Evidence Supports De-Escalation of Broad-Spectrum Antibiotics in Severe Infection


A large trial supports de-escalation from empiric, broad-spectrum antibiotic treatment for Enterobacterales bacteremia to a non-antipseudomonal agent.

Patient hospitalized and resting.

A new study suggests that de-escalation strategies can be effective in managing bacteremia caused by Enterobacterales.

De-escalation from empiric treatment of Enterbacterales bacteremia with an antipseudomonal ß-lactam to a narrower-spectrum agent after determining susceptibility was found non-inferior to maintaining the broad-spectrum treatment, in a randomized trial conducted in 21 hospitals across Spain.1

Although de-escalation is advocated to reduce exposure to broad-spectrum antibiotics and the corresponding selection pressure that hastens development of multi-drug resistant bacteria, the investigators note that there is relatively little evidence of the efficacy and outcomes from this recommended component of antibiotic stewardship.1

"Therefore, randomized trials are needed," declare Luis Lόpez-Cortés, PhD, Unidad Clinica de Enfermedades Infecciosas y Microbiologia, Instituto de Biomedicine de Sevilla, Seville, Spain, and colleagues. "Because de-escalation is a broad concept, trials should include specific clinical situations and structured de-escalation protocols to be applicable in clinical practice."1

To contribute evidence of outcomes from de-escalation to a non-antipseudomonal when an infecting Enterobacterales is determined to be susceptible in-vitro, the investigators conducted the pragmatic, open-label, randomized controlled trial, SIMPLIFY.1

What You Need to Know

The study found that de-escalation from empiric treatment with broad-spectrum antibiotics to a narrower-spectrum agent after determining susceptibility was non-inferior to maintaining broad-spectrum treatment.

The researchers emphasize the need for randomized trials to assess the efficacy and outcomes of de-escalation as a recommended component of antibiotic stewardship.

The study's results support the safety and clinical relevance of antibiotic de-escalation.

The cohort of 344 patients hospitalized with Enterobacterales bacteremia were identified between October 2016 and January 2020. Each had received empiric intravenous monotherapy with an antipseudomonal ß-lactam with in-vitro activity against the causative bacterium within 24 hours of blood sampling for cultures.1

Within 48 hours after the antimicrobial susceptibility report, participants were randomized 1:1 to continuing the empiric monotherapy, or to monotherapy with the first drug showing in-vitro activity from a predefined de-escalation list. Switching to oral therapy could occur after 5 days of active intravenous therapy in stable patients showing clinical improvement.1

The order of de-escalation was: ampicillin, trimethoprim-sulfamethoxazole (for urinary tract infections only), ciprofloxacin and ertapenem. The investigators acknowledge that ciprofloxacin is potentially active against Pseudomonas aeruginosa, included consistent with standard de-escalation practice but placed second to the last option.They note that a switch to oral fluroquinolones occurred much less frequently in the de-escalation than the control group. "The suggested rank order of drugs used for de-escalation is open to debate because high-level evidence on the differential ecological impact of the drugs is scarce," the investigators commented.1

Lόpez-Cortés and colleagues report that, in the analysis with intent to treat population, the primary measure of clinical cure was attained in 90% of the de-escalation group and 89% in the control group—well within the predefined 10% difference for noninferiority. There were 219 adverse events reported in the de-escalation group and 175 in the control group; with 24% of those in the de-escalation group and 32% in the control group considered severe.1

"De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteremia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug," the investigators concluded."These results support de-escalation in this setting."1

In accompanying, invited commentary2 Alexis Tabah, MD, Intensive Care Unit, Redcliffe Hospital, Metro North Hospital and Health Services, Redcliffe, Queensland, Australia, and colleagues welcomed the trial as an important confirmation of the safety of antibiotic de-escalation, and a contrast to the observational data and small randomized controlled trials conducted on the topic to date.

"We are confident in the results of the SIMPLIFY trial because they rely on a well conducted statistical analysis exploring endpoints selected by a desirability of outcome ranking analysis, ensuring clinical relevance," Tabah and colleagues remarked.2


1.Lόpez-Cortés LE, Delgado-Valverde M, Moreno-Mellado E, et al. Efficacy of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): An open-label, multicentre, randomised trial.Lancet Infect Dis 2024; 24:375-385.

2.Tabah A, De Bus L, Leone M. Antibiotic de-escalation: finally, some action and not only words. Comment. Lancet Infect Dis 2024; 24:331-333.

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