| Summary: | Resistance to carbapenems in <i>Enterobacterales</i> has become a matter of the highest concern in the last decade. Recently, <i>Enterobacterales</i> harboring multiple carbapenemases were detected in three hospital centers in Croatia and in the outpatient setting, posing a serious therapeutic challenge for clinicians. In this study, we analyzed eight <i>Klebsiella pneumoniae</i> and two <i>Enterobacter cloacae</i> complex isolates with multiple carbapenemases, with regard to antibiotic susceptibility, β-lactamase production and plasmid content. The isolates demonstrated uniform resistance to amoxicillin/clavulanate, piperacillin/tazobactam, cefuroxime, ceftazidime, cefotaxime, ceftriaxone and ertapenem. Among novel β-lactam/inhibitor combinations, ceftazidime/avibactam exhibited moderate activity, with 50% of isolates susceptible. All isolates demonstrated resistance to imipenem/cilastatin/relebactam, and all but one to ceftolozane/tazobactam. Four isolates exhibited a multidrug-resistant phenotype (MDR), whereas six were allocated to an extensively drug-resistant phenotype (XDR). OKNV detected three combinations of carbapenemases: OXA-48+NDM (five isolates), OXA-48+VIM (three isolates) and OXA-48+KPC (two isolates). Inter-array testing identified a wide variety of resistance genes for β-lactam antibiotics: <i>bla</i><sub>CTX-M-15</sub>, <i>bla</i><sub>TEM</sub>, <i>bla</i><sub>SHV</sub>, <i>bla</i><sub>OXA-1</sub>, <i>bla</i><sub>OXA-2</sub>, <i>bla</i><sub>OXA-9</sub>, aminoglycosides: <i>aac</i>6, <i>aad</i>, <i>rmt</i>, <i>arm</i> and <i>aph</i>, fluoroquinolones: <i>qnr</i>A, <i>qnr</i>B and <i>qnr</i>S, sulphonamides: <i>sul</i>1 and <i>sul</i>2 and trimethoprim: <i>dfrA5, dfrA7, dfrA14, dfrA17 and dfrA19</i>. <i>mcr</i> genes were reported for the first time in Croatia. This study demonstrated the ability of <i>K. pneumoniae</i> and <i>E. cloacae</i> to acquire various resistance determinants under the selection pressure of antibiotics widely used during the COVID-19 pandemic. The novel inter-array method showed good correlation with OKNV and PCR, although some discrepancies were found.
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