Assessment of the practical impact of adjusting beta-lactam dosages based on therapeutic drug monitoring in critically ill adult patients: a systematic review and meta-analysis of randomized clinical trials and observational studies.

An estimated 70% of critically ill patients receive antibiotics, most frequently beta-lactams. The pharmacokinetic properties of these substances in this patient population are poorly predictable. Therapeutic drug monitoring (TDM) is helpful in making personalized decisions in this field, but its overall impact as a clinical decision-supporting tool is debated. We aimed to evaluate the clinical implications of adjusting beta-lactam dosages based on TDM in the critically ill population by performing a systematic review and meta-analysis of available investigations. Randomized controlled trials and observational studies were retrieved by searching three major databases. The intervention group received TDM-guided beta-lactam treatment, that is, at least one dose reconsideration based on the result of the measurement of drug concentrations, while TDM-unadjusted dosing was employed in the comparison group. The outcomes were evaluated using forest plots with random-effects modeling and subgroup analysis. Eight eligible studies were identified, including 1044 patients in total. TDM-guided beta-lactam treatment was associated with improved clinical cure from infection [odds ratio (OR): 2.22 (95% confidence interval (CI): 1.78-2.76)] and microbiological eradication [OR: 1.72 (CI: 1.05-2.80)], as well as a lower probability of treatment failure [OR: 0.47 (CI: 0.36-0.62)], but the heterogeneity of studies was remarkably high, especially in terms of mortality (70%). The risk of bias was moderate. While the TDM-guided administration of beta-lactams to critically ill patients has a favorable impact, standardized study designs and larger sample sizes are required for developing evidence-based protocols in this field.

Impact of attaining aggressive vs. conservative PK/PD target on the clinical efficacy of beta-lactams for the treatment of Gram-negative infections in the critically ill patients: a systematic review and meta-analysis.

BACKGROUND: To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. RESULTS: A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15-2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01-0.29). Male gender, body mass index > 30 kg/m2, augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. CONCLUSIONS: Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated ß-Lactams against Gram-Negative Bacteria.

Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.

Resistance phenotype and virulence potential of Leclercia adecarboxylata strains isolated from different sources.

Introduction. Leclercia adecarboxylata is a member of Enterobacterales, often considered an opportunistic pathogen. Recent reports have highlighted L. adecarboxylata as an emerging pathogen harbouring virulence and resistance determinants.Gap statement. Little information exists on virulence and resistance determinants in L. adecarboxylata strains isolated from environmental, food, and clinical samples.Aim. To determine the presence of resistance and virulence determinants and plasmid features in L. adecarboxylata strains isolated from environmental, food, and clinical samples, as well as their phylogenetic relationship.Results. All strains tested showed resistance to ß-lactams and quinolones but were sensitive to aminoglycosides and nitrofurans. However, even though fosfomycin resistance is considered a characteristic trait of L. adecarboxylata, the resistance phenotype was only observed in 50 % of the strains; bla TEM was the most prevalent BLEE gene (70 %), while the quinolone qnrB gene was observed in 60 % of the strains. Virulence genes were differentially observed in the strains, with adhesion-related genes being the most abundant, followed by toxin genes. Finally, all strains carried one to seven plasmid bands ranging from 7 to 125 kbps and harboured several plasmid addiction systems, such as ParDE, VagCD, and CcdAB in 80 % of the strains.Conclusions. L. adecarboxylata is an important emerging pathogen that may harbour resistance and virulence genes. Additionally, it has mobilizable genetic elements that may contribute to the dissemination of genetic determinants to other bacterial genera.

Prevalence and antimicrobial resistance of Enterobacteriaceae in the north of Kazakhstan.

Background: An increasing number of drugs are used each year in the treatment of small pets (cats and dogs), including medicines (cephalosporins and fluoroquinolones) used in human therapy. Aim: The purpose of this study was to isolate and explore the antibiotic resistance of opportunistic Enterobacteriaceae (Escherichia coli, Klebsiella, Proteus, Ci trobacter, Enterobacter) from cats and dogs, and to isolate resistance genes in the microorganisms. Methods: In 2021, 808 samples of biological material from small domestic animals were collected in veterinary clinics in Kostanay. From these, 210 microorganisms were isolated and identified. Results: A large majority of the strains sampled belonged to E. coli-149 (70.9%), Enterobacter-11 (5.2%), Klebsiella-28 (13.3%), Proteus-12 (5.7%) and 10 Citrobacter isolates (4.8%). In all isolates identified, antibiotic resistance/sensitivity was determined by disc-diffusion method to ampicillin, cefoxitin, gentamicin, levomycetin, tetracycline, ciprofloxacin, norfloxacin, ofloxacin, cefoperazone, cefpodoxime, streptomycin, kanamycin, doxycycline, gemifloxacin, nalidixic acid, furazolidone, furadonine, amoxicillin, and enrofloxacin. Conclusion: The study has demonstrated that the greatest number of Enterobacteriaceae were sensitive to the action of meropenem, which belongs to the group of beta-lactam antibiotics; resistance was demonstrated against tetracycline, doxycycline, ampicillin, amoxicillin, ofloxacin, and cefpodoxime. The most common genes encoding antimicrobial resistance were as follows: BlaTEM and OXA in 41 and 28 isolates, respectively, encoding resistance to beta-lactams; StrA and StrB in 45 and 48 isolates encoding aminoglycosides; and tetA and tetB in 43 and 28 isolates encoding tetracyclines. Obtained data demonstrate that uncontrolled and frequent use of beta-lactam and tetracycline antibacterials, in cats and dogs, results in the spread of genotypic resistance among micro-organisms of the family Enterobacteriaceae.

Novel (±)-trans-ß-lactam ureas: Synthesis, in silico and in vitro biological profiling.

A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lactam ureas 4a-t were prepared by the condensation reaction of the amino group of b-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds 4a-t was evaluated in vitro and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized trans-b-lactam ureas 4a-c, 4f, 4h, 4n, 4o, 4p, and 4s were evaluated for in vitro antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The b-lactam urea 4o showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds 4o and 4p exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The b-lactam ureas 4a-t were estimated to be soluble and membrane permeable, moderately lipophilic molecules (logP 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds 4a-t with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules 4a and 4f can be selected as the most promising candidates for further structure modifications.

Metallo-ß-lactamase inhibitors: A continuing challenge for combating antibiotic resistance.

ß-lactam antibiotics are the most successful and commonly used antibacterial agents, but the emergence of resistance to these drugs has become a global health threat. The expression of ß-lactamase enzymes produced by pathogens, which hydrolyze the amide bond of the ß-lactam ring, is the major mechanism for bacterial resistance to ß-lactams. In particular, among class A, B, C and D ß-lactamases, metallo-ß-lactamases (MBLs, class B ß-lactamases) are considered crucial contributors to resistance in gram-negative bacteria. To combat ß-lactamase-mediated resistance, great efforts have been made to develop ß-lactamase inhibitors that restore the activity of ß-lactams. Some ß-lactamase inhibitors, such as diazabicyclooctanes (DBOs) and boronic acid derivatives, have also been approved by the FDA. Inhibitors used in the clinic can inactivate mostly serine-ß-lactamases (SBLs, class A, C, and D ß-lactamases) but have not been effective against MBLs until now. In order to develop new inhibitors particularly for MBLs, various attempts have been suggested. Based on structural and mechanical studies of MBL enzymes, several MBL inhibitor candidates, including taniborbactam in phase 3 and xeruborbactam in phase 1, have been introduced in recent years. However, designing potent inhibitors that are effective against all subclasses of MBLs is still extremely challenging. This review summarizes not only the types of ß-lactamase and mechanisms by which ß-lactam antibiotics are inactivated, but also the research finding on ß-lactamase inhibitors targeting these enzymes. These detailed information on ß-lactamases and their inhibitors could give valuable information for novel ß-lactamase inhibitors design.

Synergistic Augmentation of Beta-Lactams: Exploring Quinoline-Derived Amphipathic Small Molecules as Antimicrobial Potentiators against Methicillin-Resistant Staphylococcus aureus.

The escalation of bacterial resistance against existing therapeutic antimicrobials has reached a critical peak, leading to the rapid emergence of multidrug-resistant strains. Stringent pathways in novel drug discovery hinder our progress in this survival race. A promising approach to combat emerging antibiotic resistance involves enhancing conventional ineffective antimicrobials using low-toxicity small molecule adjuvants. Recent research interest lies in weak membrane-perturbing agents with unique cyclic hydrophobic components, addressing a significant gap in antimicrobial drug exploration. Our study demonstrates that quinoline-based amphipathic small molecules, SG-B-52 and SG-B-22, significantly reduce MICs of selected beta-lactam antibiotics (ampicillin and amoxicillin) against lethal methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, membrane perturbation, depolarization, and ROS generation drive cellular lysis and death. These molecules display minimal in vitro and in vivo toxicity, showcased through hemolysis assays, cell cytotoxicity analysis, and studies on albino Wistar rats. SG-B-52 exhibits impressive biofilm-clearing abilities against MRSA biofilms, proposing a strategy to enhance beta-lactam antibiosis and encouraging the development of potent antimicrobial potentiators.

Ureidopenicillins Are Potent Inhibitors of Penicillin-Binding Protein 2 from Multidrug-Resistant Neisseria gonorrhoeae H041.

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido ß-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R1 group. Crystal structures show that the ureido ß-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of ß-lactams with improved activity against ESC-resistant N. gonorrhoeae.

Assessing the risk of exposure to antimicrobial resistance at public beaches: Genome-based insights into the resistomes, mobilomes and virulomes of beta-lactams resistant Enterobacteriaceae from recreational beaches in Lagos, Nigeria.

The role of recreational water use in the acquisition and transmission of antimicrobial resistance (AMR) is under-explored in low- and middle-income countries (LMICs). We used whole genome sequence analysis to provide insights into the resistomes, mobilomes and virulomes of 14 beta-lactams resistant Enterobacterales isolated from water and wet-sand at four recreational beaches in Lagos, Nigeria. Carriage of multiple beta-lactamase genes was detected in all isolates except two, including six isolates carrying blaNDM-1. Most detected antibiotic resistance genes (ARGs) were located within a diverse landscape of plasmids, insertion sequences and transposons including the presence of ISKpn14 upstream of blaNDM-1 in a first report in Africa. Virulence genes involved in adhesion and motility as well as secretion systems are particularly abundant in the genomes of the isolates. Our results confirmed the four beaches are contaminated with bacteria carrying clinically relevant ARGs associated with mobile genetic elements (MGE) which could promote the transmission of ARGs at the recreational water-human interface.

Monitoring Drug-Protein Interactions in the Bacterial Periplasm by Solution Nuclear Magnetic Resonance Spectroscopy.

The rapid spread of antimicrobial resistance across bacterial pathogens poses a serious risk to the efficacy and sustainability of available treatments. This puts pressure on research concerning the development of new drugs. Here, we present an in-cell NMR-based research strategy to monitor the activity of the enzymes located in the periplasmic space delineated by the inner and outer membranes of Gram-negative bacteria. We demonstrate its unprecedented analytical power in monitoring in situ and in real time (i) the hydrolysis of ß-lactams by ß-lactamases, (ii) the interaction of drugs belonging to the ß-lactam family with their essential targets, and (iii) the binding of inhibitors to these enzymes. We show that in-cell NMR provides a powerful analytical tool for investigating new drugs targeting the molecular components of the bacterial periplasm.

Utilization of broad- versus narrow-spectrum antibiotics for the treatment of outpatient community-acquired pneumonia among adults in the United States.

PURPOSE: To characterize antibiotic utilization for outpatient community-acquired pneumonia (CAP) in the United States. METHODS: We conducted a cohort study among adults 18-64 years diagnosed with outpatient CAP and a same-day guideline-recommended oral antibiotic fill in the MarketScan® Commercial Database (2008-2019). We excluded patients coded for chronic lung disease or immunosuppressive disease; recent hospitalization or frequent healthcare exposure (e.g., home wound care, patients with cancer); recent antibiotics; or recent infection. We characterized utilization of broad-spectrum antibiotics (respiratory fluoroquinolone, ß-lactam + macrolide, ß-lactam + doxycycline) versus narrow-spectrum antibiotics (macrolide, doxycycline) overall and by patient- and provider-level characteristics. Per 2007 IDSA/ATS guidelines, we stratified analyses by otherwise healthy patients and patients with comorbidities (coded for diabetes; chronic heart, liver, or renal disease; etc.). RESULTS: Among 263 914 otherwise healthy CAP patients, 35% received broad-spectrum antibiotics (not recommended); among 37 161 CAP patients with comorbidities, 44% received broad-spectrum antibiotics (recommended). Ten-day antibiotic treatment durations were the most common for all antibiotic classes except macrolides. From 2008 to 2019, broad-spectrum antibiotic use substantially decreased from 45% to 19% in otherwise healthy patients (average annual percentage change [AAPC], -7.5% [95% CI -9.2%, -5.9%]), and from 55% to 29% in patients with comorbidities (AAPC, -5.8% [95% CI -8.8%, -2.6%]). In subgroup analyses, broad-spectrum antibiotic use varied by age, geographic region, provider specialty, and provider location. CONCLUSIONS: Real-world use of broad-spectrum antibiotics for outpatient CAP declined over time but remained common, irrespective of comorbidity status. Prolonged duration of therapy was common. Antimicrobial stewardship is needed to aid selection according to comorbidity status and to promote shorter courses.

Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units.

BACKGROUND: Only about 50% of intensive care unit (ICU) patients reach a free trough concentration above MIC (100% fT > MIC) of beta-lactam antibiotics. Although dose adjustments based on therapeutic drug monitoring (TDM) could be beneficial, TDM is not widely available. We investigated serum creatinine-based estimated GFR (eGFR) as a rapid screening tool to identify ICU patients at risk of insufficient exposure. METHOD: Ninety-three adult patients admitted to four ICUs in southeast Sweden treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Beta-lactam trough concentrations were measured. The concentration target was set to 100% fT > MICECOFF (2, 4, and 16 mg/L based on calculated free levels for meropenem, cefotaxime, and piperacillin, respectively). eGFR was primarily determined via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and compared to three other eGFR equations. Data was analysed using logistic regression and receiver operative characteristic (ROC) curves. RESULTS: With intermittent standard dosing, insufficient exposure was common in patients with a relative eGFR ≥48mL/min/1.73m2 [85%, (45/53)], particularly when treated with cefotaxime [96%, (24/25)]. This eGFR cut-off had a sensitivity of 92% and specificity of 82% (AUC 0.871, p < 0.001) in identifying insufficient exposure. In contrast, patients with eGFR <48mL/min/1.73m2 had high target attainment [90%, (36/40)] with a wide variability in drug exposure. There was no difference between the four eGFR equations (AUC 0.866-0.872, cut-offs 44-51 ml/min/1.73m2). CONCLUSION: Serum creatinine-based eGFR is a simple and widely available surrogate marker with potential for early identification of ICU patients at risk of insufficient exposure to piperacillin, meropenem, and cefotaxime.

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a ß-Lactam to Gram-Negative Bacterial Pathogens.

Developing new antibiotics and delivery strategies is of critical importance for treating infections caused by Gram-negative bacterial pathogens. Hijacking bacterial iron uptake machinery, such as that of the siderophore enterobactin (Ent), represents one promising approach toward these goals. Here, we report a novel Ent-inspired siderophore-antibiotic conjugate (SAC) employing an alternative siderophore moiety as the delivery vector and demonstrate the potency of our SACs harboring the ß-lactam antibiotic ampicillin (Amp) against multiple pathogenic Gram-negative bacterial strains. We establish the ability of N,N',N''-(nitrilotris(ethane-2,1-diyl))tris(2,3-dihydroxybenzamide) (TRENCAM, hereafter TC), a synthetic mimic of Ent, to facilitate drug delivery across the outer membrane (OM) of Gram-negative pathogens. Conjugation of Amp to a new monofunctionalized TC scaffold affords TC-Amp, which displays markedly enhanced antibacterial activity against the gastrointestinal pathogen Salmonella enterica serovar Typhimurium (STm) compared with unmodified Amp. Bacterial uptake, antibiotic susceptibility, and microscopy studies with STm show that the TC moiety facilitates TC-Amp uptake by the OM receptors FepA and IroN and that the Amp warhead inhibits penicillin-binding proteins. Moreover, TC-Amp achieves targeted activity, selectively killing STm in the presence of a commensal lactobacillus. Remarkably, we uncover that TC-Amp and its Ent-based predecessor Ent-Amp achieve enhanced antibacterial activity against diverse Gram-negative ESKAPE pathogens that express Ent uptake machinery, including strains that possess intrinsic ß-lactam resistance. TC-Amp and Ent-Amp exhibit potency comparable to that of the FDA-approved SAC cefiderocol against Gram-negative pathogens. These results demonstrate the effective application of native and appropriately designed nonnative siderophores as vectors for drug delivery across the OM of multiple Gram-negative bacterial pathogens.

Longitudinal antimicrobial susceptibility trends of canine Staphylococcus pseudintermedius.

Antimicrobial resistance within Staphylococcus pseudintermedius poses a significant risk for the treatment of canine pyoderma and as a reservoir for resistance and potential zoonoses, but few studies examine long-term temporal trends of resistance. This study assesses the antimicrobial resistance prevalence and minimum inhibitory concentration (MIC) trends in S. pseudintermedius (n=1804) isolated from canine skin samples at the Cornell University Animal Health Diagnostic Center (AHDC) between 2007 and 2020. Not susceptible (NS) prevalence, Cochran-Armitage tests, logrank tests, MIC50 and MIC90 quantiles, and survival analysis models were used to evaluate resistance prevalence and temporal trends to 23 antimicrobials. We use splines as predictors in accelerated failure time (AFT) models to model non-linear temporal trends in MICs. Multidrug resistance was common among isolates (47%), and isolates had moderate to high NS prevalence to the beta-lactams, chloramphenicol, the fluoroquinolones, gentamicin, the macrolides/lincosamides, the tetracyclines, and trimethoprim-sulfamethoxazole. However, low levels of NS to amikacin, rifampin, and vancomycin were observed. Around one third of isolates (38%) were found to be methicillin resistant S. pseudintermedius (MRSP), and these isolates had a higher prevalence of NS to all tested antimicrobials than methicillin susceptible isolates. Amongst the MRSP isolates, one phenotypically vancomycin resistant isolate (MIC >16 µg/mL) was identified, but genomic sequence data was unavailable. AFT models showed increasing MICs across time to the beta-lactams, chloramphenicol, the fluoroquinolones, gentamicin, and the macrolides/lincosamides, and decreasing temporal resistance (decreasing MICs) to doxycycline was observed amongst isolates. Notably, ATF modeling showed changes in MIC distributions that were not identified using Cochran-Armitage tests on prevalence, MIC quantiles, and logrank tests. Increasing resistance amongst these S. pseudintermedius isolates highlights the need for rational, empirical prescribing practices and increased antimicrobial resistance (AMR) surveillance to maintain the efficacy of current therapeutic agents. AFT models with non-linear predictors may be a useful, breakpoint-independent, surveillance tool alongside other modeling methods and antibiograms.

In-depth analysis of Klebsiella aerogenes resistome, virulome and plasmidome worldwide.

Klebsiella aerogenes is an emergent pathogen associated with outbreaks of carbapenem-resistant strains. To date, studies focusing on K. aerogenes have been small-scale and/or geographically restricted. Here, we analyzed the epidemiology, resistome, virulome, and plasmidome of this species based on 561 genomes, spanning all continents. Furthermore, we sequenced four new strains from Brazil (mostly from the Amazon region). Dozens of STs occur worldwide, but the pandemic clones ST93 and ST4 have prevailed in several countries. Almost all genomes were clinical, however, most of them did not carry ESBL or carbapenemases, instead, they carried chromosomal alterations (omp36, ampD, ampG, ampR) associated with resistance to ß-lactams. Integrons were also identified, presenting gene cassettes not yet reported in this species (blaIMP, blaVIM, blaGES). Considering the virulence loci, the yersiniabactin and colibactin operons were found in the ICEKp10 element, which is disseminated in genomes of several STs, as well as an incomplete salmochelin cluster. In contrast, the aerobactin hypervirulence trait was observed only in one ST432 genome. Plasmids were common, mainly from the ColRNAI replicon, with some carrying resistance genes (mcr, blaTEM, blaNDM, blaIMP, blaKPC, blaVIM) and virulence genes (EAST1, senB). Interestingly, 172 genomes of different STs presented putative plasmids containing the colicin gene.

Phytochemical Evaluation of Terminalia canescens DC. Radlk. Extracts with Antibacterial and Antibiotic Potentiation Activities against Selected ß-Lactam Drug-Resistant Bacteria.

Terminalia canescens DC. Radlk. (family: Combretaceae) is native to northern Australia. Species of the genus Terminalia are widely used as traditional medicines to treat diverse ailments, including bacterial infections. However, we were unable to find any studies that had examined the antimicrobial activity of T. canescens. In this study, T. canescens was screened against a panel of bacterial pathogens, including multi-antibiotic-resistant strains. Solvents with different polarities were used to extract different complements of phytochemicals from T. canescens leaves. Methanolic and aqueous extracts exhibited substantial antimicrobial activity against various pathogens, including those that are multidrug-resistant strains. When combined with some selected clinical antibiotics, some extracts potentiated the antibacterial inhibitory activity. This study identified two synergistic, eleven additive, eleven non-interactive and eight antagonistic interactions. The toxicities of the plant extracts were examined in the Artemia franciscana nauplii assay and were found to be non-toxic, except the aqueous extract, which showed toxicity. Metabolomic liquid chromatography-mass spectrometry (LC-MS) analyses highlighted and identified several flavonoids, including vitexin, quercetin, orientin and kaempferol, as well as the tannins ellagic acid and pyrogallol, which may contribute to the antibacterial activities observed herein. The possible mechanism of action of these extracts was further explored in this study.

Identificación y caracterización de herramientas para evaluar la alergia a las penicilinas: Revisión estructurada / Identification and characterization of tools used to assess penicillin allergy: structured review

Introducción: Las reacciones alérgicas son uno de los problemas de seguridad más graves asociadas al uso de medicamentos, siendo la alergia a los antibióticos betalactámicos la más prevalente. Las pruebas de alergia a las penicilinas pueden ayudar a identificar pacientes hospitalizados y ambulatorios que podrían tolerar y usar de manera segura este grupo de antibióticos y evitar rótulos que limiten el uso de antibióticos betalactámicos por tiempo indefinido. Objetivo: Identificar las herramientas disponibles en la literatura para valorar el antecedente de alergia a las penicilinas y proponer una herramienta que consolide la información extraída. Metodología: Revisión estructurada en PubMed/MEDLINE entre 1 junio 2015 hasta 30 noviembre 2022, utilizando los términos MeSH: (((“skin tests”[MeSH Terms]) OR (“skin irritancy tests”[MeSH Terms])) AND (“penicillins”[All Fields])) AND (“drug hypersensitivity”[MeSH Terms]). Publicaciones en inglés y español con acceso a texto completo y estudios realizados en humanos, sobre herramientas disponibles para evaluar la alergia a penicilinas fueron incluidos. Resultados: Se identificaron201 artículos, de los cuales se incluyeron 108. Dentro de las herramientas para evaluar la alergia a las penicilinas se identificaron: a) pruebas in vivo: pruebas cutáneas, pruebas de provocación oral, pruebas del parche; y b) pruebas in vitro: pruebas de IgE específica, determinación de triptasa, histamina. De los 1181 pacientes reportados con alergia a las penicilinas, sólo el 2 % de ellos se confirmó la presencia de alergia. Conclusión: Las pruebas cutáneas y de provocación oral sumado a algunas combinaciones in vivo/in vitro, fueron las herramientas más utilizadas para evaluar la alergia a las penicilinas. (AU)

Introduction: Allergic reactions are one of the most serious safety problems associated with the use of medications, with allergy to beta-lactam antibiotics being the most prevalent. In fact, the American Academy of Allergy, Asthma and Immunology (AAAAI) states that penicillin allergy testing can help identify inpatients and outpatients who could safely tolerate and use this group of antibiotics and avoid labels that limit the use of beta-lactam antibiotics indefinitely. Objective: To identify the tools available in the literature to assess the history of allergy to penicillins and propose a tool that consolidates the information extracted. Methodology: Structured review on PubMed/MEDLINE between June 1, 2015 until November 30, 2022; using the search terms MeSH: (((“skin tests”[MeSH Terms]) OR (“skin irritancy tests”[MeSH Terms])) AND (“penicillins”[All Fields])) AND (“drug hypersensitivity”[MeSH Terms]). Papers in English and Spanish with access to full text and human trials, regarding available tools used to evaluate penicillin allergies were included. Results: A total of 201 articles were identified, of which after an independent evaluation, 108 were included. Among the tools to evaluate penicillin allergy, in vivo tests were identified: skin tests, oral provocation tests, patch tests and in vitro tests: specific IgE tests, determination of tryptase, histamine, T lymphocytes and basophilic activation tests. Of the patients (1181) reported with penicillin allergy, 905 (77 %) had their allergy assessed with skin testing or oral challenge tests, and only 2 % of them had a confirmed allergic reaction. Conclusion: Skin tests and oral provocation tests added to some in vivo/in vitro combinations were the most used tools to evaluate penicillin allergy. (AU)

Safety of direct oral provocation test to delabel reported mild beta-lactam allergy in infants

Background: Around 10% of people report a drug allergy and avoid some medications because of fear of allergic reactions. However, only after a proper diagnostic workup can some of these reactions be confirmed as allergic or nonallergic hypersensitivities. Beta-lactams (BLs) are the most common medication suspected of being involved in drug hypersensivity reactions (DHRs) in children. Recently, direct oral provocation tests (DPT) with BLs gained popularity within pediatric populations as a tool for delabeling children with suspected BL allergies. This study aimed to evaluate the safety of direct provocation tests in infants with mild cutaneous non-immediate reactions to BLs. Methods: The authors retrospectively analyzed the data of 151 infants between 2015 and 2022, referred for evaluating a suspected allergy to BLs that occurred before age 24 months. Results: The mean age of the children, including 55% male kids, at the suspected reaction was 15.9 months and the mean age at the time of the DPT was 39.6 months. In most cases, antibiotics were prescribed to treat common upper respiratory infections, such as acute otitis (54.3%) and acute tonsillitis (27.2%). Amoxicillin was considered the culprit drug in 62.9% of the cases, and the combination of amoxicillin–clavulanic acid in the case of 33.8% of children. The most frequent associated cutaneous clinical manifestations were maculopapular exanthema in 74.8% and delayed urticaria/angioedema in 25.2%. Of the 151 infants evaluated, parents of 149 infants agreed for a direct DPT, and only three had a positive test (2%). Symptoms resulting from the DPT were mild and easily treatable. Conclusions: A direct DPT without prior tests is a safe and effective procedure to delabel BL allergy, even in infants... (AU)

Bacteremia due to Leuconostoc species: A 13-year single-center case series / Bacteriemia por Leuconostoc spp: serie de casos en un hospital de tercer nivel a lo largo de 13 años

Introduction: Leuconostoc spp. are facultatively anaerobic Gram-positive cocci involved in cases of hospital-acquired bacteremia, mainly in immunocompromised hosts. The available data is scarce due to its uncommon presentation. Methods: We describe all the episodes of Leuconostoc spp. bacteremia in a third level hospital in a 13-year period (2008–2021). Results: Four cases of clinically relevant bacteremia were detected. All cases were categorized as catheter-related. The following risk factors were found: previous glycopeptide therapy (75%), use of parenteral nutrition (100%) and cancer (75%). All isolates showed susceptibility to beta-lactams. Catheter removal was performed and wide spectrum antimicrobials were administered, with clinical response in all cases except one. Discussion: Apart from cancer and glycopeptide exposure, disruption of skin barrier and gastrointestinal conditions were identified as risk factors, as it was concordantly underlined in other case series. Susceptibility to beta-lactams is usually maintained. Catheter removal and administration of an active antibacterial therapy seem to be the best approach for Leuconostoc spp. catheter-related bacteremia.(AU)

Introducción: Los microorganismos del género Leuconostoc son cocos grampositivos anaerobios facultativos, involucrados en casos de bacteriemia en pacientes hospitalizados, especialmente con factores de inmunosupresión. La literatura disponible es escasa por su baja frecuencia. Métodos: Describimos todos los episodios de bacteriemia por Leuconostoc spp. en un hospital de tercer nivel en un periodo de 13 años (2008-2021). Resultados: Se detectaron 4 aislamientos clínicamente significativos. Todos ellos fueron categorizados como bacteriemia relacionada con catéter. Se identificaron como factores de riesgo: la exposición previa a glucopéptidos (75%), nutrición parenteral (100%) y cáncer (75%). Todos los aislamientos presentaron sensibilidad a betalactámicos. Se procedió a retirada del catéter y se administraron antimicrobianos de amplio espectro con buena respuesta clínica, salvo en un caso. Discusión: Además del cáncer y la exposición a glucopéptidos, la disrupción de la barrera cutánea y las enfermedades gastrointestinales se identificaron como factores de riesgo, al igual que en otras series. La sensibilidad a betalactámicos suele mantenerse. La retirada del catéter y el uso de terapia antibiótica activa parece ser la mejor alternativa terapéutica para la bacteriemia relacionada con catéter por Leuconostoc spp.(AU)