Haemophilus influenzae global epidemiology and antimicrobial susceptibility patterns including ampicillin and amoxicillin-clavulanate resistance based on β-lactamase production, 2013–2022

Abstract

INTRODUCTION: The β-lactam susceptibility of Haemophilus influenzae varies globally due to resistance mechanisms such as β-lactamase production or alteration in Penicillin-Binding Protein 3 (PBP3). Monitoring and understanding these resistance trends are crucial for guiding effective treatment strategies. We described the global antimicrobial susceptibility patterns of H. influenzae using the SENTRY Antimicrobial Surveillance Program, a large database designed to monitor antimicrobial resistance patterns. METHODS: Antimicrobial susceptibility testing was performed using broth microdilution as the reference method. Demographics and phenotypic antimicrobial resistance of H. influenzae from over 150 medical centers representing 51 countries were analyzed between 2013 and 2022. The guidelines established by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were adopted to interpret antibiotic breakpoints. A nitrocefin test was employed to assess the production of β-lactamase. For statistical analysis, we used Pearson’s Chi-square or Fisher’s exact test, considering p ≤ 0.05 as significant. RESULTS: A total of 13,869 H. influenzae isolates were analyzed; the majority came from the USA (52.2%) and the UK (4.3%). The most affected groups were males under 18 years old and those over 65 years old. β-lactamase was produced in 24.1% of the isolates, with significant variations in antibiotic resistance across regions. Asia and the West Pacific exhibited the highest resistance rates to β-lactams and other antibiotics, including β-lactamase-negative ampicillin-resistant (9.4%) and β-lactamase-positive amoxicillin-clavulanic acid-resistant (10.9%) isolates, while also having the lowest rates of intensive care unit (ICU) admissions (14.9%) and invasive infections (0.4% bloodstream infections and no central nervous system infections). Ceftriaxone and piperacillin-tazobactam were the most in vitro active antibiotics (100% susceptibility based on the CLSI breakpoints, 99.1% and 99.8% susceptibility, respectively, based on the EUCAST breakpoints). β-lactamase producing isolates had reduced susceptibility to amoxicillin-clavulanate (91.4% vs. 95.4%), trimethoprim-sulfamethoxazole (61.2% vs. 66.5%), clarithromycin (85.7% vs. 87.8%), azithromycin (97.1% vs. 98.9%), and tetracycline (95% vs. 99.6%) compared to β-lactamase negative isolates. Contrarily, susceptibility to fluoroquinolones was higher among β-lactamase-producing isolates compared to β-lactamase-negative isolates (99.6% vs. 94.1%, respectively). The in vitro susceptibility of H. influenzae isolates was higher to azithromycin compared to clarithromycin (98.4% vs. 87.2%), respectively. CONCLUSIONS: Reliance on the nitrocefin test alone to predict susceptibility to β-lactams, i.e., ampicillin, could lead to false susceptibility and a higher chance of treatment failure. The high prevalence of BLNAR and BLPACR in Asia and the West Pacific, along with rising resistance to other antibiotics, highlights the need for reliable diagnostic testing and stringent containment protocols. Empirical therapy with clarithromycin for H. influenzae infections should be used with caution, especially in high resistance settings.

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