Elsevier

The Lancet

Volume 397, Issue 10280, 27 March–2 April 2021, Pages 1195-1203
The Lancet

Articles
Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial

https://doi.org/10.1016/S0140-6736(21)00313-5Get rights and content

Summary

Background

Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of β-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment.

Methods

We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with β-lactam therapy were randomly assigned (1:1) to receive β-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete.

Findings

Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of β-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or β-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the β-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0–84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the β-lactam group (between-group difference of 9·42%, 95% CI −0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the β-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI −0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the β-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the β-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the β-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema).

Interpretation

Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing β-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption.

Funding

French Ministry of Health.

Introduction

Lower respiratory tract infections are one of the most common indications for antibiotic use in community and hospital settings.1, 2 Community-acquired pneumonia results in 600 000–800 000 admissions to hospital annually in the USA, with the highest incidence in those aged 65 years and older.3, 4, 5 The number of cases due to community-acquired pneumonia and the number of associated deaths have been increasing in parallel with the ageing of the global population over the past decade.6

US guidelines for adults with community-acquired pneumonia recommend no less than 5 days of antibiotic treatment, with discontinuation based on clinical stability criteria,7, 8, 9 as supported by a 2016 study,10 whereas according to European guidelines, 8 days of treatment is recommended.11 Therefore, the optimal duration of antibiotic therapy is not well established, and in daily practice most physicians usually treat their patients for 7–10 days.12, 13 A few studies from the 1940s and 1970s among adult patients, which were underpowered and non-randomised,14, 15, 16 and one study from 2006 that focused on mild cases of community-acquired pneumonia,17 have suggested that antibiotic treatment for fewer than 5 days could be sufficient, but these data are insufficient to recommend this treatment duration in patients admitted to hospital for community-acquired pneumonia. Shortened treatment durations would lead to reduced antibiotic consumption at the individual and population level, thus probably restricting the emergence of bacterial resistance,18, 19 and would bring several other benefits, including reducing occurrence of adverse events and costs.18, 20

We aimed to assess the need for an additional 5-day course of treatment with β-lactam treatment among patients admitted to hospital for community-acquired pneumonia, who were clinically stable after 3 days of β-lactam treatment.

Section snippets

Study design and participants

The Pneumonia Short Treatment (PTC) trial was a double-blind, randomised, placebo-controlled, non-inferiority trial with two parallel groups in 16 French hospitals (appendix p 3).

Patients were recruited in medical wards by investigators. Eligible patients were aged 18 years or older, with moderately severe community-acquired pneumonia, treated with β-lactam monotherapy according to European guidelines (ie, amoxicillin plus clavulanate [oral or intravenous] or parenteral third-generation

Results

Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, of whom 310 were eligible and randomly assigned to either the placebo group (n=157) or the β-lactam group (n=153; figure 1). Seven patients withdrew consent before initiating study medication, five in the placebo group and two in the β-lactam treatment group, leaving 303 in the ITT population (figure 1). 291 (96%) of 303 patients were included in the per-protocol analysis at day 15. Six patients did not receive

Discussion

We found that discontinuing β-lactam treatment after 3 days in patients with community-acquired pneumonia who were clinical stability resulted in outcomes that were similar and non-inferior to those in patients who continued their treatment for an additional 5 days. These data support the concept that antibiotic therapy can be safely discontinued in patients who have moderately severe community-acquired pneumonia who have early clinical response to therapy,10, 18 which could allow an important

Data sharing

Because secondary analyses are ongoing, data collected for the study, including individual participant data and a data dictionary defining each field in the set, will not be made available to others.

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