Introduction
Treatment options for infections caused by multidrug- resistant (MDR) Enterobacterales are limited and these infections are associated with high clinical failure and mortality rates, especially in vulnerable patients. In the period of 2018-2022, a total of 35,360 Enterobacterales isolates were collected from 75 medical centers in the US. Among these isolates, 7.4% (2612) were classified as multidrug-resistant (MDR). The susceptibility of the isolates was tested using reference broth microdilution methods. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes through whole genome sequencing. Klebsiella pneumoniae had the highest MDR rates (12.2%), followed by Raoultella spp. (10.9%) and Providencia stuartii (9.8%). Ceftazidime-avibactam and meropenem-vaborbactam showed excellent activity with identical susceptibility rates of 97.9% against MDR isolates.
Imipenem-relebactam (93.5% susceptible [S]) had slightly lower susceptibility rates due to its limited effectiveness against the Morganellaceae family. Among CRE isolates (n = 310), the most effective β-lactamase inhibitor combination (BLI) was ceftazidime- avibactam (84.2%S), followed by meropenem- vaborbactam (81.9%S) and imipenem-relebactam (74.8%S). All three BLIs showed high activity against KPC producers, but none were effective against MBL producers. Ceftazidime-avibactam demonstrated greater activity against OXA-48-type producers compared to meropenem-vaborbactam and imipenem-vaborbactam. These findings indicate that the recently approved BLIs, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam, are highly effective against MDR Enterobacterales.
Materials and methods
A total of 35,360 Enterobacterales isolates were collected from 75 medical centers across the United States from 2018 to 2022. The isolates were obtained from various infection types, such as bloodstream infections, intra-abdominal infections, pneumonia, urinary tract infections, skin and skin structure infections, and others. The isolates were categorized as multidrug-resistant (MDR) or extensively drug-resistant (XDR) based on specific criteria. Susceptibility testing was performed using the reference broth microdilution method, and interpretive criteria were applied to determine susceptibility or resistance. Carbapenem-resistant Enterobacterales (CRE) were screened for β-lactamase-encoding genes using genome sequencing and in silico screening methods. The findings provided information on the resistance patterns and β-lactamase alleles present in the isolates.
Results
A total of 2,612 isolates (7.4%) were categorized as MDR (Tables 1 and 2). The highest MDR rates were observed among K. pneumoniae (12.2%), followed by Raoultella spp. (10.9%), Providencia stuartii (9.8%), and Citrobacter freundii complex (7.8%; Table 1). Ceftazidime- avibactam, meropenem-vaborbactam, and imipenem- relebactam exhibited similar activity against species with the highest MDR rates, except against P. stuartii and Morganella morganii, where imipenem-relebactam was less active than the other 2 compounds (Table 1).
The study analyzed the rates of multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE) in different regions of the United States. The highest MDR and CRE rates were observed in the Middle Atlantic region, particularly in New York. The West South Central Division also had high MDR and CRE rates. The lowest rates were found in the West North Central Division. Ceftazidime-avibactam, meropenem- vaborbactam, and imipenem-relebactam showed good activity against MDR isolates. Tigecycline and meropenem were also effective. However, amikacin’s effectiveness dropped when applying revised susceptibility criteria. Against extensively drug-resistant (XDR) isolates, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam retained good activity, as did tigecycline. Ceftazidime-avibactam was highly active against KPC-producing CRE isolates and exhibited better activity against OXA-48-type producers compared to meropenem-vaborbactam and imipenem-relebactam. Overall, the three tested compounds were effective against MDR Enterobacterales and represented valuable treatment options.
Conclusion
This study evaluated the in vitro activity of three recently approved β-lactamase inhibitors (BLIs) – ceftazidime- avibactam, meropenem-vaborbactam, and imipenem- relebactam – against multidrug-resistant (MDR) Enterobacterales isolates from US hospitals. The overall MDR rate was 7.4%, with variations among different species and Census Divisions. K. pneumoniae had the highest MDR rate at 12.2%. The study found that imipenem-relebactam had limited activity against Morganellaceae family organisms, and Serratia marcescens. Ceftazidime-avibactam was more active against OXA-48-type producers compared to the other BLIs. The study also highlighted that ceftazidime-avibactam was the most active BLI against non-carbapenemase-producing CRE isolates. All three BLIs were highly active against KPC producers but showed limited activity against metallo-β-lactamase (MBL) producers. The study concluded that these BLIs are effective options for treating MDR Enterobacterales infections, but their spectrum of activity should be considered when used empiricall.
Source: Maraki, Sofia, et al. “Ceftazidime-avibactam, meropenen-vaborbactam, and imipenem-relebactam in combination with aztreonam against multidrug-resistant, metallo-β-lactamase-producing Klebsiella pneumoniae.” European Journal of Clinical Microbiology & Infectious Diseases 40 (2021): 1755-1759.