Synergistic Activity of Cefiderocol in Combination with Piperacillin-Tazobactam, Fosfomycin, Ampicillin-Sulbactam, Imipenem-Relebactam and Ceftazidime-Avibactam against Carbapenem-Resistant Gram-Negative Bacteria

Abstract

Limited treatment options are among the main reasons why antimicrobial resistance has become a leading major public health problem. In particular, carbapenem-resistant Enterobacteriales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii have been included by the World Health Organization (WHO) among the pathogens for which new therapeutic agents are needed. The combination of antibiotics represents an effective strategy to treat multidrug-resistant (MDR) pathogen infections. In this context, the aim of this study is to evaluate the in vitro activity of cefiderocol (CFD) in combination with different antimicrobial molecules against a collection of well-characterized clinical strains, exhibiting different patterns of antimicrobial susceptibility. Clinical strains were genomically characterized using Illumina iSeq100 platform. Synergy analyses were performed by combining CFD with piperacillin-tazobactam (PIP-TAZ), fosfomycin (FOS), ampicillin-sulbactam (AMP-SULB), ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL). Our results demonstrated the synergistic effect of CFD in combination with FOS and CAZ-AVI against CRE and carbapenem-resistant Acinetobacter baumannii (CR-Ab) clinical strains owing CFD-resistant profile, while the CFD and AMP-SULB combination was effective against CR-Pa strain displaying AMP-SULB-resistant profile. Moreover, the combination of CAZ-AVI/SULB showed synergistic activity in CAZ-AVI-resistant CRE strain. In conclusion, although further analyses are needed to confirm these results, our work showed the efficacy of CFD when used for synergistic formulations.

Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing <em>Klebsiella pneumoniae </em>Clinical Isolates

“…Fosfomycin demonstrated synergistic activity against KPC-producing K. pneumoniae isolates with tigecycline, colistin, and aminoglycosides [11]. Moreover, recently, synergistic activity between fosfomycin and meropenem/vaborbactam [32,33], as well as between fosfomycin and cefiderocol [34], was also reported. In the present study we assessed the antimicrobial interaction among these drugs against KPC-producing K. pneumoniae clinical isolates, demonstrating a significant in vitro and in vivo synergistic activity.…”

Delaying cefiderocol resistance development in NDM-producingEnterobacter cloacaecomplex by combining cefiderocol with aztreonamin vitro

“…The idea of combining cefiderocol with another substance to increase the efficacy of this antibiotic substance is not entirely novel. Some studies have explored the microbiological effects of combining cefiderocol with novel β-lactam/β-lactamase inhibitors, such as ceftazidime/avibactam or β-lactamase inhibitors alone, such as tazobactam, avibactam, vaborbactam, and relebactam [16, 17]. However, these studies only studied the antibacterial effect of such combinations and did not study the effect of various cefiderocol combinations on the propensity of resistance emergence and selection.…”

Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates

“…Fosfomycin demonstrated synergistic activity against KPC-producing K. pneumoniae isolates with tigecycline, colistin and aminoglycosides [ 11 ]. Moreover, recently, synergistic activity was also reported between fosfomycin and meropenem/vaborbactam [ 32 , 33 ], as well as between fosfomycin and cefiderocol [ 34 ]. In the present study, we assessed the antimicrobial interactions among these drugs against KPC-producing K. pneumoniae clinical isolates, demonstrating a significant in vitro and in vivo synergistic activity.…”