Shorter Antibiotic Treatment After Adequate Biliary Drainage Non-Inferior in Acute Cholangitis

The international Tokyo Guidelines 2018 recommend 4 to 7 days of antibiotic treatment after adequate biliary drainage, with observational data prompting investigators to conduct the non-inferiority COBRA trial to assess whether shorter treatment may be sufficient for adults with acute cholangitis.1

Data presented at Digestive Disease Week (DDW) 2026 show that 1 day of antibiotic therapy after adequate endoscopic biliary drainage was noninferior compared to 4 to 7 days in adults with acute cholangitis, with investigators suggesting 1 day should be the preferred duration of antibiotic treatment.1

Background on Acute Cholangitis and Post- Adequate Biliary Drainage Duration of Antibiotic Treatment

If not treated promptly, acute cholangitis can lead to sepsis, with general hospital mortality for biliary sepsis around 21%, and even up to 40% in severe septic shock cases.3 Study investigators describe the achievement of adequate biliary drainage by endoscopic retrograde cholangiopancreatography (ERCP) as the cornerstone of therapeutic management for acute cholangitis.1

While the Tokyo Guidelines 2018 recommend an antibiotic duration of 4 to 7 days, contradicting guidelines have led to varying clinical practice decisions. For example, the Dutch national sepsis treatment guidelines state that an antibiotic treatment of 1 to 3 days is adequate after source control.

The variation across guidelines can lead to inconsistencies in clinical practice regarding the duration of antibiotic treatment, with time ranging from 1 to 13 days after ERCP.1

COBRA’s Design and Patient Population

To examine the range in antibiotic treatment duration, study investigators conducted a multicenter, open-label, parallel group randomized controlled non-inferiority trial in 31 hospitals in the Netherlands. The primary objective was to assess whether a short-course of antibiotic treatment, defined as 1 day, following adequate biliary drainage, is non-inferior to a longer course of antibiotic treatment, defined as 4 to 7 days, in achieving clinical cure.1,2

Investigators defined the primary outcome as clinical cure, with a patient being free of symptoms by day 14 after ERCP, with no relapse or death occurring by day 30. The primary endpoint was adjudicated by an independent blinded committee. The intention-to-treat and per-protocol populations were analyzed, and the absolute risk difference for clinical cure was calculated. Investigators deemed that non-inferiority was demonstrated if the one-sided 95% confidence limit for the absolute risk difference was > -7.5%.

They randomly assigned 413 patients with acute cholangitis due to distal biliary obstruction who achieved adequate endoscopic biliary drainage and fever resolution within 24 hours after ERCP, in a 1:1 ratio, to receive antibiotics for 1 day (n = 205) or 4 to 7 days (n = 208) after ERCP.

The average age of COBRA’s patient population was 74 years, 43.4% were women, 10.0% had malignant obstruction, 57.6% had moderate/severe cholangitis, and 35.6% had gram-negative bacteraemia at the time of randomization. 3 patients in the 4 to 7 day group were lost to follow-up before the primary outcome could be assessed, excluding them from all analyses, and marking a 93.0% adherence to the allocated antibiotic treatment duration.

Results From Cobra

In the intention-to-treat analysis, investigators observed that the primary outcome occurred in 95.1% of patients (195/205) in the 1-day group compared to 93.7% in the 4 to 7 day group (192/205), with an absolute risk difference of 1.5% (one-sided 95% confidence limit: -2.4%), demonstrating non-inferiority.2

A per-protocol analysis (n = 384) showed non-inferiority (absolute risk difference 0.6%, with one-sided 95% confidence limit: -3.2%). In a worst-case sensitivity analysis (with lost to follow-up counting as failures), non-inferiority was maintained. All-cause 30-day mortality was 2/205 in the 1-day group compared to 1/205 in the 4 to 7-day group.2

Based on these results, investigators concluded that 1 day of antibiotic treatment after adequate endoscopic biliary drainage is non-inferior to 4 to 7 days in adults with acute cholangitis. Therefore, they suggest that 1 day should be the preferred duration of antibiotic treatment after adequate biliary drainage.1

References

1. Overdevest AG, Sieswerda E, Haal S, et al. Antibiotic treatment for 1 day versus 4–7 days in patients with acute cholangitis after adequate endoscopic biliary drainage (COBRA): study protocol for a randomized controlled trial. Trials. 2026;27(1). doi:https://doi.org/10.1186/s13063-026-09524-7

2. Anouk Overdevest. ONE DAY OF ANTIBIOTIC TREATMENT IS NON-INFERIOR TO 4 - 7 DAYS IN PATIENTS WITH ACUTE CHOLANGITIS AFTER ADEQUATE BILIARY DRAINAGE (COBRA): A MULTI-CENTER RANDOMIZED CONTROLLED TRIAL. Poster presented at: Digestive Disease Week; May 2-5, 2026; Chicago, IL.

3. Beliaev AM, Sof'ya Zyul'korneeva, Rowbotham D, Bergin CJ. Screening acute cholangitis patients for sepsis. ANZ Journal of Surgery. 2019;89(11):1457-1461. doi:https://doi.org/10.1111/ans.15432