Newly developed antibiotics against multidrug-resistant and carbapenem-resistant Gram-negative bacteria: action and resistance mechanisms

Abstract

Antimicrobial resistance stands as one of the most urgent global health concerns in the twenty-first century, with projections suggesting that deaths related to drug-resistant infections could escalate to 10 million by 2050 if proactive measures are not implemented. In intensive care settings, managing infections caused by multidrug-resistant (MDR) Gram-negative bacteria is particularly challenging, posing a significant threat to public health and contributing substantially to both morbidity and mortality. There are numerous studies on the antibiotics responsible for resistance in Gram-negative bacteria, but comprehensive research on resistance mechanisms against new antibiotics is rare. Considering the possibility that antibiotics may no longer be effective in combating diseases, it is crucial to comprehend the problem of emerging resistance to newly developed antibiotics and to implement preventive measures to curb the spread of resistance. Mutations in porins and efflux pumps play a crucial role in antibiotic resistance by altering drug permeability and active efflux. Porin modifications reduce the influx of antibiotics, whereas overexpression of efflux pumps, particularly those in the resistance-nodulation-cell division (RND) family, actively expels antibiotics from bacterial cells, significantly lowering intracellular drug concentrations and leading to treatment failure.

This review examines the mechanisms of action, resistance profiles, and pharmacokinetic/pharmacodynamic characteristics of newly developed antibiotics designed to combat infections caused by MDR and carbapenem-resistant Gram-negative pathogens. The antibiotics discussed include ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, meropenem-vaborbactam, aztreonam-avibactam, delafloxacin, temocillin, plazomicin, cefiderocol, and eravacycline.