MADRID – Seven days of antibiotic therapy was just as effective as 14 days for patients with Gram-negative bacteremias.

The shorter course was associated with similar cure rates and a faster return to normal activities, Dafna Yahav, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

“In patients hospitalized with Gram-negative bacteremia and sepsis, a course of 7 antibiotic days was not inferior to 14 days, and resulted in a more rapid return to baseline activity, “ said Dr. Yahav of the Rabin Medical Center, Petah Tikva, Israel. “This could lead to a change in accepted management algorithms and shortened antibiotic therapy. Potentially, though we did not show this in our trial, it may lead to reduced cost, reduced development of resistance, and fewer adverse events.”

During the past few years, a new dogma has emerged in antibiotic treatment paradigms, she said: Shorter is better. Brad Spellberg, MD, described this concept in his 2016 editorial in JAMA Internal Medicine, “The new antibiotic mantra” (Sep 1;176[9]:1254-5).

In it, Dr. Spellberg, of the University of Southern California, Los Angeles, addressed the long-held view that a full 10- or 14-day course of antibiotics was necessary to decrease the risk of creating a resistant strain, even if clinical symptoms were long resolved.

However, he noted, there is little evidence supporting the idea that longer courses suppress the rise of resistance – and, in fact, some data support the opposite.

“To the contrary, specifically for pneumonia, studies have shown that longer courses of therapy result in more emergence of antibiotic resistance, which is consistent with everything we know about natural selection, the driver of antibiotic resistance,” he noted. “In only a few types of infections does resistance emerge at the site of infection; rather, resistance typically emerges off target, among colonizing flora away from the site of infection. Thus, all that is achieved by treating an infection with antibiotics for longer than the patient has symptoms is increased selective pressure driving antibiotic resistance among our colonizing microbial flora.”

The European Union and Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America have all recently updated their antibiotic stewardship guidelines to include a strong recommendation for the shortest effective duration of antimicrobial therapy.

However, most of the supporting data were drawn from randomized, controlled studies of patients with lung, skin, and kidney infections. Short-course treatments have not been adequately studied in bacteremia patients, Dr. Yahav said.

The aim of her study, which was investigator initiated and received no external funding, was to demonstrate the noninferiority of 7 days of antibiotic therapy, compared with 14 days, in patients with bacteremia arising from Gram-negative infections.

The randomized, open-label study comprised 604 patients in three hospitals: two in Israel and one in Italy. Patients were eligible if they had an aerobic Gram-negative bacteremia of any infection source that was either community- or hospital acquired. The medication choice was left up to the treating physician. Patients were assessed at discharge, and at days 30 and 90.

The primary outcome was a composite 90-day endpoint of all-cause mortality, clinical failure (relapse, new local complications, or distant complications), and readmission or hospital stay longer than 14 days. There were a number of secondary outcomes, including new infection, emergence of antibiotic resistance, total hospital and total antibiotic days, time to return to baseline activity, and adverse events.

The cohort was a mean of 71 years old. About 60% were functionally independent, and the mean Charlson comorbidity score was 2. Most of the infections (90%) were nosocomial. The urinary tract was the largest source of infection (69%). Other sources were abdominal, respiratory, central venous catheter, and skin or soft tissue.

Escherichia coli was the most common infective organism (62%), followed by Klebsiella species and Enterobacteriaceae. A small number of patients had Acinetobacter and Pseudomonas infections.

In the intent-to-treat analysis, the primary composite outcome of all-cause mortality or extended hospital stay occurred in 46% of the 7-day group and 50% of the 14-day group – not significantly different. The results were nearly identical in the per-protocol analysis (46% vs. 49.6%).

Likewise, none of the secondary outcomes posted a significant difference in favor of one treatment arm, including relapse (2.9% vs. 2.7%) and resistance development (10.8% vs. 9.7%).

Dr. Yahav pointed out that total antibiotic-use days were significantly less in the 7-day group, (5 days) than in the 14-day group (10 days). Patients in the short-duration group returned to their normal activities a day earlier than those in the longer-term group (2 days vs. 3 days), a difference that was statistically significant.

The total hospital stay from randomization to day 90 was only half a day shorter in the short-term group (mean, 3 days vs. 3.5 days). That was not a significant finding.

There were some differences in adverse events, although none was statistically significant. The short-duration arm had slightly more cases of kidney injury (0.5%), fewer cases of liver function abnormalities (–1.5%), and half as many rashes (two vs. four). There were two cases of Clostridium difficile in the short-use arm and one in the long-use arm, also not a significant difference.

A subgroup analysis looked at outcomes among the different sources of infection (urinary tract vs. other), whether empirical antibiotics were used, and whether the induced resistance was multdrug or non–multidrug. All of those differences hovered close to the null, but generally favored short antibiotic treatment, Dr. Yahav noted.

“I would conclude from these data that is generally safe to stop antibiotics after 7 days of covering antibiotics for Gram-negative bacteremia patients, if they are hemodynamically stable and nonneutropenic at 7 days, and have no uncontrolled source of infection,” she concluded.

The investigator-initiated study had no outside funding.

msullivan@mdedge.com

SOURCE: Yahav D et al. ECCMID 2018. Oral abstract O1120.

For Gram-negative bacteremias, 7 days of antibiotics is enough