Unraveling Cefiderocol Resistance Strategies in Klebsiella pneumoniae Strains from the United Arab Emirates
Introduction: Antibiotic resistance is a significant health threat, rendering once-effective treatments ineffective against bacterial infections. This alarming trend has led to the spread of multidrug-resistant bacteria in the community, resulting in limited treatment options. Consequently, new anti...
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| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
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| Series: | International Journal of Infectious Diseases |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1201971224008336 |
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| Summary: | Introduction: Antibiotic resistance is a significant health threat, rendering once-effective treatments ineffective against bacterial infections. This alarming trend has led to the spread of multidrug-resistant bacteria in the community, resulting in limited treatment options. Consequently, new antibiotics are required to combat difficult-to-treat bacteria. Cefiderocol (CFDC) is a novel cephalosporin-catecholate antibiotic that bacteria uptake via catecholate receptors such as CirA. It is considered stable against degradation by β-lactamases. However, the causes of resistance to CFDC remain unclear, with limited data available from the UAE. This study aims to examine the genetic makeup of CFDC-susceptible (S) and non-susceptible (NS) Klebsiella pneumoniae (KPN) isolates to uncover the causes of CFDC resistance. Methods: A total of 241 KPN strains isolated from various infection sites were included in this study. The minimum inhibitory concentration (MIC) was determined for 13 antibiotics, including CFDC. Resistance mechanisms to CFDC were analyzed using short-read whole-genome sequencing (WGS) on 60 KPN isolates to correlate each strain's genetic makeup with its susceptibility profile. Results: CFDC exhibited high activity, with 97.5% of strains being susceptible, second only to tigecycline (99.1% susceptibility). CFDC demonstrated remarkable potency (MIC 0.06-4 µg/ml), with 2.5% (n=3) intermediately susceptible (MIC 8 µg/ml) and 2.5% (n=3) resistant (MIC 256 µg/ml). It inhibited strains producing various β-lactamases such as blaNDM-1, blaNDM-5, blaOXA-232, blaOXA-48, blaOXA-181, blaOXA-232, blaCTX-M-15, blaDHA-1, and blaDHA-7. These genes were carried on different plasmid types such as IncFIB(pQil), IncFIA, IncFIB(K), IncHI1B(pNDM-MAR), and ColKP3. CFDC exhibited high potency (MIC50: 4 µg/ml) even on strains producing dual carbapenemases (blaNDM and blaOXA-48-like), which showed extreme resistance to carbapenems and other drugs. MLST analysis revealed variations in the sequence types (STs) among the strains. The most prevalent sequence type was ST14 (18.9%), which aligns with previous data from the UAE. This was followed by strains with novel STs (10.3%). The CFDC-NS strains belonged to ST14, ST37, ST410, and a novel ST. Discussion: The colicin I receptor (cirA), used as a receptor for CFDC, was investigated. All CFDC-NS strains exhibited frameshift mutations in the cirA gene, resulting in a stop codon and defective receptor, which diminished the uptake of the drug. The concurrence of this mutation with blaNDM production resulted in resistance to CFDC. This mutation was absent in all CFDC-S and blaNDM positive isolates. Fortunately, since the cirA gene is encoded on the chromosome, it is unlikely to spread to other bacteria, thus preserving the drug's integrity. Conclusion: CFDC was potent against β-lactamase-producing KPN from the UAE and serves as an excellent choice for treating severe KPN infections. However, cirA mutations resulted in higher MICs for CFDC. We recommend testing for the cirA gene before administering CFDC to avoid treatment failure. |
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| ISSN: | 1201-9712 |