Current and Potential Therapeutic Options for Infections Caused by Difficult-to-Treat and Pandrug Resistant Gram-Negative Bacteria in Critically Ill Patients

Abstract

Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel β-lactam-β-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented.

In vitro activities of omadacycline, eravacycline, cefiderocol, apramycin, and comparator antibiotics against Acinetobacter baumannii causing bloodstream infections in Greece, 2020–2021: a multicenter study

“…The major problem is their limited commercial availability. Εravacycline is unavailable in Europe and cefiderocol has only been recently launched in a few European countries (United Kingdom, Germany and Italy), mostly serving compassionate use purposes [ 8 ].…”

Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

“…While double-carbapenem treatment is sometimes referred to as a therapeutic option, clinical evidence is lacking [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Moreover, in vitro data on the synergistic effects are conflicting, and there is a lack of consensus on which carbapenems should be combined to best counteract the different enzymes [ 12 , 20 , 21 , 22 , 23 , 24 ].…”

Peptaibol Analogs Show Potent Antibacterial Activity against Multidrug Resistant Opportunistic Pathogens

“…Several trichogin analogs were found to be active against epidemiologically relevant MDR and XDR clinical isolates, including WHO "critical priority" pathogens for antibiotic research and development, with negligible hemolytic activity. The peptides were also active against XDR P. aeruginosa, against which only a limited number of antibiotics currently under development are active [55,56]. A structure-activity relationship built on CD analysis under different experimental conditions indicated that a well-defined helical conformation in water is needed for the peptides to exert their antimicrobial activity.…”