Primary and secondary clarithromycin resistance in *Helicobacter pylori* and mathematical modeling of the role of macrolides

Clarithromycin is a macrolide antibiotic widely used for eradication of *Helicobacter pylori* infection, and thus resistance to this antibiotic is a major cause of treatment failure. Here, we present the results of a retrospective observational study of clarithromycin resistance (Cla-res) in 4744 *H. pylori*-infected patients from Central Hungary. We use immunohistochemistry and fluorescence in situ hybridization on fixed gastric tissue samples to determine *H. pylori* infection and to infer Cla-res status, respectively. We correlate this information with macrolide dispensing data for the same patients (available through a prescription database) and develop a mathematical model of the population dynamics of Cla-res *H. pylori* infections. Cla-res is found in 5.5% of macrolide-naive patients (primary Cla-res), with no significant sex difference. The model predicts that this primary Cla-res originates from transmission of resistant bacteria in 98.7% of cases, and derives from spontaneous mutations in the other 1.3%. We find an age-dependent preponderance of female patients among secondary (macrolide-exposed) clarithromycin-resistant infections, predominantly associated with prior use of macrolides for non-eradication purposes. Our results shed light into the sources of primary resistant cases, and indicate that the growth rate of Cla-res prevalence would likely decrease if macrolides were no longer used for purposes other than *H. pylori* eradication.

Éva Kocsmár, György Miklós Buzás, Ildikó Szirtes, Ildikó Kocsmár, Zsófia Kramer, Attila Szijártó, Petra Fadgyas-Freyler, Kató Szénás, Massimo Rugge, Matteo Fassan, András Kiss, Zsuzsa Schaff, Gergely Röst, Gábor Lotz