Reasons for Outpatient Antibiotic Stewardship

Diseases due to multidrug-resistant bacteria resistant to the antibiotics available are increasing at an alarming rate. Use of antibiotics by humans rose by 40% between 2000 and 2010, but the rate of new antibiotic development has slowed. Recent estimates of the burden of antimicrobial resistance suggest that there are approximately 700,000 deaths worldwide every year due to infections with antimicrobial resistant bacteria, with nearly 50,000 of these deaths occurring in the United States and Europe. A report led by economist Jim O’Neil on antimicrobial resistance commissioned by the British government in 2014 projected that the number of annual deaths attributable to antimicrobial resistance would surpass 10 million by the year 2050 if no meaningful interventions occur. These estimates suggests that death related to antimicrobial resistant infections will surpass cancer as the number one cause of mortality worldwide. (O’Neil, J. Review on Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. (2014).)

Antibiotic treatment for a single outpatient infection has been shown to influence resistance patterns of future infections. (Paschke AA et al, “Previous antimicrobial exposure is associated with drug-resistant UTI in children”; Pediatrics 2010; 125: 664-672.); Kuster SP et al, “Previous Antibiotic Exposure and Antimicrobial Resistance in Invasive Pneumococcal Disease: Results From Prospective Surveillance,” Clin Infect Dis 2014; 59(7): 944-952.

Prominent examples of increasing antibiotic resistance threats commonly encountered in the outpatient pediatrics setting include:

Streptococcus pneumoniae

• S. pneumoniae is a common cause of acute otitis media, community-acquired pneumonia, and sinusitis in children.
• Drug resistant S. pneumoniae is considered a serious by the CDC, with an estimated 2 million infections each year. In more than 30% of infections, the isolate will be resistant to one or more clinically useful antibiotics (CDC, Antibiotic Resistance Threat Report, 2019.)
• The nationwide Active Bacterial Core pneumococcal surveillance report from 2018 found that 4.7% of invasive pneumococcal isolates were resistant or intermediate to penicillin and 2.6% were resistant or intermediate to cefotaxime. However, resistance rates were alarmingly high to erythromycin (28.2%) and tetracycline (10.3%). (Centers for Disease Control and Prevention. 2018. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Streptococcus pneumoniae, 2018.)

Staphylococcus aureus

• Tamma PD, Robinson GL, Gerber JS, Newland JG, DeLisle CM, Zaoutis TE, Milstone AM. Pediatric Antibiotic susceptibility trends across the United States. Infect Control Hosp Epidemiol. 2013 Dec;34(12):1244-51.
  • A pooled pediatric antibiogram representing 200 pediatric healthcare institutions across the United States from 2005 and 2011 demonstrated that 50% of all Staphylococcus aureus isolates were methicillin-resistant and 21% of S. aureus isolates were resistant to clindamycin.
• Vicetti M, Mejias A, Leber A, Sanchez PJ. A decade of antimicrobial resistance in Staphylococcus aureus: A single center experience. PLoS One. 2019 Feb 12;14(2):e0212029.
  • Retrospective review of >40,000 S. aureus isolates identified from inpatient and outpatient settings in a large children’s hospital demonstrated resistance to clindamycin and TMP-SMX increased among outpatient isolates between 2005-2014.

Group A Streptococcus

• While Streptococcus pyogenes remains highly susceptible to beta-lactam antibiotics, over the past decade increasing prevalence of clindamycin and macrolide resistance are being reported worldwide.
  • A single center study evaluating susceptibility of Group A streptococcus isolates from pharyngeal specimens in children between 2010-2015 in Wisconsin, USA identified 15% of GAS isolates demonstrating nonsusceptibility for clindamycin and erythromycin, and inducible resistance detected in 12%. (DeMuri GP et al. Pediatr Infect Dis J. 2017 Mar;36(3):342-344. Macrolide and Clindamycin Resistance in Group a Streptococci Isolated From Children With Pharyngitis.)
• Globally, studies using whole genome sequencing of Streptooccus pyogenes are increasingly reporting identification of ermA and ermB genes conferring macrolide resistance.
  • Kimiko Ubukata, Takeaki Wajima, Miyuki Morozumi, Megumi Sakuma, Takeshi Tajima, Keita Matsubara, Koju Itahashi 5, Satoshi Iwata. Changes in Epidemiologic Characteristics and Antimicrobial Resistance of Streptococcus pyogenes Isolated Over 10 Years From Japanese Children With Pharyngotonsillitis. J Med Microbiol. 2020 Mar;69(3):443-450. doi: 10.1099/jmm.0.001158.
  • Dharmapalan D, Inbanathan FY, Kharche S, et al. Whole genome shotgun sequences of Streptococcus pyogenes causing acute pharyngitis from India. Data Brief. 2018;18:1340‐1349. Published 2018 Apr 1. doi:10.1016/j.dib.2018.03.129

ESBL-Producing Enterobacteriaceae in Children

• Logan LK, Braykov NP, Weinstein RA, Laxminarayan R; CDC Epicenters Prevention Program. Extended-Spectrum β-Lactamase-Producing and Third-Generation Cephalosporin-Resistant Enterobacteriaceae in Children: Trends in the United States, 1999-2011. J Pediatric Infect Dis Soc. 2014 Dec;3(4):320-8.
  • National data from The Surveillance Network Database demonstrated an increase in prevalence of third generation cephalosporin-resistant and ESBL-producing Enterobacteriaceae, from 1.39% and 0.28% in 1999–2001 to 3% and 0.92% in 2010–2011 respectively.
• Kaarme J, Riedel H, et al. Rapid Increase in Carriage Rates of Enterobacteriaceae Producing Extended-Spectrum β Lactamases in Healthy Preschool Children, Sweden. 2018 Oct;24(10):1874-1881.
  • Healthy preschool children in Sweden had high prevalence of ESBL-producing Enterobacteriaceae stool carriage.
• Islam S, Selvarangan R, et al. Intestinal Carriage of Third-Generation Cephalosporin-Resistant and Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae in Healthy US Children. 2018 Aug 17;7(3):234-240.
  • Five percent of healthy US children had intestinal carriage of 3rd generation cephalosporin-resistant Enterobacteriaceae among 519 subjects between 14 days and 14 years old enrolled from 3 US sites 2013-2015.

See the Antibiotic Resistance page for more information.

Overuse can be classified into three categories: 1) prescribing antibiotics when none are indicated, 2) prescribing antibiotic courses that are excessive in spectrum, and 3) prescribing antibiotic courses with excessive duration for the infection being treated. There is substantial evidence suggesting that antibiotics are overused in outpatient settings, and children are no exception.

(1) Unnecessary antibiotic prescriptions

• Overall, an estimated 1 in 3 outpatient prescriptions are unnecessary. (Fleming-Dutra K et al. Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011. JAMA. 2016 May 3;315(17):1864-73.) An estimated 49 million courses of antibiotics are prescribed annually in ambulatory pediatrics. (Hersh AL et al. Antibiotic prescribing in ambulatory pediatrics in the United States. Pediatrics. 2011 Dec;128(6):1053-61). The total number of excess prescriptions for acute respiratory illnesses is estimated to be 11.5 million. (Kronman M et al. Bacterial prevalence and Antibiotic prescribing trends for acute respiratory tract infections. Pediatrics. 2014 Oct;134(4):e956-65.)

(2) Use of broad-spectrum and non-first-line antibiotics

• Proportion of broad-spectrum antibiotic prescribing increased from 2000 to 2010 among children and adolescents by 143%, more than in any other age group. (Lee GC, Reveles KR, Attridge RT, et al. Outpatient antibiotic prescribing in the United States: 2000 to 2010. BMC Med. 2014;12:96)
• Between one third and one half of children with otitis media, sinusitis, or pharyngitis receive non-first-line antibiotics, despite evidence that no more than 20% of children (and probably far less) have a contraindication to first-line antibiotics. (Hersh AL et al. Frequency of First-line Antibiotic Selection Among US Ambulatory Care Visits for Otitis Media, Sinusitis, and Pharyngitis. JAMA Internal Medicine 2016; 176:1870.

(3) Antibiotic duration

Antibiotics should prescribed for the minimal effective duration. The following studies and guidelines support the use of shorter duration of therapy than historically used for select infectious conditions:

Pyelonephritis

• AAP Clinical Practice Guidelines from 2011 recommend treating children with pyelonephritis for 7 to 14 days, citing insufficient data to recommend a more specific treatment duration.
• A multicenter retrospective cohort study of children with pyelonephritis used an inverse probability of treatment weighted propensity score analysis and found the odds of treatment failure were similar in children treated with a short course (6-9 days) compared with those treated with a long course (10 days or more) (Fox MT et al 2020 ).

Acute otitis media, age < 2 years

• AAP Clinical Practice Guidelines from 2013 recommend 10 days of therapy for children younger than 2 years with severe symptoms, based on strong evidence.

Acute otitis media, age > 2 years

• Based on data suggesting that shorter antibiotic courses in children > 2 years of age with acute otitis media are equally effective, AAP Clinical Practice Guidelines from 2013 recommend a 7 day course of first-line antibiotic therapy for children ages 2-5 years and a 5-7 day course for children ages 6 years and older with mild or moderate AOM.

Regional Variation in Antibiotic Prescribing

• Unexplained variation in antibiotic prescribing suggests unnecessary use in certain areas. There is substantial regional and state-to-state variation in outpatient antibiotic prescribing rates. For children aged 2 and under, there is a nearly five-fold difference in antibiotic prescriptions per child per year between the states using the least and most antibiotics. (Hicks LA et al. US Outpatient Antibiotic Prescribing Variation According to Geography, Patient Population, and Provider Specialty in 2011. Clin Infect Dis 2015; 60:1308–1316.)

Antibiotic Overuse in Various Settings

Children are prescribed antibiotics in a variety of settings: primary care, outpatient subspecialty care, dentistry, emergency departments, urgent care centers, retail clinics, and direct-to-consumer telemedicine. Each presents unique challenges with overuse of antibiotics.

• Direct-to-consumer telemedicine is growing in popularity, but antibiotic prescribing for children is much more common and much more likely to be guideline-discordant compared to primary-care and urgent-care settings. Five percent of children in one study were diagnosed with streptococcal pharyngitis in telemedicine visits with no testing performed in 96% of those patients. (Ray KN, Shi Z, Gidengil CA, Poon SJ, Uscher-Pines L, Mehrotra A. Antibiotic Prescribing During Pediatric Direct-to-Consumer Telemedicine Visits. Pediatrics 2019; 143:e20182491.)
• For all age groups, urgent care centers are most likely to prescribe antibiotics inappropriately, followed by emergency departments, medical offices, and retail clinics. (Palms DL et al. Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States. JAMA Intern Med 2018; 178:1267–1269.)

• Antibiotics account for almost half of all ED visits for adverse drug events that result from systemic medication. (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.)
• The frequency of adverse drug reactions related to trimethoprim-sulfamethoxazole in children has increased from 2000 to 2009, coincident with the increase in prescribing this drug for skin and soft tissue infections (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.)8
• For every 14 children treated with an antibiotic for acute otitis media, one will experience an adverse drug reaction (e.g., vomiting, diarrhea, rash). (Venenkamp RP et al. Antibiotics for acute otitis media in children. Cochrane Database Syst Rev. 2015 Jun23;(6):CD000219.)

• The incidence of Clostridiodes difficile infections in children has increased over the past decade. Sammons JS, Toltzis P. Recent trends in the epidemiology and treatment of C. difficile infection in children. Curr Opin Pediatr. 2013 Feb;25(1):116-21.
• Community-associated C. difficile infections in children are associated with recent receipt of antibiotics regularly prescribed in pediatric practice - notably fluoroquinolones, clindamycin, and third-generation cephalosporins. Risk Factors for Community-Associated Clostridium difficile Infection in Children. Adams DJ, Eberly MD, Rajnik M, Nylund CM. J Pediatr. 2017 July; 186: 105-109