Increasing trend in invasive non-typeable Haemophilus influenzae disease and molecular characterization of the isolates, Italy, 2012-2016.

Routine immunization of infants with conjugate vaccines against Haemophilus influenzae type b (Hib) has greatly reduced the incidence of invasive Hib disease; however changes in the epidemiology of H. influenzae disease have occurred. We describe the epidemiology of invasive H. influenzae disease and the characterization of isolates collected in Italy between 2012 and 2016. Trends in the overall incidence of invasive H. influenzae disease were calculated. Isolates were characterized by PCR capsular genotyping, antimicrobial susceptibility testing, ampicillin resistance-associated gene sequencing and MLST. Trends in incidence by serotype and serotype-specific distribution were estimated using multiple imputation of missing data. The overall incidence of invasive H. influenzae disease increased 22.5% yearly (from 0.11/100,000 in 2012 to 0.24/100,000 in 2016). Most cases (82.0%) were due to non-typeable H. influenzae (NTHi). An increasing trend in NTHi disease burden was estimated; the highest rise was among infants <12 months (40.8% annual increase). Invasive Hib disease showed a fluctuating trend with a clear increase in 2016, while we found an increasing trend for disease due to non-Hib capsulated serotypes in the elderly (32.9% annual increase). Ampicillin resistance mediated by either β-lactamase or altered penicillin-binding proteins 3 (PBP3) increased. In spite of genetic diversity of NTHi, sequence types (STs) associated with ampicillin resistance status were identified (ST103/ST106 linked to β-lactamase production and ST14 linked to a specific PBP3 substitution pattern). The increasing trend in invasive NTHi disease in infants is of concern underlying the need for the development of a future vaccine against NTHi.