This poster was originally presented at European Congress of Clinical Microbiology and Infectious Diseases 2023, held April 15-18 in Copenhagen, Denmark.
Alina Iovleva, Christi L. McElheny, Erin L. Fowler, Carol Hill, Keri Baum, Vance G. Fowler, Jr., Henry F. Chambers, Kerryl E. Greenwood-Quaintance, Robin Patel, Robert A. Bonomo, David van Duin, Yohei Doi
Conclusions
- Sulbactam-Durlobactam (SUL-DUR) is active against majority of colistin-resistant and cefiderocol-non-susceptible Carbapenem-resistant A. baumannii (CRAb)
- Imipenem (IPM) further lowers MIC50 by 2- to 4-fold
- Additional mechanisms of resistance are present as 5/10 SUL-DUR resistant isolates did not possess known mutations
Background
- Carbapenem-resistant A. baumannii (CRAb)
- Major cause of healthcare-associated infections
- Highly drug resistant
- High morbidity and mortality
- Lack of reliable treatment optins
- Sulbactam-durlobactam (SUL-DUR)
- Novel β-lactamase inhibitor combination
- SUL inhibits A. baumannii penicillin-binding protein 3 (PBP3)
- DUR inhibits class A, C, and D β –lactamases
- Non-inferior to colistin when combined with IPM in phase 3 trial
- Resistance mechanisms include: metallo-β-lactamase production, metallo-β-lactamase production, adeJ mutations
Materials and Methods
- 87 CRAb isolates from US
- 68 were colistin-resistant (MIC, >2 μg/mL)
- 26 were cefiderocol-non- susceptible (MIC, ≥8 μg/mL)
- 7 were both
- Whole genome sequence data evaluated for cgSNPs, β- lactamase gene content, ftsI, and adeJ gene mutations
Results
- 10 isolates were resistant to SUL-DUR; 3 to IPM:SUL-DUR
- Genetically diverse: cgSNPs of 1052 (range, 0 to 46634)
- PBP3 substitutions identified among the isolates: Y196S, V346A, H370Y, K389E, T511S, A515V, T526S, and F548I
- PBP3 substitutions were more common in SUL-DUR-resistant isolates however also present in susceptible isolates
- Reduced Ertapenem Susceptibility Due to OXA-2 Production in Klebsiella pneumoniae ST258
- (5/10 [50%] vs 6/77 [8%]; p= 0.002)
- adeJ mutations were identified in two isolates, one resistant, another susceptible
- No metallo-β-lactamases were identified
Table 1. MIC50/90 for cefiderocol-non-susceptible isolates (n=26)
| MIC (μg/mL) | IPM | SUL | SUL-DUR | IPM: SUL-DUR |
|---|---|---|---|---|
| Min | 4 | 1 | 1 | 0.5 |
| Max | 64 | 64 | 16 | 8 |
| MIC50 | 32 | 16 | 4 | 1 |
| MIC90 | 64 | 64 | 8 | 4 |
Table 2. MIC50/90 for colistin-resistant isolates (n=68)
| MIC (μg/mL) | IPM | SUL | SUL-DUR | IPM: SUL-DUR |
|---|---|---|---|---|
| Min | 4 | 2 | 0.5 | 0.25 |
| Max | 64 | 64 | 32 | 8 |
| MIC50 | 32 | 8 | 2 | 1 |
| MIC90 | 64 | 32 | 8 | 4 |
Figure 1. MICs of colistin-resistant (A) and cefiderocol-non-susceptible (B) isolates.
Funding
Funding: This study was supported by a grant from the National Institutes of Health to HFC and VGF (UM1AI104681), AI (KL2TR001856), and YD (R01AI104895). The authors thank Entasis for the provision of broth microdilution plates for the study.
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