Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

Abstract

We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidimeavibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum ␤-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-␤-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenemrelebactam MICs (P Ͻ 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P ϭ 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P Ͻ 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

“…67 Another study of 26 K. pneumoniae possessing KPC-3 carbapenemases also demonstrated 100% IMI-REL susceptibility. 57 When IMI-REL was evaluated against 14 K. pneumoniae with OXA-48-type enzyme expression, REL did not restore susceptibility in any of the strains, demonstrating the lack of IMI-REL activity against OXA-48-type carbapenemase. 67 In a study evaluating in vitro IMI-REL susceptibility among K. pneumoniae with class B metallo-β-lactamases, including VIM, IMP, and NDM, 0/113 isolates were susceptible.…”

“…IMI‐REL has been evaluated against Enterobacteriaceae in several studies (Table 1). Overall, IMI‐REL demonstrates excellent in vitro activity, with susceptibility rates above 95% for Klebsiella pneumoniae , Escherichia coli , Citrobacter spp . , and Enterobacter spp .…”

“…In one study evaluating 92 K. pneumoniae with KPC‐2 and KPC‐3 type carbapenemases, IMI‐REL susceptibility was 100% . Another study of 26 K. pneumoniae possessing KPC‐3 carbapenemases also demonstrated 100% IMI‐REL susceptibility . When IMI‐REL was evaluated against 14 K. pneumoniae with OXA‐48‐type enzyme expression, REL did not restore susceptibility in any of the strains, demonstrating the lack of IMI‐REL activity against OXA‐48‐type carbapenemase .…”

“…Enterobacteriaceae IMI-REL has been evaluated against Enterobacteriaceae in several studies (Table 1). 48,[55][56][57][58][59][60][61][62][63][64][65][66] Overall, IMI-REL demonstrates excellent in vitro In one study evaluating 92 K. pneumoniae with KPC-2 and KPC-3 type carbapenemases, IMI-REL susceptibility was 100%. 67 Another study of 26 K. pneumoniae possessing KPC-3 carbapenemases also demonstrated 100% IMI-REL susceptibility.…”

Prevalence and resistance profile of extended-spectrum -lactamases-producing Enterobacteriaceae in Ouagadougou, Burkina Faso

“…Also, Patwardhan and Singh (2017) in India reported 1,223 (96.5%) ESBL-producing Gram negative isolates that were susceptible to fosfomycin. This gives a glimpse of hope as this two antibiotics are still very much active against ESBL-E and can serve as a ready remedy when clinicians are confronted with multidrug resistant ESBL-E. Conversely there should be caution in the use of these molecules as resistance to imipenem is beginning to emerge (Haidar et al, 2017). In Burkina Faso, as in many other African countries, the lack of antibiotic surveillance system, unfavorable hygiene conditions in hospitals, may be attributed to the spread of ESBL, as has been reflected in this study.…”