Cephalosporins, Penicillin-BLI Linked to Increased Anti-Drug Antibodies in Patients With IBD

Anti-drug antibody (ADA) formation is associated with microbial composition in patients with inflammatory bowel disease (IBD), and the risk for ADA development is increased in those exposed to cephalosporins or penicillin with β-lactamase inhibitors (BLI) before or during anti-tumor necrosis factor (TNF) therapy, according to a study in Gut.

Investigators evaluated the potential effects of antibiotic treatment on immunogenicity to anti-TNF agents among patients with IBD. They used data from the epidemiology group of the Israeli IBD research nucleus (epi-IIRN), a registry of all patients with IBD in Israel from 2000 to 2002.

Eligible patients had IBD and were treated with infliximab and/or adalimumab and had available ADA levels. The researchers conducted univariate survival analysis and tested the association between use of each antibiotic class during the 3 years prior to anti-TNF initiation and ADA formation. To evaluate the causative effects of antibiotic treatment and the associated gut microbiome dysbiosis on ADA formation, specific pathogen and germ-free C57BL mice were treated with antibiotics and challenged with infliximab.

Among 46,303 patients with IBD, 1946 (mean age, 29 years; 53% men) were treated with infliximab or adalimumab and had available ADA levels during the treatment (54.7% adalimumab, 45.3% infliximab). Positive ADA levels were measured in 363 patients (18.6%), and the median follow-up from anti-TNF treatment was 651 (interquartile range, 1175) days.

Multivariable adjusted hazard ratios (HRs) showed an increased risk for ADA development during anti-TNF therapy in patients who used cephalosporins (HR, 1.97; 95% CI, 1.58 to 2.44) and penicillin-BLI (HR, 1.40; 95% CI, 1.13 to 1.74). However, a reduced risk was found in patients who received macrolides (HR, 0.36; 95% CI, 0.16 to 0.82) and fluoroquinolones (HR, 0.20; 95% CI, 0.12 to 0.35).

Patients who used both cephalosporins and penicillin-BLI had higher rates of ADA development compared with patients who used either treatment alone.

Comparable to the human findings, the study authors observed a trend for higher ADA levels in cefuroxime-pretreated mice and lower ADA levels in azithromycin-pretreated mice vs the control group; significant differences in median ADA levels were also noted between cefuroxime- and azithromycin-pretreated mice (13,732 ng/mL vs 6948 ng/mL, respectively; adjusted P =.04).

The researchers noted that substantial variation occurred in first and last antibody measurement times between patients with and without antibiotic dispensations for all analyzed treatment classes. Additionally, antibiotics that were administered in hospitals were not available in the registry. The inability to adjust exposure to antibiotics to type and severity of the infection for which patients were prescribed treatment may be a substantial confounder for ADA development.

“Specific antibiotic classes such as fluoroquinolones, or macrolides can potentially be used to reduce the risk of immunogenicity,” stated the researchers. “Thoughtful selection of antimicrobial therapy is required in patients with IBD treated with anti-TNF therapy,” they concluded.

Disclosure: Some of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.


Gorelik Y, Freilich S, Gerassy-Vainberg S, et al. Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN. Gut. Published online August 3, 2021. doi: 10.1136/gutjnl-2021-325185