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The emergence of \u03b2-lactamase-negative ampicillin-resistant (BLNAR) strains and unclear correlations between genotypic (i.e., gBLNAR) and phenotypic resistance are challenging empirical treatments and patient management. Thus, we sought to revisit molecular resistance mechanisms and to identify new resistance determinants of\n                      <jats:italic>H. influenzae<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a systematic meta-analysis of\n                      <jats:italic>H. influenzae<\/jats:italic>\n                      isolates (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009291) to quantify the association of phenotypic ampicillin and cefotaxime resistance with previously defined resistance groups, i.e., specific substitution patterns of the penicillin binding protein PBP3, encoded by\n                      <jats:italic>ftsI<\/jats:italic>\n                      . Using phylogenomics and a genome-wide association study (GWAS), we investigated evolutionary trajectories and novel resistance determinants in a public global cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009555) and a new clinical cohort from three European centers (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009298), respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our meta-analysis confirmed that PBP3 group II- and group III-related isolates were significantly associated with phenotypic resistance to ampicillin (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), while only group III-related isolates were associated with resistance to cefotaxime (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.02). The vast majority of\n                      <jats:italic>H. influenzae<\/jats:italic>\n                      isolates not classified into a PBP3 resistance group were ampicillin and cefotaxime susceptible. However, particularly group II isolates had low specificities (&lt;\u200916%) to rule in ampicillin resistance due to clinical breakpoints classifying many of them as phenotypically susceptible. We found indications for positive selection of multiple PBP3 substitutions, which evolved independently and often step-wise in different phylogenetic clades. Beyond\n                      <jats:italic>ftsI<\/jats:italic>\n                      , other possible candidate genes (e.g.,\n                      <jats:italic>oppA, ridA,<\/jats:italic>\n                      and\n                      <jats:italic>ompP2<\/jats:italic>\n                      ) were moderately associated with ampicillin resistance in the GWAS. The PBP3 substitutions M377I, A502V, N526K, V547I, and N569S were most strongly related to ampicillin resistance and occurred in combination in the most prevalent resistant haplotype H1 in our clinical cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Gradient agar diffusion strips and broth microdilution assays do not consistently classify isolates from PBP3 groups as phenotypically resistant\n                      <jats:italic>.<\/jats:italic>\n                      Consequently, when the minimum inhibitory concentration is close to the clinical breakpoints, and genotypic data is available, PBP3 resistance groups should be prioritized over susceptible phenotypic results for ampicillin. The implications on treatment outcome and bacterial fitness of other extended PBP3 substitution patterns and novel candidate genes need to be determined.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-024-01406-4","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:01:06Z","timestamp":1733270466000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Revisiting mutational resistance to ampicillin and cefotaxime in Haemophilus influenzae"],"prefix":"10.1186","volume":"16","author":[{"given":"Margo","family":"Diricks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Bartels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi\u00ean-Tr\u00ed","family":"L\u00e2m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Claus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paula","family":"Bajanca-Lavado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Hauswaldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Stolze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar Jim\u00e9nez","family":"V\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Utpatel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Niemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inken","family":"Wohlers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1386-2331","authenticated-orcid":false,"given":"Matthias","family":"Merker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"1406_CR1","unstructured":"Factsheet about Invasive Haemophilus influenzae disease. 2017. 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Therefore, the study did not require direct informed consent. All data were obtained in a blinded manner. The L\u00fcbeck study protocol was in addition approved by the local ethics committee of the University of L\u00fcbeck (Az 13-072). The research was conducted in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they do not have any competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"140"}}