Antibiotic treatment of critically ill patients with sepsis: From FK/FD to novel drugs
Authors: Šurbatović Maja , Perić Aneta , Rakić Goran , Jevđić Jasna 
Published: May 2023

Early detection of sepsis and its severity is critical for initiating proper therapy, including antibiotics, as soon as possible to maximize survival chances. Understanding the pathophysiological changes in septic shock that impact antimicrobial pharmacokinetics and pharmacodynamics (PK/PD), understanding the basics of PK/PD, and knowing PK-PD strategies in septic shock patients are all critical for appropriate therapy. By definition multi-drug resistant (MDR) microorganisms are those with acquired non-susceptibility to at least one agent in three or more antimicrobial categories. In the race between bacteria and novel antibiotics development, unfortunately, the number of new antibiotics/indications is not keeping pace with resistance and needs, especially for MDR Gram-negative microorganisms. When we fast forward to the approved antibiotics in the last five years, the list is rather short. Lefamulin is a novel pleuromutilin antibiotic which manifests activity against most Gram-positive pathogens. Cefiderocol is an injectable siderophore cephalosporin. Like other b-lactam antibiotics, it inhibits Gram-negative bacterial cell wall formation by binding to penicillin-binding proteins. Imipenem/cilastatin/relebactam is a new b-lactam/b-lactamase inhibitor combination with activity against MDR Gram-negative bacteria, including many CRE but excluding Metallo-b-lactamase (MBL)-producing Enterobacterales and CRAB. Those three antibiotics were FDA approved in 2019 and European Medicines Agency (EMA) approved in 2020. Plazomicin is a new semisynthetic aminoglycoside with activity against several MDR Gram-negative organisms, including CRE (FDA-approved in 2018). Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid b-lactamase inhibitor with potent activity against resistant Gram-negative bacteria like Klebsiella pneumoniae carbapenemase (KPC)-producing CRE; it is inactive against CRAB (FDA-approved in 2017; EMA-approved in 2018). Eravacycline is a new completely synthesized fluorocycline. It has a high level of effectiveness against Grampositive and Gram-negative bacterial strains that have developed tetracycline-specific resistance mechanisms; it is inactive against Pseudomonas aeruginosa (FDAand EMA-approved in 2018). Concluding this list of recently approved antibiotics is omadacycline, novel aminomethylcycline and a derivative of minocycline, with a chemical structure similar to tigecycline. Like other tetracyclines, omadacycline inhibits bacterial protein synthesis and possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria including CRAB. It is inactive against Pseudomonas aeruginosa (FDA-approved in 2018). There are three novel carbapenems sulopenem, tebipenem pivoxil hydrobromide and benapenem. There is a group of antibiotics in phase III clinical trials: the combination aztreonam/ avibactam, sulbactam/durlobactam, cefepime/enmetazobactam, cefepime/zidebactam, cefepime/taniborbactam. An interesting approach to antimicrobial treatment is antimicrobial drug repurposing. Drug combinations could be a strategy to extend the life of antibiotics in the XXI century due to the multi-targeting mechanisms of agents. New active substances are urgently required to stop the spread of antibiotic-resistant bacteria. However, it could be a rather cumbersome and expensive procedure. Antimicrobial misuse and/or overuse contribute greatly to this very important global healthcare problem.