A genomics-informed mechanism-based pharmacokinetic/pharmacodynamic model of cefiderocol and ceftazidime/avibactam against carbapenem-resistant <i>Achromobacter xylosoxidans</i>

<i>Achromobacter xylosoxidans</i> harbors robust intrinsic and acquired resistance mechanisms and is responsible for severe nosocomial infections in high-risk individuals. Here, we investigated the effectiveness of β-lactam antibiotic combinations against three sequentially collected <i>A. xylosoxidans</i> isolates from a pediatric patient with chronic myeloid leukemia, which were previously genotyped and sequenced to assess and characterize the evolution of resistance. The time course killing activity from <i>in vitro</i> static concentration time-kill (SCTK) assays and genomics of these longitudinally collected isolates guided the development of an <i>in silico</i> mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. As previously described, the sequentially collected <i>A. xylosoxidans</i> isolates developed resistance to meropenem and ceftazidime/avibactam during treatment, along with reduced susceptibility to cefiderocol, driven by the acquisition of β-lactamase genes, point mutations, and increased β-lactamase expression. Building on these findings, SCTK assays showed that the combination of ceftazidime/avibactam and cefiderocol achieved ≥2-log reductions in bacterial colony-forming units. The PK/PD model included two bacterial subpopulations, one resistant to ceftazidime but susceptible to cefiderocol and another resistant to both. Avibactam's mechanistic synergy restored ceftazidime activity. However, the acquisition of resistance genes and mutations led to a 14-fold and 1.5-fold reduction in susceptibility to ceftazidime/avibactam and cefiderocol, respectively. Simulations with the developed model at clinical exposures revealed that this combination had bactericidal activity, and the infusion duration was a critical driver of efficacy. These findings underscore the therapeutic promise of combining ceftazidime/avibactam with cefiderocol for managing complex <i>A. xylosoxidans</i> bacteremia and highlight the potential of integrated mechanism-based modeling to guide treatment strategies in resistant infections.