Omadacycline is active and against ciprofloxacin-resistant .

, the causative agent of anthrax, is among the most likely bacterial pathogens to be used in a biological attack. Inhalation anthrax is a serious, life-threatening form of infection, and the mortality from acute inhaled anthrax can approach 100% if not treated early and aggressively. Food and Drug Administration-approved antibiotics indicated for post-exposure prophylaxis (PEP) or treatment of anthrax are limited.

Efficacies of omadacycline + amikacin + imipenem and an all-oral regimen omadacycline + clofazimine + linezolid in a mouse model of lung disease.

Treatment outcomes for (, also known as ) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against .

Efficacies of three drug regimens containing omadacycline to treat Mycobacteroides abscessus disease.

Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) causes opportunistic pulmonary and soft tissue infections that are difficult to cure with existing treatments. Omadacycline, a new tetracycline antibiotic, exhibits potent in vitro and in vivo activity against Mab. As regimens containing multiple antibiotics are required to produce a durable cure for Mab disease, we assessed efficacies of three three-drug combinations in a pre-clinical mouse model of pulmonary Mab disease to identify companion drugs with which omadacycline exhibits the highest efficacy.

A Review of Omadacycline for Potential Utility in the Military Health System for the Treatment of Wound Infections.

Introduction: Combat-related wound infections complicate the recovery of wounded military personnel, contributing to overall morbidity and mortality. Wound infections in combat settings present unique challenges because of the size and depth of the wounds, the need to administer emergency care in the field, and the need for subsequent treatment in military facilities. Given the increase in multidrug-resistant pathogens, a novel, broad-spectrum antibiotic is desired across this continuum of care when the standard of care fails.

Efficacy of Omadacycline-Containing Regimen in a Mouse Model of Pulmonary Mycobacteroides abscessus Disease.

Mycobacteroides abscessus is an opportunistic pathogen in people with structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Pulmonary M. abscessus infection causes progressive symptomatic and functional decline as well as diminished lung function and is often incurable with existing antibiotics.

Pathogens susceptible to tetracycline are also susceptible to omadacycline: tetracycline as a one-sided surrogate to predict omadacycline susceptible pathogens.

This study used surveillance data from a global program of clinical bacterial isolates to determine whether a tetracycline susceptible result can be used to predict an omadacycline susceptible result. Categorical agreement, very major error rates, and minor error rates were calculated for Staphylococcus aureus (MSSA and MRSA; n=38,364), S. lugdunensis (n=335), Streptococcus pneumoniae (n=11,725), S.

Omadacycline and : A Systematic Review of Preclinical and Clinical Evidence.

Objective: The objective of this systematic review is to summarize in vitro, preclinical, and human data related to omadacycline and infection (CDI).

Data Sources: PubMed and Google Scholar were searched for "omadacycline" AND ("" OR "" OR "") for any studies published before February 15, 2022. The US Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) was searched for omadacycline (for reports including "" or "CDI" or "gastrointestinal infection").

Activity of omadacycline in vitro against Clostridioides difficile and preliminary efficacy assessment in a hamster model of C. difficile-associated diarrhoea.

Objectives: Antibiotics are associated with increased risk of Clostridioides difficile infection, which has limited treatment options. We assessed in vitro activity of omadacycline (an aminomethylcycline antibiotic) against the C. difficile infection strain and efficacy in a hamster model of C.

Sub-growth-inhibitory concentrations of omadacycline inhibit haemolytic activity .

Objectives: To evaluate the effect of sub-growth-inhibitory concentrations of omadacycline on ATCC 10832 haemolytic activity .

Methods: Following determination of the MICs of omadacycline and comparator antibiotics, the strain was grown in the presence of individual antibiotics and the percentage of haemolysis assayed; 'washout' experiments were performed with omadacycline only.

Results: Omadacycline inhibited haemolytic activity at sub-growth-inhibitory concentrations.

Activity of Omadacycline in Rat Methicillin-Resistant Staphylococcus aureus Osteomyelitis.

Omadacycline, vancomycin, and rifampin, as well as rifampin combination therapies, were evaluated in an experimental rat model of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. All treatment groups had less MRSA recovered than saline-treated animals. The emergence of rifampin resistance was observed in 3 of 16 animals with rifampin monotherapy and none with rifampin combination therapy.

Potency of Omadacycline against Mycobacteroides abscessus Clinical Isolates and in a Mouse Model of Pulmonary Infection.

The incidence of nontuberculous mycobacterial diseases in the United States is rising and has surpassed that of tuberculosis. Most notable among the nontuberculous mycobacteria is Mycobacteroides abscessus, an emerging environmental opportunistic pathogen capable of causing chronic infections. M.

Potent LpxC Inhibitors with Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against We report here the antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials.

Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase.

A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against and , respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents.

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety.

Plazomicin Is Active Against Metallo-β-Lactamase-Producing Enterobacteriaceae.

Plazomicin is an aminoglycoside that was approved in June 2018 by the US Food and Drug Administration for the treatment of complicated urinary tract infections, including pyelonephritis, due to , , , and . Plazomicin was engineered to overcome the most common aminoglycoside resistance mechanism, inactivation by aminoglycoside-modifying enzymes, but is not active against the less common 16S ribosomal RNA methyltransferases (16S-RMTase), which confer target site modification. As an aminoglycoside, plazomicin maintains activity against Enterobacteriaceae that express resistance mechanisms to other antibiotic classes, including metallo-β-lactamases.

In vitro activity of Plazomicin against Enterobacteriaceae isolates carrying genes encoding aminoglycoside-modifying enzymes most common in US Census divisions.

Aminoglycoside-nonsusceptible isolates of Escherichia coli, Klebsiella, Proteus, and Enterobacter species (480/3675) from US hospitals collected during 2014-2015 were screened for 16S rRNA methyltransferase and aminoglycoside-modifying enzyme (AME) genes. Only 5 isolates had high aminoglycoside MICs and carried 16S rRNA methyltransferases. AME genes were observed among 89.

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation.

Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally.

Activity of plazomicin compared with other aminoglycosides against isolates from European and adjacent countries, including Enterobacteriaceae molecularly characterized for aminoglycoside-modifying enzymes and other resistance mechanisms.

Background: Plazomicin is a next-generation aminoglycoside that was developed to overcome common aminoglycoside-resistance mechanisms.

Objectives: We evaluated the activity of plazomicin and comparators against clinical isolates collected from 26 European and adjacent countries during 2014 and 2015 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends (ALERT) global surveillance programme.

Methods: All 4680 isolates collected from 45 hospitals were tested for susceptibility to antimicrobials using the reference broth microdilution method.

Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes.

Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program.

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes.

Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compound was designed by chemical modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chemically alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one aminoglycoside resistance enzymes.

Antimicrobial activity of plazomicin against Enterobacteriaceae-producing carbapenemases from 50 Brazilian medical centers.

Plazomicin is a next-generation aminoglycoside with activity against Enterobacteriaceae, including carbapenemase-producing Enterobacteriaceae (CPE). The aim of this study was to evaluate the activity of plazomicin against CPE (Klebsiella spp., Escherichia coli, Serratia spp.

Aminoglycosides: An Overview.

Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes. They were among the first antibiotics to be introduced for routine clinical use and several examples have been approved for use in humans. They found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones.