SynthesisGenome medicine2024
Revisiting mutational resistance to ampicillin and cefotaxime in Haemophilus influenzae.
Synthesis in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Comparative study of piperacillin-tazobactam versus ampicillin in the treatment of severe pneumonia in children: A retrospective study.Medicine · 2026Article
- β-Lactamase-ProducingJournal of general and family medicine · 2026Article
- Surveillance of epidemiological characteristics and temporal trends in antimicrobial resistance of Haemophilus influenzae in pediatric lower respiratory tract infections (2021-2024).Scientific reports · 2026Article
- Metabolic activation of pyruvate cycle by protocatechualdehyde triggers oxidative killing of ampicillin-resistantMicrobiology spectrum · 2026Article
- First identification and molecular characterization of CTX-M-15 extended-spectrum β-lactamase and OXA-9 β-lactamase inAntimicrobial agents and chemotherapy · 2026Article
- Antimicrobial resistance databases: opportunities and challenges for public health.npj antimicrobials and resistance · 2026Review
- Article
- Evolution of beta-lactam resistance causes fitness reductions and several cases of collateral sensitivities in the human pathogenAntimicrobial agents and chemotherapy · 2025Article
- A Novel nor@DHB Matrix for Direct Microbial Analysis in Lung Cancer Tissues.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Genomic profiling of cefotaxime-resistantFrontiers in microbiology · 2025Article
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Authors and funding
14 authors.
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Abstract
backgroundHaemophilus influenzae is an opportunistic bacterial pathogen that can cause severe respiratory tract and invasive infections. The emergence of β-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 H. influenzae.
methodsWe performed a systematic meta-analysis of H. influenzae isolates (n = 291) 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 ftsI. Using phylogenomics and a genome-wide association study (GWAS), we investigated evolutionary trajectories and novel resistance determinants in a public global cohort (n = 555) and a new clinical cohort from three European centers (n = 298), respectively.
resultsOur meta-analysis confirmed that PBP3 group II- and group III-related isolates were significantly associated with phenotypic resistance to ampicillin (p < 0.001), while only group III-related isolates were associated with resistance to cefotaxime (p = 0.02). The vast majority of H. influenzae isolates not classified into a PBP3 resistance group were ampicillin and cefotaxime susceptible. However, particularly group II isolates had low specificities (< 16%) 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 ftsI, other possible candidate genes (e.g., oppA, ridA, and ompP2) 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.
conclusionsGradient agar diffusion strips and broth microdilution assays do not consistently classify isolates from PBP3 groups as phenotypically resistant. 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.
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