STOP-IT

Published

Sawyer RG, et al. "Trial of short-course antimicrobial therapy for intraabdominal infection". The New England Journal of Medicine. 2015. 372(21):1996-2005.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with intraabdominal infections, does a shorter course of antibiotics (3-5 days) increase the risk of surgical-site infection, recurrent intraabdominal infection, or death within 30 days?

Bottom Line

Among patients with intraabdominal infections who have achieved source control, a 3-5 day course of antibiotics was not found to lead to higher rates of surgical-site infection, recurrent intra-abdominal infection, or death as compared with continuing antibiotics until 2 days after resolution of fever, leukocytosis, and ileus.

Major Points

The optimal duration of antibiotics for intraabdominal infections is not known. Traditionally therapy is continued until SIRS markers have resolved (typically 7-14 days), but courses as short as 3-5 days may be equally efficacious and more in keeping with antibiotic stewardship, cost containment, and other goals. IDSA guidelines in 2010 recommended 4-7 days, though this recommendation was based on relatively low-quality evidence. There was a critical need to assess varying durations of anticoagulation in this patient population.

The Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial enrolled 518 patients with complicated intraabdominal infections who achieved surgical source control. Patients were randomized to 3-5 days of antibiotics (experimental arm) or continuation of antibiotics for a maximum of 10 days, with cessation of antibiotics 2 days after afebrile, resolution of leukocytosis, resolution of ileus (control arm). There were no differences between the groups in the primary outcome of surgical-site infection, recurrent intra-abdominal infection, or death at 30 days. The experimental arm had fewer days of antibiotic exposure. This trial was closed after about 50% of its target enrollment because of loss of funding, though the authors suggest that there was futility in continuing the trial because of the similar event rate in each group. It's unclear if futility was decided as part of a planned interim analysis or after it was clear they were not going to receive further funding. This trial suggests that shorter durations of antibiotics might be appropriate in this patient population.

Guidelines

As of January 2020, no guidelines have been published that reflect the results of this trial.

Design

• Open label, multicenter randomized trial
• N=518
  • Control (n=260)
  • Experimental (n=258)
• Setting: 23 sites in the US and Canada
• Enrollment: 2008-2013
• Follow-up: 30 days
• Analysis: Intention-to-treat
• Primary outcome: Surgical-site infection, recurrent intra-abdominal infection, or death at 30 days

Population

Inclusion Criteria

• Age 16 or older
• Complicated intra-abdominal infection with ≥1 of the following:
  • Temperature ≥38.0°C
  • Leukocytosis with WBC count ≥11,000
  • Gastrointestinal dysfunction due to peritonitis precluding intake within 24 hours of operative
• Intervention carried out to achieve source control (either percutaneously or surgically)

Exclusion Criteria

• Patients who did not have an adequate source control procedure, per the opinion of the local PI or the overall PI
• Planned laparotomy after index procedure
• Perforated gastric or duodenal ulcer treated in first day of symptom onset
• Traumatic injury treated within first 12 hours of injury
• Appendicitis that's non-perforated and non-gangrenous
• Cholecystitis that's non-perforated and non-gangrenous
• Gangrenous appendicitis or peritonitis without culture data (e.g., without bacterial growth) or with fungal growth

Baseline Characteristics

From the control group.

• Demographics: Mean age 52 years, 56% male, 80% white race, 16% black race
• Mean APACHE II scores: 9.9
• WBC count: 15.6/mm³
• Infection origin: Colorectal 31%, appendiceal 13%, small bowel 12%
• Procedure for source control: Percutaneous 33%, resection and anastomosis or closure 26%, surgical drainage alone 21%, resection and proximal diversion 10%, simple closure 8%, surgical drainage and diversion 1%

Interventions

• After adequate source control has been attained, patients were randomized to a group:
  • Control - Continue antibiotics for 2 days after afebrile, resolution of leukocytosis, resolution of ileus (maximum of 10 days)
  • Experimental - Antibiotics for 4±1 days
• Did not dictate choice of antimicrobial agents. Appropriateness was determined based on SIS-IDSA guidelines

Outcomes

Comparisons are control vs. experimental group.

Primary Outcomes

Surgical-site infection, recurrent intra-abdominal infection, or death at 30 days

22.3% vs. 21.8% (P=0.92)

Components of the primary outcome are presented here for simplicity, but themselves were not primary outcomes.

Surgical site infection: 8.8% vs. 6.6% (P=0.43)

Recurrent intraabdominal infection: 13.8% vs. 15.6% (P=0.67)

Death: 0.8% vs. 1.2% (P=0.99)

Secondary Outcomes

Surgical site infection or recurrent intraabdominal infection with a resistant pathogen

3.5% vs. 2.3% (P=0.62)

Median duration of antimicrobial therapy for the index infection

8 vs. 4 days (CI -4.7 to -3.3 for the absolute difference; P<0.001)

Median antimicrobial-free days at 30 days

21 vs. 25 (P<0.001)

Additional Analyses

Adherence to the protocol

72.7% vs. 81.8% (P=0.02)

Subgroup Analysis

All of the below subgroup analyses showed no significant effect on the primary composite outcome:

• APACHE II score of 10 or higher
• Health care-associated infection
• Appendiceal vs. non-appendiceal source of index infection
• Index infection treated by surgical drainage vs. percutaneous drainage

Criticisms

• Nonadherence was 18% during follow-up
• Stopped early for funding gap and concern for futility, which led to underpowering with only about 50% of the target enrollment was achieved
• No information about antibiotics adverse events or specific regimens used
• Few patients with immunosuppression were included

Funding

• National Institutes of Health
• Multiple personal conflicts of interest are reported, including consulting and advisory relationships with pharmaceutical companies