Developments for the Treatment of Invasive Infections Due to Multidrug-resistant Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a significant pathogen in healthcare settings (specifically prominent in healthcare-and ventilator-associated pneumonia) due primarily to its virulence and resistance to a wide variety of antimicrobial drug classes, including carbapenems (CRAB). Existing therapies (notably polymyxins, minocycline, tigecycline, amikacin, and sulbactam) often result in suboptimal tissue concentrations, high rates of toxicity, and increasing rates of resistance. Although utilizing combinations of antibiotics (specifically those containing colistin) have been employed, results have been mixed, and control trials are lacking. Eravacycline is a novel tetracycline with an improved pharmacokinetic profile and more potent activity against A. baumannii relative to tigecycline. Cefiderocol has a unique mechanism of action that has performed well in vitro against multidrugresistant (MDR) and CRAB isolates. Limited clinical data exists with each of these agents. Other novel antimicrobials are still in early phase clinical trials (ETX2514/sulbactam, TP-271, TP-6076, VNRX-5133/cefepime, cefepime/zidebactam, AIC-499, GSK3342830, and SPR741) while further research is underway for non-antibiotic approaches, specifically monoclonal antibodies and bacteriophage therapies.

The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol

“…Addition of avibactam (a serine β-lactamase inhibitor), decreased cefiderocol MICs of PER-producing strains for more than 4-fold. NDA producing strains showed ≥4-fold lower MICs only when combination of avibactam and dipicolinic acid (metallo-β-lactamase inhibitor) were added indicating that resistance mechanism of these strains was due to additional β-lactamases ( Laurent et al, 2019 ). Resistance to cefiderocol may arise from mutations in genes involved in iron uptake.…”

Siderophore‑antibiotic conjugates: structural diversity and antibacterial activity

“…Цефидерокол 46 и его антибактериальная актив ность является предметом обсуждения во многих об зорных статьях, подробно ознакомиться с которыми можно по ссылкам [112][113][114]. В одной из послед них публикаций [114] была проведена оценка актив ности in vitro большого числа антибиотиков в отноше нии нескольких штаммов Stenotrophomonas maltophilia.…”

“…Цефидерокол стал первым конъюгатом сидеро форбеталактамный антибиотик, одобренным FDA. Ни один другой подобный конъюгат (например, цефетекол 49 и GSK3342830 50 [113,[115][116][117][118][119]) не прошел да лее I фазы клинических испытаний [115] (Рисунок 20). Активность цефетекола in vitro не подтвердилась в экс периментах in vivo, а конъюгат GSK3342830 обладал плохой переносимостью при применении у доброволь цев [117,120].…”