Epidemiology, resistance genomics and susceptibility of Acinetobacter species: results from the 2020 Spanish nationwide surveillance study.

BackgroundAs increasing antibiotic resistance in Acinetobacter baumannii poses a global healthcare challenge, understanding its evolution is crucial for effective control strategies.AimWe aimed to evaluate the epidemiology, antimicrobial susceptibility and main resistance mechanisms of Acinetobacter spp. in Spain in 2020, and to explore temporal trends of A. baumannii.MethodsWe collected 199 single-patient Acinetobacter spp. clinical isolates in 2020 from 18 Spanish tertiary hospitals. Minimum inhibitory concentrations (MICs) for nine antimicrobials were determined. Short-read sequencing was performed for all isolates, and targeted long-read sequencing for A. baumannii. Resistance mechanisms, phylogenetics and clonality were assessed. Findings on resistance rates and infection types were compared with data from 2000 and 2010.ResultsCefiderocol and colistin exhibited the highest activity against A. baumannii, although colistin susceptibility has significantly declined over 2 decades. A. non-baumannii strains were highly susceptible to most tested antibiotics. Of the A. baumannii isolates, 47.5% (56/118) were multidrug-resistant (MDR). Phylogeny and clonal relationship analysis of A. baumannii revealed five prevalent international clones, notably IC2 (ST2, n = 52; ST745, n = 4) and IC1 (ST1, n = 14), and some episodes of clonal dissemination. Genes bla OXA-23, bla OXA-58 and bla OXA-24/40 were identified in 49 (41.5%), eight (6.8%) and one (0.8%) A. baumannii isolates, respectively. ISAba1 was found upstream of the gene (a bla OXA-51-like) in 10 isolates.ConclusionsThe emergence of OXA-23-producing ST1 and ST2, the predominant MDR lineages, shows a pivotal shift in carbapenem-resistant A. baumannii (CRAB) epidemiology in Spain. Coupled with increased colistin resistance, these changes underscore notable alterations in regional antimicrobial resistance dynamics.

Antimicrobial Activity of Cefiderocol against the Carbapenemase-Producing Enterobacter cloacae Complex and Characterization of Reduced Susceptibility Associated with Metallo-ß-Lactamase VIM-1.

Emergence of cefiderocol resistance among carbapenemase-producing Enterobacterales, particularly those in the Enterobacter cloacae complex (ECC), is becoming of alarming concern; however, the mechanistic basis of this phenomenon remains poorly understood. We describe the acquisition of VIM-1-mediated reduced cefiderocol susceptibility (MICs 0.5 to 4 mg/L) in a collection of 54 carbapenemase-producing isolates belonging to the ECC. MICs were determined by reference methodologies. Antimicrobial resistance genomic analysis was performed through hybrid WGS. The impact of VIM-1 production on cefiderocol resistance in the ECC background was examined at microbiological, molecular, biochemical, and atomic levels. Antimicrobial susceptibility testing yielded 83.3% susceptible isolates and MIC50/90 values of 1/4 mg/L. Decreased susceptibility to cefiderocol was mainly associated with isolates producing VIM-1, with cefiderocol MICs 2- to 4-fold higher than for isolates carrying other types of carbapenemases. E. cloacae and Escherichia coli VIM-1 transformants displayed significantly enhanced cefiderocol MICs. Biochemical assays with purified VIM-1 protein revealed low but detectable cefiderocol hydrolysis. Simulation studies revealed how cefiderocol is anchored to the VIM-1 active site. Additional molecular assays and WGS data analysis highlighted the implication of SHV-12 coproduction and suggested the inactivation of the FcuA-like siderophore receptor as further contributors to the higher cefiderocol MICs. Our findings warn of the potential of the VIM-1 carbapenemase to at least partly limit the activity of cefiderocol in the ECC. This effect is probably enhanced due to combination with additional mechanisms, such as ESBL production and siderophore inactivation, and indicates the need for active surveillance to extend the life span of this promising cephalosporin.

Activity of aztreonam in combination with novel ß-lactamase inhibitors against metallo-ß-lactamase-producing Enterobacterales from Spain.

Metallo-ß-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all ß-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine ß-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel ß-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. ß-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum ß-lactamases and class C ß-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.