During the study period, in vitro activity of MEM/VAB has been evaluated against 62 KPC-Kp strains isolated from patients with BSIs. The KPC-Kp distribution revealed that 45.2% of bacteremic patients were hospitalized in intensive care units (ICUs), 34% in medicine, 9.7% in haemato-oncology, 6.4% in surgical and 4.7% in transplantation wards.
According to EUCAST breakpoints, 54 out of 62 strains (87%) were susceptible to meropenem/vaborbactam with a median MIC of 0.5 mg/L (interquartile range [IQR] 0,25-1). On opposite, eight KPC-Kp were resistant to meropenem/vaborbactam by exhibiting a median MIC of 256 mg/L (IQR 64–256), as shown in Table 1. Of note, three out of eight (37.5%) meropenem/vaborbactam-resistant KPC-Kp strains were also resistant to ceftazidime/avibactam (median MIC 32, IQR 32-256), while others meropenem/vaborbactam-resistant strains showed a CAZ/AVI MIC equal to 8 mg/L (Table 1).
Genomic analysis showed that meropenem/vaborbactam-resistant strains belonged to Clonal Complex 258 (ST1519, ST258 and ST512) and shared similar genetic resistance determinants responsible for resistance to ß-lactams, aminoglycoside, fluoroquinolone and fosfomycin (Table 1). In particular, analysis of ß-lactam resistance genes showed that all isolates shared wild-type blaKPC-3 gene, while 5 out of 8 carried blaSHV-182 variant. In addition, environment of blaKPC-3 gene demonstrated that all three KPC-Kp strains harbored Tn4401 isoform a. Genetic analysis of porin genes showed that all meropenem/vaborbactam-resistant KPC-Kp strains had truncated OmpK35 and the insertion of glycine and aspartic acid within OmpK36 at position 134-135 (GD134-135).
Based on genome alignment, a total of 234 SNPs in KpBO3, 336 in KpBO6, 137 in KpBO7, 137 in KpBO8, 115 in KpBO11, 111 in KpBO12, 156 in KpBO13 and 110 in KpBO14 were observed against genome of the KpBO3 strain as reference. Comparative analysis of single nucleotide polymorphisms (SNPs) and insertion-deletions (Indels) between MEM/VAB-resistant KPC-Kp strains showed that most SNPs were located intergenic regions or in hypothetical proteins and that no significant difference between MEM/VAB-resistant strains and cross-resistant (i.e. MEM/VAB and CAZ/AVI–resistant) KPC-Kp strains were observed in genes encoding antimicrobial resistance. In addition, phylogenetic analysis showed that genomes of KPC-Kp strains resistant to meropenem/vaborbactam clustered into a single clade (Figure S1, Supplementary data).
Retrospective clinical analysis showed that patients with BSI due to KPC-Kp resistant both to ceftazidime/avibactam and meropenem/vaborbactam had short time of CPE colonization (median 4 days, IQR 0-7). Clinical characteristics of patients with meropenem/vaborbactam-resistant KPC-Kp are shown in Table 2. The 30-days mortality rates were 100% (3/3) for patients with SOFA score between 10-20, 50% (1/2) for patients with score ranging from 5 to 10 and 0% (0/3) for patients below 4.
Clinical success was achieved in 50% (4/8) of patients. None of patients were treated with meropenem/vaborbactam-based treatment. Of note, clinical failure occurred for different antimicrobial treatments and in 33% (1/3) of meropenem/vaborbactam and ceftazidime/avibactam –resistant KPC-Kp strains. In particular, no relapsing infection was observed for all antimicrobial combination treatment. At the same time, microbiological failure was achieved in one patient treated with colistin-meropenem therapy due to persistent bacteremia.