Don’t Kid Yourself: Broad- versus Narrow-Spectrum Antibiotics in Children

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Gerber JS, Ross RK, Bryan M, et al. Association of broad- vs. narrow-spectrum antibiotics with treatment failure, adverse events, and quality of life in children with acute respiratory tract infections. JAMA. 2017;318:2325-2336.

What do group A streptococcal pharyngitis, acute sinusitis, and acute otitis media have in common? These are all respiratory tract infections in kids that are very frequently treated with antibiotic; all too often – 50% of time – with broad-spectrum antibiotics.1 But should we be routinely prescribing broad-spectrum antibiotics for these common respiratory tract infections? Overuse of broad-spectrum antibiotics can lead to antimicrobial resistance, increased cost, and higher prevalence of adverse drug reactions. Nearly 2 million infections and 23,000 deaths are caused by bacteria that are antibiotic-resistant each year in the United States costing the healthcare system an estimated 20 billion dollars.2 Moreover, adverse reactions to antibiotics are the most common reason for pediatric patients to visit the emergency department.3  From 2002 to 2010, while the total number of prescribed antibiotics decreased, the number of broad-spectrum antibiotics prescriptions increased.1 For those requiring antibiotics, clinical practice guideline recommendations are inconsistent with regard to prescribing narrow- versus broad-spectrum antibiotics. Empiric antibiotic recommendations for pediatric patients with acute respiratory tract infections (excluding alternatives due to penicillin allergies) can be found in Table 1. Narrow-spectrum antimicrobials are generally preferred, but there are instances where broader coverage is recommended. For example, for acute sinusitis the American Academy of Pediatrics guidelines recommend narrow-spectrum antibiotics while the Infectious Diseases Society of America guidelines recommended a broad-spectrum agent.

 

Table 1. Current guideline recommended therapies for acute upper respiratory tract infections in children4-7

 

 

American Academy of Pediatrics (AAP)

Infectious Diseases Society of America (IDSA)

Acute Otitis Media (AOM)

Antibiotics recommended if:

  • ≥ 6 months of age with severe infectiona
  • < 2 years of age with bilateral AOM
  • Failure to improve after 48-72 hours of observation in patients not initially treated with antibiotics

 

Preferred: Amoxicillin 80-90 mg/kg/day in 2 divided doses

 

Alternative: Amoxicillin-clavulanate (90 mg amoxicillin/kg/day with 6.4 mg of clavulanate/kg/day) in two divided dosesb

 

Duration:

  • 10 days if < 2 years of age or if severe symptoms present                         
  • 7 days for mild/moderate if 2-5 years of age
  • 5-7 days for mild/moderate if ≥ 6 years

 

Acute Sinusitis

Preferred: Amoxicillin 45 mg/kg/day or 80-90 mg/kg/day in two divided doses in communities with ≥ 10%  nonsusceptible S. pneumoniae

 

Alternative: Amoxicillin-clavulanate (80-90 mg amoxicillin/kg/day with 6.4 mg of clavulanate/kg/day) in two divided dosesc or ceftriaxone 50 mg/kg x 1 dosewith oral antibiotics initiated after 24 hoursd

 

Duration: 10-28 days OR 7 days after patient is symptom free

Preferred: Amoxicillin-clavulanate (90 mg amoxicillin/kg/day) in two divided dosese

 

Alternative: Ceftriaxone 50 mg/kg x 1 dosewith oral antibiotics initiated after 24 hoursd

 

Duration: 10-14 days

Group A Streptococcal Pharyngitis

 

Preferred: Penicillin VK 250 mg 2-3 times daily, amoxicillin 50 mg/kg once daily, amoxicillin 25 mg/kg twice daily, or IM benzathine penicillin G x 1 dosef

 

Duration: 10 days for oral regimens

a. Moderate or severe otalgia or lasting ≥ 48 hours, or temperature 102.2°F

b. Preferred first-line in patients that received amoxicillin in previous 30 days or have otitis-conjunctivitis syndrome

c. Preferred first-line for the following patients: moderate to severe illness, age < 2 years, those who attend child care, or recently treated with antimicrobial

d. For patients unable to tolerate oral medication or unlikely to be adherent to initial doses of antibiotic

e. For patients from communities with ≥ 10% penicillin-nonsusceptible S. pneumoniae, have severe infections (evidence of systemic toxicity with fever 102°F or higher and threat of suppurative complications), attend daycare, age < 2 or > 65 years, recent hospitalization, antibiotic use within past month, or who are immunocompromised

f. Dosing based on weight; < 27 kg: 600,000 U; ≥ 27 kg: 1,200,000 U

 

A recent study attempts to “clean up” the debate by examining the benefits and risks of using narrow- versus broad-spectrum antibiotics in children with acute respiratory tract infections.  The study included retrospective and prospective cohorts who were patients at 31 pediatric primary care practices in southern Pennsylvania and southern New Jersey.  See Table 2.  Patients aged 6 months to 12 years with a diagnosis of acute respiratory tract infection (acute otitis media, group A streptococcal pharyngitis, or acute sinusitis) and prescribed oral antibiotics were included. A positive rapid test was required for all patients with group A streptococcal pharyngitis.

 

Patients were excluded from the prospective cohort if they used antibiotics in the past 30 days, had not started the antibiotics prescribed, had no confirmed diagnosis, could not be contacted by the investigators, or were diagnosed with group A streptococcal pharyngitis and under the age of 3 years.Patients were excluded from the retrospective cohort if they used antibiotics in the past 30 days, diagnosed with a complex chronic condition, diagnosed with group A streptococcal pharyngitis and under the age of 3 years, unwilling to give consent, diagnosed with multiple bacterial infections, or prescribed inappropriate therapy (defined as antibiotics other than penicillins, aminopenicillins +/- beta-lactamase inhibitor, 1st-3rd generation cephalosporins, or macrolides). Broad-spectrum antibiotics, defined as those with activity beyond pneumococcus, included amoxicillin-clavulanate, cephalosporins, and macrolides. Penicillin and amoxicillin were classified as narrow-spectrum antibiotics.

 

In the retrospective analysis, broad-spectrum antibiotics were not superior to narrow-spectrum antibiotics in terms of clinical outcomes. Broad-spectrum agents were associated with a higher risk of adverse drug events compared with narrow-spectrum alternatives. In children with group A streptococcal pharyngitis infections, broad-spectrum antibiotics were associated with a reduced risk of treatment failure but an increased rate of adverse events.

 

In the prospective group, broad-spectrum antibiotics were associated with a slightly lower quality of life (PedsQL) score and more adverse events. The most common adverse events seen in the study included diarrhea (69.6%), rash (40.1%), and upset stomach, vomiting or both (21.4%).

 

 

Table 2. Retrospective versus prospective cohorts

 

 

Retrospective Cohort

Prospective Cohort

Methods

Outcomes assessed

Clinical outcomes (treatment failure and adverse reactions)

Patient-centered outcomes (quality of sleep, missed school, requirement of additional childcare, time to resolution of symptoms, child suffering, and adverse reactions)

Data collection

Electronic medical record

Electronic medical record and

telephone conversations at 5-10 days and 14-20 days after diagnosis

Dates of data collection

January 2015 - April 2016

January 2015 - December 2015

Data analysis

Stratified analysis by provider as well as a propensity score full matched analysis

Stratified analysis by provider as well as a propensity score full matched analysis

Results

Number of patients included in analysis

30,086 children

2,472 children

Patients prescribed broad-spectrum antibiotics

4,296 (14.3%)

860 (35.4%)

Outcomes

No difference in rate of treatment failure (3.4% in broad-spectrum vs. 3.1% for narrow-spectrum, p=.88 in stratified and p=.39 in full matched)

No difference in missed school, time to resolution of symptoms, disturbance of sleep, or requirement of additional childcare

Adverse Effects Outcomes

Difference in adverse reactions (3.7% in broad-spectrum vs. 2.7% for narrow-spectrum, p=.001 in stratified and p=<.001 in full matched)

Difference in adverse events (35.6% in broad-spectrum vs. 25.1% for narrow-spectrum, p=<.001 in stratified and full matched) and quality of life as measured by Pediatric Quality of Life Inventory score (90.2 in broad-spectrum vs. 91.5 for narrow-spectrum, p=.006 in stratified and p=.008 in full matched)

 

 

Strengths of this study included the diverse pediatric population, the analysis of quality of life, and the consistency of findings in each group and analysis. Uniquely, this study evaluated both clinical and quality of life outcomes.1,8 Two statistical analyses were conducted for each arm of the study in order to minimize confounding and increase the reliability of the findings. Additional strengths were the follow-up assessment up to 20 days after diagnosis to assess for adverse drug reactions.  Lastly, the inclusion criteria mirrored current clinical practice guidelines.

 

However, the study has substantial limitations. There was a portion of the population that undoubtedly had viral infections and were treated with antibiotics.  None-the-less, this mimics real world antimicrobial use. Also, children who had recurrent infections were excluded from the study, so these findings cannot be extrapolated to kids how had a recent respiratory tract infection. In the prospective arm, possible recall bias is a potential limitation. Additionally, only 29% of patients initially identified were included in the prospective cohort due to a low follow-up contact rate.  While there was a significant difference in the PedsQL score that favored the use of narrow-spectrum antibiotics, the PedsQL score has not been specifically validated for use in the setting of respiratory tract infections. While a 1.2 difference in the PedsQL score was statistically significant, previous studies have shown that a 4-point difference is indicative of a clinically meaningful difference.9 Importantly, the majority of the PedsQL surveys were completed by parents which may have resulted in incomplete surveys and skewed results. Broad-spectrum antimicrobials are indicated in certain severe acute respiratory tract infections based on current guidelines, but data regarding the severity of the infections were not included in this study report. Likewise, previous respiratory tract infections were not assessed, which may have impacted provider’s choice in prescribed antimicrobial. Similarly, allergies were not documented, so any patients with penicillin allergies would likely have been prescribe a broad-spectrum antibiotic out of necessity.

 

A perplexing finding in this study was the increased risk of treatment failure observed in patients with group A streptococcal pharyngitis who were prescribed narrow-spectrum agents. Susceptibility testing is not routinely performed for group A streptococcus because it is universally susceptible to penicillin. Thus, the validity of this finding is questionable. Could adherence to antibiotic regimens have played a role in this finding? Unfortunately, adherence to treatment was not accessed in this study. Amoxicillin-clavulanate ES contains less clavulanate than other formulations, thus theoretically causing less diarrhea. Would different formulations affect the observed difference in adverse event rates? Possibly, but the authors did not specify which formulations were used. Combining acute otitis media, acute sinusitis, and group A streptococcal pharyngitis make it a bit difficult to tease out disease-specific findings. Thus, a more transparent and in-depth analysis taking into account disease severity, medication dosing, product formulations, and treatment adherence would have made this study far more robust.

 

This study found a statistically significant difference in adverse events and patient centered outcomes favoring the use of narrow-spectrum antibiotics. Did the numerically improved quality of life score truly impact patients in the narrow-spectrum group? Probably not. On the other hand, the increased rate of adverse effects reported with the use of broad-spectrum antibiotics in this study is a clinically meaningful finding. These findings confirm what we already know ­— there is no benefit in routinely using broad-spectrum agents over narrow-spectrum antibiotics in most respiratory tract infections in kids. However, there are situations when broad-spectrum antibiotics should be recommended based on the severity of the infection, past medical history, prior adverse drug reactions, and patient allergies. And, of course, local resistance patterns must be considered too. But in the absence of compelling reasons to prescribe a broad-spectrum agent, to be good stewards of antimicrobials, narrow-spectrum antibiotics should be consistently chosen for the majority of pediatric respiratory tract infections.

 

 

Acknowledgments

 

The authors would like to thank Kristen Turner, PharmD, BCPS, BCPPS for sharing her wisdom on all things involved with pediatrics.