The last six months have seen the publication of three papers from both sides of the Atlantic looking at antibiotic use in the management of children with lower respiratory tract infections. We’ll run through the key findings of each of these and take a look at some practical implications.
Paper One: CAP-IT
Nat Clarke and Tessa Davis wrote an excellent summary of the CAP-IT trial. It was a multi-centre study, across the UK and Ireland. Children diagnosed with community-acquired pneumonia, AND over the age of 6 months AND weighing between 6 and 24kg, were randomised to different doses and durations (3 or 7 days) of amoxicillin. In terms of the primary outcome, there was no statistically significant difference in treatment groups for patients requiring antibiotic re-treatment at 28 days. The cough, in those in the shorter duration arm, lasted two days longer (12 vs 10 days) but other outcomes (such as the resolution of fever, vomiting, fast breathing, wheezing, phlegm production, interference with normal activities or reduced appetite) did not show any statistically significant difference.
Paper Two: SCOUT-CAP
Joe Mullaly gave a concise rundown of the SCOUT-CAP study in the 58th Bubble Wrap. This was a multi-centre study, performed in the USA, in which children with community-acquired pneumonia, aged 6 to 71 months, were randomised to a 5 or 10-day course of one of three different beta-lactam antibiotics (amoxicillin, co-amoxiclav or cefdinir). The primary outcome was a composite index Response Adjusted For Duration Antibiotic Risk, (or RADAR), that looked for inadequate clinical response, resolution of symptoms and adverse events. There was no statistically significant difference when each of the individual components of RADAR was looked at. However, when the composite RADAR score was calculated, the shorter course appeared to be superior and was statistically significant (69% probability of a more desirable outcome, CI 63-75).
Paper Three: ARTIC-PC
The final paper worthy of mention is ARTIC-PC. This took a slightly different approach compared to the two previous papers. This double-blind, randomised controlled trial was conducted in the primary care setting in England. Children were included if they were over the age of 6 months AND diagnosed with a ‘lower respiratory tract infection’. This was defined as cough being the predominant symptom AND less than 21 days duration combined with other features localising to the lower respiratory tract – shortness of breath, sputum or pain. Patients were excluded if they were deemed to have ‘pneumonia’, although this wasn’t defined in the paper. Participants were randomised in a 1:1 ratio to either amoxicillin at 50mg/kg/day in 3 divided doses over 7 days or a placebo. Participants and investigators were blinded to the treatment arm they were placed in.
The primary outcome was the length of time the child’s symptoms were rated as ‘moderately bad’ or ‘worse’, by carers in their daily diary. Secondary outcomes included the severity of symptoms (cough, phlegm, shortness of breath, wheeze, blocked or runny nose, disturbed sleep, feeling generally unwell, fever and interference with normal activities), total symptom duration, re-consultation with new or worsening symptoms, side effects, healthcare resource use and adherence to treatment.
A total of 438 children were randomised, fewer than the 938 calculated in the initial power calculations, although the authors did provide justification for the revised sample size.
Looking at the primary outcome, the median duration of symptoms rated as ‘moderately bad’ or ‘worse’ was 5 days in the antibiotic group [IQR 4-11] and 6 days [IQR 4-15] in the placebo group. This difference was not statistically significant (hazard ratio of 1.13 and 95% CI 0.90-1.42).
Participants reported slightly higher symptom severity at days 2 to 4 in the placebo group (2.1, SD 1.1) compared to those in the antibiotic group (1.8, SD 1.1). Given that a score of 2 represented ‘a slight problem’ and a score of 1 meant ‘very little problem’, this difference is unlikely to carry any clinical significance. No significant difference was found in time taken for symptom resolution, re-consultation rates with new or worsening symptoms, hospital admission or adverse effects due to medication.
There was a lack of clearly defined criteria to distinguish between pneumonia or an LRTI. The appropriateness of recruitment was based on the impression of the treating clinician. Incomplete data was also an issue. Only 73% of participants provided a complete data set, leaving the remaining 27% of participants to require imputed results.
ARTIC-PC aimed to answer a pragmatic question for both primary care and the Emergency Department with outcomes that were relevant to both clinicians and parents. The lack of a clearly defined patient population affected the validity of the trial. Perhaps our definition of a ‘lower respiratory tract infection’ requiring antibiotic treatment should be challenged.
What does this mean when I’m faced with a child with an acute cough in the middle of a busy winter season?
Assessment does not change – a sick child with pneumonia needs admission.
Looking at CAP-IT and SCOUT-CAP, a shorter course (3 days) of antibiotics seems just as effective as a longer one (7-10 days). CAP-IT also included children with community-acquired pneumonia who were then discharged from the ward after receiving IV antibiotics. Should we extend the practice of prescribing short-course oral antibiotics to patients discharged after receiving IV antibiotics?
The ARTIC-PC trial takes things a step further and suggests that children with a lower respiratory tract infection may not require antibiotics at all, however, the lack of clearly defined criteria for ‘LRTI’ does affect the applicability of the results. On the other hand, this study may suggest that many children that we see with acute respiratory infections may not even need antibiotics in the first place.
These assumptions only hold true if the rate of penicillin-resistant pneumococci in the community is low. Pneumococcal disease is a major contributor to morbidity and mortality for people of all ages globally. The introduction of the pneumococcal vaccine into the immunisation schedule in 2006 in the UK has averted an estimated 4809 pneumonia-related admissions in children between 2003-2015. Data from 2019-2020 shows that the coverage rate of the pneumococcal vaccine for children aged under the age of 1 in England is 93.2%. This could be one of the reasons why a shorter course of antibiotics is now adequate to treat pneumonia. Clinicians working in communities with low vaccine uptake, or where it is not part of the routine immunisation schedule, should be cautious about applying the results from these three studies.
Shorter courses of antibiotics, or no antibiotics at all, would lead to lower rates of antibiotic resistance. Recent opinion has also indicated that the dogma of insisting patients complete a fixed course of antibiotics as not being particularly grounded in evidence and these papers can perhaps help us change our practice in this aspect.
What about chest x-rays?
In the less is more theme, do we really need a chest x-ray to diagnose pneumonia? In considering the assessment of children who present with community-acquired pneumonia, it is worth noting the guidance from the British Thoracic Society that a chest x-ray should not be considered a routine investigation in this population. In addition to that, NICE in its ‘Fever in under-5s’ guidance, specifically states that children with symptoms and signs suggestive of pneumonia, who are not being admitted to hospital, should not routinely have a chest x-ray.
A final thought that I would like to leave you with is the impact of COVID, bearing in mind that all three papers we discussed ran before the start of the pandemic. It is important to consider how this new information will affect our decision to manage children in whom COVID is in the differential. Will it make us less likely to prescribe an antibiotic or would it not alter our line of thinking?
Bielicki JA, Stöhr W, Barratt S, Dunn D, Naufal N, Roland D, et al. Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children with Community-Acquired Pneumonia. JAMA. 2021 Nov 2; 326(17):1713-24. doi: 0.1001/jama.2021.17843
Little P, Francis NA, Stuart B, O’Reilly G, Thompson N, Becque T, et al. Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double blind, randomised, placebo-controlled trial. Lancet. 2021 Sep 22; 398(10309):1417-26. Doi: 10.1016/S0140-6736(21)01431-8
Shiri T, McCarthy ND, Petrou S. The impact of childhood pneumococcal vaccination on hospital admissions in England: a whole population observational study. BMC Infect. Dis. [Internet]. 2019 Jun 10 [cited 2022 Mar 18];19(1):510. doi: 10.1186/s12879-019-4119-
Williams DJ, Creech B, Walter EB, Martin JM, Gerber JS, Newland JG, et al. Short-vs Standard-Course Outpatient Antibiotic Therapy for Community-Acquired Pneumonia in Children The SCOUT-CAP Randomized Clinical Trial. JAMA Pediatr. 2022 Jan 18. Doi: 10.1001/jamapediatrics.2021.5547