Shorter Antibiotic Course Effective for Sepsis, Study Finds

Veronica Hackethal, MD

December 21, 2018

Hospitalized patients with uncomplicated blood infections may only need 7 days of antibiotics instead of the standard 14-day course, according to a study published online December 11 in Clinical Infectious Diseases.

The study is the first randomized controlled trial (RCT) to test whether shortening the course of antibiotic therapy would make a difference with respect to outcomes for patients with sepsis caused by gram-negative bacteria.

"In this randomized controlled trial including hospitalized patients with Gram-negative bacteremia, hemodynamically stable by day 7, we found 7 days of antibiotic therapy to be noninferior to 14 days in terms of mortality, clinical failure, readmissions and prolonged hospitalization," write Dafna Yahav, MD, of Rabin Medical Center, Petah-Tikva, Israel, and colleagues.

Although antibiotics have been a great boon for treating many types of infections, decreasing unnecessary use of them is a public health priority. Shorter courses of antibiotics have been associated with fewer adverse events and shorter hospitalizations. Shorter courses may also help limit antibiotic resistance and decrease other infections, most importantly Clostridium difficile infections, which cause a significant amount of morbidity and mortality.

Several RCTs have suggested that shorter courses of antibiotics may yield results similar to longer-term courses. But these studies did not include patients with serious blood infections, for which guidelines are unclear about the appropriate length of treatment.

The researchers conducted a randomized, open-label noninferiority trial in three academic medical centers between January 2013 and August 2017. The study included 604 inpatients with aerobic gram-negative bacteremia. Of these patients, 66.9% (404 of 604) were aged 65 years or older; for 68% (411 of 604), the source of infection was urinary. To be included, patients had to have been afebrile and their blood pressure had to have been stable for at least 48 hours before randomization. Participants were assigned to receive either 7 days (n = 306) or 14 days (n = 298) of antibiotics. The study excluded patients with an uncontrolled focus of infection, Brucella or Salmonella infection, and immunosuppression.

Results showed that 45.8% (140 of 306) of patients in the 7-day group and 48.3% (144 of 298) in the 14-day group experienced the primary outcome, a composite of events within 90 days of randomization. The composite included all-cause mortality, clinical failure (relapse of bacteremia, local pus, or distant complications), and readmission or hospital stay for longer than 14 days.

The risk difference was -2.6% (95% confidence interval [CI], -10.5% to 5.3%; P = .527), which met the predefined noninferiority margin of 10%.

The analysis showed no significant differences for 16 secondary outcomes, including 90-day all-cause mortality (7-day group: 11.8% [n = 36]; 14-day group: 10.7% [n = 32]; risk difference, 1.0%; 95% CI, -4% to 6.1%; P = .702) and development of antibiotic resistance (P = .690).

In addition, the 7-day group had significantly fewer cumulative days on which they received antibiotics compared with the 14-day group (10 days vs 16 days; risk difference, P < .001) and significantly faster return to baseline activity, as determined by patient self-assessment (median, 2 weeks [interquartile range, 0 - 8.3 weeks] vs 3 weeks [interquartile range, 1 - 12 weeks]).

In addition, there were no significant differences between the two groups with respect to adverse events, including acute kidney injury (P = .842), liver function abnormalities (P = .494), diarrhea at 90 days (P = .491), rash (P = .445), and C difficile infection (P = .322).

In a linked editorial, Nick Daneman, MD, and Robert Fowler, MD, both from Sunnybrook Health Sciences Center and the University of Toronto, in Ontario, Canada, write that the study has "filled a crucial evidence void" and that the results may contribute to a "major change in practice in North America."

The results "suggest that we are heading towards a paradigm shift in the recommended treatment durations for patients with bloodstream infection," they add.

In addition to minimizing potential harms of antibiotic treatment, shortening the course of treatment may result in cost savings: an estimated CAD$678 - $798 million per year in North America, and CAD$1.4 - $1.6 billion per year in Europe, according to Daneman and Fowler.

However, the study only included patients who survived sepsis up to day 7, so results may not be generalizable to sicker patients. Also, 90% (543 of 604) had Enterobacteriaceae infection. Results may not apply to other types of infection that are important causes of morbidity and mortality in hospitalized patients, such as Pseudomonas and Acinetobacter infections. In addition, a noninferiority margin of 10% could have been too large to identify harm caused by a shorter course of antibiotics.

An ongoing RCT, the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE), is evaluating 7 vs 14 days of antibiotics in patients with bacteremia who undergo treatment in intensive care units.

The trial received no external funding. The authors and editorialists have disclosed no relevant financial relationships.

Clin Infect Dis. Published online December 11, 2018. Abstract, Editorial

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