Though a single antibiotic may not overcome all resistance mechanisms, knowledge of the particular resistance mechanisms that are present in a bacterial strain can lead to effective directed combination therapy. For example, carbapenem resistant Enterobacteriaceae (CRE) containing metallo-β-lactamases (MBL) often have a complex molecular background in which multiple β-lactamases are present. Though routine genotyping to determine bacterial resistance mechanisms is not yet commonplace in the clinical setting, such practice can be useful in certain situations. Examples include the novel aminoglycoside plazomicin, novel cephalosporin ceftolozane (which was paired with tazobactam), and novel β-lactamase inhibitors such as avibactam, vaborbactam, and relebactam that were combined with existing β-lactam antibiotics to form drugs such as ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and aztreonam-avibactam. Food and Drug Administration (FDA)-approved for antibiotic use. These agents have been generally been developed through modification of drug classes that have previously been U.S. The study of resistance mechanisms has also been important in the pharmaceutical industry, as multiple novel agents have emerged to circumvent known resistance mechanisms. In the broadest sense, understanding the mechanisms of antibiotic resistance sheds light on how resistance arises and how it is transmitted between bacteria and to patients. Understanding the mechanisms and epidemiology of these resistance mechanisms is critical. Bacteria have demonstrated a diverse set of mechanisms for degrading antibiotics, modifying the antibiotic target site, or modulating the influx/efflux of antibiotic into or out of the bacterial cell. The adoption of genotyping and whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our knowledge of how antibiotic resistance emerges. This increased resistance has been quite meaningful to patients, clinicians, and the healthcare system generally as antibiotic resistance in gram-negative bacterial infections has been associated with both increased mortality and increased healthcare costs relative to infections with more susceptible bacterial strains. Due in large part to the selective pressure of antibiotic use, resistance has significantly increased in gram-negative bacteria over the past two decades. Gram-negative bacteria are ubiquitous in nature and cause infection in multiple body sites including the urinary tract, lower respiratory tract, biliary tract, and bloodstream, among others. This is distinct from the gram-positive bacteria which have a thick peptidoglycan cell wall. Gram-negative bacteria have a thin peptidoglycan cell wall sandwiched between their inner and outer membranes. 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. 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. 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. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. 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. 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.
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