Effects of antihistamines on innate immune responses to severe bacterial infection in mice.

Background: Sedating and non-sedating histamine H(1) receptor (H1R) antagonists and H2R blockers are widely used drugs which are generally considered to be safe medications. However, recently, these drugs have been shown to possibly impair the outcome of perforating appendicitis in children.

Objective: It was the aim of this study to characterize the effects of histamine receptor blockade in severe bacterial infections in more detail.

Methods: To obtain information on the safety of histamine receptor blockade in more detail, we used pharmacological and genetic approaches targeting histamine receptors and performed cecal ligation and puncture (CLP), a mouse model of septic peritonitis. After induction of septic peritonitis, morbidity and mortality were monitored closely.

Results: Here, we show that oral treatment with first-generation H1R antihistamine diphenhydramine, H2R blocker cimetidine and H3/4R blocker thioperamide impairs optimal innate immune responses in severe murine bacterial sepsis. However, these adverse effects are not mediated by H1R, as mice deficient for H1R show similar rates of morbidity and mortality after CLP as their wild-type controls. Similarly, the second-generation antihistamine desloratadine neither affects morbidity nor mortality after CLP.

Conclusion: Our findings indicate that sedating first-generation H1R antihistamines and H2R blockers might impair innate immune responses to bacteria and that these drugs should be used with caution in patients with severe bacterial infections.