI, antibiotic stewardship programs should be implemented along with minimizing frequency and duration of high-risk antibiotic therapy and the number of antibiotic agents prescribed. Restriction of certain antimicrobials should also be considered to minimize CDI risk. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practices 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). Clin Infect Dis. 2018; 66(7): e1-e48