Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistant in a murine infection model.

LPC-233 (a.k.a.

Engineered antibodies targeted to bacterial surface integrate effector functions with toxin neutralization to provide superior efficacy against bacterial infections.

Anti-bacterial monoclonal antibody (mAb) therapies either rely on toxin neutralization or opsonophagocytic killing (OPK). Toxin neutralization protects the host from toxin-induced damage, while leaving the organism intact. OPK inducing antibodies clear the bacteria but leave the released toxins unencountered.

Tolfenpyrad Derivatives Exhibit Potent -Specific Antibacterial Activity without Toxicity to Mammalian Cells .

Tularemia is a deadly disease caused by , an emerging intracellular bacterial pathogen that can be disseminated rapidly through aerosols and vector-borne transmission. Recent surveillance data demonstrate an increasing incidence in several countries. Although clinical isolates of strains are sensitive to currently used antibiotics, engineered or horizontal acquisition of antibiotic resistance is a constant threat to public health.

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.

A Resistance-Evading Antibiotic for Treating Anthrax.

The antimicrobial resistance crisis (AMR) is associated with millions of deaths and undermines the franchise of medicine. Of particular concern is the threat of bioweapons, exemplified by anthrax. Introduction of novel antibiotics helps mitigate AMR, but does not address the threat of bioweapons with engineered resistance.

Tolfenpyrad displays -targeted antibiotic activity that requires an oxidative stress response regulator for sensitivity.

species are highly pathogenic bacteria that pose a threat to global health security. These bacteria can be made resistant to antibiotics through facile methods, and we lack a safe and protective vaccine. Given their history of development as bioweapons, new treatment options must be developed to bolster public health preparedness.

The BALB/c Mouse Model for the Evaluation of Therapies to Treat Infections with Aerosolized .

, the causative agent of the disease melioidosis, has been isolated from the environment in 45 countries. The treatment of melioidosis is complex, requiring lengthy antibiotic regimens, which can result in the relapse of the disease following treatment cessation. It is important that novel therapies to treat infections with be assessed in appropriate animal models, and discussions regarding the different protocols used between laboratories are critical.

Gepotidacin is efficacious in a nonhuman primate model of pneumonic plague.

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode and has the potential to treat a number of bacterial diseases. Development of this new agent to treat pneumonic plague caused by depends on the U.S.

Rational design of a new antibiotic class for drug-resistant infections.

The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including β-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of β-lactamases, the primary resistance mechanism associated with β-lactam therapy in Gram-negative bacteria.

and Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens.

and , causative pathogens for anthrax and plague, respectively, along with and are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the activity and efficacy of tebipenem against biothreat pathogens.

Validated Methods for Removing Select Agent Samples from Biosafety Level 3 Laboratories.

The Federal Select Agent Program dictates that all research entities in the United States must rigorously assess laboratory protocols to sterilize samples being removed from containment areas. We validated procedures using sterile filtration and methanol to remove the following select agents: Francisella tularensis, Burkholderia pseudomallei, B. mallei, Yersinia pestis, and Bacillus anthracis.

GC-072: A Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens.

(), the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from varies depending on the type of infection and extent of available health care, but in the case of septicemia left untreated it can range from 50 - 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for two weeks or longer, followed by oral eradication-phase treatment lasting several months.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively.

Antibiotic Susceptibilities of Francisella tularensis Determined by Broth Microdilution following CLSI Methods.

susceptibilities for 47 antibiotics were determined in 30 genetic diverse strains of by the broth microdilution method following Clinical and Laboratory Standards Institute (CLSI) methods. The strains demonstrated susceptibility to aminoglycosides, fluoroquinolones, and tetracyclines. There was a distinct difference in macrolide susceptibilities between A and B type strains, as has been noted previously.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.

TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active against a panel of 29 isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.

Natural History of Francisella tularensis in Aerosol-Challenged BALB/c Mice.

The objective of this study was to evaluate the natural history and pathogenesis of Francisella tularensis in a murine model of inhalational tularemia with the SchuS4 strain. Before the efficacy of antimicrobials could be assessed in this model, further model development was required to determine the optimal time to start therapy. This study helped define the time course of infection after aerosol challenge by quantifying the presence of bacteria in lung, blood, and spleen at multiple harvest points.

In vitro antibiotic susceptibilities of Yersinia pestis determined by broth microdilution following CLSI methods.

In vitro susceptibilities to 45 antibiotics were determined for 30 genetically and geographically diverse strains of Yersinia pestis by the broth microdilution method at two temperatures, 28°C and 35°C, following Clinical and Laboratory Standards Institute (CLSI) methods. The Y. pestis strains demonstrated susceptibility to aminoglycosides, quinolones, tetracyclines, β-lactams, cephalosporins, and carbapenems.

Evaluation of imipenem for prophylaxis and therapy of Yersinia pestis delivered by aerosol in a mouse model of pneumonic plague.

It has been previously shown that mice subjected to an aerosol exposure to Yersinia pestis and treated with β-lactam antibiotics after a delay of 42 h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic-treated mice accounted for the accelerated death rate in the mice exposed to aerosol Y. pestis.

Natural history of Yersinia pestis pneumonia in aerosol-challenged BALB/c mice.

After a relatively short untreated interval, pneumonic plague has a mortality approaching 100%. We employed a murine model of aerosol challenge with Yersinia pestis to investigate the early course of pneumonic plague in the lung, blood, and spleen. We fit a mathematical model to all data simultaneously.

Impact of spores on the comparative efficacies of five antibiotics for treatment of Bacillus anthracis in an in vitro hollow fiber pharmacodynamic model.

Bacillus anthracis, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for B. anthracis infections is unknown.

Differential effects of linezolid and ciprofloxacin on toxin production by Bacillus anthracis in an in vitro pharmacodynamic system.

Bacillus anthracis causes anthrax. Ciprofloxacin is a gold standard for the treatment of anthrax. Previously, using the non-toxin-producing ΔSterne strain of B.

Comparative efficacies of candidate antibiotics against Yersinia pestis in an in vitro pharmacodynamic model.

Yersinia pestis, the bacterium that causes plague, is a potential agent of bioterrorism. Streptomycin is the "gold standard" for the treatment of plague infections in humans, but the drug is not available in many countries, and resistance to this antibiotic occurs naturally and has been generated in the laboratory. Other antibiotics have been shown to be active against Y.

Comparison of Etest method with reference broth microdilution method for antimicrobial susceptibility testing of Yersinia pestis.

The utility of Etest for antimicrobial susceptibility testing of Yersinia pestis was evaluated in comparison with broth microdilution and disk diffusion for eight agents. Four laboratories tested 26 diverse strains and found Etest to be reliable for testing antimicrobial agents used to treat Y. pestis, except for chloramphenicol and trimethoprim-sulfamethoxazole.

Efficacy of Daptomycin against Bacillus anthracis in a murine model of anthrax spore inhalation.

Daptomycin demonstrated in vitro (MIC(90), 4 μg/ml) and in vivo activities against Bacillus anthracis. Twice-daily treatment with a dose of 50 mg/kg of body weight was begun 24 h after challenge and continued for 14 or 21 days; results were compared to those for controls treated with phosphate-buffered saline or ciprofloxacin. Day 43 survival rates were 6/10 mice for the 14-day and 9/10 mice for the 21-day treatment groups, compared to survival with ciprofloxacin: 8/10 and 9/10 mice, respectively.

Pharmacokinetic-pharmacodynamic assessment of faropenem in a lethal murine Bacillus anthracis inhalation postexposure prophylaxis model.

There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B.