Richard R. Watkins, MD, MS, FACP
Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
Dr. Watkins receives research support from Forest Pharmaceuticals.
SYNOPSIS: A multi-center, randomized trial comparing patients with complicated intra-abdominal infections found no difference in outcomes between those who received 4 days of antibiotic therapy vs. 8 days after adequate source control.
SOURCE: Sawyer RG, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med 2015;372:1996-2005.
Complicated intra-abdominal infections (IAIs) cause significant morbidity and mortality, especially in the elderly. Often IAIs are treated with antibiotics until all the signs and symptoms of the systemic inflammatory response syndrome (SIRS) resolve, typically for 7 to 14 days. However, guidelines from the IDSA recommend 4 to 7 days based on clinical response.1 Because of differences in clinical practice, Sawyer and colleagues conducted a randomized trial that compared outcomes of fixed-duration antibiotic therapy for 4 days following source control to a traditional strategy of continuing antibiotics until 2 days after the resolution of SIRS.
What the study looked like
The study enrolled patients aged 16 years and older from 23 centers who presented with a complicated intra-abdominal infection and either fever, leukocytosis, or gastrointestinal dysfunction due to peritonitis and subsequently underwent a procedure for source control.
They were randomized in a 1:1 ratio to receive 4 full days of antibiotic therapy (experimental group) following the source-control procedure or to receive antibiotic therapy until 2 days after resolution of SIRS (control group). The primary endpoint was the development of a surgical-site infection or recurrent intra-abdominal infection or death within 30 days after the source-control procedure. The secondary endpoints were duration of antibiotics for the original infection, overall exposure to antimicrobial agents, rates of subsequent extra-abdominal infection, and adherence to the protocol.
A total of 508 patients were randomized to either the experimental or control group. The most common site of infection was the colon or rectum; one-third of the infections were managed by a percutaneous procedure, and there were no significant demographic differences between the two groups. The primary endpoint occurred in 21.8% of the experimental group and 22.3% in the control group (P = 0.92).
The median duration of antibiotic therapy in the experimental group was 4.0 days compared to 8.0 days in the control group (P < 0.001). There were significantly fewer antibiotic-free days at 30 days in the control group and no differences between the two groups in rates of extra-abdominal infections, Clostridium difficile infection, or secondary infections with resistant pathogens. The rate of nonadherence to the protocol was 18% in the experimental group.
COMMENTARY
The most salient finding from the study was that 4 days of antibiotic therapy after a successful source-control procedure resulted in the same outcomes as longer courses. This implies that antibiotics are most effective in the first 4 days after the procedure and there is little benefit to prolonging them beyond 4 days.
There are a multitude of potential benefits from shorter antibiotic courses, including reduced collateral damage to commensal flora, less risk for developing Clostridium difficile infection, fewer adverse medication events, less risk of promoting antibiotic resistance, and reduced costs.
An accompanying editorial estimated the cost saving based on the antibiotics prescribed in the study would be $97 million annually in the United States.2 Reducing the duration of antibiotic therapy is one of the central tenets of antibiotic stewardship, and the data presented by Sawyer and colleagues will likely be useful in these efforts.
Important limitations
However, there are important limitations of the study worth noting. First, the rate of nonadherence to the protocol was high, creating bias toward the null hypothesis of no difference between the two groups. Second, the study did not reach the calculated sample size to detect equivalence between the two groups. These methodological flaws lessen the clinical impact of the study and necessitate that further studies be conducted to elucidate the duration of therapy for IAIs.
Overall, my impression of the study is that better source control is needed for complicated IAIs, and antibiotics have an important yet secondary role to play. Notably, the rate of infectious complications was > 20% in both the experimental and control groups, most of which were recurrent IAIs. Thus, infectious disease physicians need to be strong advocates for optimal source control early in the clinical course of IAIs, along with maintaining their traditional role of promoting the judicious use of antibiotic therapy.
REFERENCES
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Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infections in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133-164.
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Wenzel RP, Edmond MB. Antibiotics for abdominal sepsis. N Engl J Med 2015;372:2062-2063.
