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Emergence and Spread of Enterobacterales with Multiple Carbapenemases after COVID-19 Pandemic
Branka Bedenić1,2, Josefa Luxner3, Haris Car4
1Department of Microbiology, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
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: dfrA5, dfrA7, dfrA14, dfrA17 and dfrA19. 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.
Insights
Multiple carbapenemase resistance in Enterobacterales is a growing concern. This study found extensively drug-resistant Klebsiella pneumoniae and Enterobacter cloacae in Croatia, highlighting the need for new therapeutic strategies.
Area of Science:
- Microbiology
- Infectious Diseases
- Antimicrobial Resistance
Background:
- Carbapenem resistance in Enterobacterales poses a significant global health threat.
- Recent detection of multidrug-resistant Enterobacterales in Croatian healthcare and outpatient settings necessitates urgent investigation.
Purpose of the Study:
- To analyze antibiotic susceptibility, beta-lactamase production, and plasmid content of Enterobacterales isolates with multiple carbapenemases.
- To evaluate the efficacy of novel beta-lactam/inhibitor combinations against these resistant strains.
- To identify carbapenemase combinations and other resistance genes present in the isolates.
Main Methods:
- Analysis of ten clinical isolates (eight Klebsiella pneumoniae, two Enterobacter cloacae complex) exhibiting multiple carbapenemases.
- Antibiotic susceptibility testing against various agents, including novel combinations like ceftazidime/avibactam and imipenem/cilastatin/relebactam.
- Detection of beta-lactamase genes using Open Reading Frame (ORF) sequencing (OKNV) and inter-array testing, alongside PCR for other resistance genes.
Main Results:
- Isolates showed uniform resistance to common antibiotics and carbapenems, with 50% susceptible to ceftazidime/avibactam.
- Four isolates were multidrug-resistant (MDR), and six were extensively drug-resistant (XDR).
- Common carbapenemase combinations included OXA-48+NDM, OXA-48+VIM, and OXA-48+KPC. Novel resistance genes, including mcr genes, were identified.
Conclusions:
- Klebsiella pneumoniae and Enterobacter cloacae can acquire diverse resistance determinants under antibiotic selection pressure, exacerbated by COVID-19 pandemic treatments.
- The emergence of extensively drug-resistant Enterobacterales with multiple carbapenemases in Croatia presents a critical therapeutic challenge.
- The study highlights the need for continuous surveillance and development of effective antimicrobial strategies against carbapenem-resistant Enterobacterales.
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