Original article
Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial

https://doi.org/10.1016/j.cmi.2021.09.001Get rights and content

Abstract

Objective

To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes.

Methods

A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis.

Results

248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments.

Conclusions

7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.

Introduction

The duration of antimicrobial treatment for bloodstream infections caused by members of the Enterobacterales (eBSIs) has traditionally been supported by experts' opinions. Different scientific societies propose treating catheter-related eBSI for a variable duration of between 7 and 14 days [1,2], and no recommendations exist for other sources. The current scenario of rapidly spreading bacterial resistance at a global level mandates initiatives to stop this threat [3], and shortening the duration of antibiotic treatments is probably one of the most effective measures to avoid the emergence of resistance [4]. Producing good-quality evidence to support the effectiveness of shorter courses of antibiotics should be a priority, especially for common clinical situations. Hitherto, two non-inferiority trials have been published showing similar outcomes in patients receiving 7 versus 14 days of antibiotic treatment for bacteraemia caused by Gram-negative bacilli [5,6]. However, the question remains open for specific subgroups of patients—such as immunocompromised patients or males with urinary tract infections—for whom short courses may not be as effective as longer ones [7,8]. Thus, additional evidence would be still useful to allow balancing more accurately the theoretical benefits of shortening antibiotic treatments (i.e. reduced risk of adverse reactions or superinfections) versus the potential for impaired effectiveness in some patients.

The aim of the present trial was to prove that a 7-day course of antibiotics will allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of the traditional 14-day schemes for treating patients with eBSI.

Section snippets

Design

This was an open-label, multicentre, randomized, controlled, phase IV trial. Five Spanish hospitals participated in the trial between September 2014 and September 2016.

Participants

Adults over the age of 18 years with a diagnosis of eBSI were recruited. Hospitalized patients and outpatients were eligible. Exclusion criteria were: (a) pregnancy, (b) eBSI with a non-controlled source and no expectation of being controlled in the subsequent 24 h, (c) patients undergoing chemotherapy with neutropenia

Baseline characteristics

Among 248 randomized patients, 231 (93.1%) were assessed for the primary and secondary outcomes, with 17 patients lost to follow-up (nine in the short-treatment arm and eight in the prolonged-treatment arm) (Fig. 2, Supplementary Material Files 3 and 4). Baseline characteristics were in general well balanced between groups, except for respiratory source and chronic kidney disease, which were more frequent in the control group (Table 1).

Outcomes

The median length of antibiotic treatment at the end of the

Discussion

The results of this trial suggest that 7-day courses of antibiotics may be the preferential strategy for treating bacteraemic infections caused by Enterobacteriaceae, whenever an adequate control of the source is provided.

In order to ensure the safety of the intervention, some secondary endpoints were settled. Compared to 14-day treatments, non-inferiority was shown for clinical cure and relapse of eBSI. The predefined non-inferiority margin was barely unmet for the relapse of fever. It should

Author contributions

JMC and JM conceived and designed the study. CRF and BS supervised and coordinated the accomplishment of legal procedures required for the trial as well as its monitoring. JM, JPS, MH, ELJ, CN, EL, RAM, AIAG, AC, BGG, JEC, IMG and AVM recruited and performed the clinical follow-up of patients. CR and CI recorded data in the trial database. EM performed the statistical analysis. JM, JMC, JP, JMR, JEC, JT and JRB collaborated in the achievement of the public funds and provided the team with the

Transparency declaration

LELC declares consulting fees from Novartis and MSD, honoraria for lectures from Correvio, ViiV and Gilead, and participation on the advisory board for Angelini. AC declares honoraria for lectures from Pfizer and Shionogu. The remaining authors declare no conflicts of interests. The SHORTEN trial is a non-commercial, investigator-driven clinical trial supported by a grant from the Regional Ministry of Health of Andalusia (PI-0161/2013) and by Plan Nacional de I+D+i and Instituto de Salud Carlos

Acknowledgements

This work received technical support from the Spanish Network of Research in Infectious Diseases (REIPI) and the Spanish Clinical Research Network (SCReN) of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government (PT13/0002/0010). The REIPI collaborated in the provision of human resources required for the trial tasks, and also provided the platform for the electronic case report form. We also acknowledge the endless availability of Alejandro

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