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Community acquired bacterial pneumoniae (CABP) infections is the major cause of mortality and morbidity, especially in elderly patients. India accounts for 23% of global pneumonia burden with case fatality rates between 14 and 30%. There is an urgent unmet medical need for safe and effective antibiotic for CABP, due to lack of effective empirical therapy because of widespread resistance to β-lactams antibiotics. On other hand, fluoroquinolone antibiotics have poor tolerability, like hypersensitive reactions and associated disabilities. Hence, our objective was to find an antibiotic having broad coverage of multidrug resistance (MDR) pathogens including typical and atypical respiratory pathogens, with good lung penetration and safety features. Nafithromycin (MIQNAF®) is a novel "lactone-ketolide" antibiotic developed by Wockhardt Ltd. for the treatment of CABP infections. Recently it has completed phase III clinical trials in India and NDA submitted to drug controller general of India (DCGI). Distinctive features of nafithromycin are ultra-short duration of therapy, oral dosing, high concentration build up in lung i.e. target organ and safety profile. Structurally, it features novel amidoxime core with 2-pyridine-1,3,4-thiadiazole biaryl tether separated with non-flexible four atom spacer having cis double bond and chiral methyl with (S)- configuration resulted in dual target interaction. The novel conformational arrangement interacts favorably with 23S rRNA and domain V of 50S ribosome subunit to elicit outstanding potency against gram-positive bacteria. The preclinical data provided strong scientific evidences for its effectiveness against difficult-to-treat respiratory tract infections (RTIs) caused by multidrug-resistant pathogens such as macrolide-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes as well as other important pathogens including Haemophilus influenzae. Upon successful phase I clinical findings, nafithromycin was granted Qualified Infectious Disease Product (QIDP) status by the US Food and Drug Administration (USFDA). Presently besides India specific phase III clinical study completion with partial funding support from Biotechnology Industry Research Assistance Council (BIRAC), it has successfully completed global phase II clinical development, including pharmacokinetic study (NCT02770404) and study for the treatment of community-acquired bacterial pneumonia (NCT02903836). In Europe it has completed single ascending dose (SAD) and multiple ascending dose (MAD) phase I pharmacokinetic studies. This mini review covers relevant published data on nafithromycin and its potential role in management of infections caused by gram-positive pathogens along with summary of different clinical trials conducted in United States, Europe and India. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae isolates from the United States (n = 1038; 2019–2021) were susceptible to omadacycline (99.8%), levofloxacin (99.7%), and ceftriaxone (98.1%), whereas doxycycline (80.2%), oral penicillin (63.5%), cefpodoxime (76.8%), and azithromycin (54.4%) activity was limited. Tet (M) did not affect omadacycline activity but altered activity of older tetracyclines including doxycycline, suggesting omadacycline is an important option for treatment of community-acquired bacterial pneumonia. [ABSTRACT FROM AUTHOR]

The role of Calcium ions (Ca2+) is extensively documented and comprehensively understood in eukaryotic organisms. Nevertheless, emerging insights, primarily derived from studies on human pathogenic bacteria, suggest that this ion also plays a pivotal role in prokaryotes. In this review, our primary focus will be on unraveling the intricate Ca2+ toolkit within prokaryotic organisms, with particular emphasis on its implications for plant growth-promoting rhizobacteria (PGPR). We undertook an in silico exploration to pinpoint and identify some of the proteins described in the existing literature, including prokaryotic Ca2+ channels, pumps, and exchangers that are responsible for regulating intracellular Calcium concentration ([Ca2+]i), along with the Calcium-binding proteins (CaBPs) that play a pivotal role in sensing and transducing this essential cation. These investigations were conducted in four distinct PGPR strains: Pseudomonas chlororaphis subsp. aurantiaca SMMP3, P. donghuensis SVBP6, Pseudomonas sp. BP01, and Methylobacterium sp. 2A, which have been isolated and characterized within our research laboratories. We also present preliminary experimental data to evaluate the influence of exogenous Ca2+ concentrations ([Ca2+]ex) on the growth dynamics of these strains. [ABSTRACT FROM AUTHOR]

Introduction and aim. Nowadays, the increasing resistance of bacteria is a concerning and challenging issue in terms of effective treatment of bacterial infections. The amount of available antibiotics has been quite constant for many years. The search for substances alternative to older classes of drugs, among which resistance is growing, has been ongoing for years. One of the newly introduced available alternatives is lefamulin. The aim of this paper is to present the potential benefits of its use in comunity-acquired bacterial pneumonia (CABP). Material and methods. A review of the available literature was performed by searching the PubMed and GoogleScholar databases using the following key words: lefamulin; BC3781; pleuromutilin; CABP; community acquired pneumonia. Analysis of literature. Lefamulin is a bacteriostatic antibiotic from the group of pleuromutilins, which has a unique mechanism of action consisting in binding to the bacterial 50S ribosomal subunit in the peptidyl transferase center. Thanks to this, it rarely causes resistance among other groups of antibiotics and is characterized by a safe action profile. Its spectrum of action includes bacteria causing CABP. In phase III studies, the efficacy of lefamulin monotherapy was comparable to that of moxifloxacin with or without linezolid in CABP. Thanks to broad spectrum of action its usefulness may also extend to treatment of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and multidrug-resistant organisms associated with sexually transmitted infections, e.g., Neisseria gonorrhoeae, Mycoplasma genitalium, although more additional clinical and pharmacodynamic data is needed. Conclusion. Lefamulin is a promising addition to the antibiotic armamentarium for treating CABP. Its unique mechanism of action, activity against typical and atypical bacteria, flexible dosing options, and favorable safety profile make it a beneficial choice for clinicians.

ABSTRACT: Objectives: Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. Methods: In LEAP 1, adults (PORT risk class III‒V) received intravenous (IV) lefamulin 150 mg every 12 h (q12h) for 5‒7 days or moxifloxacin 400 mg every 24 h (q24h) for 7 days, with optional IV-to-oral switch. In LEAP 2, adults (PORT II‒IV) received oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Primary outcomes were early clinical response (ECR) at 96 ± 24 h after treatment start and investigator assessment of clinical response (IACR) 5‒10 days after the last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen testing, serology and/or real-time PCR). Results: Baseline CABP pathogens were detected in 709/1289 patients (55.0%; microbiological intention-to-treat population). The most frequently identified pathogens were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. Conclusion: Lefamulin is a valuable IV and oral monotherapy option for empirical and directed CABP treatment in adults.

ABSTRACT: Objectives: Omadacycline was tested against 7000 bacterial isolates collected prospectively from medical centres in the USA during 2019. Methods: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: Omadacycline was active against: Staphylococcus aureus (MIC50/90, 0.12/0.25 mg/L; 98.3% susceptible), including methicillin-resistant S. aureus (MRSA); Enterococcus faecalis (MIC50/90, 0.06/0.25 mg/L; 100.0% susceptible), including vancomycin-resistant enterococci (VRE); Streptococcus pneumoniae (MIC50/90, 0.06/0.06 mg/L; 99.8% susceptible); viridans group streptococci, including Streptococcus anginosus group (MIC50/90, 0.03/0.06 mg/L; 100.0% susceptible); β-haemolytic streptococci, including Streptococcus pyogenes (MIC50/90, 0.06/0.12 mg/L; 99.2% susceptible); Enterobacterales (MIC50/90, 1/8 mg/L; 86.9% inhibited at ≤4 mg/L), including Escherichia coli (MIC50/90, 0.5/2 mg/L; 99.6% inhibited at ≤4 mg/L); Enterobacter cloacae (MIC50/90, 2/4 mg/L; 98.5% susceptible); Klebsiella pneumoniae (MIC50/90, 1/4 mg/L; 93.2% susceptible); Acinetobacter baumannii (MIC50/90, 0.5/4 mg/L; 90.8% inhibited at ≤4 mg/L); Haemophilus influenzae (MIC50/90, 0.5/1 mg/L; 100.0% susceptible); and Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/L). Conclusion: The 2019 in vitro activity of omadacycline against key Gram-positive and Gram-negative pathogens has not changed compared with the prior 3 years of surveillance in the SENTRY Antimicrobial Surveillance Program. Omadacycline merits further study in serious infections where resistant pathogens may be encountered.

The role of Calcium ions (Ca2+) is extensively documented and comprehensively understood in eukaryotic organisms. Nevertheless, emerging insights, primarily derived from studies on human pathogenic bacteria, suggest that this ion also plays a pivotal role in prokaryotes. In this review, our primary focus will be on unraveling the intricate Ca2+ toolkit within prokaryotic organisms, with particular emphasis on its implications for plant growth-promoting rhizobacteria (PGPR). We undertook an in silico exploration to pinpoint and identify some of the proteins described in the existing literature, including prokaryotic Ca2+ channels, pumps, and exchangers that are responsible for regulating intracellular Calcium concentration ([Ca2+]i), along with the Calcium-binding proteins (CaBPs) that play a pivotal role in sensing and transducing this essential cation. These investigations were conducted in four distinct PGPR strains: Pseudomonas chlororaphis subsp. aurantiaca SMMP3, P. donghuensis SVBP6, Pseudomonas sp. BP01, and Methylobacterium sp. 2A, which have been isolated and characterized within our research laboratories. We also present preliminary experimental data to evaluate the influence of exogenous Ca2+ concentrations ([Ca2+]ex) on the growth dynamics of these strains.

Delafloxacin is a novel fluoroquinolone with peculiar characteristics such as a weak acid character, frequent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), and a low potential for resistance selection compared with other fluoroquinolones. The present narrative review summarizes the available data on the use of delafloxacin for the treatment of community-acquired bacterial pneumonia (CABP). Delafloxacin is a novel fluoroquinolone with a unique profile and some interesting characteristics for the treatment of CABP, such as its marked activity against gram-positive bacteria, including MRSA, the possible use as monotherapy (owing to anti-Gram-negative and anti-atypical bacteria activity), the retained activity against many Gram-positive organisms resistant to other fluoroquinolones, and the availability of both oral and intravenous formulations. The results of the DEFINE-CABP phase-3 randomized controlled trial have shown noninferiority of delafloxacin vs. moxifloxacin for the treatment of CABP, thereby providing a further option for this indication. Against this background, future post-marketing experiences remain of crucial importance for further refining the place in therapy of delafloxacin in the real-life management algorithms of CABP, either as first-line option or step-down/outpatient treatment. [ABSTRACT FROM AUTHOR]

Bryan J Donald,1,2 Salim Surani,3–5 Harmeet S Deol,1,6 Uche J Mbadugha,1 George Udeani1,7 1Department of Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, 2Department of Clinical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 3Department of Pulmonology/Critical Care, Corpus Christi Medical Center, Corpus Christi, TX, 4Department of Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, 5Department of Medicine, College of Osteopathic Medicine, University of North Texas Health Science Center, Denton, TX, 6Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT, 7Pharmacy Practice, College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX, USA Abstract: Community-acquired bacterial pneumonia (CABP) is a leading cause of death worldwide. However, antibacterial agents used to treat common pathogens in CABP are marked by adverse drug events and increasing antimicrobial resistance. Solithromycin is a new ketolide antibiotic, based on the macrolide antibiotic structure, being studied for use in CABP. It has efficacy in vitro against the common causative pathogens in CABP including Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens. In Phase II and Phase III clinical trials, it has been demonstrated efficacious as a single agent for treatment of CABP with an apparently milder adverse event profile than alternative agents. Keywords: solithromycin, macrolide antibiotics, community-acquired bacterial pneumonia, CABP

Travis M Jones,1,2 Steven W Johnson,1,3 V Paul DiMondi,1,4 Dustin T Wilson,1,2 1Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, 2Department of Pharmacy, Duke University Hospital, Durham, 3Department of Pharmacy, Forsyth Medical Center, Novant Health, Winston-Salem, 4Department of Pharmacy, Durham VA Medical Center, Durham, NC, USA Abstract: JNJ-Q2 is a novel, fifth-generation fluoroquinolone that has excellent in vitro and in vivo activity against a variety of Gram-positive and Gram-negative organisms. In vitro studies indicate that JNJ-Q2 has potent activity against pathogens responsible for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), such as Staphylococcus aureus and Streptococcus pneumoniae. JNJ-Q2 also has been shown to have a higher barrier to resistance compared to other agents in the class and it remains highly active against drug-resistant organisms, including methicillin-resistant S. aureus, ciprofloxacin-resistant methicillin-resistant S. aureus, and drug-resistant S. pneumoniae. In two Phase II studies, the efficacy of JNJ-Q2 was comparable to linezolid for ABSSSI and moxifloxacin for CABP. Furthermore, JNJ-Q2 was well tolerated, with adverse event rates similar to or less than other fluoroquinolones. With an expanded spectrum of activity and low potential for resistance, JNJ-Q2 shows promise as an effective treatment option for ABSSSI and CABP. Considering its early stage of development, the definitive role of JNJ-Q2 against these infections and its safety profile will be determined in future Phase III studies. Keywords: JNJ-Q2, fluoroquinolone, ABSSSI, CABP, MRSA

Calcium controls numerous biological processes by interacting with different classes of calcium binding proteins (CaBP’s), with different affinities, metal selectivities, kinetics, and calcium dependent conformational changes. Due to the diverse coordination chemistry of calcium, and complexity associated with protein folding and binding cooperativity, the rational design of CaBP’s was anticipated to present multiple challenges. In this paper we will first discuss applications of statistical analysis of calcium binding sites in proteins and subsequent development of algorithms to predict and identify calcium binding proteins. Next, we report efforts to identify key determinants for calcium binding affinity, cooperativity and calcium dependent conformational changes using grafting and protein design. Finally, we report recent advances in designing protein calcium sensors to capture calcium dynamics in various cellular environments.

Rubisco is the key enzyme in photosynthesis, catalyzing fixation of carbon dioxide from the atmosphere into energy storage molecules. Several inefficiencies in Rubisco limit the rate of photosynthesis, and, therefore, the growth of the plant. Rubisco is sensitive to light, making deactivation of the enzyme upon sampling likely. Moreover, the indirect methods often used to study its activity make obtaining reliable data difficult. In this Chapter, we describe an approach to generate reliable and repeatable data for Rubisco activities, activation state and abundance in plant leaves. We include methods to sample and extract proteins, minimizing Rubisco degradation and deactivation. We describe radiometric techniques to measure Rubisco activities and calculate its activation state at the time of sampling, and to quantify its abundance., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Community-acquired bacterial pneumonia (CABP) represents a significant clinical and financial burden within infectious disease. In the advent of increasing resistance from bacteria such as Streptococcus pneumoniae to available antibiotic therapies, there is a need for new drugs with novel mechanisms to treat such infections. Areas covered: Lefamulin, the first semi-synthetic pleuromutilin for systemic administration, is nearing completion of Phase III studies for CABP; the manufacturer plans to file for a new drug application (NDA) in Q4 2018. This paper details available data on the pharmacokinetic, pharmacodynamic, in vitro and clinical data of the drug to date, derived from published literature, conference posters and data provided by the manufacturer. Expert commentary: Lefamulin offers a unique spectrum of activity as a potential monotherapy treatment agent for CABP and alternative to fluoroquinolone therapy. The drug displays potent activity against several pathogens common in both acute bacterial skin and skin structure infections (ABSSSIs) and CABP, and a lack of cross-resistance with other antibiotic classes for S. pneumoniae and Staphylococcus aureus. Lefamulin has met predefined noninferiority endpoints of clinical response for CABP compared to moxifloxacin ± linezolid in two Phase III trials (LEAP 1 and 2) and presents an alternative therapy for CABP. [ABSTRACT FROM AUTHOR]

Community-acquired bacterial pneumonia (CABP) is a leading cause of death worldwide. However, antibacterial agents used to treat common pathogens in CABP are marked by adverse drug events and increasing antimicrobial resistance. Solithromycin is a new ketolide antibiotic, based on the macrolide antibiotic structure, being studied for use in CABP. It has efficacy in vitro against the common causative pathogens in CABP including Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens. In Phase II and Phase III clinical trials, it has been demonstrated efficacious as a single agent for treatment of CABP with an apparently milder adverse event profile than alternative agents. [ABSTRACT FROM AUTHOR]

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (% fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented. [ABSTRACT FROM AUTHOR]

The Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) is a multicenter retrospective study, conducted in the USA, describing the contemporary use of ceftaroline fosamil. Ceftaroline is primarily excreted by the kidneys and the dose should be reduced in patients with moderate to severe renal insufficiency. This article describes the clinical effectiveness of ceftaroline fosamil in the treatment of acute bacterial skin and skin structure infection (ABSSSI) or community-acquired bacterial pneumonia (CABP) patients with renal insufficiency. There were 985 ABSSSI patients and 344 CABP patients, of which 22 and 31%, respectively, had renal insufficiency. Ceftaroline fosamil was mostly administered to patients as second-line therapy. Overall clinical success was 78-91% among ABSSSI or CABP patients with renal insufficiency and, overall, >50% of patients were discharged to home. Ceftaroline fosamil is an effective treatment option for ABSSSI or CABP patients with renal insufficiency. [ABSTRACT FROM AUTHOR]

Caleosins or related sequences have been found in a wide range of higher plants. In Arabidopsis, seed-specific caleosins are viewed as oil-body (OB)-associated proteins that possess Ca2+-dependent peroxygenase activity and are involved in processes of lipid degradation. Recent experimental evidence suggests that one of the Arabidopsis non-seed caleosins, AtCLO3, is involved in controlling stomatal aperture during the drought response; the roles of the other caleosin-like proteins in Arabidopsis remain largely uncharacterized. We have demonstrated that a novel stress-responsive and OB-associated Ca2+-binding caleosin-like protein, AtCLO4, is expressed in non-seed tissues of Arabidopsis, including guard cells, and down-regulated following exposure to exogenous ABA and salt stress. At the seed germination stage, a loss-of-function mutant (atclo4) was hypersensitive to ABA, salt and mannitol stresses, whereas AtCLO4-overexpressing (Ox) lines were more hyposensitive to those stresses than the wild type. In adult stage, atclo4 mutant and AtCLO4-Ox plants showed enhanced and decreased drought tolerance, respectively. Following exposure to exogenous ABA, the expression of key ABA-dependent regulatory genes, such as ABF3 and ABF4, was up-regulated in the atclo4 mutant, while it was down-regulated in AtCLO4-Ox lines. Based on these results, we propose that the OB-associated Ca2+-binding AtCLO4 protein acts as a negative regulator of ABA responses in Arabidopsis. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (InsP3Rs) were recently demonstrated to be activated independently of InsP3 by a family of calmodulin (CaM)-like neuronal Ca2+binding proteins (CaBPs). We investigated the interaction of both naturally occurring long and short CaBP1 isoforms with InsP3Rs, and their functional effects on InsP3Revoked Ca2+ signals. Using several experimental paradigms, including transient expression in COS cells, acute injection of recombinant protein into Xenopus oocytes and 45Ca2+ flux from permeabilised COS cells, we demonstrated that CaBPs decrease the sensitivity of InsP3-induced Ca2+ release (IICR). In addition, we found a Ca2+-independent interaction between CaBP1 and the NH2-terminal 159 amino acids of the type 1 InsP3R. This interaction resulted in decreased InsP3 binding to the receptor reminiscent of that observed for CaM. Unlike CaM, however, CaBPs do not inhibit ryanodine receptors, have a higher affinity for InsP3Rs and more potently inhibited IICR. We also show that phosphorylation of CaBP1 at a casein kinase 2 consensus site regulates its inhibition of IICR. Our data suggest that CaBPs are endogenous regulators of InsP3Rs tuning the sensitivity of cells to InsP3. [ABSTRACT FROM AUTHOR]

We report almost complete sequence specific 1H, 13C and 15N NMR assignments of a 151-residue long calmodulin-like calcium-binding protein from Entamoeba histolytica ( EhCaM). [ABSTRACT FROM AUTHOR]

Calcium controls numerous biological processes by interacting with different classes of calcium binding proteins (CaBP's), with different affinities, metal selectivities, kinetics, and calcium dependent conformational changes. Due to the diverse coordination chemistry of calcium, and complexity associated with protein folding and binding cooperativity, the rational design of CaBP's was anticipated to present multiple challenges. In this paper we will first discuss applications of statistical analysis of calcium binding sites in proteins and subsequent development of algorithms to predict and identify calcium binding proteins. Next, we report efforts to identify key determinants for calcium binding affinity, cooperativity and calcium dependent conformational changes using grafting and protein design. Finally, we report recent advances in designing protein calcium sensors to capture calcium dynamics in various cellular environments. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is the prominent cause of mortality and morbidity with important clinical impact across the globe. India accounts for 23 per cent of global pneumonia burden with case fatality rates between 14 and 30 per cent, and Streptococcus pneumoniae is considered a major bacterial aetiology. Emerging pathogens like Burkholderia pseudomallei is increasingly recognized as an important cause of CAP in Southeast Asian countries. Initial management in the primary care depends on clinical assessment while the hospitalized patients require combinations of clinical scores, chest radiography and various microbiological and biomarker assays. This comprehensive diagnostic approach together with additional sampling and molecular tests in selected high-risk patients should be practiced. Inappropriate therapy in CAP in hospitalized patients lengthens hospital stay and increases cost and mortality. In addition, emergence of multidrug-resistant organisms poses tough challenges in deciding empirical as well as definitive therapy. Developing local evidence on the cause and management should be a priority to improve health outcomes in CAP., Competing Interests: None

Background The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin's shape and charge profile uniquely impact its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin with moxifloxacin for the treatment of CABP. Methods A randomized, double-blind, comparator-controlled, multicenter, global phase 3 study compared the efficacy and safety of delafloxacin 300 mg twice daily or moxifloxacin 400 mg once daily in adults with CABP. The primary end point was early clinical response (ECR), defined as improvement at 96 (±24) hours after the first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. Results In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events that were considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Conclusions Intravenous/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for Gram-positive, Gram-negative, and atypical pathogens. ClinicalTrials.gov Identifier NCT03534622. [ABSTRACT FROM AUTHOR]

Early diagnosis, noninvasive detection, and staging of various diseases, remain one of the major clinical barriers to effective medical treatment and prevention of disease progression toward major clinical consequences. Molecular imaging technologies play an indispensable role in the clinical field in overcoming these major barriers. The increasing application of imaging techniques and agents in early detection of different diseases such as cancer has resulted in improved treatment response and clinical patient management. In this chapter we will first introduce criteria for the design and engineering of calcium-binding protein (CaBP) parvalbumin as a protein Gd-MRI contrast agent (ProCA) with unprecedented metal selectivity for Gd 3+ over physiological metal ions. We will then discuss the further development of targeted MRI contrast agent for molecular imaging of PSMA biomarker for early detection of prostate cancer.

Ca 2+ regulation in living systems occurs via specific structural alterations, subtle or drastic, in the Ca 2+ -binding domains of sensor proteins. Sensor proteins perform designated nonredundant roles within the dense network of Ca 2+ -binding proteins. A detailed understanding of the structural changes in calcium sensor proteins due to Ca 2+ spikes that vary spatially, temporally, and in magnitude would provide better insights into the mechanism of Ca 2+ sensing. This chapter describes a method to study various stages during apo to the holo transition of Ca 2+ -binding proteins by Trp-mediated scanning of individual EF-hand motifs. We describe the applicability of this procedure to caldendrin, which is a neuronal Ca 2+ -binding protein and to integrin-binding protein. Tryptophan mutants of full-length caldendrin were designed to reveal local structural changes in each EF-hand of the protein. This method, referred to as "EF-hand scanning tryptophan mutagenesis," not only allows the identification of canonical and noncanonical EF-hands using very low concentrations of protein but also enables visualization of the hierarchical filling of Ca 2+ into the canonical EF-hands.

Cyclic di-AMP (c-di-AMP) is a newly discovered bacterial second messenger. However, regulation of c-di-AMP homeostasis is poorly understood. In Streptococcus pneumoniae , a sole diadenylate cyclase, CdaA, produces c-di-AMP and two phosphodiesterases, Pde1 and Pde2, cleave the signaling dinucleotide. To expand our knowledge of the pneumococcal c-di-AMP signaling network, we performed whole-genome sequencing of Δ pde1 Δ pde2 heat shock suppressors. In addition to their effects on surviving heat shock, these suppressor mutations restored general stress resistance and improved growth in rich medium. Mutations in CdaA or in the potassium transporter TrkH paired with an insertion leading to a frameshift at the C terminus of CdaA significantly reduced c-di-AMP levels. These observations indicate that the elevated c-di-AMP levels in the Δ pde1 Δ pde2 mutant enhance susceptibility of S. pneumoniae to the stress conditions. Interestingly, we have previously shown that TrkH complexes with a Trk family c-di-AMP-binding protein, CabP, to mediate potassium uptake. In this study, we found that deletion of cabP significantly reduced pneumococcal c-di-AMP levels. This is the first observation that a c-di-AMP effector protein modulates bacterial c-di-AMP homeostasis. IMPORTANCE Second messengers, including c-di-AMP, are prevalent among bacterial species. In S. pneumoniae , c-di-AMP phosphodiesterase-encoding gene null mutants are attenuated during mouse models of infection, but the role of c-di-AMP signaling in pneumococcal pathogenesis is enigmatic. In this work, we found that heat shock suppressor mutations converge on undermining c-di-AMP toxicity by changing intracellular c-di-AMP concentrations. These mutations improve the growth and restore the stress response generally in c-di-AMP phosphodiesterase-deficient pneumococci, thereby demonstrating the essentiality for tight regulation of c-di-AMP homeostasis in order to respond to stress. Likewise, this work demonstrates that a c-di-AMP effector protein, CabP, affects c-di-AMP homeostasis, which provides new perception into c-di-AMP regulation. This study has implications for c-di-AMP-producing bacteria since many species contain CabP homologs., (Copyright © 2018 American Society for Microbiology.)

Phytovigilance consists in supervision of side effects and drug interactions consequential to use of herbal medicinal products, herbal food supplements, herbal cosmetics and/or medicinal plants. It includes thus pharmacovigilance applied to phytotherapy, nutrivigilance and cosmetovigilance but also addictovigilance in case of plants, which lead to drug addiction, and toxicovigilance in case of toxic plants. Becoming necessary owing to (acute or chronic) toxicity risks or to drug interactions risks (of pharmacocinetical or pharmacodynamical kind)--as far as it concerns interactions between several associated plants or between a plant and a chemical or biotechnological allopathic medicine--phytovigilance represents moreover a legal obligation. Pharmacovigilance--in case of herbal medicinal products--is indeed becoming mandatory according to title IX of the European directive 2001/83/EC, whereas nutrivigilance is imposed by the European Food Safety Agency (EFSA)., (Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ −10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106). Results The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (−2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (−1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. Conclusions Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP. [ABSTRACT FROM PUBLISHER]

Ceftaroline fosamil, the prodrug of the active metabolite, ceftaroline, is a new, broad-spectrum cephalosporin recently approved in the USA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Ceftaroline has potent in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common Gram-negative organisms. The high affinity of ceftaroline for penicillin-binding proteins is responsible for the potent activity observed against clinically relevant pathogens. With respect to the treatment of CABP, the activity of ceftaroline against pathogens such as S. pneumoniae, S. aureus, Haemophilus influenzae and Moraxella catarrhalis demonstrates coverage across a broad range of pathogens typically encountered in clinical practice. Ceftaroline is also very active against common pathogens seen in ABSSSIs such as S. aureus (methicillin-susceptible S. aureus and methicillin-resistant S. aureus) and Streptococcus pyogenes. Ceftaroline exhibits a dose-proportional pharmacokinetic profile, similar to other renally excreted cephalosporins, and has a well-tolerated safety profile consistent with the cephalosporin class. Ceftaroline fosamil is compatible via Y-site administration with many other commonly administered parenteral drugs. [ABSTRACT FROM PUBLISHER]

Objectives Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ −10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). Results Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (−0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. Conclusions Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP. [ABSTRACT FROM PUBLISHER]