in Non-Cystic Fibrosis Bronchiectasis: Prevalence and Genomic Basis of High Inoculum β-Lactam Resistance.

The pathobiology of in non-cystic fibrosis bronchiectasis (nCFB) is poorly defined. When present at high density or "inoculum," some methicillin-sensitive (MSSA) can inefficiently degrade antistaphylococcal β-lactam antibiotics via BlaZ penicillinases (termed the "inoculum effect" [IE]). Given the high burden of organisms in bronchiectatic airways, this is particularly relevant. Drawing from a prospectively collected biobank, we sought to understand the prevalence, natural history, potential for transmission, and antibiotic resistance profiles among nCFB-derived MSSA isolates. All individuals attending a regional consultancy nCFB clinic with sputum collected between 1981 and 2017 were considered, and those with one or more -positive cultures composed the cohort. Each individual's most recent biobank isolate was subjected to whole-genome sequencing (including the gene), antibacterial susceptibility testing, and comparative β-lactam testing at standard (5 × 10 colony-forming unit [cfu]/ml) and high (5 × 10 cfu/ml) inocula to assess for the IE and pronounced IE. Seventy-four (35.4%) of 209 individuals had one or more sputum samples with (68 MSSA, 6 methicillin-resistant ). Those with infection were more likely to be female. Among 60 of 74 MSSA isolates subjected to whole-genome sequencing, no evidence of transmission was identified, although specific multilocus sequence typing types were prevalent, including ST-1, ST-15, ST-30, and ST-45. Antibiotic resistance was uncommon, except for macrolides (∼20%). Among the 60 MSSA samples, the prevalence of IE and pronounced IE was observed to be drug specific: meropenem (0% and 0%, respectively), cefepime (3% and 5%, respectively), ceftazidime (8% and 0%, respectively), cloxacillin (12% and 0%, respectively), cefazolin (23% and 0%, respectively), and piperacillin-tazobactam (37% and 17%, respectively). The cefazolin IE was associated with type A ( < 0.01) and ST-30 ( < 0.01), whereas the piperacillin-tazobactam IE was associated with type C ( < 0.001) and ST-15 ( < 0.05). infection was common, although no evidence of transmission was apparent in our nCFB cohort. Although routine susceptibility testing did not identify significant resistance, inoculum-related resistance was found to be relevant for commonly used nCFB antibiotics, including cefazolin and piperacillin-tazobactam. Given previous associations between IEs and negative patient outcomes, further work is warranted to understand how this phenotype impacts nCFB disease progression.