An elevated procalcitonin level following 7 days of antibiotic therapy may reflect the intensity of the host inflammatory response rather than the burden of bacterial infection, researchers suggested in a secondary analysis of the BALANCE trial.
Researchers conducted a planned cohort analysis within BALANCE, an open-label randomized noninferiority trial that compared 7 vs 14 days of antibiotic therapy among hospitalized patients with bloodstream infections. The analysis included 125 patients from 12 Canadian centers who had serum collected on day 7 of treatment. Procalcitonin (PCT) was later quantified with an antibody-based assay, and the results were not available to treating clinicians or study investigators during the trial.
Of the 125 patients, 120, or 96%, were enrolled while in an intensive care unit, and 40, or 32%, were mechanically ventilated at enrollment. Sixty-five patients had day 7 PCT levels below 250 pg/mL, and 60 had levels of 250 pg/mL or greater.
The primary outcome was all-cause mortality within 90 days of the index positive blood culture. Ninety-day mortality occurred in 13 of 60 patients with high PCT levels, or 22%, compared with four of 65 patients with lower levels, or 6%.
Patients in the high-PCT group had higher baseline Sequential Organ Failure Assessment scores and were more likely to have diabetes, dialysis dependency, and community-onset bloodstream infections. The paper did not report a multivariable-adjusted mortality estimate.
In-hospital mortality was also higher among patients with elevated PCT. No statistically significant differences were observed between the high- and low-PCT groups in intensive care unit mortality, intensive care unit–free days, hospital-free days, antibiotic-free days, or adherence to the assigned treatment duration.
The researchers then examined outcomes among the 60 patients with day 7 PCT levels of 250 pg/mL or greater. Twenty-nine had been randomly assigned to 7 days of antibiotics, and 31 had been assigned to 14 days.
Ninety-day mortality occurred in three patients assigned to 7 days and 10 assigned to 14 days. Randomization to the longer course was not associated with improved 90-day mortality or secondary outcomes. In a sensitivity analysis that defined high PCT as greater than 500 pg/mL, the researchers similarly reported no difference in 90-day mortality between the treatment-duration groups.
The researchers suggested that circulating PCT may reflect the intensity of the host inflammatory response rather than the burden of bacterial infection itself. Host factors, including immune dysregulation and comorbidities, may contribute to PCT elevations independently of bacterial antigen load, limiting the biomarker’s usefulness as a stand-alone guide for antibiotic duration.
In an accompanying commentary, Brad Spellberg, MD, of Los Angeles General Medical Center, wrote that an elevated PCT result was not clinically useful for determining whether antibiotic treatment should be prolonged. He contrasted this with evidence from previous randomized trials suggesting that a low PCT result can help physicians discontinue unnecessary antibiotics when they remain uncertain whether treatment is needed.
The analysis had several limitations. It included only 125 of the 3,608 patients enrolled in BALANCE, with samples obtained from selected Canadian centers. The researchers noted that the small sample limited statistical power. Spellberg similarly noted that these patients may not have optimally represented the full BALANCE population, although he considered a benefit from prolonged therapy in patients with less severe illness unlikely.
PCT was measured only once, preventing the researchers from assessing changes from baseline or determining whether levels remained elevated over time. The researchers also cautioned that the findings may not be generalizable to other countries.
The parent trial excluded bloodstream infections caused by Staphylococcus aureus and Staphylococcus lugdunensis. The researchers said the findings were therefore not generalizable to infections involving those pathogens.
The researchers concluded that a fixed 7-day course appeared sufficient for most patients represented in the analysis regardless of day 7 PCT level and that PCT measurement was not required, for most patients, to support discontinuing antibiotic therapy at 7 days.
Disclosures: Julie K. Wright, MD, reported grant and scholarship support during the study. John Muscedere, MD, reported nonfinancial support from N8 Medical outside the submitted work. No other disclosures were reported. Brad Spellberg, MD, reported no conflicts of interest.
Source: JAMA Network Open
