Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

Abstract

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.

Epidemiology, Mechanisms of Resistance and Treatment Algorithm for Infections Due to Carbapenem-Resistant Gram-Negative Bacteria: An Expert Panel Opinion

“…The latter one can protect imipenem from degradation by Ambler class A and class C beta-lactamases and from Pseudomonas -derived cephalosporinase (PDC); however, relebactam is not active against class B metallo-beta-lactamases or class D oxacillinases [ 70 ]. At any rate, the addition of relebactam does not enhance the activity of imipenem against A. baumannii and Stenotrophomonas maltophilia [ 76 ]. Imipenem/cilastatin/relebactam is approved in the United States, as well as in the European Union, in adults for the treatment of nosocomial pneumonia, cUTIs, cIAIs and other infections by antibiotic-resistant Gram-negative pathogens (essentially carbapenem-resistant Enterobacterales and Pseudomonas ) in the case of limited or no alternative treatment options [ 75 ].…”

Meropenem/Vaborbactam and Cefiderocol as Combination or Monotherapy to Treat Multi-Drug Resistant Gram-Negative Infections: A Regional Cross-Sectional Survey from Piedmont Infectious Disease Unit Network (PIDUN)

“…Among the most difficult resistance mechanisms to treat are the production of extended-spectrum beta-lactamases (ESBL), ampicillinase C (AmpC), carbapenemases (CP), Metallo-beta-lactamases (MBL) and oxacillinase (OXA) enzymes released by Gram-negative bacteria [ 1 ]. However, exciting developments of new antimicrobial drugs, especially anti-Gram-negative antibiotics with a spectrum covering multidrug-resistant microorganisms (MDROs), have characterised research innovations in the last several years [ 2 , 3 , 4 ]. Although, the rapid evolution of antimicrobial regimens and options against MDROs requires infectious diseases specialists to constantly update their knowledge and engage in continuous research to make the best use of new molecules and insert them correctly into antimicrobial stewardship programmes (ASPs) [ 5 ].…”

“…Meropenem/vaborbactam is a novel carbapenem-boronic acid β-lactamase inhibitor formulation that presents antimicrobial activity against classes A and C β-lactamase-producing Enterobacterales , especially those producing the ESBL, KPC and AmpC determinants [ 2 , 3 ]. The efficacy, tolerability, and safety of meropenem/vaborbactam for the treatment of complicated urinary tract infections (cUTIs) and acute pyelonephritis have been investigated in phase 3 non-inferiority trial, TANGO I [ 10 ].…”

“…Second, cefiderocol is a combination of a catechol-type siderophore and a cephalosporin core with side chains similar to cefepime and ceftazidime [ 2 , 4 ]; its structure and mechanism of action confer enhanced stability against hydrolysis by many β-lactamases, such as CTX-M, and carbapenemases, such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58 [ 2 , 4 ]. Cefiderocol has a broad antibacterial spectrum against a variety of aerobic bacteria, including Enterobacterales , Acinetobacter spp., Pseudomonas spp., Burkholderia spp.…”

“…Cefiderocol has a broad antibacterial spectrum against a variety of aerobic bacteria, including Enterobacterales , Acinetobacter spp., Pseudomonas spp., Burkholderia spp. and Stenotrophomonas maltophilia [ 2 , 4 ]. In cefiderocol studies, there appears to be a trend towards poorer outcomes compared to standard antibiotic therapy if the bacterium is not multi-drug resistant [ 2 , 4 , 12 , 13 ].…”