Insights and Opinions of Critical Care Healthcare Professionals in the Management of Carbapenem-resistant Enterobacteriaceae Cases and Antibiotic-Resistant Infections in the Intensive Care Unit Setting: A Survey-Based Approach.

INTRODUCTION: A survey-based approach to managing antibiotic-resistant infections in the intensive care unit (ICU) setting, with a focus on carbapenem-resistant Enterobacteriaceae (CRE) cases, was conducted. Among CRE, New Delhi metallo-ß-lactamase 1 (NDM-1) is a carbapenemase that is resistant to ß-lactam antibiotics and has a broader spectrum of antimicrobial resistance than other carbapenemase types. The article explains that healthcare-associated infections (HAIs) are a significant problem, particularly in low- and middle-income countries, and that carbapenem in combination with other antibiotics are the most potent class of antimicrobial agents effective in treating life-threatening bacterial infections, including those caused by resistant strains. AIM: The survey aimed to gather critical care healthcare professionals (HCPs') opinions on their current practices in managing infections acquired in the hospital and ICU settings, with a focus on CRE cases, specifically NDM-1 and other antibiotic-resistant infections. METHODS: Responses from critical care healthcare professionals, including online surveys and in-person interviews, to gain insights into the management of infections caused by multidrug-resistant bacteria. The findings related to the insights on the prevalence of bacterial flora, clinical experiences on efficacy and safety of meropenem sulbactam ethylenediaminetetraacetic acid (EDTA) (MSE) in CRE cases, and various combination therapies of antibiotics used to treat antibiotic-resistant infections in ICU setting were evaluated. RESULTS: Klebsiella pneumoniae bacteria were the most common bacteria in cultures, followed by Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. NDM-1 was the type of carbapenemase found in around 50% of CRE patients. MSE is among the most preferred antibiotics besides colistin, polymyxin B, and ceftazidime avibactum for CRE cases and specifically for NDM-1 cases due to its high rate of efficacy and safety. CONCLUSION: The article concludes with a discussion on the antibiotics used in response to CRE cases, reporting that critical care HCP considers MSE with high efficacy and safe antibiotic combination and was used as both monotherapy and in combination with other antibiotics. The survey highlights the need for exploring and better understanding the role of MSE in the management of CRE infections, especially in NDM-1.

Dynamics of Drop Formation in the Presence of Interfacial Mass Transfer.

The dynamics of drop formation have been investigated in the presence of interfacial mass transfer through controlled flow visualization experiments. The mixtures of n-hexane (solvent) and acetone (solute) were used as a dispersed phase, having different initial compositions varying over a broad range. Drops were formed at the submerged position in the continuous phase (water) at the same operating flow conditions. The unsteady force balance model is developed to analyze the implications of the simultaneously occurring interfacial transfer of the solute on the formation dynamics in real time, and predictions are validated with experimental results. Based on initial compositions, the analysis of the transient drop shape shows a sharp transition in the drop formation regime. At lower initial solute concentrations, i.e., ϕ0 < 0.2, axisymmetric drop formation occurs and the interfacial solute transfer has negligible effects on the formation dynamics. Over an intermediate range of solute concentrations, i.e., 0.2 < ϕ0 < 0.5, Marangoni instability is triggered along the evolving interface, and therefore, the interface deformations and contractions occur during the drop formation. At ϕ0 = 0.5, the drop takes highly nonaxisymmetric shapes and remains away from equilibrium until its detachment from an orifice. For ϕ0 > 0.5, the spontaneous ejection of plumes of the solute results in the rapid generation of multiple droplets of smaller size. This work shows that higher solute concentration gradients not only lead to faster solute transport but also induce strong interfacial instability simultaneously. Thus, the coupled effects of transient change in composition and fluid properties govern the drop size and its formation time in such systems under non-equilibrium.

Direct amidation of acids in a screw reactor for the continuous flow synthesis of amides.

A simple and efficient solvent-free protocol for continuous flow synthesis of amides at room temperature is developed using easily available starting materials. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was used as the reagent for the formation of an amide bond without using any metal catalyst or additives. A jacketed screw reactor when operated over a residence time of 30 300 s helped achieve almost complete conversion. This approach is extended for the synthesis of 36 derivatives and 2 bioactive molecules using different substrates having different aliphatic mono and di-acids as well as aromatic acids, including aromatic hetero-acid compounds and phenyl hydrazine. The target amide was scaled up to 100 g with an average 90% yield.

Insights into the Synthesis and Kinetics of Silver-on-Silica Core-Shell Particles.

In this study, a heterogeneous nucleation and growth model has been developed to explore the formation mechanism of silver-deposited silica core-shell particles based on the reaction kinetics. To validate the core-shell model, the time-dependent experimental data were quantitatively examined and in situ reduction, nucleation, and growth rates were estimated by optimizing the concentration profiles of reactants and deposited silver particles. Using this model, we also attempted to predict the change in the surface area and diameter of core-shell particles. The concentration of the reducing agent, metal precursor, and reaction temperature were found to have a strong influence on the rate constants and morphology of core-shell particles. Higher rates of nucleation and growth often produced thick, asymmetric patches that covered the entire surface, whereas lower rates produced sparsely deposited silver particles with a spherical shape. The result revealed that by simply tuning the process parameters and controlling the relative rates, the morphology of deposited silver particles and the surface coverage can be controlled while retaining the spherical shape of the core. The present study aims to offer comprehensive data pertaining to the nucleation, growth, and coalescence processes of core-shell nanostructures which will aid in the development and understanding of the principles that govern the formation of nanoparticle-coated materials.

Leveraging Active Learning for Failure Mode Acquisition.

Identifying failure modes is an important task to improve the design and reliability of a product and can also serve as a key input in sensor selection for predictive maintenance. Failure mode acquisition typically relies on experts or simulations which require significant computing resources. With the recent advances in Natural Language Processing (NLP), efforts have been made to automate this process. However, it is not only time consuming, but extremely challenging to obtain maintenance records that list failure modes. Unsupervised learning methods such as topic modeling, clustering, and community detection are promising approaches for automatic processing of maintenance records to identify failure modes. However, the nascent state of NLP tools combined with incompleteness and inaccuracies of typical maintenance records pose significant technical challenges. As a step towards addressing these challenges, this paper proposes a framework in which online active learning is used to identify failure modes from maintenance records. Active learning provides a semi-supervised machine learning approach, allowing for a human in the training stage of the model. The hypothesis of this paper is that the use of a human to annotate part of the data and train a machine learning model to annotate the rest is more efficient than training unsupervised learning models. Results demonstrate that the model is trained with annotating less than ten percent of the total available data. The framework is able to achieve ninety percent (90%) accuracy in the identification of failure modes in test cases with an F-1 score of 0.89. This paper also demonstrates the effectiveness of the proposed framework with both qualitative and quantitative measures.

NONSURGICAL RESOLUTION OF FULL-THICKNESS MACULAR HOLES WITHOUT VITREOMACULAR TRACTION.

BACKGROUND/PURPOSE: The purpose of this study was to report a case series of full-thickness macular holes without vitreomacular traction that resolved without surgery. METHODS: This study is a retrospective case series of 11 patients who demonstrated closure of full-thickness macular holes without surgical intervention. RESULTS: All full-thickness macular holes closed, with all patients having improvement in visual acuity. All but one of the cases had visual acuity better than 20/40 at last recorded visit. Most cases presented with associated epiretinal membrane (73%), cystoid changes (64%), defects <150 µ m (80%), and resolved within 2 months (91%). Topical anti-inflammatory drops were used in 7 of 11 cases, and dorzolamide was used in one case. CONCLUSION: Full-thickness macular holes can develop in eyes without the presence of vitreomacular traction. Topical therapy without vitrectomy may be particularly helpful in closure of full-thickness macular holes with associated cystoid macular edema. Holes with a lamellar hole component may spontaneously resolve as part of a retinal remodeling process.

Mitral Annulus Disjunction and Arrhythmic Mitral Valve Prolapse: Emerging Role of Cardiac Magnetic Resonance Imaging in the Workup.

Mitral valve prolapse is a commonly described entity with a highly variable and benign course. However, it is associated with ventricular arrhythmias and sudden cardiac death in a small subset of patients. Recent studies have yielded insight into myocardial mechanics and the causation of ventricular arrhythmias in these groups of patients. Mitral annular disjunction (MAD) characterized by detachment of mitral annulus from left ventricular myocardium is associated with morphological and functional remodeling of the left ventricular myocardium. Resultant fibrosis acts as a substrate of ventricular arrhythmia and sudden cardiac death. We present two such cases of arrhythmic mitral valve prolapse associated with MAD. Cardiac magnetic resonance imaging provides excellent morphological information and also helps in the assessment of fibrosis.

Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation.

The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1ß and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.

Sensor Selection Framework for Designing Fault Diagnostics System.

In a world of rapidly changing technologies, reliance on complex engineered systems has become substantial. Interactions associated with such systems as well as associated manufacturing processes also continue to evolve and grow in complexity. Consider how the complexity of manufacturing processes makes engineered systems vulnerable to cascading and escalating failures; truly a highly complex and evolving system of systems. Maintaining quality and reliability requires considerations during product development, manufacturing processes, and more. Monitoring the health of the complex system while in operation/use is imperative. These considerations have compelled designers to explore fault-mechanism models and to develop corresponding countermeasures. Increasingly, there has been a reliance on embedded sensors to aid in prognosticating failures, to reduce downtime, during manufacture and system operation. However, the accuracy of estimating the remaining useful life of the system is highly dependent on the quality of the data obtained. This can be enhanced by increasing the number of sensors used, according to information theory. However, adding sensors increases total costs with the cost of the sensors and the costs associated with information-gathering procedures. Determining the optimal number of sensors, associated operating and data acquisition costs, and sensor-configuration are nontrivial. It is also imperative to avoid redundant information due to the presence of additional sensors and the efficient display of information to the decision-maker. Therefore, it is necessary to select a subset of sensors that not only reduce the cost but are also informative. While progress has been made in the sensor selection process, it is limited to either the type of the sensor, number of sensors or both. Such approaches do not address specifications of the required sensors which are integral to the sensor selection process. This paper addresses these shortcomings through a new method, OFCCaTS, to avoid the increased cost associated with health monitoring and to improve its accuracy. The proposed method utilizes a scalable multi-objective framework for sensor selection to maximize fault detection rate while minimizing the total cost of sensors. A wind turbine gearbox is considered to demonstrate the efficacy of the proposed framework.

Multi-Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry.

Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.

Direct interaction between ABCA1 and HIV-1 Nef: Molecular modeling and virtual screening for inhibitors.

HIV-1 infection impairs cellular cholesterol efflux by downmodulating the cholesterol transporter ABCA1, leading to metabolic co-morbidities like cardio-vascular disease. The main mechanism of this effect is impairment by the HIV-1 protein Nef of the ABCA1 interaction with the endoplasmic reticulum chaperone calnexin, which leads to a block in ABCA1 maturation followed by its degradation. However, ABCA1 is also downmodulated by Nef delivered with the extracellular vesicles, suggesting involvement of a direct Nef:ABCA1 interaction at the plasma membrane. Here, we present an optimized model of the Nef:ABCA1 interaction, which identifies interaction sites and provides an opportunity to perform a virtual screening for potential inhibitors. Interestingly, the predicted sites on Nef involved in the ABCA1 interaction overlap with those involved in the interaction with calnexin. The compounds previously shown to block Nef:calnexin interaction were among the top ranking ligands in docking simulations with ABCA1-interacting sites on Nef, suggesting the possibility that both interactions can be inhibited by the same chemical compounds. This study identifies a series of compounds for potential development as inhibitors of Nef-mediated co-morbidities of HIV infection.

Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats.

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase (p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.

Inkjet printing of silver nanowires on flexible surfaces and methodologies to improve the conductivity and stability of the printed patterns.

Silver nanowires (AgNWs) are known to be used for printing on rigid as well as flexible surfaces. Here we have developed a systematic approach for using AgNWs synthesized by the polyol method for printing on flexible surfaces using a simple inkjet printing method. Optimized ink formulation used in this work comprises a mixture of Ag NWs suspended in ethylene glycol directly taken after synthesis and isopropyl alcohol. Using such formulation saves time and loss of material while transferring to other solvents, which is the usual practice. The printed patterns demonstrate high conductivity and stability over many months, which can revolutionize the applications of functional nanomaterials in low-cost printed electronics. The importance of fragmentation of nanowires only to achieve specific aspect ratios, to facilitate easy jetting and to prevent clogging is demonstrated. Varied concentrations (10 mg mL-1 to 50 mg mL-1) of Ag NWs are used in ink formulations in order to print highly conductive patterns (resistance < 50 Ω sq-1) in a minimal number of passes. The same composition was also seen to facilitate simple and time-efficient nano-welding at room temperature, which improves the conductivity and stability of the printed patterns.

Aloe vera Compositions Used for Medicinal Applications: A Patent Review (2013-till 2020).

BACKGROUND: Aloe vera is a plant traditionally used for medicinal purposes. It is also used as a cosmetic. Aloe vera gel/extract/juice is used in hair care, moisturizing, cleansing, and thickening agent in formulations. Aloe vera gel is rarely used for burns, wounds, infections, and gastric diseases. OBJECTIVES: To study the patents filed recently and understand the trend in the application of Aloe vera for therapeutic purposes. METHODS: This patent review focuses on granted patents during the year 2013 to 2020. The patents were analyzed, and their therapeutic use was studied to assess the recent trends in Aloe vera formulations. RESULTS: Most of the patents studied in this article are based on skincare products. Out of those, the maximum patents are on moisturizing compositions. Most of the patents are found in US jurisdiction and a few in Europe and China. As there are certain restrictions on patenting inventions related to composition and natural products in various jurisdictions, patents are only found in a few jurisdictions. CONCLUSION: The trend of the use of Aloe vera is still towards cosmetic products. Also, Aloe vera is used in oral care composition, deodorant compositions, anti-inflammatory composition, vitamin compositions, antibiotic compositions, etc.

Isatin Hybrids and Their Pharmacological Investigations.

Hybridization is an important strategy to design molecules that can be effectively used to treat fatal diseases known to mankind. Molecular hybrids and their pharmacological investigations aided in discovering several potent isatin (Indole 2, 3 dione) derivatives with anti-HIV, antimalarial, antitubercular, antibacterial, and anticancer activities. Indole-2,3-dione and their derivatives have diverse pharmacological properties and have a prominent role in the discovery of new drugs. To understand the various approaches for designing new molecules based on isatin nucleus analysis of various pharmacophore hybrids, spacers/linkers between pharmacophores and isatin for hybridization and their biological activities are important. This review discusses the progress in developing isatin hybrids as biologically effective agents and their crucial aspects of design and structure-activity relationships.

In Situ Tremor in Vitreoretinal Surgery.

OBJECTIVE: Surgeon tremor was measured during vitreoretinal microscopic surgeries under different hand support conditions. BACKGROUND: While the ophthalmic surgeon's forearm is supported using a standard symmetric wrist rest when operating on the patient's same side as the dominant hand (SSD), the surgeon's hand is placed directly on the patient's forehead when operating on the contralateral side of the dominant hand (CSD). It was hypothesized that more tremor is associated with CSD surgeries than SSD surgeries and that, using an experimental asymmetric wrist rest where the contralateral wrist bar gradually rises and curves toward the patient's operative eye, there is no difference in tremor associated with CSD and SSD surgeries. METHODS: Seventy-six microscope videos, recorded from three surgeons performing macular membrane peeling operations, were analyzed using marker-less motion tracking, and movement data (instrument path length and acceleration) were recorded. Tremor acceleration frequency and magnitude were measured using spectral analysis. Following 47 surgeries using a conventional symmetric wrist support, surgeons incorporated the experimental asymmetric wrist rest into their surgical routine. RESULTS: There was 0.11 mm/s2 (22%) greater (p = .05) average tremor acceleration magnitude for CSD surgeries (0.62 mm/s2, SD = 0.08) than SSD surgeries (0.51 mm/s2, SD = 0.09) for the symmetric wrist rest, while no significant (p > .05) differences were observed (0.57 mm, SD = 0.13 for SSD and 0.58 mm, SD = 0.11 for CSD surgeries) for the experimental asymmetric wrist rest. CONCLUSION: The asymmetric wrist support reduced the difference in tremor acceleration between CSD and SSD surgeries.

Structural Optimization of 2,3-Dihydro-1H-cyclopenta[b]quinolines Targeting the Noncatalytic RVxF Site of Protein Phosphatase 1 for HIV-1 Inhibition.

Combination antiretroviral therapy (cART) suppresses human immunodeficiency virus-1 (HIV-1) replication but is unable to permanently eradicate HIV-1. Importantly, cART does not target HIV-1 transcription, which is reactivated in latently infected reservoirs, leading to HIV-1 pathogenesis including non-infectious lung, cardiovascular, kidney, and neurodegenerative diseases. To address the limitations of cART and to prevent HIV-1-related pathogenesis, we developed small molecules to target the noncatalytic RVxF-accommodating site of protein phosphatase-1 (PP1) to prevent HIV-1 transcription activation. The PP1 RVxF-accommodating site is critical for the recruitment of regulatory and substrate proteins to PP1. Here, we confirm that our previously developed 1E7-03 compound binds to the PP1 RVxF-accommodating site. Iterative chemical alterations to 1E7-03 furnished a new analogue, HU-1a, with enhanced HIV-1 inhibitory activity and improved metabolic stability compared to 1E7-03. In a Split NanoBit competition assay, HU-1a primarily bound to the PP1 RVxF-accommodating site. In conclusion, our study identified HU-1a as a promising HIV-1 transcription inhibitor and showed that the PP1 RVxF-accommodating site is a potential drug target for the development of novel HIV-1 transcription inhibitors.

Design, synthesis, and screening of sulfonylurea-derived NLRP3 inflammasome inhibitors.

Inflammasomes are multiprotein assemblies that produce robust inflammatory responses upon stimulation with pathogen- and/or danger-associated molecular patterns. Uncontrolled inflammasome activation has been linked to the pathophysiology of a wide array of disorders including life-threatening pathogenic infections, e.g., Francisella tularensis. There has been a great deal of interest in the development of small molecule inflammasome inhibitors. Using computational modeling based on chalcone derivatives, we have developed novel tertiary sulfonylurea compounds as inhibitors of the NLRP3 inflammasome. The polar enone functional alert of chalcone was replaced with a sulfonylurea scaffold while maintaining the relative positions of the two aromatic rings. These compounds were evaluated for their ability to inhibit NLRP3 and AIM2 inflammasome activation triggered by Francisella tularensis infection.

Optimization of a liquid chromatography method for the analysis of related substances in daclatasvir tablets using design of experiments integrated with the steepest ascent method and Monte Carlo simulation.

Analytical method for the determination of related substances (RS) in Daclatasvir tablets was optimised using quality by design (QbD) approach. Seven degradants (each more than 1.0%) generated during oxidation study, adversely affected the selectivity of the method. Coelution of the degradant peaks with API and known impurities, suggested failure in developing a stability indicating method. To overcome the shortcomings and develop a robust method, QbD principles were incorporated. Resolution was the critical quality attribute (CQA) and buffer pH, column oven temperature, gradient slope and flow rate were the critical method variables (CMVs) studied through design of experiments (DoE). Discovery of an unknown impurity (named as impurity D, about1.0%) was a key finding from this DoE study. The most crucial responses viz. Resolution between impurity D and the main peak and resolution between the main peak and impurity E demanded contradictory pH requirements. To select the right pH, responses were prioritised and eventually to attain the desired resolution between Daclatasvir and impurity E the value for pH was fixed to 3.0. Next, to improve resolution between impurity D and Daclatasvir, method of steepest ascent was applied to locate an apt value for column oven temperature. Accordingly, experiments were performed at different temperatures along the path of rapid increase in response. Finally, at 45 °C (pH :3.0), both the critical pairs were well resolved. The global optimum was determined through a Response surface methodology (RSM) design with pH and column oven temperature as critical factors. pH 3.0, column oven temperature 44 °C, % MP. B 45% and flow rate 1.0 mL min-1 was found to be the optimum condition. Further, the design space was complimented by establishment of a robust zone through Monte Carlo simulation and capability analysis. An analytical control strategy (ACS) was set up to ensure that the method repeatedly meets its acceptance criteria. The optimised method was successfully validated within the factor ranges mentioned in the ACS. Despite various intricacies, the QbD approach facilitated systematic optimisation of a stability indicating robust method.

In Vivo Pharmacokinetic/Pharmacodynamic Targets of Levonadifloxacin against Staphylococcus aureus in a Neutropenic Murine Lung Infection Model.

Levonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant Staphylococcus aureus A phase 3 trial for levonadifloxacin and its oral prodrug was recently completed. The present study identified area under the concentration-time curve for the free, unbound fraction of a drug divided by the MIC (fAUC/MIC) as an efficacy determinant for levonadifloxacin in a neutropenic murine lung infection model. Mean plasma fAUC/MIC requirement for static and 1 log10 kill effects against 9 S. aureus were 8.1 ± 6.0 and 25.8 ± 12.3, respectively. These targets were employed in the selection of phase 3 doses.