Short-course amoxicillin: Good enough for paediatric CAP?

A short-course high-dose amoxicillin regimen may be sufficient in treating children with community-acquired pneumonia (CAP) who do not require hospitalization, according to results of the SAFER* trial.

The study was conducted over two periods: December 2012–March 2014 (single-centre pilot study) and August 2016–December 2019 (two-centre follow-up). Participants were 281 children aged 6 months to 10 years (median age 2.6 years, 57.3 percent boys) with symptoms consistent with CAP (fever within 48 hours before presentation, respiratory symptoms, and chest radiography findings consistent with CAP), and a primary diagnosis of pneumonia when presenting at the emergency departments (EDs) of the McMaster Children’s Hospital or the Children’s Hospital of Eastern Ontario, Ontario, Canada. They were randomized to receive high-dose amoxicillin for 5 days followed by 5 days of placebo (intervention) or high-dose amoxicillin for 5 days followed by another formulation of high-dose amoxicillin for 5 days (control group).

Children who required hospitalization, those with conditions predisposing them to severe disease and/or pneumonia of atypical origin, exposure to β-lactam antibiotics pre-presentation, and those who received intravenous cephalosporin or azithromycin in the ED were among those excluded.

Outcomes were obtainable from 252 participants. Mean baseline respiratory rate was similar between the intervention and control groups (30.6 vs 31.5 breaths/minute), 71.4 and 76.6 percent had radiologist-confirmed pneumonia, and 36.5 and 38.1 percent, respectively, tested negative for all respiratory viruses assessed. Five and seven patients, respectively, had a nasopharyngeal swab test positive for Mycoplasma pneumoniae at baseline.

Clinical cure at 14–21 days was comparable between patients assigned the intervention and control antibiotic regimens as per the intention-to-treat (ITT) analysis (85.7 percent vs 84.1 percent; risk difference [RD], 0.023, 97.5 percent confidence limit [CL], -0.061 [noninferiority established]), per-protocol analysis** (88.6 percent vs 90.8 percent; RD, -0.016, 97.5 percent CL, -0.087 [noninferiority not established]), and the strict per-protocol group*** (89.0 percent vs 89.2 percent; RD, -0.011, 97.5 percent CL, -0.096). [JAMA Pediatr 2021;doi:10.1001/jamapediatrics.2020.6735]

The rate of clinical cure without the need for additional interventions^# was also comparable between the intervention and control groups (95.5 percent vs 95.4 percent; RD, -0.006, 97.5 percent CL, -0.055 in the per-protocol analysis).

Per-protocol analyses showed that child absenteeism form school or daycare was similar between groups (median 1 day each; incident rate ratio [IRR], 0.93), as was incidence of mild drug adverse reactions (median 1 day each; IRR, 0.89) and respiratory illness recurrence following primary outcome visit but before 30-day follow-up (9.3 percent vs 9.0 percent). Caregiver work absenteeism was significantly reduced in the intervention vs control group (median 2 vs 3 days; IRR, 0.76; p<0.001).

Seven patients required hospitalization for progressive bacterial respiratory illness.

Shorter regimen better?

“[T]he optimal duration of antimicrobial therapy for paediatric CAP is unclear [with] current treatment duration recommendations … based on sparse evidence,” said the researchers.

While a 5-day antibiotic regimen has been noted as effective in adults with CAP, [Clin Infect Dis 2003;37:752-760] evidence of the efficacy of a shorter course in the paediatric population has been scarce with multiple limitations.

“[W]e judge that the results of the present study are evidence that short-course antibiotic treatment for children with CAP who do not require hospitalization is comparable to standard care,” said the researchers.

“In this era of widespread antimicrobial resistance, … it is important that antibiotic treatment durations for common infections are as short as possible and based on evidence rather than custom,” they continued. “Clinical practice guidelines should consider recommending 5 days of amoxicillin for paediatric pneumonia management in accordance with antimicrobial stewardship principles,” the researchers noted.

They advocated for baseline nasopharyngeal testing among children diagnosed with CAP to identify viral or atypical co-infections, an action that could potentially prevent unnecessary antibiotic treatment escalation in the instance of persistent or recurrent symptoms.