An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris.

Pharmacodynamic Evaluation of Omadacycline against Staphylococcus aureus in the Neutropenic Mouse Pneumonia Model.

Omadacycline is an effective therapy for community-acquired bacterial pneumonia (CABP). Given its potent activity against methicillin-susceptible (MSSA) and methicillin-resistant (MRSA), we sought to determine the pharmacodynamic activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with a therapeutic effect in the neutropenic mouse pneumonia model against 10 MSSA/MRSA strains. The area under the concentration-time curve (AUC)/MIC associated with 1-log kill was noted at 24-h epithelial lining fluid (ELF) and plasma AUC/MIC exposures of ∼2 (ELF range, <0.

Pharmacodynamic Target Determination for Delafloxacin against Klebsiella pneumoniae and Pseudomonas aeruginosa in the Neutropenic Murine Pneumonia Model.

Delafloxacin is a broad-spectrum anionic fluoroquinolone that has completed a phase 3 study for community-acquired bacterial pneumonia. We investigated the pharmacodynamic target for delafloxacin against 12 and 5 strains in the neutropenic murine lung infection model. The median 24-h free-drug area under the curve (AUC)/MIC values associated with net stasis and 1-log kill were 28.

Pharmacodynamics of Omadacycline against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model.

Omadacycline is a novel aminomethylcycline antibiotic with potent activity against , including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA). We investigated the pharmacodynamic activity of omadacycline against 10 MSSA/MRSA strains in a neutropenic murine thigh model. The median 24-h area under the concentration-time curve (AUC)/MIC values associated with net stasis and 1-log kill were 21.

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against in an Model of Invasive Pulmonary Aspergillosis.

APX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6  isolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.

Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model.

NOSO-502 is a novel odilorhabdin antibiotic with potent activity against The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six and 6 isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter.

Identification of the Pharmacokinetics and Pharmacodynamic Driver of Iclaprim.

The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against ATCC 29213 and ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for (, 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (%>MIC) were strongly associated with effect (, 0.

Pharmacokinetics and Pharmacodynamics of APX001 against Candida spp. in a Neutropenic Disseminated Candidiasis Mouse Model.

APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for ( = 5), ( = 5), and ( = 4). MIC values ranged from 0.

Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model.

Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six isolates were utilized for the studies.

Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model.

Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the pharmacodynamic activity of omadacycline against Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.

Targeting Fibronectin To Disrupt In Vivo Candida albicans Biofilms.

New drug targets are of great interest for the treatment of fungal biofilms, which are routinely resistant to antifungal therapies. We theorized that the interaction of Candida albicans with matricellular host proteins would provide a novel target. Here, we show that an inhibitory protein (FUD) targeting Candida-fibronectin interactions disrupts biofilm formation in vitro and in vivo in a rat venous catheter model.

Intraluminal Release of an Antifungal β-Peptide Enhances the Antifungal and Anti-Biofilm Activities of Multilayer-Coated Catheters in a Rat Model of Venous Catheter Infection.

is the most prevalent cause of hospital-acquired fungal infections and forms biofilms on indwelling medical devices that are notoriously difficult to treat or remove. We recently demonstrated that the colonization of on the surfaces of catheter tube segments can be reduced in vitro by coating them with polyelectrolyte multilayers (PEMs) that release a potent antifungal β-peptide. Here, we report on the impact of polymer structure and film composition on both the inherent and β-peptide-mediated ability of PEM-coated catheters to prevent or reduce the formation of biofilms in vitro and in vivo using a rat model of central venous catheter infection.

Host contributions to construction of three device-associated Candida albicans biofilms.

Among the most fascinating virulence attributes of Candida is the ability to transition to a biofilm lifestyle. As a biofilm, Candida cells adhere to a surface, such as a vascular catheter, and become encased in an extracellular matrix. During this mode of growth, Candida resists the normal immune response, often causing devastating disease.

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model.

Antibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example.

Nontoxic antimicrobials that evade drug resistance.

Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century.

Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model.

Echinocandins inhibit the synthesis of β-1,3-D-glucan in Candida and are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors.

In vivo pharmacokinetics and pharmacodynamics of the lantibiotic NAI-107 in a neutropenic murine thigh infection model.

NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model.

Rat indwelling urinary catheter model of Candida albicans biofilm infection.

Indwelling urinary catheters are commonly used in the management of hospitalized patients. Candida can adhere to the device surface and propagate as a biofilm. These Candida biofilm communities differ from free-floating Candida, exhibiting high tolerance to antifungal therapy.

Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus.

Invasive pulmonary aspergillosis (IPA) continues to rise in concert with increasing numbers of immune suppression techniques to treat other medical conditions and transplantation. Despite these advances, morbidity and mortality rates remain unacceptably high. One strategy used to optimize outcomes is antifungal pharmacodynamic (PD) examination.

Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model.

Pharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively for Candida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole.

Synthesis and antibacterial activity of doxycycline neoglycosides.

A set of 37 doxycycline neoglycosides were prepared, mediated via a C-9 alkoxyamino-glycyl-based spacer reminiscent of that of tigecycline. Subsequent in vitro antibacterial assays against representative drug-resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2'-amino-α-D-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline-susceptible strain E.

Impact of in vivo triazole and echinocandin combination therapy for invasive pulmonary aspergillosis: enhanced efficacy against Cyp51 mutant isolates.

Previous studies examining combination therapy for invasive pulmonary aspergillosis (IPA) have revealed conflicting results, including antagonism, indifference, and enhanced effects. The most commonly employed combination for this infection includes a mold-active triazole and echinocandin. Few studies have evaluated combination therapy from a pharmacodynamic (PD) perspective, and even fewer have examined combination therapy against both wild-type and azole-resistant Cyp51 mutant isolates.

Preparation of Candida albicans Biofilms Using an in vivo Rat Central Venous Catheter Model.

biofilms grown on medical devices are necessary to understand the interactions of the fungal biofilm and the host environment in which it is most commonly found. This protocol describes a way to grow biofilms on the interior lumen of central venous catheters surgically implanted into rats, which mimics quite well the clinical cases of biofilms found on human central venous catheters. These infected catheters can then be studied via a multitude of different experiments, including cell counting by plating, imaging the catheters under light or electron microscopy, or comparing the relative content of biofilms to biofilms and planktonic cultures.

Posaconazole pharmacodynamic target determination against wild-type and Cyp51 mutant isolates of Aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A.

Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation.

A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed 'reverse' reaction to enable the facile attachment of an alkoxyamine-bearing sugar to the vancomycin core. Neoglycosylation of the corresponding aglycon led to a novel set of vancomycin 1,6-disaccharide variants.