Abstract
Klebsiella pneumoniae carbapenemases (KPCs) are a family of serine β-lactamases that confer broad antibiotic resistance by hydrolyzing virtually all β-lactam (BL) agents. Contemporary β-lactamase inhibitors (BLIs) such as avibactam were developed to neutralize the activity of KPCs and other clinically important carbapenemases. Ceftazidime-avibactam (CZA), a BL/BLI combination in which the cephalosporin ceftazidime is protected from KPC-mediated hydrolysis, demonstrated improved outcomes in early clinical use. However, CZA-resistant isolates soon emerged. Herein, we describe a challenging clinical case in which high-level resistance to CZA evolved during therapy for a complicated infection caused by carbapenem-resistant Serratia marcescens harboring bla(KPC-2). Whole-genome sequencing, analysis of antibiotic resistance genes, and phenotypic susceptibility assays of serial S. marcescens isolates revealed that resistance arose via a 45-nucleotide in-frame duplication within bla(KPC-2), yielding KPC variant 44 (bla(KPC-44)). Notably, the evolution of bla(KPC-44) not only conferred resistance to CZA but also marked cross-resistance to meropenem-vaborbactam and imipenem-relebactam while remaining susceptible to cefiderocol. To our knowledge, this report represents the first description of bla(KPC-44) emerging outside of K. pneumoniae and among the few documenting a CZA-resistance-conferring KPC variant emerging in a non-K. pneumoniae Enterobacterales species. Ultimately, the evolved strain persisted despite therapy throughout a fatal clinical course, underscoring the potential for CZA selective pressure to drive treatment-emergent resistance to multiple contemporary BL/BLI agents.