In Vitro Combination of Six Antibacterial Associations Against Enterobacterales Isolates Producing KPC or NDM With Intrinsic or Acquired Resistance to Polymyxin B

Therapeutic alternatives for infections caused by Gram-negative bacilli of the order Enterobacterales producing KPC or NDM (E-KPC/NDM) and resistant to polymyxins are virtually nonexistent; therefore, combining antibacterial agents emerges as a promising strategy. This study aimed to evaluate the in vitro activity of six antimicrobial combinations against E-KPC/NDM isolates with intrinsic or acquired resistance to polymyxins (PM-RI and PM-RA). Three E-KPC/NDM isolates intrinsically resistant to polymyxins were tested: Proteus vulgaris , Providencia stuartii , and Morganella morganii , all NDM producers; and three isolates with acquired resistance: two Klebsiella pneumoniae (one producing KPC and the other NDM) and one Escherichia coli producing KPC. Combinations were performed using the checkerboard method with the following antibacterials: polymyxin B (PMB), meropenem (MEM), fosfomycin (FOS), and tigecycline (TGC). The minimum inhibitory concentrations (MICs) for PMB among isolates varied between 8 and 1024 µg/mL. The PMB+TGC combination was the most effective, showing synergism in 66% (4/6) of isolates, three PM-RA and one PM-RI. PMB+FOS showed synergistic activity in 50% (3/6) of isolates, two PM-RI and one PM-RA. MEM+FOS showed synergism in 50% (3/6) of isolates, two KPC producers and one NDM producer. For MEM+TGC, synergism was obtained in 33% (2/6) of isolates, both NDM producers. FOS+TGC showed synergism in 33% (2/6) of isolates, one KPC and one NDM producer. There was no difference in synergism between isolates with intrinsic or acquired resistance to PMB. Despite being one of the most widely used combinations, MEM+PMB showed synergism in only one isolate (PM-RA, KPC producer). No antagonism was observed in any combination, and even when synergism was absent, there was a decrease in the MIC, allowing the recovery of antibacterial activity. The results show that the association between antibacterials can be an alternative for effective treatment against E-KPC/NDM isolates resistant to PMB, highlighting the PMB+TGC combination. Interestingly, the MEM+PMB combination, although widely used, showed limited synergism, suggesting the importance of considering other therapeutic options to optimize the treatment of infections caused by multidrug-resistant bacteria.