麻豆传媒

For critically ill patients on antibiotics for suspected sepsis, monitoring one biomarker safely shortened the course of these medications in the ADAPT-Sepsis randomized trial.

Daily assessment of procalcitonin (PCT), rather than standard care alone, led to patients spending significantly less time on antibiotics cumulatively in the first 28 days (9.8 days vs 10.7 days, P=0.01) while meeting noninferiority criteria for all-cause mortality (20.9% vs 19.4% at 28 days).

Meanwhile, in another analysis of the three-arm trial, the use of C-reactive protein (CRP) monitoring atop standard care made no difference in the duration of antibiotic therapy (10.6 days vs 10.7 days, P=0.79). On top of that, the associated borderline excess mortality (21.1% vs 19.4%) could only be described as "inconclusive," according to researchers led by Paul Dark, MD, PhD, of the University of Manchester and Northern Care Alliance NHS Foundation Trust in England.

"The ADAPT-Sepsis trial strengthens substantially international recommendations for the routine use of protocolized daily PCT-guided antibiotic discontinuation in critically ill adults with sepsis and no evidence was found to recommend protocolized daily CRP-guided antibiotic discontinuation," the investigators concluded from the study, and also presented at the Critical Care Reviews Down Under meeting.

PCT and CRP are both established serum inflammatory biomarkers used to diagnose and manage patients with sepsis. However, the former has been thought to have an inherent advantage given that many tissues -- not just cells at the local site of infection -- produce PCT such that any elevations can be detected faster.

Derek Angus, MD, MPH, of University of Pittsburgh Medical Center, said there were surprises in ADAPT-Sepsis: "I would have guessed CRP and PCT would have behaved similarly," he told 麻豆传媒. "Given prior [randomized controlled trials] of PCT in the ICU [intensive care unit] population, I might have guessed there would be no benefit compared to usual care."

He also cited the mixed literature for PCT, including his group’s negative ProACT study in the emergency department setting.

In 2021, lacking more definitive evidence, guidelines for the management of sepsis and septic shock were released only PCT and clinical evaluation together to decide when to discontinue antimicrobials. This was endorsed by dozens of international medical societies.

In ADAPT-Sepsis, "it is likely that the differential clinical effectiveness findings for daily PCT-guided and daily CRP-guided protocols are explained by the differences in the utility of these biomarkers to track inflammation caused by bacterial infection in the setting of critical illness, where PCT concentrations are known to increase earlier and normalize more rapidly than CRP in response to treatment," Dark and colleagues explained.

"I could imagine the trial would lead to a change in practice in the U.K. Whether the results affect practice in the U.S. is less clear," Angus said. "I would like to see the findings replicated in a U.S. setting."

The cheaper CRP test may make it hard to abandon.

"Right now, CRP is typically less expensive. If PCT were to be priced similarly, then there'd be little reason to use CRP going forward in this setting. If cost remains a factor, folks may want to consider trying to unpack why CRP did worse and, if they have some thoughts on how to better use CRP, then try again in another trial," according to Angus, who was not involved with ADAPT-Sepsis.

This multicenter randomized trial was conducted in 41 U.K. National Health Service centers from 2018 to 2024. Participants were 2,760 adults in critical care or ICUs who had recently (within 24 hours of enrollment) initiated IV antibiotics for acute organ dysfunction associated with suspected infection.

Study protocol randomized them to a daily PCT-guided protocol, a daily CRP-guided protocol, or standard care. Each person had blood drawn daily until antibiotic withdrawal or hospital discharge.

The cohort averaged 60.2 years of age and was 60.3% men. The three study groups shared similar baseline characteristics, including a mean APACHE II score of 17.3 and SOFA score of 7. Investigators noted that the group was roughly split between sepsis patients and those with septic shock. Over two-thirds of patients had sepsis traced to a community-acquired infection.

No one group experienced disproportionately more serious adverse events than others. No differences could be detected in all-cause mortality at 90 days, either.

Dark's group acknowledged a potential flaw in the ADAPT-Sepsis study protocol that could have led clinicians to stop antibiotics later in the standard care group while awaiting the return of stop advice. Another limitation was that the patient-level randomization could have led to contamination as treatment protocols and standard care were carried out in a shared environment.

"Critically ill patients recruited to this trial had already commenced antibiotics for sepsis, so this study does not provide evidence for biomarker use in initiating antibiotic therapy," they also cautioned. "In addition, this clinical research evidence was generated within a high-income country; therefore, it is unclear if this evidence is generalizable to low-resource settings."

Enrollment in ADAPT-Sepsis had been paused for a few months during the lockdowns of the COVID-19 pandemic. There were only 19 people with known SARS-CoV-2 infection during the study, the researchers noted.

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