Low-dose amoxicillin noninferior to higher dose for pediatric pneumonia
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A lower dose of oral amoxicillin was noninferior to a higher dose in children with community-acquired pneumonia who were discharged from an ED or hospital ward, according to results of a 2x2 factorial, randomized clinical trial in JAMA.
The trial also showed that a shorter treatment duration was noninferior to a longer treatment duration.
“Few trials have compared different durations of the same antibiotic for treatment of community-acquired pneumonia (CAP) in adults or children, and none to our knowledge have compared both dose and duration in the same trial for childhood CAP,” Julia A. Bielicki, PhD, a researcher of pediatric infectious diseases in the Medical Research Council Clinical Trial Unit at University College London, and colleagues wrote.
Bielicki and colleagues enrolled 814 patients aged 6 months or older who were clinically diagnosed with CAP and received oral amoxicillin at discharge from an ED or inpatient center in the U.K. or Ireland between February 2017 and April 2019. The children were randomly assigned in a 1:1 ratio to receive either a lower dose of amoxicillin (35 mg/kg/d to 50 mg/kg/d) or a higher dose (70 mg/kg/d to 90 mg/kg/d) for 3 days or 7 days.
The researchers established a noninferiority margin of 8%. The primary outcome was clinically indicated antibiotic retreatment for a respiratory infection 28 days after randomization.
Antibiotic retreatment occurred within 28 days in 12.6% of patients who received a lower dose of amoxicillin compared with 12.4% of those who received a higher dose, according to Bielicki and colleagues. Also, retreatment occurred in 12.5% of patients in both the 3-day and 7-day treatment groups.
Although the shorter treatment duration was noninferior to the longer duration, the researchers found a significant difference between the two groups for cough duration, which persisted longer in the 3-day treatment group (12 days vs. 10 days; HR = 1.2; 90% CI, 1-1.4).
Among children with severe CAP, 17.3% in the low-dose group received retreatment compared with 13.5% in the high-dose group, as well as 16% in the shorter treatment group and 14.8% in the longer treatment group.
By the end of the study, 5% of children experienced a serious adverse event, 6% discontinued the trial medication early and 14% took fewer doses or a lower amount than prescribed.
“Among children with CAP discharged from an ED or hospital ward (within 48 hours), low-dose outpatient oral amoxicillin was noninferior to high dose, and 3-day duration was noninferior to 7 days, with regard to need for further antibiotic retreatment,” Bielicki and colleagues wrote. “However, disease severity, treatment setting, prior antibiotics, and acceptability of the noninferiority margin require consideration when interpreting the findings.”
Perspective
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C. Buddy Creech, MD, MPH
While the phrase “less is more” is first attributed in print to the poet Robert Browning in 1855, it’s applicability to medicine feels more recent. We can see it hinted at in Voltaire’s quip that “the art of medicine consists in amusing the patient while nature cures the disease,” but the notion that doing less (or more appropriately, just enough) in the treatment of infectious diseases can be daunting. We construct treatment regimens based on arbitrary weeks, or even months, and we rarely use response to therapy as a metric for antibiotic discontinuation.
In the CAP-IT study by Bielicki and colleagues, over 800 children 6 months of age and older with clinically diagnosed community-acquired pneumonia were treated with either standard dose or high dose amoxicillin at either a shorter (3 day) or longer (7 day) duration. The primary outcome was need for re-treatment for a respiratory infection in the month following the illness. The authors warn that the results may not be generalizable to very severe cases of CAP, nor to patients admitted for a more prolonged hospitalization due to CAP. However, what can be said is children with CAP who are improving after initial antibiotic therapy, even those seen in the emergency setting or admitted for 24 to 48 hours, can be treated for shorter periods of time than we have traditionally. Moreover, lower doses of amoxicillin may be suitable in some geographic areas, based principally on the prevalence of penicillin non-susceptibility among circulating pneumococci. These data are consistent with both the SAFER trial, as well as the recently completed NIH-funded SCOUT-CAP trial. In both of these studies, 5 days of therapy for pediatric CAP was either non-inferior (SAFER trial) or superior (SCOUT-CAP) to the standard 10-day course.
What should clinicians do? First, recognize that in the age of conjugate pneumococcal vaccine, the majority of pediatric CAP appears to be viral, rather than bacterial, in origin (CDC Epic Study). Second, high-dose amoxicillin, which we have all used routinely for 2 decades, may no longer be necessary, depending on local epidemiology. Third, shorter course therapy is appropriate for a substantial number of children with garden variety CAP who are at low risk for complication.
Our colleagues in antimicrobial stewardship continue to teach us many things. Right now, it seems that for many infections, less may indeed be more. By limiting antibiotic exposure, while maintaining drug effectiveness, we almost certainly will reap benefits by reducing antibiotic side effects and antimicrobial resistance.
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