Epidemiology and Mechanisms of Resistance of Extensively Drug Resistant Gram-Negative Bacteria

Abstract

Antibiotic resistance has increased markedly in gram-negative bacteria over the last two decades, and in many cases has been associated with increased mortality and healthcare costs. The adoption of genotyping and next generation whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our understanding of how antibiotic resistance develops and transmits among bacteria and between patients. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. These fundamental insights into the mechanisms of gram-negative antibiotic resistance have influenced the development of novel antibiotics and treatment practices in highly resistant infections. Here, we review the mechanisms and global epidemiology of antibiotic resistance in some of the most clinically important resistance phenotypes, including carbapenem resistant Enterobacteriaceae, extensively drug resistant (XDR) Pseudomonas aeruginosa, and XDR Acinetobacter baumannii. Understanding the resistance mechanisms and epidemiology of these pathogens is critical for the development of novel antibacterials and for individual treatment decisions, which often involve alternatives to β-lactam antibiotics.

Non‐invasive, ratiometric determination of intracellular pH in Pseudomonas species using a novel genetically encoded indicator

“…On the other hand, the phenomenon of pH increase upon antibiotic treatment could be affected by the nature of the bacteria tested [e.g. Gram‐positive versus Gram‐negative species (Eichenberger and Thaden, )], and also the experimental conditions used (e.g. addition of antibiotics at the onset of the cultivation or during active growth of the bacterial cells).…”

Constructing and deconstructing the bacterial cell wall

“…Gram-negative bacteria use their second membrane as a barrier to antibiotic permeation, and to populate their periplasmic "moat" with both plasmid-encoded resistance enzymes and multiprotein motility and virulence complexes. 37,208,209 Given our long-standing interest in the β-lactamases as a pre-eminent Gram-negative defense against β-lactams 210 our focus turned several years ago to the relationship between β-lactamase expression and the peculiar mechanism used by Gram-negative bacteria to expand (grow) their peptidoglycan polymer. Extensive portions of the Gramnegative peptidoglycan are removed, degraded, and recycled during peptidoglycan growth.…”

“…And indeed, less than a century after the widespread medical use of antibiotics, extensively resistant-and thus powerfully pathogenic bacteriahave arrived. [30][31][32][33][34][35][36][37] Their emergence was not a surprise. 38 Notwithstanding the widespread scientific appreciation of the monumental difficulty to secure new generations of antibiotic structure to vanquish these multidrug and extensively-drug resistant bacteria, [39][40][41] the paths toward surmounting this response are recognized.…”

“…The result is antibiotic‐resistant bacteria. And indeed, less than a century after the widespread medical use of antibiotics, extensively resistant—and thus powerfully pathogenic bacteria—have arrived …”

Some Properties of Adsorptive Carbon Dressing Applicable to Questions of Postoperative Treatment of Wounds in Rats With Guerin Carcinoma

“…Многообразие биохимических механизмов антибиотикорезистентности, включает: модификацию мишени действия АБП; снижение/утрату способности мишени связываться с АБП; их инактивацию; эффлюкс АБП из микробной клетки; модуляцию проницаемости оболочки микробной клетки и резкое снижение эффективности транспорта АБП, и, наконец, способность бактерий синтезировать белки, предотвращающие связы-вание АБП с мишенью [5,6] и лежит в основе «системы быстрого реагирования» и появления новых устойчивых форм микроорганизмов [7]. Неуклонный рост лекарственно-устойчивых инфекций, высокая стоимость создания новых АБП и растущее нежелание фармацевтических компаний заниматься этим диктуют необходимость разработки новых антимикробных стратегий, одной из которых является разработка раневых покрытий, противомикробное действие которых носит неспецифический характер.…”