Aztreonam/avibactam activity against a large collection of carbapenem-resistant Enterobacterales (CRE) collected in hospitals from Europe, Asia and Latin America (2019-21).

Background: Aztreonam/avibactam is under development to treat infections caused by Gram-negative bacteria. We evaluated the in vitro activities of aztreonam/avibactam and comparators against a global collection of carbapenem-resistant Enterobacterales (CRE), including ceftazidime/avibactam-resistant isolates. Methods: Isolates were consecutively collected (24 924; 1/patient) from 69 medical centres in 36 countries during 2019-21. Isolates were susceptibility tested by CLSI broth microdilution. All CRE isolates (n = 1098; 4.4%) were in silico screened for carbapenemase (CPE) genes after genome sequencing. CRE susceptibility results were stratified by CPE, geography and resistance phenotype. Results: Aztreonam/avibactam inhibited 99.6% of CREs at ≤8 mg/L (MIC50/90, 0.25/0.5 mg/L), including 98.9% (345/349) of ceftazidime/avibactam-resistant isolates. Aztreonam/avibactam activity was consistent across geographical regions (98.9%-100.0% inhibited at ≤8 mg/L), but susceptibility to comparators varied markedly. Susceptibility (CLSI criteria) for ceftazidime/avibactam and meropenem/vaborbactam ranged from 80.2% and 77.5% in Western Europe to 39.5% and 40.3% in the Asia-Pacific region, respectively. Aztreonam/avibactam retained activity against isolates non-susceptible to colistin (99.7% inhibited at ≤8 mg/L) or tigecycline (98.6% inhibited at ≤8 mg/L). A CPE gene was identified in 972 CRE isolates (88.5%). The most common CPEs were KPC (43.1% of CREs), NDM (26.6%) and OXA-48-like (18.7%); 57 isolates (5.2%) had >1 CPE gene. Aztreonam/avibactam inhibited 99.9% of CPE producers at ≤8 mg/L, whereas ceftazidime/avibactam and meropenem/vaborbactam exhibited limited activity against isolates producing MBL and/or OXA-48-like enzymes. Conclusions: Aztreonam/avibactam activity was not adversely affected by clinically relevant CPEs. Our results support aztreonam/avibactam development to treat infections caused by CRE, including MBL producers.

Impact of the Recent Clinical and Laboratory Standards Institute Breakpoint Changes on the Antimicrobial Spectrum of Aminoglycosides and the Activity of Plazomicin Against Multidrug-Resistant and Carbapenem-Resistant Enterobacterales From United States Medical Centers.

Background: The Clinical and Laboratory Standards Institute (CLSI) lowered the Enterobacterales-susceptible/-resistant breakpoints for amikacin in 2023 from ≤16/≥64 mg/L to ≤4/≥16 mg/L and the breakpoints for gentamicin and tobramycin from ≤4/≥16 mg/L to ≤2/≥8 mg/L. Because aminoglycosides are frequently used to treat infections caused by multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE), we evaluated the impact of these changes on the susceptibility rates (%S) of Enterobacterales collected from US medical centers. Methods: A total of 9809 Enterobacterales isolates were consecutively collected (1/patient) from 37 US medical centers in 2017-2021 and susceptibility was tested by broth microdilution. Susceptibility rates were calculated using CLSI 2022, CLSI 2023, and US Food and Drug Administration 2022 criteria. Aminoglycoside-nonsusceptible isolates were screened for genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases (16RMT). Results: The CLSI breakpoint changes mostly affected amikacin, especially against MDR (94.0%S to 71.0%S), extended-spectrum ß-lactamase (ESBL)-producing (96.9%S to 79.7%S), and CRE (75.2%S to 59.0%S) isolates. Plazomicin was active against 96.4% of isolates and retained potent activity against CRE (94.0%S), ESBL-producing (98.9%S), and MDR (94.8%S) isolates. Gentamicin and tobramycin showed limited activity against resistant subsets of Enterobacterales. The AME-encoding genes and 16RMT were observed in 801 (8.2%) and 11 (0.1%) isolates, respectively. Plazomicin was active against 97.3% of the AME producers. Conclusions: The spectrum of activity of amikacin against resistant subsets of Enterobacterales was drastically reduced when interpretative criteria based on pharmacokinetic/pharmacodynamic parameters that are currently used to establish breakpoints for other antimicrobials were applied. Plazomicin was markedly more active than amikacin, gentamicin, or tobramycin against antimicrobial-resistant Enterobacterales.

Meropenem-Vaborbactam Activity against U.S. Multidrug-Resistant Enterobacterales Strains, Including Carbapenem-Resistant Isolates.

Carbapenems are a common first-line therapy for serious Gram-negative infections, but carbapenem-resistant Enterobacterales (CRE) isolates have become an urgent health concern. Klebsiella pneumoniae serine carbapenemases (KPCs) now have been disseminated worldwide and are endemic in many hospitals globally. Isolates producing metallo-ß-lactamases (MBLs) or class D OXA-48 carbapenemases are also increasingly common in Europe, although they are less common in the United States. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a ß-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. multidrug-resistant (MDR) isolates to meropenem-vaborbactam. A total of 1,697 MDR Enterobacterales isolates were collected in 31 U.S. medical centers in 2016 to 2020. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR Enterobacterales strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. There were 222 CRE isolates (13.1%). KPC was the most common carbapenemase (81.1%). Thirteen CRE isolates produced NDM (n = 7), VIM (n = 3), and/or OXA-48-like (n = 4) carbapenemases; 29 CRE isolates (13.1%) had no detected carbapenemase. The rate of susceptibility of all CRE strains to meropenem-vaborbactam was 93.2%, and the rate of susceptibility of the KPC-producing isolates to meropenem-vaborbactam was 98.9%. The primary carbapenemase in the United States continues to be KPC, while MBL and OXA-48-like carbapenemases remain uncommon. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam was 99.1%, indicating that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR organisms. IMPORTANCE Carbapenems are a common first-line therapy for serious Gram-negative infections, but CRE isolates have become an urgent health concern. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a ß-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. MDR Gram-negative isolates to meropenem-vaborbactam. A total of 1,697 U.S. MDR Enterobacterales isolates collected in 2016 to 2020 were tested. Susceptibility testing was performed using the CLSI broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR Enterobacterales strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. A total of 13.1% of the isolates were CRE strains, and KPC was the most common carbapenemase. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam indicates that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR Gram-negative pathogens.

In Vitro Activity of Tebipenem against Various Resistant Subsets of Escherichia coli Causing Urinary Tract Infections in the United States (2018 to 2020).

This study investigated the activity of an oral carbapenem, tebipenem, against various molecularly characterized subsets of Escherichia coli. A total of 15.0% of E. coli isolates (360/2,035 isolates) met the MIC criteria for screening for ß-lactamases. Most of those isolates (74.7% [269/360 isolates]) carried blaCTX-M. The CTX-M distribution varied (50% to 86%) among Census Regions, as did that of plasmid AmpC genes (up to 41% among E. coli isolates from the New England Region). Tebipenem and intravenous carbapenems showed uniform activity against various E. coli subsets.

Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018.

The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division). Among the CRE isolates, 134 carried carbapenemase genes, and these included 72 isolates carrying blaKPC-3, 51 isolates carrying blaKPC-2, 4 isolates carrying blaNDM-1, 3 isolates carrying blaSME-4, 2 isolates carrying blaVIM-1, 1 isolate carrying blaOXA-232, and 1 isolate carrying blaKPC-4 Meropenem-vaborbactam was active against 95.4% of the CRE isolates and 94.8% of the carbapenem-producing Enterobacterales (CPE) isolates when applying the CLSI breakpoints. All isolates producing serine carbapenemases were inhibited by meropenem-vaborbactam at ≤8 mg/liter. One Citrobacter freundii isolate carrying blaKPC-3 had a meropenem-vaborbactam MIC of 8 mg/liter and was resistant according to CLSI breakpoints (the isolate was susceptible when the EUCAST criterion of an MIC of ≤8 mg/liter for susceptible was applied), had disrupted OmpC and OmpF sequences, and overexpressed AcrAB-TolC. All carbapenemase-negative CRE isolates (n = 18) were inhibited by meropenem-vaborbactam at ≤4 mg/liter, and the MIC values of this combination ranged from 0.25 to 4 mg/liter. Among 7 isolates carrying metallo-ß-lactamases and/or oxacillinases with carbapenemase activity, meropenem-vaborbactam susceptibility was 14.3% and 57.1% when applying CLSI and EUCAST breakpoints, respectively. CRE isolates were resistant to many comparator agents, and the most active agents were tigecycline, colistin, and amikacin (to which 63.2% to 96.7% of the isolates were susceptible). Understanding the epidemiology of CRE isolates in U.S. hospitals and the resistance mechanisms among these isolates is important to form guidelines for the treatment of infections caused by these organisms, which have high mortality rates.