New antimicrobial treatment options for severe Gram-negative infections

Abstract

Purpose of reviewThis review will provide rationale for the development of new antibiotics to treat severe or multidrug-resistant (MDR) Gram-negative infections. It will also provide an overview of recently approved and pipeline antibiotics for severe/MDR Gram-negative infections.Recent findingsMDR Gram-negative infections are recognized as critical threats by global and national organizations and carry a significant morbidity and mortality risk. Increasing antibiotic resistance amongst Gram-negative bacteria, including carbapenem-resistant Acinetobacter baumannii, extended-spectrum β-lactamase-producing Enterobacterales, carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa, with difficult-to-treat-resistance has made both empiric and definitive treatment of these infections increasingly problematic. In recent years, several antibiotics have been approved for treatment of MDR Gram-negative infections and ongoing clinical trials are poised to provide additional options to clinicians’ armamentarium. These agents include various β-lactam/β-lactamase inhibitor combinations, eravacycline, plazomicin and cefiderocol.SummarySevere/MDR Gram-negative infections continue to be important infections due to their impact on patient outcomes, especially in critically ill and immunocompromised hosts. The availability of new antibiotics offers an opportunity to improve empiric and definitive treatment of these infections.

Update on the Management of Surgical Site Infections

“…Cefiderocol has also demonstrated activity against Acinetobacter and is currently the only β-lactam displaying such activity against this microorganism [ 61 ]. While Eravacycline has demonstrated some in vitro activity against A. baumannii [ 83 ], only Colistin and cefiderocol have shown significant activity against this pathogen [ 61 , 83 ]. The cefiderocol treatment reached predefined non-inferiority status in clinical trials, despite a mortality imbalance reported in the CREDIBLE-CR study [ 61 ].…”

“…Eravacycline has successfully completed phase three of the clinical trial for the treatment of cIAI (complicated intra-abdominal infections) [ 93 ] and it was non inferior to Ertapenem or Meropenem in a phase III, randomized, double-blind clinical trial of patients with appendicitis, cholecystitis, diverticulitis, gastric or duodenal perforation and peritonitis [ 93 ]. It could be a suitable candidate for the treatment of cIAI caused by XDR, and even PDR pathogens, such as Enterobacterales ESBL, KPC and MBL; A. baumannii , taking into account that its spectrum of action also includes Enterococci ; and MRSA and anaerobes [ 83 ]. Therefore, further clinical studies addressing the efficacy of Eravacycline in difficult-to-treat infections is required.…”

“…It is not active against Acinetobacter baumannii , Stenotrophomonas maltophilia and anaerobes, but its activity is variable activity against Pseudomonas aeruginosa . It is currently approved for complicated urinary tract infections, including pyelonephritis, caused by aerobic Gram-negative bacilli [ 83 , 94 ].…”

Clinical Approach to Nosocomial Bacterial Sepsis

“…Cefiderocol is a siderophore cephalosporin with activity against most gram-negative bacteria, including ESBL and carbapenemase-producing organisms) and multidrug-resistant pseudomonas, acinetobacter, stenotrophomonas and burkholderia [19].…”

The effect of Lactobacillus with prebiotics on KPC-2-producing Klebsiella pneumoniae

“…Among MDROs, carbapenem-resistant gram-negative bacteria, including carbapenem-resistant Enterobacterales (CREs), Acinetobacter baumannii and Pseudomonas aeruginosa , have become the common cause of health care-associated infections and pose a great threat to global health ( Dadgostar, 2019 ; Lai and Yu, 2021 ; Wozniak et al, 2022 ; Jean et al, 2022b ). Both the World Health Organization and Centers for Disease Control and Prevention have designated that CRE, such as Klebsiella species, Escherichia coli and Enterobacter species, are the most crucial emerging resistance threats worldwide ( Hetzler et al, 2022 ; Lodise et al, 2022 ; Oka et al, 2022 ; Sy et al, 2022 ; Jean et al, 2022a ). The most common resistance mechanism of carbapenem resistance in Enterobacterales is the synthesis of carbapenemase enzymes, which include class A Klebsiella pneumoniae carbapenemase (KPC), class B metallo-β-lactamases, and class D OXA β-lactamases ( Durante-Mangoni et al, 2019 ).…”