New randomized data presented at Digestive Disease Week® 2026 challenged long-standing guidance on antibiotic duration in acute cholangitis, suggesting that treatment may be safely shortened to just 24 hours following successful biliary drainage.
In a multicenter, open-label, randomized controlled noninferiority trial conducted across 31 hospitals in the Netherlands, investigators found that a one-day course of antibiotics after adequate endoscopic biliary drainage was noninferior to the guideline-recommended four to seven days in achieving clinical cure. The findings have potential implications for antimicrobial stewardship and clinical practice in gastroenterology, as presented by lead author Anouk G. Overdevest, MD, of the Department of Gastroenterology and Hepatology at Amsterdam UMC, Amsterdam, the Netherlands.
Acute cholangitis remains a serious infection characterized by biliary obstruction and bacterial overgrowth, most commonly due to gallstones, and is typically managed with a combination of urgent biliary decompression and systemic antibiotics. However, as Dr. Overdevest noted in her presentation, the optimal duration of antibiotic therapy after source control has remained uncertain despite widespread adherence to international recommendations.
“Once there is source control, what is the optimal antibiotic treatment duration after [endoscopic retrograde cholangiopancreatography (ERCP)]?” she said, emphasizing that reducing antibiotic exposure is increasingly critical in the context of rising antimicrobial resistance, particularly among gram-negative pathogens such as Escherichia coli and Klebsiella species.
The COBRA trial enrolled adults with acute cholangitis due to distal biliary obstruction who achieved adequate drainage and fever resolution within 24 hours after (ERCP). Participants were randomized to receive either one day or four-to-seven days of antibiotic therapy, with stratification by etiology (benign vs malignant obstruction) and blood culture status.
The primary endpoint — clinical cure, defined as being symptom-free by day 14 without relapse or death by day 30 — was adjudicated by a blinded independent committee. A total of 413 patients were randomized between 2023 and 2025, with 205 patients in each treatment arm included in the intention-to-treat analysis.
Clinical cure was achieved in 95.1% of patients in the one-day group compared with 93.7% in the four- to seven-day group, yielding an absolute risk difference of 1.5% (one-sided 95% confidence limit, −2.4%), meeting the prespecified criterion for noninferiority. These findings were consistent in per-protocol and sensitivity analyses.
Importantly, outcomes were similar across clinically relevant subgroups, including patients with malignant obstruction and those with gram-negative bacteremia at baseline. Mortality rates were low and comparable between groups, with 30-day all-cause mortality of two cases in the short-course arm and one case in the longer-course arm.
Rates of relapse were also similar, and time-to-event analyses showed overlapping curves between the treatment groups, indicating no difference in recurrence risk following ERCP.
Notably, shorter antibiotic therapy was associated with a marked reduction in antibiotic exposure and adverse events. By day 30, the median duration of antibiotic use was one day in the short-course group versus five days in the standard-treatment group. Antibiotic-related adverse events occurred significantly more often in the longer-course group (60.6% vs 8.3%).
“These findings support the principle that limiting antibiotic duration is not only safe but may also reduce patient burden and adverse effects,” Dr. Overdevest said.
The trial was designed with a noninferiority margin of −7.5%, based on an anticipated clinical cure rate of approximately 90% in both groups. High protocol adherence (93%-94%) strengthened the reliability of the results.
While the study included patients with moderate to severe cholangitis, only a small proportion had severe disease, leaving some uncertainty about the generalizability of findings in critically ill populations. However, Dr. Overdevest suggested that the results broadly support shorter antibiotic courses once adequate biliary drainage is achieved.
The investigators concluded that a one-day antibiotic regimen after successful ERCP should be considered the preferred treatment duration for acute cholangitis. If adopted, this approach could represent a significant shift from current Tokyo Guidelines recommendations and align clinical practice more closely with antimicrobial stewardship goals.
Dr. Overdevest reported no relevant disclosures.
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