Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial

Prof Paul Little FRCGP a

, Beth Stuart PhD a, Michael Moore FRCGP a, Prof Samuel Coenen DMSc b, Prof Christopher C Butler FRCGP d, Prof Maciek Godycki-Cwirko PhD f, Prof Artur Mierzecki PhD g, Slawomir Chlabicz PhD h, Prof Antoni Torres PhD i j, Jordi Almirall MD k l, Mel Davies MSc m, Tom Schaberg PhD n, Prof Sigvard Mölstad PhD o p, Prof Francesco Blasi MD q, An De Sutter PhD r, Prof Janko Kersnik PhD s, Helena Hupkova PhD t, Pia Touboul MD u, Prof Kerenza Hood PhD e, Mark Mullee MSc a, Gilly O'Reilly PhD a, Curt Brugman MSc v, Prof Herman Goossens PhD c, Prof Theo Verheij PhD v, on behalf of the GRACE consortium

Summary

Background

Lower-respiratory-tract infection is one of the most common acute illnesses managed in primary care. Few placebo-controlled studies of antibiotics have been done, and overall effectiveness (particularly in subgroups such as older people) is debated. We aimed to compare the benefits and harms of amoxicillin for acute lower-respiratory-tract infection with those of placebo both overall and in patients aged 60 years or older.

Methods

Patients older than 18 years with acute lower-respiratory-tract infections (cough of ≤28 days' duration) in whom pneumonia was not suspected were randomly assigned (1:1) to either amoxicillin (1 g three times daily for 7 days) or placebo by computer-generated random numbers. Our primary outcome was duration of symptoms rated “moderately bad” or worse. Secondary outcomes were symptom severity in days 2—4 and new or worsening symptoms. Investigators and patients were masked to treatment allocation. This trial is registered with EudraCT (2007-001586-15), UKCRN Portfolio (ID 4175), ISRCTN (52261229), and FWO (G.0274.08N).

Findings

1038 patients were assigned to the amoxicillin group and 1023 to the placebo group. Neither duration of symptoms rated “moderately bad” or worse (hazard ratio 1·06, 95% CI 0·96—1·18; p=0·229) nor mean symptom severity (1·69 with placebo vs 1·62 with amoxicillin; difference −0·07 [95% CI −0·15 to 0·007]; p=0·074) differed significantly between groups. New or worsening symptoms were significantly less common in the amoxicillin group than in the placebo group (162 [15·9%] of 1021 patients vs 194 [19·3%] of 1006; p=0·043; number needed to treat 30). Cases of nausea, rash, or diarrhoea were significantly more common in the amoxicillin group than in the placebo group (number needed to harm 21, 95% CI 11—174; p=0·025), and one case of anaphylaxis was noted with amoxicillin. Two patients in the placebo group and one in the amoxicillin group needed to be admitted to hospital; no study-related deaths were noted. We noted no evidence of selective benefit in patients aged 60 years or older (n=595).

Interpretation

When pneumonia is not suspected clinically, amoxicillin provides little benefit for acute lower-respiratory-tract infection in primary care both overall and in patients aged 60 years or more, and causes slight harms.

Funding

European Commission Framework Programme 6, UK National Institute for Health Research, Barcelona Ciberde Enfermedades Respiratorias, and Research Foundation Flanders.