1. Maximally precise combinations to overcome metallo-β-lactamase-producing Klebsiella pneumoniae .
- Author
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Kaur JN, Klem JF, Liu Y, Boissonneault KR, Holden PN, Kreiswirth B, Chen L, Smith NM, and Tsuji BT
- Subjects
- Humans, Klebsiella Infections drug therapy, Klebsiella Infections microbiology, Drug Resistance, Multiple, Bacterial genetics, Drug Resistance, Multiple, Bacterial drug effects, Drug Therapy, Combination, Klebsiella pneumoniae drug effects, beta-Lactamases metabolism, beta-Lactamases genetics, Azabicyclo Compounds pharmacology, Anti-Bacterial Agents pharmacology, Ceftazidime pharmacology, Aztreonam pharmacology, Polymyxin B pharmacology, Microbial Sensitivity Tests, Drug Combinations, Imipenem pharmacology
- Abstract
Gram-negatives harboring metallo-β-lactamases (MBLs) and extended-spectrum β-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against Klebsiella pneumoniae ( Kp CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log
10 fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log10 and 7.4 log10 fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 log10 CFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic mgrB and blaNDM-1 resistance, polymyxin B and β-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives., Competing Interests: The authors declare no conflict of interest.- Published
- 2024
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