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Objective: To evaluate optimal regimens for perioperative antimicrobial prophylaxis in transurethral procedures by examining antimicrobial susceptibility patterns in the United States., Materials and Methods: Through several methods, we attempted to attain an antibiogram for each state. We focused on microbes known to cause infections after transurethral surgeries and antibiotics referred to in current or prior recommendations and compared susceptibility rates across states using Kruskal Walis tests and the Dwass, Steel, Critchlow-Fligner tests. We also examined susceptibility to (non-ceftazidime) third generation cephalosporins., Results: Data is included from 40 states. For each microbe studied, there was significant variability in sensitivity to antibiotics studied. Current first line recommendations for antimicrobial prophylaxis include first generation cephalosporins with 82%, 80%, and 87% mean coverage for E coli, Proteus, and Klebsiella respectively and trimethoprim-sulfamethoxazole with 74%, 80%, and 93% coverage, respectively. Susceptibility to aminoglycosides is 91%, 92%, and 96%, respectively and to third generation cephalosporin, it is 92%, 99%, and 94%., Conclusion: Current first line recommended antimicrobials for prophylaxis in transurethral procedures provide overall poor predicted coverage based on our database of antibiograms. Alternatives exist that have higher predicted susceptibility, though clinical significance of this and risk of resultant antimicrobial resistance is unknown. Urologists should consider local patterns when selecting antimicrobial prophylaxis for their patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The WHO Model List of Essential Medicines classified antibiotics into Access, Watch, and Reserve (AWaRe) categories for the treatment of 31 priority bacterial infections as a tool to facilitate antibiotic stewardship and optimal use. We compared the listing of antibiotics on national essential medicines lists (NEMLs) to those in the 2019 WHO Model List and the AWaRe classification database to determine the degree to which NEMLs are in alignment with the AWaRe classification framework recommended by WHO., Methods: In this cross-sectional study, we obtained up-to-date (data after 2017) NEMLs from our Global Essential Medicines (GEM) database, WHO online resources, and individual countries' websites. From the 2019 WHO Model List we extracted, as a reference standard, a list of 37 antibiotics (44 unique antibiotics after accounting for combination drugs or therapeutically equivalent drugs as specified by WHO) that were considered essential in treating 31 of the most common and severe clinical infectious syndromes (priority infections). From the WHO AWaRe Classification Database, which contains commonly used antibiotics globally, we extracted a list of 122 AWaRe antibiotics listed by at least one country in the GEM database. We then assessed individual countries' NEMLs for listing of the 44 essential and 122 commonly used antibiotics, overall and according to AWaRe classification group. We also evaluated and summarised the listing of both first-choice and second-choice treatments for the 31 priority infections. A total coverage score was calculated for each country by assigning a treatment score of 0-3 for each priority infection on the basis of whether first-choice and second-choice treatments, according to the 2019 WHO Model List, were included in the country's NEML. Coverage scores were then compared against the score of the 2019 WHO Model List and across World Bank income groups and WHO regions., Findings: As of July 7, 2020, we had up-to-date NEMLs for 138 countries. Of the 44 unique essential antibiotics, 24 were Access, 15 were Watch, and five were Reserve. The median number of total essential antibiotics listed across the 138 NEMLs was 26 (IQR 21-32). 102 (74%) countries listed at least 22 (50%) of the 44 essential antibiotics. The median number of total AWaRe antibiotics listed by the 138 countries was 35 (IQR 29-46), of Access antibiotics was 18 (16-21), of Watch antibiotics was 16 (11-22), and of Reserve antibiotics was one (0-2). 56 (41%) countries did not list any essential Reserve antibiotics. 131 (95%) countries had coverage scores of at least 60, equivalent to at least 75% of the score of the 2019 WHO Model List, which was 80. Nine (7%) countries listed fewer than 12 of 24 essential Access antibiotics, and seven (5%) did not list sufficient first-choice and second-choice treatments for priority infections (ie, they had coverage scores lower than 60). Of the 31 priority infections, acute neonatal meningitis and high-risk febrile neutropenia did not have enough listed treatments, with 82 (59%) countries listing no treatment for acute neonatal meningitis and 84 (61%) countries listing only a first-choice treatment, only a second-choice treatment, or no treatment for high-risk febrile neutropenia. Coverage scores differed between countries on the basis of World Bank income groups (p=0·025)., Interpretation: Our findings highlight potential changes to the antibiotics included in NEMLs that would increase adherence to international guidance aimed at effectively treating infectious diseases while addressing antimicrobial resistance., Funding: Canadian Institutes of Health Research and Ontario Strategy for Patient Oriented Research Support Unit., Competing Interests: Declaration of interests NP reports grants from Canadian Institutes of Health Research and Ontario Strategy for Patient Oriented Research Support Unit, during the conduct of the study. ML reports grants and personal fees from WHO and Sunovion Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Evidence-based needs assessments for novel antibiotics against highly-resistant Gram-negative infections (GNIs) are scarce. We aimed to use real-world data from an electronic health record repository to identify treatment opportunities in US hospitals for GNIs resistant to all first-line drugs., Methods: For this retrospective cohort study, population estimates with an unmet need for novel Gram-negative antibiotics were quantified using the Cerner Health Facts database (2009-15), aggregating episodes of infection in US hospitals with pathogens displaying difficult-to-treat resistance (DTR; resistance to carbapenems, other β-lactams, and fluoroquinolones) and episodes involving empirical coverage with reserve drugs (colistin or polymyxin B and aminoglycosides). Episodes displaying extended-spectrum cephalosporin resistance (ECR) were also estimated. Episodes were multiplied by site-specific and fixed 14-day treatment durations for conservative and liberal days-of-therapy (DOT) estimates and stratified by site and taxon. Hospital type-specific DOT rates were reliability adjusted to account for random variation; cluster analyses quantified contribution from outbreaks., Findings: Across 2 996 271 inpatient encounters and 134 hospitals, there were 1352 DTR-GNI episodes, 1765 episodes involving empirical therapy with colistin or polymyxin B, and 16 632 episodes involving aminoglycosides. Collectively, these yielded 39·0 (conservative estimate) to 138·2 (liberal estimate) DOT per 10 000 encounters for a novel DTR-GNI-targeted drug, whereas greater treatment opportunities were identified for ECR (six times greater) and β-lactam susceptible GNIs (70 times greater). The most common DTR-GNI site and pathogen was lower respiratory (14·3 [43·3%] of 33 DOT per 10 000 encounters) and Pseudomonas aeruginosa (522 [38·1%] of 1371 episodes), whereas Enterobacteriaceae urinary-tract infections dominated the ECR or carbapenem-sparing niche (59·0% [5589 of 9535 episodes]) equating to 210·7 DOT per 10 000 encounters. DTR Stenotrophomonas maltophilia, Burkholderia spp, and Achromobacter spp represented less than 1 DOT per 10 000 encounters each. The estimated need for DTR-GNI-targeted antibiotics saw minor contributions by outbreaks and varied from 0·5 to 73·1 DOT per 10 000 encounters by hospital type., Interpretation: Suspected or documented GNIs with no or suboptimal treatment options are relatively infrequent. Non-revenue-based strategies and innovative trial designs are probably essential to the development of antibiotics with improved effectiveness for these GNIs., Funding: Center for Drug Evaluation and Research, US Food and Drug Administration; Intramural Research Program, National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and the National Cancer Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To investigate severe infectious complications after intravesical treatment with bacillus Calmette-Guérin (BCG). We examine a retrospective case series of 10 patients between 2006 and 2018 with severe cystitis or systemic infection after BCG., Methods: Patients with BCG cystitis or disseminated infection were retrospectively identified between 2006 and 2018 at our institution. Cases were reviewed for bladder cancer treatments, demographics, treatment of infection, and outcomes., Results: There was a 0.8% rate of severe BCG cystitis or disseminated infection. Seven patients experienced delayed-onset infections >3 months after last BCG instillation. Four had isolated bladder symptoms, and 5 had diverse systemic manifestations. One patient was asymptomatic and diagnosed on cystoscopic findings. All were treated with varied antibiotic regimens; 9 included antituberculous therapy, and 1 was treated with levofloxacin alone. Two underwent cystectomy for end-stage bladder. The remaining patients are asymptomatic with no residual effects. All are in remission for bladder cancer., Conclusion: Severe infectious complications after BCG are rare and thus difficult to study. Treatment regimens can vary widely. Thorough reporting of patient outcomes is essential to expand the limited body of knowledge., (Copyright © 2019 Elsevier Inc. All rights reserved.)

An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host. Sadly, no such antibiotics exist. What exist are many effective Gram-positive antibacterial agents as well as broad-spectrum agents that provide treatment of certain Gram-negative bacteria but not holistic treatment of all bacteria. However effectiveness of all antibacterial agents is being rapidly eroded due to resistance. This viewpoint provides an overview of today's antibiotics, challenges and potential path forward of discovery and development of new (ideal) antibiotics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of morbidity and mortality in human populations. This review presents a brief history of discovery of the main antimicrobial classes (arsphenamines, β-lactams, sulphonamides, polypeptides, aminoglycosides, tetracyclines, amphenicols, lipopeptides, macrolides, oxazolidinones, glycopeptides, streptogramins, ansamycins, quinolones, and lincosamides) that have changed the landscape of contemporary medicine. Given within a historical timeline context, the review discusses how the introduction of certain antimicrobial classes affected the morbidity and mortality rates due to bacterial infectious diseases in human populations. Problems of resistance to antibiotics of different classes are also extensively discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Antibiotics have dramatically changed the prognoses of patients with severe infectious diseases over the past 50 years. However, the emergence and dissemination of resistant organisms has endangered the effectiveness of antibiotics. One possible approach to the resistance problem is the appropriate use of antibiotic drugs for preventing and treating infections. This Review describes how the volume and appropriateness of antibiotic use in hospitals vary between countries, hospitals, and physicians. At each specific level-cultural, contextual, and behavioural-we discuss the determinants that influence hospital antibiotic use and the possible improvement strategies to make it more appropriate. Changing hospital antibiotic use is a challenge of formidable complexity. On each level, many determinants play a part, so that the measures or strategies undertaken to improve antibiotic use need to be equally diverse. Although various strategies for improving antibiotic use are available, a programme with activities at all three levels is needed for hospitals. Evaluating these programme activities in a way that provides external validity of the conclusions is crucial., (2010 Elsevier Ltd. All rights reserved.)

A number of 3,5-bis(benzylidene)-4-piperidones 1 and some N-4-(2-aminoethoxy)phenylcarbonyl analogs 3-6 display excellent in vitro antimycobacterial properties. In particular, 1c and 6d are potent antimycobacterials which are well tolerated in mice and are identified as important lead molecules. The nature of both the benzylidene aryl rings and the terminal basic groups which affect the antimycobacterial potencies and the absence of neurotoxic side effects were identified. Several representative compounds stimulated respiration in mitochondria isolated from rat liver and this effect was not caused by the swelling of these organelles. Various guidelines for the creation of further related novel antimycobacterial agents are provided.

In this investigation, metabolic profiles of Staphylococcus aureus treated by berberine and nine antibacterial substances with known modes of action were acquired by HPLC/ESI-MS. After data pretreatment, those profiles acquired were reduced into several MS vectors. Then, principal component analysis was carried out upon those vectors to classify those drugs according to their mechanisms. From the result obtained by principal component analysis, the possible antibacterial mode of berberine was evaluated.

Metabolomics is a new branch of systems biology exerting its influence in many aspects. In order to appraise the effects of antibiotics on central carbon metabolism, a CE based method was set up. With this platform, we estimated the organic acid metabolite pools' fluctuation of Escherichia coli and Pseudomonas aeruginosa cultured under 11 different antibiotics' stimuli. Multivariate data analysis showed that different antibiotics had clustered distributions for each strain and could be easily distinguished. Genetic, metabolic and antibiotic mechanism differences could also be deduced by the aid of further correlation analysis. For P. aeruginosa, even synergy action amid antibiotics could be ascertained.

The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.

The oxazolidinones are a promising new class of synthetic antibacterial agents. Here, we review recent efforts directed at the discovery of new antibacterial compounds of this class. New structures and structure-activity relationships (SAR) are discussed in the context of earlier work in the field. Key issues of potency, spectrum, selectivity, in vivo efficacy, and pharmacokinetic profile of the new analogs are addressed.

Chlamydial infections are very common worldwide. All chlamydial species have a tendency to cause persistent infections, which have been associated to several chronic diseases including blinding trachoma, infertility and coronary heart disease (CHD). At present, no efficient treatment for the eradication of chronic chlamydial infections exists and, thus, new antichlamydial compounds are urgently needed. This study was designed to screen antichlamydial activity of natural flavonoids and other natural and structurally similar synthetic compounds against Chlamydia pneumoniae in human cell line (HL). HL cells were infected with C. pneumoniae and incubated 72 h with studied compounds. Reduction in the number of inclusions was determined with immunofluorescence staining. In vitro minimum inhibitory concentration was also determined for some of the most active compounds. Thirty seven percentage of the studied compounds (57 in total) were highly active against C. pneumoniae and all the studied compounds were non-toxic to the host cells at studied concentrations. Our study revealed direct antichlamydial effect for selected polyphenolic compounds against C. pneumoniae, in vitro. We also demonstrated the ability of some of the investigated compounds to accumulate inside cells or into cell membranes and cause inhibition, even when present only prior to infection.

Antimicrobial peptides play a major role in innate immunity. The penaeidins, initially characterized from the shrimp Litopenaeus vannamei, are a family of antimicrobial peptides that appear to be expressed in all penaeid shrimps. As of recent, a large number of penaeid nucleotide sequences have been identified from a variety of penaeid shrimp species and these sequences currently reside in several databases under unique identifiers with no nomenclatural continuity. To facilitate research in this field and avoid potential confusion due to a diverse number of nomenclatural designations, we have made a systematic effort to collect, analyse, and classify all the penaeidin sequences available in every database. We have identified a common penaeidin signature and subsequently established a classification based on amino acid sequences. In order to clarify the naming process, we have introduced a 'penaeidin nomenclature' that can be applied to all extant and future penaeidins. A specialized database, PenBase, which is freely available at , has been developed for the penaeidin family of antimicrobial peptides, to provide comprehensive information about their properties, diversity and nomenclature.

Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine pharmacophore shared by all aminoglycoside antibiotics that contain the 2-deoxystreptamine ring. A discovery library of molecules was prepared by attaching different side chains to both sides of the 1,3-diamine motif. Several of these diamines showed inhibitory activity toward two or three different representative aminoglycoside-modifying enzymes (AGMEs). These studies yielded the first non-carbohydrate inhibitor N-cyclohexyl-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound G,H) that is competitive with respect to the aminoglycoside binding to the enzyme aminoglycoside-2''-nucleotidyltransferase-Ia (ANT2''). Another diamine molecule N-[2-(3,4-dimethoxyphenyl)-ethyl]-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound H,I) was shown to be a competitive inhibitor of two separate enzymes (aminoglycoside-3'-phosphotransferase-IIIa (APH3') and ANT2'') with respect to metal-ATP. Thermodynamic and structural-binding properties of the complexes of APH3' with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.

A method is described to determine the values of the equilibrium (K) and rate (k(2)) constants for enzyme inactivations which occur according to two-step pathways involving a first non-covalent complex and a covalent, irreversibly inactivated adduct. The method rests on a competition between a reference compound [R] for which the k(2) and K values are already known and another inactivator [C]. During the experiments, the disappearance of the reference compound or the appearance of the ER(*) adduct is monitored. The analysis shows that under conditions where the k(2) and K values for the competing substrate can be determined, the measured apparent first-order rate constant for the disappearance of the reference compound is not the sum of the rate constants obtained for each inactivator in the absence of the other. The method can be used to determine the K and k(2) constants when an adequate reference compound is available, in particular, for the interactions between beta-lactam antibiotics and penicillin-binding proteins. The precautions which must be taken to avoid large errors on the estimation of the parameters of the competing inactivator are discussed. Examples found in the literature are discussed where an erroneous simplified equation has been utilised, thus yielding incorrect values for k(2) and K. Interestingly, the correct values can be calculated on the basis of the published results which do not contain the raw experimental data. But some of the values should be considered with a lot of caution since the experiments have not been performed under optimal conditions.

The TOpological MOlecular COMputer Design (TOMOCOMD-CARDD) approach has been introduced for the classification and design of antimicrobial agents using computer-aided molecular design. For this propose, atom, atom-type, and total quadratic indices have been generalized to codify chemical structure information. In this sense, stochastic quadratic indices have been introduced for the description of the molecular structure. These stochastic fingerprints are based on a simple model for the intramolecular movement of all valence-bond electrons. In this work, a complete data set containing 1006 antimicrobial agents is collected and presented. Two structure-based antibacterial activity classification models have been generated. The models (including nonstochastic and stochastic indices) classify correctly more than 90% of 1525 compounds in training sets. These models permit the correct classification of 92.28% and 89.31% of 505 compounds in an external test sets. The TOMOCOMD-CARDD approach, also, satisfactorily compares with respect to nine of the most useful models for antimicrobial selection reported to date. Finally, a virtual screening of 87 new compounds reported in the antiinfective field with antibacterial activities is developed showing the ability of the TOMOCOMD-CARDD models to identify new leads as antibacterial.

A humoral immune response in larvae of the coleopteran insect, Anomala cuprea has been examined for exploring the molecular basis of host-pathogen interactions. The antibacterial activity against the Gram-positive strain, Micrococcus luteus was detected at a low level in absence of injection. The activity increased strikingly in the hemolymph of the larvae challenged with Escherichia coli, showing the fluctuating profile through a time course, which consists of the static induction phase, the production phase rising to a maximum level, and the reduction phase extending over a long duration. Two peptides were purified and characterized by reverse-phase HPLC, Edman degradation and mass spectrometry. They were isoforms, composed of similar sequences with two amino acid substitutions in 43 residues, and novel members of the insect defensins, cysteine-rich antibacterial peptides. Anomala defensins A and B showed potent activity against Gram-positive bacteria, with slight differences in activity against a few strains of tested bacteria. Anomala defensin B was active at high concentration of 40 microM against the Gram-negative strain, Xenorhabdus japonicus, a pathogen toward the host, A. cuprea larvae.

In this review article, we make suggestions on how to approach the increasing problem worldwide of bacterial acute respiratory infections resistant to antibiotics. After a brief description of the main mechanisms of bacterial resistance, i.e., enzymatic inactivation by beta-lactamases, reduction in the permeability of the outer membrane and the development of PBPs that have decreased affinity for the antibiotic, we analyze documented experiences on the response to different groups of antibiotics (beta- lactam antibiotics, cephalosporins, carbapenems and quinolones), of the most commonly isolated bacteria from invasive respiratory infections (Haemophilus influenzae, Streptococcus pneumoniae and Moraxela (Branhamella) catarrhalis. Antimicrobial agent susceptibility in vivo and in vitro testing and the correlation of their results provide the basic information for the adoption of adequate policies and strategies for better use of antibiotics in bacterial respiratory infections; proper surveillance would allow to make intelligent changes in such a policy. Standardized recommendations for clinical practice on the use of antibiotics could be misleading, iatrogenic, and could complicate the resistance problem. To prevent and control the rise and spread of bacterial resistance, an interdisciplinary approach is needed.