Ceftazidime/avibactam and aztreonam combined with an aminoglycoside combat metallo-β-lactamase-producing <i>Klebsiella pneumoniae</i>

There is an urgent need for additional therapeutic solutions to treat serious bacterial infections caused by metallo-β-lactamase (MBL)-producing <i>Klebsiella pneumoniae</i>. Aztreonam, when partnered with ceftazidime/avibactam, has <i>in vitro</i> activity against most MBL-producing <i>K. pneumoniae</i>, but clinical outcomes may be suboptimal. The purpose of this study was to determine if aminoglycosides can enhance the pharmacodynamic activity of ceftazidime/avibactam plus aztreonam against MBL-producing <i>K. pneumoniae</i>. <i>K. pneumoniae</i> isolates harboring MBL genes (<i>bla</i>_NDM, <i>bla</i>_VIM, and <i>bla</i>_IMP) were evaluated in time-kill assays (<i>n</i> = 4 isolates) and the hollow fiber infection model (HFIM, <i>n</i> = 2 isolates). Clinically relevant doses of antibiotics were simulated in the HFIM, and observed antibiotic exposures represented the upper end of the expected patient plasma concentrations. Resistance was tracked during the HFIM, and confocal microscopy was used to assess cell morphology following antibiotic exposure. Both ceftazidime/avibactam + aztreonam and plazomicin were effective individually at reducing viable bacterial counts of susceptible MBL-producing <i>K. pneumoniae</i>, particularly in the HFIM. Combination regimens with aminoglycosides (amikacin or plazomicin) occasionally demonstrated synergy using traditional definitions based on viable colony counting, but they were able to consistently reduce bacterial turbidity and the emergence of filamentous cells that were observed during exposure to ceftazidime/avibactam + aztreonam. Combinations between ceftazidime/avibactam, aztreonam, and an aminoglycoside are a potentially promising therapeutic strategy to combat the rising threat posed by MBL-producing <i>K. pneumoniae</i>.