The role of new β-lactamase inhibitors in gram-negative infections

Abstract

Purpose of review In recent years, traditional β-lactams have dramatically reduced their effectiveness against gram-negative bacteria mainly because of their ability to express multiple β-lactamase or carabapenemases that are not hydrolyzed by the old β-lactam inhibitors (BLIs) such as clavulanic acid, tazobactam, and sulbactam. New BLIs molecules have been developed to face the need of compounds that are active against multidrug or pandrug resistant gram-negative pathogens. The aim of this review is to summarize the new generation of BLIs and β-lactams combinations. Recent findings A number of new molecules with activity against Ambler class A (e.g., extended-spectrum β-lactamases, serine carbapenemases), class C (e.g., AmpC), or class D (e.g., oxacillinase-48) have been recently approved in combination with old β-lactams for the treatment of multidrug-resistant bacteria, and other agents are under investigation. These new compounds include diazabicyclooctanones non-β-lactam inhibitors (e.g., avibactam, relebactam, nacubactam) and boronic acid inhibitors (e.g., vaborbactam). Summary Newly approved and investigational new BLIs are expected to offer many advantages for the management of patients with multidrug-resistant gram-negative pathogens. Promising characteristics of new compounds include high activity against multi drug resistance gram-negative bacteria and a favorable safety profile.

Clinical Experience with Ceftazidime-Avibactam for the Treatment of Infections due to Multidrug-Resistant Gram-Negative Bacteria Other than Carbapenem-Resistant Enterobacterales

“…In the absence of porin deficient mutations or efflux pumps, gram-negative resistance to pivotal antibiotics in our area is mainly mediated by the production of β-lactamases, such as class A (such as ESBL, KPC), class C (AmpC), and some class D enzymes (e.g., OXA 48) [22]. None of these affects ceftazidime-avibactam [23] and this context represents, in our opinion, the situation in which the drug could be used as an alternative to carbapenem for the treatment of MDR gram-negative pathogens [24].…”

In Vitro Activity of Cefiderocol, a Siderophore Cephalosporin, against Multidrug-Resistant Gram-Negative Bacteria

“…8,9 However, none of these combinations are active against Enterobacterales with MBLs, nor against the vast majority of carbapenemase-producing Pseudomonas aeruginosa and Acinetobacter baumannii. 10,11 Cefiderocol is a novel parenteral siderophore cephalosporin approved in the US for the treatment for complicated urinary tract infections (cUTI), and in the EU for the treatment of infections due to aerobic gram-negative bacteria in adults with on October 29, 2020 by guest http://aac.asm.org/ Downloaded from limited treatment options. It has a catechol moiety attached via its 3-side chain, allowing uptake into gram-negative bacteria via the ferric iron transporter system.…”

Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance

“…In our opinion, CAZ-AVI should be also considered as a possible therapeutic option for the treatment of severe infections due to ESBL- or AmpC-producing species, as well as DTR P. aeruginosa . The merits of this choice should be weighed up against those of reserving it for carbapenem-resistant strains [ 35 ] ( Table 2 and Table 3 ).…”

“…Cefepime/zidebactam has demonstrated potent in vitro activity against DTR GNB, against Enterobacteriales (including ESBL AmpC, KPCs, and OXA-48-producing strains), P. aeruginosa isolates with multiple resistance mechanisms including upregulated efflux, loss of OprD porins, and AmpC overproduction and Acinetobacter [ 35 , 87 ] ( Table 2 ).…”

“…The combination of avibactam with ceftaroline expands its antimicrobial spectrum covering ESBL, KPC, and AmpC-producing strains. Nevertheless, no activity against non-fermenting bacteria has been found [ 35 ] ( Table 2 ).…”