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

• Published in: Nature communications Vol. 12; no. 1; pp. 2255 - 12
• Main Authors: Kocsmár, Éva, Buzás, György Miklós, Szirtes, Ildikó, Kocsmár, Ildikó, Kramer, Zsófia, Szijártó, Attila, Fadgyas-Freyler, Petra, Szénás, Kató, Rugge, Massimo, Fassan, Matteo, Kiss, András, Schaff, Zsuzsa, Röst, Gergely, Lotz, Gábor
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/32; 631/326/107; 631/326/22/1434; 692/308/174; 692/4020/1503/1828/1500; Adult; Age; Age Factors; Aged; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Clarithromycin; Clarithromycin - pharmacology; Clarithromycin - therapeutic use; Consumption; Drug Resistance, Bacterial - drug effects; Eradication; Female; Fluorescence; Fluorescence in situ hybridization; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Growth rate; Helicobacter Infections - drug therapy; Helicobacter Infections - epidemiology; Helicobacter Infections - microbiology; Helicobacter Infections - transmission; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - isolation & purification; Humanities and Social Sciences; Humans; Hungary - epidemiology; Immunohistochemistry; Infections; Male; Mathematical analysis; Mathematical models; Microbial Sensitivity Tests; Middle Aged; Model testing; Models, Biological; multidisciplinary; Mutation; Observational studies; Population dynamics; Prevalence; Retrospective Studies; Risk Factors; Science; Science (multidisciplinary); Sex Factors; Young Adult; Hungary
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22557-7

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. Clarithromycin is a macrolide antibiotic widely used for eradication of Helicobacter pylori infection. Here, Kocsmár et al. study clarithromycin resistance and previous macrolide consumption in 4,744 H. pylori -infected patients, shedding light into the sources of primary resistant cases and the role played by prior consumption of macrolides for non-eradication purposes.