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Numerous nonantibiotic drugs have potent antibacterial activity and can adversely affect the human microbiome. The mechanistic underpinning of this toxicity remains largely unknown. We investigated the antibacterial activity of 200 drugs using genetic screens with thousands of barcoded Escherichia coli knockouts. We analyzed 2 million gene-drug interactions underlying drug-specific toxicity. Network-based analysis of drug-drug similarities revealed that antibiotics clustered into modules that are consistent with the mode of action of their established classes, whereas nonantibiotics remained unconnected. Half of the nonantibiotics clustered into separate modules, potentially revealing shared and unexploited targets for new antimicrobials. Analysis of efflux systems revealed that they widely affect antibiotics and nonantibiotics alike, suggesting that the impact of nonantibiotics on antibiotic cross-resistance should be investigated closely in vivo.

The discovery of novel structural classes of antibiotics is urgently needed to address the ongoing antibiotic resistance crisis 1-9 . Deep learning approaches have aided in exploring chemical spaces 1,10-15 ; these typically use black box models and do not provide chemical insights. Here we reasoned that the chemical substructures associated with antibiotic activity learned by neural network models can be identified and used to predict structural classes of antibiotics. We tested this hypothesis by developing an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. We determined the antibiotic activities and human cell cytotoxicity profiles of 39,312 compounds and applied ensembles of graph neural networks to predict antibiotic activity and cytotoxicity for 12,076,365 compounds. Using explainable graph algorithms, we identified substructure-based rationales for compounds with high predicted antibiotic activity and low predicted cytotoxicity. We empirically tested 283 compounds and found that compounds exhibiting antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from rationales. Of these structural classes of compounds, one is selective against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, evades substantial resistance, and reduces bacterial titres in mouse models of MRSA skin and systemic thigh infection. Our approach enables the deep learning-guided discovery of structural classes of antibiotics and demonstrates that machine learning models in drug discovery can be explainable, providing insights into the chemical substructures that underlie selective antibiotic activity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options 1 . No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years 1 . Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB 2 FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB 2 FGC as a tractable target for antimicrobial drug development., (© 2024. The Author(s).)

BACKGROUND The human microbiota modulates the immune system and forms the surface flora. Antibiotic administration causes dysbiosis in the intestinal flora. It is not clear if antibiotic administration in the community effects the upper airway flora in the mid-term or long-term. This study aims to define long-term influence of antibiotics on upper airway flora. MATERIAL AND METHODS In this prospective study, aerobic microbiological analysis of nasal and nasopharyngeal surfaces was performed. Antibiotic administration history of the last 6 months was retrieved using the social insurance database. Culture results of antibiotic-treated and antibiotic-naïve subjects were compared by Pearson's chi-square test or Fisher's exact test. RESULTS A total of 210 subjects were included in the study. Normal flora were documented in 86 nasal swabs and 99 nasopharyngeal swabs. Most of the remaining cases demonstrated gram-positive bacterial overgrowth. There were 113 subjects who did not receive any antibiotic, and 93% of the remaining 97 patients received broad-spectrum antibiotics. Statistical analysis showed that nasal and nasopharyngeal flora did not change upon antibiotic administration, but antibiotic administration during the last month caused increased methicillin resistance development of coagulase-negative Staphylococcus and Staphylococcus aureus microorganisms. CONCLUSIONS Antibiotic exposure did not lead to perturbations in general composition of upper airway flora within 6 months, although the incidence of methicillin resistance in coagulase-positive and -negative Staphylococci demonstrated significant increases when patients received antibiotic during the last month. This should be considered in case of broad-spectrum antibiotic administration, since methicillin resistance increases the morbidity and mortality of nosocomial Staphylococcus infections.

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.)

The term "antibiotics" is a broadly used misnomer to designate antibacterial drugs. In a recent article, we have proposed to replace, e.g., the term "antibiotics" by "antibacterial drugs", "antibiosis" by "antibacterial therapy", "antibiogram" by "antibacteriogram", and "antibiotic stewardship" by "antibacterial stewardship" (Seifert and Schirmer Trends Microbiol, 2021). In the present article, we show that many traditional terms related to antibiotics are used much more widely in the biomedical literature than the respective scientifically precise terms. This practice should be stopped. Moreover, we provide arguments to end the use of other broadly used terms in the biomedical literature such as "narrow-spectrum antibiotics" and "reserve antibiotics", "chemotherapeutics", and "tuberculostatics". Finally, we provide several examples showing that antibacterial drugs are used for non-antibacterial indications and that some non-antibacterial drugs are used for antibacterial indications now. Thus, the increasing importance of drug repurposing renders it important to drop short designations of drug classes such as "antibiotics". Rather, the term "drug" should be explicitly used, facilitating the inclusion of newly emerging indications such as antipsychotic and anti-inflammatory. This article is part of an effort to implement a new rational nomenclature of drug classes across the entire field of pharmacology., (© 2021. The Author(s).)

Objective: To determine the difference in rate of weight gain from birth to 5 years based on exposure to maternal group B streptococcal (GBS) intrapartum antibiotic prophylaxis (IAP)., Design: Retrospective cohort study of 13 804 infants., Setting: Two perinatal centres and a primary paediatric care network in Philadelphia., Participants: Term infants born 2007-2012, followed longitudinally from birth to 5 years of age., Exposures: GBS IAP defined as penicillin, ampicillin, cefazolin, clindamycin or vancomycin administered ≥4 hours prior to delivery to the mother. Reference infants were defined as born to mothers without (vaginal delivery) or with other (caesarean delivery) intrapartum antibiotic exposure., Outcomes: Difference in rate of weight change from birth to 5 years was assessed using longitudinal rate regression. Analysis was a priori stratified by delivery mode and adjusted for relevant covariates., Results: GBS IAP was administered to mothers of 2444/13 804 (17.7%) children. GBS IAP-exposed children had a significantly elevated rate of weight gain in the first 5 years among vaginally-born (adjusted rate difference 1.44% (95% CI 0.3% to 2.6%)) and caesarean-born (3.52% (95% CI 1.9% to 5.2%)) children. At 5 years, the rate differences equated to an additional 0.24 kg among vaginally-born children and 0.60 kg among caesarean-born children., Conclusion: GBS-specific IAP was associated with a modest increase in rate of early childhood weight gain. GBS IAP is an effective intervention to prevent perinatal GBS disease-associated morbidity and mortality. However, these findings highlight the need to better understand effects of intrapartum antibiotic exposure on childhood growth and support efforts to develop alternate prevention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The role of anaerobic organisms in the cystic fibrosis (CF) lung microbiome is unclear. Our objectives were to investigate the effect of broad (BS) versus narrow (NS) spectrum antianaerobic antibiotic activity on lung microbiome diversity and pulmonary function, hypothesizing that BS antibiotics would cause greater change in microbiome diversity without a significant improvement in lung function., Methods: Pulmonary function tests and respiratory samples were collected prospectively in persons with CF before and after treatment for pulmonary exacerbations. Treatment antibiotics were classified as BS or NS. Gene sequencing data from 16S rRNA were used for diversity analysis and bacterial genera classification. We compared the effects of BS versus NS on diversity indices, lung function and anaerobic/aerobic ratios. Statistical significance was determined by multilevel mixed-effects generalized linear models and mixed-effects regression models., Results: Twenty patients, 6-20 years of age, experienced 30 exacerbations. BS therapy had a greater effect on beta diversity than NS therapy when comparing time points before antibiotics to after and at recovery. After antibiotics, the NS therapy group had a greater return toward baseline forced expiratory volume at 1 second and forced expiratory flow 25%-75% values than the BS group. The ratio of anaerobic/aerobic organisms showed a predominance of anaerobes in the NS group with aerobes dominating in the BS group., Conclusions: BS antianaerobic therapy had a greater and possibly longer lasting effect on the lung microbiome of persons with CF, without achieving the recovery of pulmonary function seen with the NS therapy. Specific antibiotic therapies may affect disease progression by changing the airway microbiome., Competing Interests: A.H. and the data in this study were funded by the National Heart, Lung and Blood Institute award number K12HL119994; partially supported by the National Center for Advancing Translational Sciences, award number UL1TR000075. A.H. is also supported by a Harry Shwachman Award through the Cystic Fibrosis Foundation. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease 1 . Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species 2 . Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal 3-5 and human 6,7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern 1 . For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings 2 . Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the [Formula: see text] nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The aim of this research study was to compare the situation concerning the use of microbiology testing, the epidemiology of healthcare-associated infection (HAI) and antimicrobial consumption (AMC) in Polish long-term care facilities (LTCFs) with other European countries, using the most recent findings available in the European databases. Furthermore, this study aimed to highlight several basic factors that contribute to the observable differences in AMC between countries participating in the HALT-3 study, especially the relationship with demographic indicators, as well as the health care resources utilization rates., Patients and Methods: The most recent HAIs in Long-Term care facilities Point Prevalence Survey (HALT PPS) was carried out in EU/EEA countries in 2016-2017, and in Poland it was carried out in April-June 2017 in 24 LTCFs. AMC data was collected with use of methodology of the Anatomical Therapeutic Chemical (ATC) classification system of the WHO., Results: In total total in HALT-3 study on the day of the PPS, 5035 out of the 102,301 eligible residents received at least one antimicrobial agent, with prevalence of 4.9%, and in Poland 3.2%. The most common HAIs in the countries included into the study was urinary tract infection with relative frequency of 32%, in Poland it was skin infection, 30.4%. The respiratory tract infections, excluding pneumonia (PNU) were observed in 29.5% of residents in total, in Poland 17.4%, the prevalence rate of PNU were 1.4% and 5.4%, respectively. The lack of microbiological results of HAIs testing concerned the vast majority of all HAIs, 75.8% in total and 81.5% in Poland. The most frequently used antibacterial for systemic use were beta-lactams and the most frequently prescribed antimicrobial agent was 'amoxicillin and enzyme inhibitor'. AMC was closely correlated with the age of the general population (65 years of age and more) and the availability of doctors in general population., Conclusions: A significant problem observed in LTCFs was the empirical use of antibiotics and the scarcity of microbiological testing. In the studied Polish LTCFs, where the age of residents was low, also the AMC was found to be lower., (© 2021. The Author(s).)

Understating how antibiotic tolerance impacts subsequent resistance development in the clinical setting is important to identifying effective therapeutic interventions and prevention measures. This study describes a patient case of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia which rapidly developed resistance to three primary MRSA therapies and identifies genetic and metabolic changes selected in vivo that are associated with rapid resistance evolution. Index blood cultures displayed susceptibility to all (non-beta-lactam) antibiotics with the exception of trimethoprim/ sulfamethoxazole. One month after initial presentation, during the same encounter, blood cultures were again positive for MRSA, now displaying intermediate resistance to vancomycin and ceftaroline and resistance to daptomycin. Two weeks later, blood cultures were positive for a third time, still intermediate resistant to vancomycin and ceftaroline and resistant to daptomycin. Mutations in mprF and vraT were common to all multidrug resistant isolates whereas mutations in tagH, agrB and saeR and secondary mprF mutation emerged sequentially and transiently resulting in distinct in vitro phenotypes. The baseline mutation rate of the patient isolates was unremarkable ruling out the hypermutator phenotype as a contributor to the rapid emergence of resistance. However, the index isolate demonstrated pronounced tolerance to the antibiotic daptomycin, a phenotype that facilitates the subsequent development of resistance during antibiotic exposure. This study exemplifies the capacity of antibiotic-tolerant pathogens to rapidly develop both stable and transient genetic and phenotypic changes, over the course of a single patient encounter., Competing Interests: The authors have declared that no competing interests exist.

In the European Union, the use of veterinary drugs belonging to the A6 group is prohibited in food-producing animals according to Commission Regulation (EU) No. 2010/37. The aim of this study was to improve the analytical control strategy by developing a single method to analyse residues of prohibited pharmacologically active substances in milk. For this, a single method was developed to analyse 16 prohibited pharmacologically active substances belonging to five different substance classes at required or recommended levels: nitroimidazoles at 3 μg kg -1 , nitrofurans at 0.5 μg kg -1 , chloramphenicol at 0.1 μg kg -1 , dapsone at 5 μg kg -1 and chlorpromazine at 1 μg kg -1 . Milk sample preparation started with an acid hydrolysis combined with a derivatisation. These steps were followed by a clean-up consisting of a dispersive solid-phase extraction and a liquid-liquid extraction. Finally, the sample extracts were analysed by liquid chromatography combined with tandem mass spectrometry, operating alternately in the positive and negative mode. The method was fully validated according to Commission Decision 2002/657/EC for bovine milk and additionally validated for caprine milk. The validation proved that the method is highly effective to detect and confirm all 16 substances in bovine and caprine milk and, additionally to quantify 15 of these substances in bovine milk and 13 of these substances in caprine milk. This study resulted in a new multi-class method to detect, quantify and confirm the identity of 16 prohibited pharmacologically active substances belonging to five different substance classes in two types of milk.

Macrolides are critically important antimicrobials for both human and animal health and should be prioritized in risk assessments, as inappropriate use may result in antimicrobial resistance. The antimicrobials erythromycin, oleandomycin, spiramycin, tilmicosin and tylosin were analysed in infant formula samples by HPLC-MS/MS using a validated analytical method based on a modified QuEChERS extraction. The results of the occurrence study were employed to perform a dietary exposure assessment of infants to residues. In a total of 30 analysed samples, 73% contained spiramycin residues and 27%, tilmicosin residues. Calculated daily intakes ranged from 1.47 × 10 -6 to 2.71 × 10 -4 mg kg -1 body weight considering all analytes, representing 0.01-0.59% of acceptable daily intakes. The results of the dietary exposure assessment were all below acceptable daily intakes, indicating low potential health concerns. However, according to Brazilian regulations, infant formulas containing residues of one or more of the investigated analytes were deemed as non-compliant.

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.)

Purpose of Review: To review the most recent literature studying the classifications, immunochemistry, and crossreactivity of allergy reactions to cephalosporins., Recent Findings: Over the last five years, research interest has focused on three areas related to cephalosporin allergy: cross-reactivity among cephalosporins and with other beta-lactams; the incidence of adverse reactions in penicillin allergy patients or in reported penicillin allergy labels; and new cephalosporins structures involved in the immunological recognition., Summary: Meta-analysis of a substantial number of studies shows that cephalosporins are safer than previously thought. Evidence supports two main conclusions in that regard. First, there is a relatively low percentage of cross-reactivity between cephalosporins and other beta-lactams with penicillins in penicillin allergy patients. Second, there is a very low incidence of allergy reactions in nonselected as well as in selected penicillin allergy patients when cephalosporins are used prior to surgical intervention.On the other hand, few structures have been discovered related to the immune mechanism of cephalosporin allergy reactions, and these are far from being ready to use in clinical practice., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: If wounds are infected with bacteria resistant to an empirical antibiotic regimen, effective wound treatment will be delayed. This can delay wound healing and lengthen hospital stays, increasing the costs to patients. Long-term antibiotic use can also result in minor and major complications, such as diarrhea, antibiotic resistance, or life-threatening leukopenia. Multidrug-resistant (MDR) bacteria make wound treatment even more difficult. Traditionally, surgeons thought that adequate infection control should be established before soft tissue coverage. However, wounds infected by MDR do not heal well with this traditional method and there are no optimal treatment guidelines for MDR bacteria-contaminated wounds.We reviewed 203 patients who underwent vascularized flap surgery from 2012 to 2019 to cover wounds. Class IV and I wounds were compared according to the Centers for Disease Control and Prevention classification. Class IV was further classified as antibiotic-resistant (ARB) and antibiotic-sensitive (ASB) bacteria. Wound size, mode, location, pathogens, healing time, and basic demographics were evaluated. Data were compared using Cramer's V and one-way ANOVA or independent t tests.The average healing time was longer in the ARB (19.7 [range 7-44] days) and ASB (17.9 [range 2-36] days) groups than in the Clean group (16.5 [range 7-28] days). Healing time differed in the 3 groups (P = .036). It was longer in the class IV group than in the class I group (P = .01). However, it was not statistically different between the ARB and ASB groups (P = .164).In our study the difference in healing time was small when vascularized tissue transfer was done in ARB-infected wound compared with ASB-infected and clean wound. It is necessary to perform surgery using vascularized tissue for the infected wound of antibiotic-resistant bacteria., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Case Presentation: A 70-year-old man presented to the ED with sudden onset of left thigh pain followed by transient chest discomfort. His history included cerebrovascular disease, hypertension, and cocaine and methamphetamine use. Physical examination revealed an uncomfortable male subject with a temperature of 37 °C, heart rate of 129 beats/min, BP of 130/65 mm Hg, and 98% oxygen saturation on room air. There was point tenderness in the left lateral thigh without erythema, swelling, or overlying skin changes. His cardiac examination revealed an irregular tachycardia at 129 beats/min and normal first and second heart sounds without murmurs, gallops, or rubs. The remainder of the examination was unremarkable., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

The gut bacterial community prevents many pathogens from colonizing the intestine. Previous studies have associated specific bacteria with clearing Clostridioides difficile colonization across different community perturbations. However, those bacteria alone have been unable to clear C. difficile colonization. To elucidate the changes necessary to clear colonization, we compared differences in bacterial abundance between communities able and unable to clear C. difficile colonization. We treated mice with titrated doses of antibiotics prior to C. difficile challenge, resulting in no colonization, colonization and clearance, or persistent colonization. Previously, we observed that clindamycin-treated mice were susceptible to colonization but spontaneously cleared C. difficile Therefore, we investigated whether other antibiotics would show the same result. We found that reduced doses of cefoperazone and streptomycin permitted colonization and clearance of C. difficile Mice that cleared colonization had antibiotic-specific community changes and predicted interactions with C. difficile Clindamycin treatment led to a bloom in populations related to Enterobacteriaceae Clearance of C. difficile was concurrent with the reduction of those blooming populations and the restoration of community members related to the Porphyromonadaceae and Bacteroides Cefoperazone created a susceptible community characterized by drastic reductions in the community diversity and interactions and a sustained increase in the abundance of many facultative anaerobes. Lastly, clearance in streptomycin-treated mice was associated with the recovery of multiple members of the Porphyromonadaceae , with little overlap in the specific Porphyromonadaceae observed in the clindamycin treatment. Further elucidation of how C. difficile colonization is cleared from different gut bacterial communities will improve C. difficile infection treatments. IMPORTANCE The community of microorganisms, or microbiota, in our intestines prevents pathogens like C. difficile from colonizing and causing infection. However, antibiotics can disturb the gut microbiota, which allows C. difficile to colonize. C. difficile infections (CDI) are primarily treated with antibiotics, which frequently leads to recurrent infections because the microbiota has not yet returned to a resistant state. The recurrent infection cycle often ends when the fecal microbiota from a presumed resistant person is transplanted into the susceptible person. Although this treatment is highly effective, we do not understand the mechanism. We hope to improve the treatment of CDI through elucidating how the bacterial community eliminates CDI. We found that C. difficile colonized susceptible mice but was spontaneously eliminated in an antibiotic treatment-specific manner. These data indicate that each community had different requirements for clearing colonization. Understanding how different communities clear colonization will reveal targets to improve CDI treatments., (Copyright © 2021 Lesniak et al.)

Urethritis refers to inflammation of the urethra and is classified as gonococcal (caused by Neisseria gonorrhoeae) or nongonococcal in origin (most commonly caused by Chlamydia trachomatis, Mycoplasma genitalium, or Trichomonas vaginalis). The most common signs and symptoms include dysuria, mucopurulent urethral discharge, urethral discomfort, and erythema. Diagnostic criteria include typical signs, symptoms, or history of exposure in addition to mucopurulent discharge, Gram stain of urethral secretions showing at least two white blood cells per oil immersion field, first-void urinalysis showing at least 10 white blood cells per high-power field, or a positive leukocyte esterase result with first-void urine. First-line empiric treatment consists of ceftriaxone and doxycycline; however, the antibiotic regimen may be targeted to the isolated organism. Repeat testing is not recommended less than three weeks after treatment because false-positive results are possible during this time. Patients treated for a sexually transmitted infection should have repeat screening in three months, with shared decision-making about future screening intervals. Patients treated for urethritis should abstain from sex for seven days after the start of treatment, until their partners have been adequately treated, and until their symptoms have fully resolved.

We describe rapid spread of multidrug-resistant gram-negative bacteria among patients in dedicated coronavirus disease care units in a hospital in Maryland, USA, during May-June 2020. Critical illness, high antibiotic use, double occupancy of single rooms, and modified infection prevention practices were key contributing factors. Surveillance culturing aided in outbreak recognition and control.

Zoonotic transmission is likely a pathway for antibiotic resistance. Data from a randomized trial of pediatric antibiotic administration were secondarily evaluated to determine if poultry ownership was significantly associated with the presence of gut genetic antibiotic resistance determinants among 118 children in Burkina Faso. Antimicrobial resistance (AMR) determinants were classified using DNA sequencing. We measured the relationship between genetic resistance determinants and chicken ownership using a logistic regression model adjusted for confounding variables. Children in households reporting poultry ownership had four times the odds of tetracycline resistance determinants in the gut compared with those without household poultry (odds ratio [OR]: 4.08, 95% CI: 1.08-15.44, P = 0.04). There was no statistically significant difference found for other antibiotic classes. Understanding the origins of antibiotic resistance may help spur the development of interventions to combat the global AMR crisis.

Background: Caesarean section increases the risk of postpartum infection for women and prophylactic antibiotics have been shown to reduce the incidence; however, there are adverse effects. It is important to identify the most effective class of antibiotics to use and those with the least adverse effects.  OBJECTIVES: To determine, from the best available evidence, the balance of benefits and harms between different classes of antibiotic given prophylactically to women undergoing caesarean section, considering their effectiveness in reducing infectious complications for women and adverse effects on both mother and infant., Search Methods: For this 2020 update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (2 December 2019), and reference lists of retrieved studies., Selection Criteria: We included randomised controlled trials (RCTs) comparing different classes of prophylactic antibiotics given to women undergoing caesarean section.  RCTs published in abstract form were also included. We excluded trials that compared drugs with placebo or drugs within a specific class; these are assessed in other Cochrane Reviews. We excluded quasi-RCTs and cross-over trials. Cluster-RCTs were eligible for inclusion but none were identified., Data Collection and Analysis: Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We assessed the certainty of the evidence using the GRADE approach., Main Results: We included 39 studies, with 33 providing data (8073 women). Thirty-two studies (7690 women) contributing data administered antibiotics systemically, while one study (383 women) used lavage and was analysed separately. We identified three main comparisons that addressed clinically important questions on antibiotics at caesarean section (all systemic administration), but we only found studies for one comparison, 'antistaphylococcal cephalosporins (1 st and 2 nd generation) versus broad spectrum penicillins plus betalactamase inhibitors'.   We found no studies for the following comparisons: 'antistaphylococcal cephalosporins (1 st and 2 nd generation) versus lincosamides' and 'antistaphylococcal cephalosporins (1 st and 2 nd generation) versus lincosamides plus aminoglycosides'. Twenty-seven studies (22 provided data) included comparisons of cephalosporins (only) versus penicillins (only). However for this update, we only pooled data relating to different sub-classes of penicillins and cephalosporins where they are known to have similar spectra of action against agents likely to cause infection at caesarean section. Eight trials, providing data on 1540 women, reported on our main comparison, 'antistaphylococcal cephalosporins (1 st and 2 nd generation) versus broad spectrum penicillins plus betalactamase inhibitors'. We found data on four other comparisons of cephalosporins (only) versus penicillins (only) using systemic administration: antistaphylococcal cephalosporins (1 st and 2 nd generation) versus non-antistaphylococcal penicillins (natural and broad spectrum) (9 studies, 3093 women); minimally antistaphylococcal cephalosporins (3 rd generation) versus non-antistaphylococcal penicillins (natural and broad spectrum) (4 studies, 854 women); minimally antistaphylococcal cephalosporins (3 rd generation) versus broad spectrum penicillins plus betalactamase inhibitors (2 studies, 865 women); and minimally antistaphylococcal cephalosporins (3rd generation) versus broad spectrum and antistaphylococcal penicillins (1 study, 200 women). For other comparisons of different classes of antibiotics, only a small number of trials provided data for each comparison, and in all but one case data were not pooled. For all comparisons, there was a lack of good quality data and important outcomes often included few women. Three of the studies that contributed data were undertaken with drug company funding, one was funded by the hospital, and for all other studies the funding source was not reported. Most of the studies were at unclear risk of selection bias, reporting bias and other biases, partly due to the inclusion of many older trials where trial reports did not provide sufficient methodological information. We undertook GRADE assessment on the only main comparison reported by the included studies, antistaphylococcal cephalosporins (1 st and 2 nd generation) versus broad spectrum penicillins plus betalactamase inhibitors, and the certainty ranged from low to very low, mostly due to concerns about risk of bias, wide confidence intervals (CI), and few events. In terms of the primary outcomes for our main comparison of 'antistaphylococcal cephalosporins (1 st and 2 nd generation) versus broad spectrum penicillins plus betalactamase inhibitors': only one small study reported sepsis, and there were too few events to identify clear differences between the drugs (risk ratio (RR) 2.37, 95% CI 0.10 to 56.41, 1 study, 75 women, very low-certainty evidence). There may be little or no difference between these antibiotics in preventing endometritis (RR 1.10; 95% CI 0.76 to 1.60, 7 studies, 1161 women; low-certainty evidence). None of the included studies reported on infant sepsis or infant oral thrush. For our secondary outcomes, we found there may be little or no difference between interventions for maternal fever (RR 1.07, 95% CI 0.65 to 1.75, 3 studies, 678 women; low-certainty evidence). We are uncertain of the effects on maternal: wound infection (RR 0.78, 95% CI 0.32 to 1.90, 4 studies, 543 women), urinary tract infection (average RR 0.64, 95% CI 0.11 to 3.73, 4 studies, 496 women), composite adverse effects (RR 0.96, 95% CI 0.09 to 10.50, 2 studies, 468 women), and skin rash (RR 1.08, 95% CI 0.28 to 4.1, 3 studies, 591 women) (all very low certainty evidence). Although maternal allergic reactions were reported by two studies, there were no events. There were no infant outcomes reported in the included studies. For the other comparisons, the results for most outcomes had wide CIs, few studies and few women included. None of the included trials reported on longer-term maternal outcomes, or on any infant outcomes., Authors' Conclusions: Based on the best currently available evidence, 'antistaphylococcal cephalosporins' and 'broad spectrum penicillins plus betalactamase inhibitors' may have similar efficacy at caesarean section when considering immediate postoperative infection, although we did not have clear evidence for several important outcomes. Most trials administered antibiotics at or after cord clamping, or post-operatively, so results may have limited applicability to current practice which generally favours administration prior to skin incision. We have no data on any infant outcomes, nor on late infections (up to 30 days) in the mother; these are important gaps in the evidence that warrant further research. Antimicrobial resistance is very important but more appropriately investigated by other trial designs., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Staphylococcus aureus has a great ability to form biofilms on implant-related biomaterials. This study aimed to investigate the resistance, biofilm and molecular characteristics of S. aureus strains isolated from patients with postoperative infections after arthroplasty in two Chinese tertiary care hospitals during 2017 to 2018., Methods: Antimicrobial susceptibility was determined by the agar dilution method. Bacterial biofilm formation was determined by crystal violet staining. The genes related to biofilm formation and molecular typing were analyzed by PCR amplification., Results: A total of 33 isolates were collected, 21 of which were from Henan. The strains were completely sensitive to vancomycin, linezolid, and nitrofurantoin. All the isolates had adhesion ability and could produce biofilms. Of the isolates, 75.0% from Chongqing and 85.7% from Henan had stronger biofilm formation abilities. The strains from Henan had slightly higher resistance, adhesion and biofilm-forming abilities than those from Chongqing. The strains in both hospitals carried at least two genes related to biofilm formation, and the ica and fnb genes were the most frequently detected genes. Three SCC mec types and seven sequence types (STs) were found in Henan, and two SCC mec types and six STs were found in Chongqing. ST239-SCC mec III was the main epidemic clone in the two hospitals., Conclusion: The resistance phenotype and molecular characteristics of S. aureus strains varied in different hospitals. The results reflect the potential risks of S. aureus infection in postoperative arthroplasty patients. Our study provides a powerful basis for the clinical treatment, infection control and monitoring of outbreaks of epidemic strains.

Aim: To study the epidemiology and clinical outcomes of catheter-related infections of Serratia species in peritoneal dialysis (PD) patients., Methods: We retrospectively reviewed the patient characteristics, antibiotics susceptibility/resistance patterns and treatment outcomes of exit site infection (ESI) and peritonitis due to Serratia in PD patients during the period of 2004 to 2017., Results: One hundred and sixty-one patients had Serratia ESI, of which 10 (6.2%) progressed to tunnel tract involvement and 11 (6.8%) developed PD peritonitis. Nineteen (11.8%) patients with Serratia ESI failed to respond to medical treatment and required catheter removal. Fifty-six (34.8%) patients had repeat Serratia ESI, which occurred at 12.9 ± 13.6 months after the previous episode. Twenty-two patients had Serratia peritonitis, which accounted for 1% of peritonitis during the study period. Ten (45.5%) patients responded to medical treatment while 12 (54.5%) patients required catheter removal. Nine patients (36.4%) failed to resume PD and were converted to long-term haemodialysis. Two patients had repeat peritonitis at 2 months and 3 years, respectively, after the initial episode. Serratia species in PD patients showed high rates of resistance to ampicillin, and first- and second-generation cephalosporins, but were generally susceptible to aminoglycosides, carboxy-/ureido-penicillins and carbapenems., Conclusion: Our results suggest that Serratia ESI show low risk of progression to peritonitis and favourable response to medical therapy, while Serratia peritonitis was associated with high rates of catheter removal and peritoneal failure., (© 2020 Asian Pacific Society of Nephrology.)

In this study, we aimed to characterize lactic acid bacteria strains derived from infants' feces, to evaluate the probiotic potential and explore the wide-spectrum antimicrobial activity. Of 800 isolates, 20 inhibited the growth of enterotoxigenic Escherichia coli K88 and Salmonella enterica ATCC 13076. On the basis of 16S rRNA sequence analysis, the 20 isolates were assigned to Lactobacillus casei (7), Lactobacillus paracasei (2), Lactobacillus plantarum (4), Lactobacillus rhamnosus (2), Enterococcus avium (3), Enterococcus faecium (1), and Enterococcus lactis (1) species. In addition, 12 strains with high antimicrobial activity were investigated for the presence of probiotic properties such as physiological-biochemical characteristics, antimicrobial susceptibility, hemolytic activity, hydrophobicity, and aggregation activity. Wide-spectrum antimicrobial activity analysis revealed that approximately all tested strains inhibited the ten pathogens, and four strains (ZX221, ZX633, ZX3131, and ZX3875) had good probiotic properties and survived after being exposed to simulated gastrointestinal tract conditions. Moreover, we investigated the influence of pH on the wide-spectrum antimicrobial activity and found that four strains inhibited most pathogens at pH 4.5 and pH 5, whereas only ZX633 had an inhibitory effect on Bacillus subtilis ATCC 6633 and Micrococcus luteus ATCC 4698 at pH 5.5. Overall, Lact. casei ZX633 had wide-spectrum antimicrobial activity and could be considered a potential probiotic.

Background: Data describing antibiotic use in U.S. nursing homes remain limited. We report antibiotic use among skilled nursing facility residents from 29 U.S. nursing homes and assessed correlations between antibiotics prescribed to residents in skilled care and nursing home characteristics., Design: Retrospective cohort study., Setting: Twenty-nine U.S. nursing homes in the same healthcare corporation., Participants: Residents receiving skilled care in 2016., Measurements: We used pharmacy invoice and nursing home census data to calculate the days of antibiotic therapy per 1,000 days of skilled care (1,000 DOSC), the rate of antibiotic starts per 1,000 DOSC, the length of antibiotic therapy, and the average antibiotic spectrum index. We also assessed correlations between antibiotic use and nursing home characteristics., Results: Antibiotics accounted for an average of 9.6% (±0.6%) of systemic medications prescribed among residents receiving skilled care. On average, 26.8% (±2.9%) of antibiotics were intravenous. Fluoroquinolones were prescribed at the highest rates (19% across all facilities), followed by beta-lactam/beta-lactamase inhibitors (11%), first- and second-generation cephalosporins, sulfonamides, and oral tetracyclines (each at 9%). Both the proportion of residents using enrolled in Medicare and number of unique prescribers responsible for systemic prescriptions positively correlated with the rate of antibiotic starts., Conclusions: Our study demonstrates that pharmacy invoices represent a useful and preexisting source of data for assessing antibiotic prescriptions among individuals receiving skilled nursing care. The correlation between the number of unique prescribers and antibiotic starts suggests that prescribers are central to efforts to improve antibiotic use in nursing homes., (© 2020 The American Geriatrics Society.)

Despite the unique physiology and metabolic pathways of microbiomes from cold environments providing key evolutionary insights and promising leads for discovering new bioactive compounds, cultivable bacteria entrapped in perennial ice from caves remained a largely unexplored life system. In this context, we obtained and characterized bacterial strains from 13,000-years old ice core of Scarisoara Ice Cave, providing first isolates from perennial ice accumulated in caves since Late Glacial, and first culture-based evidences of bacterial resistome and antimicrobial compounds production. The 68 bacterial isolates belonged to 4 phyla, 34 genera and 56 species, with 17 strains representing putative new taxa. The Gram-negative cave bacteria (Proteobacteria and Bacteroidetes) were more resistant to the great majority of antibiotic classes than the Gram-positive ones (Actinobacteria, Firmicutes). More than 50% of the strains exhibited high resistance to 17 classes of antibiotics. Some of the isolates inhibited the growth of clinically important Gram-positive and Gram-negative resistant strains and revealed metabolic features with applicative potential. The current report on bacterial strains from millennia-old cave ice revealed promising candidates for studying the evolution of environmental resistome and for obtaining new active biomolecules for fighting the antibiotics crisis, and valuable cold-active biocatalysts.

Background: The antibiotic resistance profile of Helicobacter pylori (H. pylori) is constantly changing. Up-to-date and reliable data for the effectiveness of first-line H. pylori treatment protocols are necessary to provide evidence-based best-practice guidelines., Objectives: To determine the effectiveness, compliance and safety of first-line treatment for H. pylori in Israel., Methods: An observational, prospective, multicenter study was conducted in tertiary referral centers in Israel, as part of the European registry on H. pylori management (Hp-EuReg). H. pylori-infected patients were included from 2013 to March 2020. Data collected included demographics, clinical data, diagnostic tests, previous eradication attempts, current treatment, compliance, adverse events, and treatment outcome result., Results: In total, 242 patients were registered, including 121 (50%) who received first-line therapy, 41% of these individuals received clarithromycin based triple therapy and 58.9% received a four-drug regimen. The overall effectiveness of first-line therapy was 85% and 86% by modified intention-to-treat and per protocol analyses, respectively. The effectiveness of both sequential and concomitant therapies was 100% while clarithromycin-based triple therapy achieved an eradication rate of 79%. Treatment eradication was higher among patients who received high dose proton pump inhibitor (PPI) compared to those treated with low dose PPI (100% vs. 81.5% respectively, P < 0.01). No difference in treatment effectiveness was found between 7-, 10-, and 14-day treatment., Conclusions: The effectiveness of clarithromycin-based triple therapy is suboptimal. First-line treatment of H. pylori infection should consist of four drugs, including high dose PPI, according to international guidelines.

Antibiotic resistance is a global threat that should be urgently resolved. Finding a new antibiotic is one way, whereas the repression of the dissemination of virulent pathogenic bacteria is another. From this point of view, this paper summarizes first the mechanisms of conjugation and transformation, two important processes of horizontal gene transfer, and then discusses the approaches for disarming virulent pathogenic bacteria, that is, virulence factor inhibitors. In contrast to antibiotics, anti-virulence drugs do not impose a high selective pressure on a bacterial population, and repress the dissemination of antibiotic resistance and virulence genes. Disarmed virulence factors make virulent pathogens avirulent bacteria or pathobionts, so that we human will be able to coexist with these disarmed bacteria peacefully.

Objective: The indiscriminate prescription of antibiotics has led to the emergence of resistance microbes worldwide. This study aimed to investigate the antibiotic prescribing practices amongst general dental practitioners and specialists in managing endodontic infections in the United Arab Emirates (UAE)., Design: General dental practitioners and specialists in the UAE were invited to participate in an online questionnaire survey which included questions on socio-demographics, practitioner's antibiotic prescribing preferences for various pulpal and periapical diseases, and their choice, in terms of the type, dose and duration of the antibiotic. The link to the survey questionnaire was sent to 250 invited dentists. Data were analyzed by descriptive statistics and chi-square tests for independence and level of significance was set at 0.05., Results: A total of 174 respondents participated in the survey (response rate = 70%). The respondents who prescribed antibiotics at least once a month were 38.5% while 17.2% did so, more than three times a week; amoxicillin 500 mg was the antibiotic of choice for patients not allergic to penicillin (43.7%), and in cases of penicillin allergies, erythromycin 500 mg (21.3%). There was a significant difference in the antibiotic prescribing practices of GDPs compared to endodontists and other specialties especially in clinical cases such as acute apical abscesses with swelling and moderate to severe pre-operative symptoms and retreatment of endodontic cases (p<0.05). Approximately, three quarters of the respondents (78.7%) did not prescribe a loading dose when prescribing antibiotics. About 15% respondents prescribed antibiotics to their patients if they were not accessible to patients due to a holiday/weekend., Conclusions: In general, the antibiotic prescribing practices of UAE dentists are congruent with the international norms. However, there were occasions of inappropriate prescriptions such as in patients with irreversible pulpitis, necrotic pulps with no systemic involvement and/or with sinus tracts., Competing Interests: The authors have declared no competing interests exist.

Approval by the US Food and Drug Administration (FDA) of a drug for a given indication is thought to reassure clinicians, other health care providers, and patients that substantial evidence of effectiveness exists for specific indicated populations (patients and diseases). This study examines whether FDA approval of certain antibiotics should be so reassuring for all patient populations identified in the FDA-approved labels. Specifically, this study compared patient populations covered by FDA-approved labels for 21 novel antibiotics approved between 1999 and 2018 to the patient exclusion and inclusion criteria of pivotal trials that supported those approvals. We found that every FDA-approved label for these antibiotics included at least one identifiable patient population that was explicitly excluded from enrolling in the supporting pivotal trials. Two antibiotics, bedaquiline and ceftazidime-avibactam, were approved for use in populations that were fully excluded from enrolling in registration trials., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: Infection near metal implants is a problem that presents challenging treatment dilemmas for physicians. The aim of this study was to analyse the efficacy of two treatment protocols for acute fracture-related infections., Methods: Seventy-one patients in two level-1 trauma centres in the Netherlands were retrospectively included in this study. These trauma centres had different standardised protocols for acute infection after osteosynthesis: 39 patients were selected from protocol A and 32 from protocol B. Both protocols involve immediate surgical debridement and soft tissue coverage, but differ in antibiotic approach: (A) immediate empirical combination antibiotic therapy with rifampicin, or (B) postponed (1-5 days) targeted antibiotic therapy. The primary outcome of these protocols was success, defined as a fracture healing in the absence of infection. The secondary outcome was antibiotic resistance patterns. Logistic regression was conducted on patients and treatment-related factors in association with primary success., Results: Primary success was achieved in 72% of protocol A patients, in 47% of those in protocol B (P = 0.033), and with prolongation of treatment success was achieved in 90% and 78% of patients, respectively. Protocol A exhibited a better primary success rate (adjusted OR 3.45, CI 1.13-10.52) when adjusted for age and soft tissue injury. There was no significant difference in antibiotic resistance between the two protocols., Conclusion: Both protocols yielded high overall success rates. Immediate empirical antibiotics can be used safely without additional bacterial resistance and may contribute to increased success rates.

Bacteriocins are ribosomally synthesized peptides with antibacterial activity against food-borne pathogenic bacteria that cause spoilage, possessing important potential for use as a natural preservative in the food industry. The novel bacteriocin BM1300 produced by Lactobacillus crustorum MN047 was identified after purification in this study. It displayed broad-spectrum antibacterial activity against some selected Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration (MIC) values of BM1300 against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 were 13.4 μg/mL and 6.7 μg/mL, respectively. Moreover, BM1300 showed excellent thermal (between 60 and 120 °C), pH (2-11), and chemical (Tween-40, Tween-80, Triton X-100, and EDTA) stabilities. Time-kill curves revealed that BM1300 exhibited bactericidal activity against S. aureus and E. coli. The scanning and transmission electron microscopy indicated that BM1300 acted by disrupting the cell membrane integrity and increasing cell membrane permeabilization of indicator bacteria. The disruption of cell membrane integrity caused by BM1300 was further demonstrated by the uptake of propidium iodide (PI) and the release of intracellular lactate dehydrogenase (LDH) and nucleic acid and proteins. Moreover, BM1300 affected cell cycle distribution to exert antibacterial activity collaboratively. Meanwhile, BM1300 inhibited the growth of S. aureus and E. coli of beef meat and improved the microbiological quality of beef meat. These findings place BM1300 as a potential biopreservative in the food industry.

Background: Despite the possible association between antibiotic overuse and childhood obesity, studies on this association are lacking in Asia. This study aimed to determine whether there is an association between the number, duration of antibiotic exposure, timing of antibiotics initiation and childhood obesity., Methods: In this retrospective cohort study, Korean children born between January 1, 2008 and December 31, 2012, who underwent government-provided health examinations at age 4-6 and 30-36 months, were included. The main outcome was obesity (body mass index in 95th percentile) at 30-36 months. The exposure variable was antibiotic prescription during the first 24 months of life. The number, prevalence, and odds ratio (OR) of obese children based on antibiotic exposure were analyzed using logistic regression., Results: Of 31,733 children, 31,457 (99.1%) children used antibiotics and 2843 (9%) were obese at 30-36 months. There was a clear dose-response relationship between obesity and number of antibiotic classes, cumulative days, and earlier antibiotic initiation. Children who used five or more antibiotic classes had higher odds of obesity than those who used only one class (OR 1.42, 95% CI 1.12-1.8). Children with >180 days of antibiotic exposure had higher risk of obesity than those with 1-30 exposure days (OR 1.40, 95% CI 1.19-1.64). Children with earlier initiation of antibiotics had higher risk of obesity (OR 1.15 per 6 months, 95% CI 1.08-1.22)., Conclusion: Increased number of antibiotic classes, longer duration of antibiotic prescription and earlier antibiotic initiation before 24 months was associated with childhood obesity at 30-36 months. This South Korean retrospective study supports judicious use of antibiotics in the first 24 months of life to avoid the potential risk of childhood obesity. Future studies need to be performed to confirm or refute the results presented herein., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Use of antibiotics in early life has been linked with childhood inflammatory bowel disease (IBD), but data for adults are mixed, and based on smaller investigations that did not compare risk among siblings with shared genetic or environmental risk factors. We aimed to investigate the association between antibiotic therapy and IBD in a large, population-based study., Methods: In this prospective case-control study, we identified people living in Sweden aged 16 years or older, with a diagnosis of IBD based on histology and at least one diagnosis code for IBD or its subtypes (ulcerative colitis and Crohn's disease). We identified consecutive patients with incident IBD from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, cross-referenced with the Swedish Patient Register and the Prescribed Drug Register. We accrued data for cumulative antibiotic dispensations until 1 year before time of matching for patients and up to five general population controls per patient (matched on the basis of age, sex, county, and calendar year). We also included unaffected full siblings as a secondary control group. Conditional logistic regression was used to estimate multivariable-adjusted odds ratios (aORs) and 95% CIs for diagnosis of incident IBD., Findings: We identified 23 982 new patients with IBD (15 951 ulcerative colitis, 7898 Crohn's disease, 133 unclassified IBD) diagnosed between Jan 1, 2007, and Dec 31, 2016. 117 827 matched controls and 28 732 siblings were also identified. After adjusting for several risk factors, aOR in patients who had used antibiotics versus those who had never used antibiotics was 1·88 (95% CI 1·79-1·98) for diagnosis of incident IBD, 1·74 (1·64-1·85) for ulcerative colitis, and 2·27 (2·06-2·49) for Crohn's disease. aOR was higher in patients who had received one antibiotic dispensation (1·11, 1·07-1·15), two antibiotic dispensations (1·38, 1·32-1·44), and three or more antibiotic dispensations (1·55, 1·49-1·61) than patients who had none. Increased risk was noted for ulcerative colitis (aOR with three or more antibiotic dispensations 1·47, 95% CI 1·40-1·54) and Crohn's disease (1·64, 1·53-1·76) with higher estimates corresponding to broad-spectrum antibiotics. Similar but attenuated results were observed when siblings were used as the reference group, with an aOR of 1·35 (95% CI 1·28-1·43) for patients who had received three or more dispensations, compared with general population controls., Interpretation: Higher cumulative exposure to systemic antibiotic therapy, particularly treatments with greater spectrum of microbial coverage, may be associated with a greater risk of new-onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not appear to differ when predisposed siblings were used as the reference controls. Our findings, if substantiated by longer-term prospective studies in humans or mechanistic preclinical investigations, suggest the need to further emphasise antibiotic stewardship to prevent the rise in dysbiosis-related chronic diseases, including IBD., Funding: National Institutes of Health. Crohn's and Colitis Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Data on antimicrobial use were collected for the 2016 and 2017 calendar years from swine producers in the United States. Nine large systems, collectively producing over 20 million market pigs annually, voluntarily provided data to advance understanding of antimicrobial use in the industry and to support antimicrobial stewardship initiatives. The scope of the study was limited to growing pigs, and the granularity of data varied across the systems. Data were summarized both qualitatively and quantitatively by antimicrobial class, active ingredient and route of administration (injection, water and feed). Data on the purpose of administration, doses and durations of administration were not available, but some information was provided by the responsible veterinarians. Aggregate data were similar both qualitatively and quantitatively in 2016 and 2017, although marked changes between years were evident within systems for some antimicrobials. Antimicrobial use (by weight) was dominated by the tetracycline class (approximately 60% of total use). Antimicrobials in classes categorized as critically important constituted 4.5% and 5.3% of total use in 2016 and 2017, respectively. In both years, fluoroquinolone (0.23%, 0.46%) and 3rd generation cephalosporin (0.15%, 0.11%) use collectively accounted for <1% of total use. Administration was predominantly oral in feed and water, and injection comprised approximately 2% of use overall, but around 12% for critically important antimicrobials. There was considerable variability among systems in patterns of antimicrobial use. This pilot project demonstrates the feasibility of acquiring antimicrobial use data via voluntary sharing. It is currently being expanded among larger swine production systems, and further efforts to enable confidential data sharing and benchmarking for smaller producers are being pursued by the swine industry. Recognized biases in the data caution against over-interpretation of these data as an index of national use., (© 2020 The Authors. Zoonoses and Public Health published by Wiley-VCH GmbH.)

Background: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR., Methods: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed., Results: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively., Conclusion: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

Background: In Indian subcontinent where tuberculosis is endemic, the spinal infection was thought to be due to mycobacterium tuberculosis in most of the cases. Hence there is a practice of treating these patients with empirical antitubercular treatment. However, recent guidelines advice biopsy and tissue diagnosis before starting antibiotics., Objective of Study: Our retrospective study analyses the role of biopsy in establishing the microbiological diagnosis and thus identifying the incidence of pyogenic and tubercular spondylodiscitis presented to a tertiary care centre., Materials and Methods: All patients who were diagnosed as spondylodiscitis by clinical and radiological criteria and who underwent biopsy were included in the study and data was retrieved from medical records and PACS. Criteria for tubercular spondylodiscitis included presence of mycobacterium tuberculosis either in smear/gene Xpert, or histopathological evidence of tuberculosis. Organism isolation other than MTB or absence of tubercular granuloma and response to antibiotics were considered as non-tubercular aetiology., Results: Our study achieved 84% (n-63) accuracy for first biopsy and 34 patients (53.96%) were diagnosed as pyogenic spondylodiscitis. Organisms were isolated in 11 cases (32%) of pyogenic spondylodiscitis and tubercular bacilli in 17 cases (65%) of tubercular spondylodiscitis. Aspiration of pus yielded better isolation of organisms (P < 0.001) in pyogenic spondylodiscitis. 11% of cases showed drug resistant tuberculosis., Conclusion: We conclude that there is an increasing trend of pyogenous spondylodiscitis compared to tubercular spondylodiscitis in patients presenting to tertiary care centre, hence biopsy is essential to start antimicrobials., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. 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.)

Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics 1 . Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins 2 , potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome 3 . Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed 2 . Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.

Although Pseudomonas aeruginosa (P. aeruginosa) can infect both animals and humans, there is a paucity of veterinary studies on antimicrobial resistance of P. aeruginosa in South Africa. Secondary data of canine clinical cases presented at the hospital from January 2007 to December 2013 was used. The following information was recorded: type of sample, the date of sampling and the antimicrobial susceptibility results. Frequencies, proportions and their 95% confidence intervals were calculated for all the categorical variables. In total, 155 P. aeruginosa isolates were identified and included in this study. All the isolates were resistant to at least one antimicrobial (AMR), while 92% were multi-drug resistant (MDR). Most isolates were resistant to lincomycin (98%), penicillin-G (96%), orbifloxacin (90%), trimethoprim-sulfamethoxazole (90%) and doxycycline (87%). A low proportion of isolates was resistant to imipenem (6%), tobramycin (12%), amikacin (16%) and gentamicin (18%). A high proportion of MDR-P. aeruginosa isolates was resistant to amoxycillin-clavulanic acid (99%), tylosin (99%), chloramphenicol (97%) and doxycycline (96%). Few (6%) of MDR-P. aeruginosa isolates were resistant to imipenem. Pseudomonas aeruginosa was associated with infections of various organ systems in this study. All P. aeruginosa isolates of P. aeruginosa exhibited resistance to β-lactams, fluoroquinolones and lincosamides. Clinicians at the hospital in question should consider these findings when treating infections associated with P. aeruginosa.

In this study, molecular topology was used to develop several discriminant equations capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four equations were constructed, named DF1, DF2, DF3, and DF4, all with good statistical parameters such as Fisher-Snedecor's F (over 25 in all cases), Wilk's lambda (below 0.36 in all cases) and percentage of correct classification (over 80% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. From the four discriminant functions, it can be extracted that the presence of sp 3 carbons, ramifications, and secondary amine groups in a molecule enhance antibacterial activity, whereas the presence of 5-member rings, sp 2 carbons, and sp 2 oxygens hinder it. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of antibacterial activity.

Background: Suspected antibiotic hypersensitivity in children is a frequent reason for consultation. Skin test performance and drug provocation test (DPT) duration are controversial issues. The objective of this study was to assess the effectiveness of diagnostic tests used in the study of antibiotic hypersensitivity and to estimate an optimal duration for DPT., Methods: Sixty-two children with a suspected hypersensitivity reaction to antibiotics were studied. Skin tests were performed on all patients. In the case of negative results, DPTs were performed for a duration similar to the time elapsed from the start of treatment until the onset of the reaction., Results: The frequency of antibiotic hypersensitivity in the study population was 8.1% (5 of 62). Only 1 patient showed positive skin tests. The other allergic patients were diagnosed by DPT, which reproduced the reaction within the first 6 hours in all but one of them., Conclusions: Shortening DPT duration may decrease the sensitivity of the test for the diagnosis of non-IgE-mediated hypersensitivity; however, it should be considered as an opportunity to reduce the resulting microbial resistances.

Machine learning techniques can be applied to MALDI-TOF mass spectral data of drug-treated cells to obtain classification models which assign the mechanism of action of drugs. Here, we present an example application of this concept to the screening of antibacterial drugs that act at the major bacterial target sites such as the ribosome, penicillin-binding proteins, and topoisomerases in a pharmacologically relevant phenotypic setting. We show that antibacterial effects can be identified and classified in a label-free, high-throughput manner using wild-type Escherichia coli and Staphylococcus aureus cells at variable levels of target engagement. This phenotypic approach, which combines mass spectrometry and machine learning, therefore denoted as PhenoMS-ML, may prove useful for the identification and development of novel antibacterial compounds and other pharmacological agents.

In 2019, a project designed to develop a system for measuring and comparing antibiotic usage in hospitals was launched in Korea. As part of this project, we developed a means to classify antibiotic usage in Korean hospitals using a modified Delphi method. In results, the following categories of antibiotic classification were accepted for use in Korean hospitals: 1) broad-spectrum antibacterial agents predominantly used for hospital-onset infections in adults, 2) broad-spectrum antibacterial agents predominantly used for community-acquired infections in adults, 3) antibacterial agents predominantly used for resistant gram-positive infections in adults, 4) narrow-spectrum beta-lactam agents in adults, 5) antibacterial agents predominantly used for extensive antibiotic resistant gram-negative bacteria in adults, and 6) total antibacterial agents., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)