Emergence and Spread of Enterobacterales with Multiple Carbapenemases after COVID-19 Pandemic

Abstract

Resistance to carbapenems in Enterobacterales has become a matter of the highest concern in the last decade. Recently, Enterobacterales 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 Klebsiella pneumoniae and two Enterobacter cloacae 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: blaCTX-M-15, blaTEM, blaSHV, blaOXA-1, blaOXA-2, blaOXA-9, aminoglycosides: aac6, aad, rmt, arm and aph, fluoroquinolones: qnrA, qnrB and qnrS, sulphonamides: sul1 and sul2 and trimethoprim: dfrA9, dfrA14 and dfrA19n. mcr genes were reported for the first time in Croatia. This study demonstrated the ability of K. pneumoniae and E. cloacae 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.

Trends in Antibiotic-Resistant Bacteria Isolated from Screening Clinical Samples in a Tertiary Care Hospital over the 2018–2022 Period

“…In the future, it would be interesting to sequence representative isolates of such strains to better describe them and get a deeper understanding of their dissemination pattern. A similar rise in isolates producing multiple carbapenemases has been reported in three hospitals in Croatia post-COVID-19, with the same OXA48/NDM being the most frequent [ 15 ]. This might be preoccupying as these strains are extremely drug-resistant and could be the cause of therapeutic dead-ends in the near future.…”

Bloodstream Infections by AmpC-Producing Enterobacterales: Risk Factors and Therapeutic Outcome

“…One C. freundii isolate produced double carbapenemase (KPC + NDM). Such isolates were reported previously with increasing frequency in UHCZ, but in the previous studies a combination of OXA-48 with MBLs prevailed [ 43 ]. Carbapenemases were produced by 11.11% of our strains, which was higher than the rate in the Spanish study (4.35%) [ 40 ] and notably less in contrast to the German study (86.54%) [ 42 ].…”

Antimicrobial and Diagnostic Stewardship of the Novel β-Lactam/β-Lactamase Inhibitors for Infections Due to Carbapenem-Resistant Enterobacterales Species and Pseudomonas aeruginosa

“…Finally, the use of novel BL/BLIs synergies has been studied in the treatment of double carbapenemase producers. Double carbapenemase producers are frequently associated with high-carbapenem MICs and an extensive resistance profile, reducing the available antimicrobial agents [ 97 ]. The treatment of such isolates is further complicated by the inability of many phenotypic testing methods to accurately detect and characterize double carbapenemase production ( Table 1 ).…”