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OBJECTIVES: We aimed to compare the stability of the newly developed ß-lactams (cefiderocol) and ß-lactam/ß-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable ß-lactam resistance in Pseudomonas aeruginosa. METHODS: We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to ß-lactams. The other 43 constructs expressed transferable ß-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. RESULTS: Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable ß-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. CONCLUSIONS: Cefiderocol and new ß-lactam/ß-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa ß-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient ß-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged.
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BackgroundAs increasing antibiotic resistance in Acinetobacter baumannii poses a global healthcare challenge, understanding its evolution is crucial for effective control strategies.AimWe aimed to evaluate the epidemiology, antimicrobial susceptibility and main resistance mechanisms of Acinetobacter spp. in Spain in 2020, and to explore temporal trends of A. baumannii.MethodsWe collected 199 single-patient Acinetobacter spp. clinical isolates in 2020 from 18 Spanish tertiary hospitals. Minimum inhibitory concentrations (MICs) for nine antimicrobials were determined. Short-read sequencing was performed for all isolates, and targeted long-read sequencing for A. baumannii. Resistance mechanisms, phylogenetics and clonality were assessed. Findings on resistance rates and infection types were compared with data from 2000 and 2010.ResultsCefiderocol and colistin exhibited the highest activity against A. baumannii, although colistin susceptibility has significantly declined over 2 decades. A. non-baumannii strains were highly susceptible to most tested antibiotics. Of the A. baumannii isolates, 47.5% (56/118) were multidrug-resistant (MDR). Phylogeny and clonal relationship analysis of A. baumannii revealed five prevalent international clones, notably IC2 (ST2, n = 52; ST745, n = 4) and IC1 (ST1, n = 14), and some episodes of clonal dissemination. Genes bla OXA-23, bla OXA-58 and bla OXA-24/40 were identified in 49 (41.5%), eight (6.8%) and one (0.8%) A. baumannii isolates, respectively. ISAba1 was found upstream of the gene (a bla OXA-51-like) in 10 isolates.ConclusionsThe emergence of OXA-23-producing ST1 and ST2, the predominant MDR lineages, shows a pivotal shift in carbapenem-resistant A. baumannii (CRAB) epidemiology in Spain. Coupled with increased colistin resistance, these changes underscore notable alterations in regional antimicrobial resistance dynamics.
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Infecções por Acinetobacter , Acinetobacter baumannii , Humanos , Colistina/farmacologia , beta-Lactamases/genética , Proteína 1 Semelhante a Receptor de Interleucina-1 , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/epidemiologia , Antibacterianos/farmacologia , Acinetobacter baumannii/genética , Genômica , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/genéticaRESUMO
OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.
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Antibacterianos , Compostos Azabicíclicos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Cefiderocol , Ceftazidima , Cefalosporinas , Ciclo-Octanos , Combinação de Medicamentos , Escherichia coli , Lactamas , Testes de Sensibilidade Microbiana , Triazóis , Inibidores de beta-Lactamases , beta-Lactamases , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Ciclo-Octanos/farmacologia , Ceftazidima/farmacologia , Cefepima/farmacologia , Ácidos Borônicos/farmacologia , Meropeném/farmacologia , Aztreonam/farmacologia , Imipenem/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacosRESUMO
SCOPE: Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen considered one of the paradigms of antimicrobial resistance, is among the main causes of hospital-acquired and chronic infections associated with significant morbidity and mortality. This growing threat results from the extraordinary capacity of P. aeruginosa to develop antimicrobial resistance through chromosomal mutations, the increasing prevalence of transferable resistance determinants (such as the carbapenemases and the extended-spectrum ß-lactamases), and the global expansion of epidemic lineages. The general objective of this initiative is to provide a comprehensive update of P. aeruginosa resistance mechanisms, especially for the extensively drug-resistant (XDR)/difficult-to-treat resistance (DTR) international high-risk epidemic lineages, and how the recently approved ß-lactams and ß-lactam/ß-lactamase inhibitor combinations may affect resistance mechanisms and the definition of susceptibility profiles. METHODS: To address this challenge, the European Study Group for Antimicrobial Resistance Surveillance (ESGARS) from the European Society of Clinical Microbiology and Infectious Diseases launched the 'Improving Surveillance of Antibiotic-Resistant Pseudomonas aeruginosa in Europe (ISARPAE)' initiative in 2022, supported by the Joint programming initiative on antimicrobial resistance network call and included a panel of over 40 researchers from 18 European Countries. Thus, a ESGARS-ISARPAE position paper was designed and the final version agreed after four rounds of revision and discussion by all panel members. QUESTIONS ADDRESSED IN THE POSITION PAPER: To provide an update on (a) the emerging resistance mechanisms to classical and novel anti-pseudomonal agents, with a particular focus on ß-lactams, (b) the susceptibility profiles associated with the most relevant ß-lactam resistance mechanisms, (c) the impact of the novel agents and resistance mechanisms on the definitions of resistance profiles, and (d) the globally expanding XDR/DTR high-risk lineages and their association with transferable resistance mechanisms. IMPLICATION: The evidence presented herein can be used for coordinated epidemiological surveillance and decision making at the European and global level.
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Antibacterianos , Infecções por Pseudomonas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , beta-Lactamases/genética , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas , Pseudomonas aeruginosa/genética , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
Introducción: El internado vertical en Medicina Intensiva y Emergencias forma parte de las nuevas estrategias del Ministerio de Salud Pública para la formación de profesionales en un menor tiempo, con el fin de vencer los múltiples retos que enfrenta la salud pública. Por esa razón, la educación médica superior cubana actual tiene, entre sus múltiples retos, el perfeccionamiento de los contenidos del trabajo metodológico en algunos de sus niveles y formas. Objetivo: Elaborar una alternativa metodológica basada en la semipresencialidad, para el proceso de enseñanza-aprendizaje del módulo Trauma del internado vertical de la especialidad de Medicina Intensiva y Emergencias. Métodos: Se realizó una investigación descriptiva, prospectiva y cuasiexperimental. El universo incluyó a 20 profesores relacionados de forma directa con el internado vertical. Se aplicó un post-test a los encuestados. Resultados: El diagnóstico sirvió de base para el diseño de la alternativa metodológica basada en la semipresencialidad, la cual es pertinente, oportuna y útil para elevar el nivel epistémico y el metodológico de buenas prácticas en la impartición eficaz del referido módulo en entornos virtuales de aprendizaje. Los resultados del post-test aplicado 30 días después de someter a consideración la alternativa metodológica, se informa en escalas de Likert, los cuales fueron óptimos. Conclusiones: La implementación de la alternativa metodológica basada en la semipresencialidad, para impartir los contenidos del módulo Trauma, es factible y necesaria.
Introduction: The vertical internship in Intensive Care and Emergency Medicine is part of the new strategies of the Ministry of Public Health for the training of professionals in a shorter time, in order to overcome the multiple challenges that public health faces. For this reason, current Cuban higher medical education has, among its many challenges, the improvement of the contents of methodological work in some of its levels and forms. Objective: To develop a methodological alternative based on blended attendance, for the teaching-learning process of the Trauma module of the vertical internship in the specialty of Intensive Care and Emergency Medicine. Methods: A descriptive, prospective, quasi-experimental research was carried out. The universe included 20 teachers directly related to the vertical internship. A post-test was applied to the respondents. Results: The diagnosis served as the basis for the design of the methodological alternative based on blended attendance, which is relevant, timely and useful to raise the epistemic and methodological level of good practices in the effective delivery of the aforementioned module in virtual learning environments. The result of the post-test applied 30 days after submitting the methodological alternative for consideration are reported on Likert scales, which were optimal. Conclusions: The implementation of the methodological alternative based on blended attendance to teach the contents of the Trauma module, is feasible and necessary.
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The organ donation and transplantation (ODT) system heavily relies on the willingness of individuals to donate their organs. While it is widely believed that public trust plays a crucial role in shaping donation rates, the empirical support for this assumption remains limited. In order to bridge this knowledge gap, this article takes a foundational approach by elucidating the concept of trust within the context of ODT. By examining the stakeholders involved, identifying influential factors, and mapping the intricate trust relationships among trustors, trustees, and objects of trust, we aim to provide a comprehensive understanding of trust dynamics in ODT. We employ maps and graphs to illustrate the functioning of these trust relationships, enabling a visual representation of the complex interactions within the ODT system. Through this conceptual groundwork, we pave the way for future empirical research to investigate the link between trust and organ donation rates, informed by a clarified understanding of trust in ODT. This study can also provide valuable insights to inform interventions and policies aimed at enhancing organ donation rates.
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Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Humanos , Confiança , Inquéritos e Questionários , Conhecimentos, Atitudes e Prática em Saúde , Doadores de TecidosRESUMO
Background: Pseudomonas aeruginosa healthcare-associated infections are one of the top antimicrobial resistance threats world-wide. In order to analyze the current trends, we performed a Spanish nation-wide high-resolution analysis of the susceptibility profiles, the genomic epidemiology and the resistome of P. aeruginosa over a five-year time lapse. Methods: A total of 3.180 nonduplicated P. aeruginosa clinical isolates from two Spanish nation-wide surveys performed in October 2017 and 2022 were analyzed. MICs of 13 antipseudomonals were determined by ISO-EUCAST. Multidrug resistance (MDR)/extensively drug resistance (XDR)/difficult to treat resistance (DTR)/pandrug resistance (PDR) profiles were defined following established criteria. All XDR/DTR isolates were subjected to whole genome sequencing (WGS). Findings: A decrease in resistance to all tested antibiotics, including older and newer antimicrobials, was observed in 2022 vs 2017. Likewise, a major reduction of XDR (15.2% vs 5.9%) and DTR (4.2 vs 2.1%) profiles was evidenced, and even more patent among ICU isolates [XDR (26.0% vs 6.0%) and DTR (8.9% vs 2.6%)] (p < 0.001). The prevalence of Extended-spectrum ß-lactamase/carbapenemase production was slightly lower in 2022 (2.1%. vs 3.1%, p = 0.064). However, there was a significant increase in the proportion of carbapenemase production among carbapenem-resistant strains (29.4% vs 18.1%, p = 0.0246). While ST175 was still the most frequent clone among XDR, a slight reduction in its prevalence was noted (35.9% vs 45.5%, p = 0.106) as opposed to ST235 which increased significantly (24.3% vs 12.3%, p = 0.0062). Interpretation: While the generalized decrease in P. aeruginosa resistance, linked to a major reduction in the prevalence of XDR strains, is encouraging, the negative counterpart is the increase in the proportion of XDR strains producing carbapenemases, associated to the significant advance of the concerning world-wide disseminated hypervirulent high-risk clone ST235. Continued high-resolution surveillance, integrating phenotypic and genomic data, is necessary for understanding resistance trends and analyzing the impact of national plans on antimicrobial resistance. Funding: MSD and the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea-NextGenerationEU.
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OBJECTIVES: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones. METHODS: Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of ß-lactam/ß-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies. RESULTS: Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning. CONCLUSIONS: Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections.
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BACKGROUND: During the COVID-19 pandemic, a great number of patients required Mechanical Ventilation (MV). Tracheostomy is the preferred procedure when difficult weaning is presented. Surgical techniques available for performing tracheostomy are open and percutaneous, with contradictory reports on the right choice. This paper aims to describe the clinical results after performing a tracheostomy in patients with COVID-19, regarding both surgical techniques. METHODS: An observational, analytical study of a retrospective cohort was designed. All patients admitted to the Hospital Universitario Mayor Méderi, between March 2020 and April 2021 who presented COVID-19 requiring MV and who underwent tracheostomy were reviewed. Open versus percutaneous tracheostomy groups were compared and the primary outcome evaluated was in-hospital mortality. RESULTS: A total of 113 patients were included in the final analysis. The median age was 66.0 (IQR: 57.2 - 72.0) years old and 77 (68.14%) were male. Open tracheostomy was performed in 64.6% (n = 73) of the patients and percutaneous tracheostomy in 35.4% (n = 40) with an in-hospital mortality of 65.7% (n = 48) and 25% (n = 10), respectively (p < 0.001). In a multivariate analysis, open tracheostomy technique [OR 9.45 (95% CI 3.20-27.92)], older age [OR 1.05 (95% CI 1.01-1.09)] and APACHE II score [OR 1.10 (95% CI 1.02-1.19)] were identified as independent risk factors for in-hospital mortality. Late tracheostomy (after 14 days) [OR 0.31 (95% CI 0.09-1.02)] and tracheostomy day PaO2/FiO2 [OR 1.10 (95% CI 1.02-1.19)] were not associated to in-hospital mortality. CONCLUSIONS: Percutaneous tracheostomy was independently associated with lower in-hospital mortality and should be considered the first option to perform this type of surgery in patients with COVID-19 in extended MV or difficulty weaning.
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COVID-19 , Traqueostomia , Humanos , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Pandemias , Mortalidade HospitalarRESUMO
Emerging evidence indicates the critical roles of microbiota in mediating host cardiac functions in ageing, however, the mechanisms underlying the communications between microbiota and cardiac cells during the ageing process have not been fully elucidated. Bacterial DNA was enriched in the cardiomyocytes of both ageing humans and mice. Antibiotic treatment remarkably reduced bacterial DNA abundance in ageing mice. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into cardiomyocytes in ageing mice, causing cardiac microbial DNA enrichment. Vsig4+ macrophages efficiently block the spread of gut mEVs whereas Vsig4+ cell population was greatly decreased in ageing mice. Gut mEV treatment resulted in cardiac inflammation and a reduction in cardiac contractility in young Vsig4-/- mice. Microbial DNA depletion attenuated the pathogenic effects of gut mEVs. cGAS/STING signaling is critical for the effects of microbial DNA. Restoring Vsig4+ macrophage population in ageing WT mice reduced cardiac microbial DNA abundance and inflammation and improved heart contractility.
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Envelhecimento , Miocardite , Humanos , Camundongos , Animais , DNA Bacteriano , Macrófagos , Inflamação , Contração MiocárdicaRESUMO
The OXA-10 class D ß-lactamase has been reported to contribute to carbapenem resistance in non-fermenting Gram-negative bacilli; however, its contribution to carbapenem resistance in Enterobacterales is unknown. In this work, minimum inhibitory concentrations (MICs), whole genome sequencing (WGS), cloning experiments, kinetic assays, molecular modelling studies, and biochemical assays for carbapenemase detection were performed to determine the impact of OXA-10 production on carbapenem resistance in two XDR clinical isolates of Escherichia coli with the carbapenem resistance phenotype (ertapenem resistance). WGS identified the two clinical isolates as belonging to ST57 in close genomic proximity to each other. Additionally, the presence of the blaOXA-10 gene was identified in both isolates, as well as relevant mutations in the genes coding for the OmpC and OmpF porins. Cloning of blaOXA-10 in an E. coli HB4 (OmpC and OmpF-deficient) demonstrated the important contribution of OXA-10 to increased carbapenem MICs when associated with porin deficiency. Kinetic analysis showed that OXA-10 has low carbapenem-hydrolysing activity, but molecular models revealed interactions of this ß-lactamase with the carbapenems. OXA-10 was not detected with biochemical tests used in clinical laboratories. In conclusion, the ß-lactamase OXA-10 limits the activity of carbapenems in Enterobacterales when combined with low permeability and should be monitored in the future.
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Emergence of cefiderocol resistance among carbapenemase-producing Enterobacterales, particularly those in the Enterobacter cloacae complex (ECC), is becoming of alarming concern; however, the mechanistic basis of this phenomenon remains poorly understood. We describe the acquisition of VIM-1-mediated reduced cefiderocol susceptibility (MICs 0.5 to 4 mg/L) in a collection of 54 carbapenemase-producing isolates belonging to the ECC. MICs were determined by reference methodologies. Antimicrobial resistance genomic analysis was performed through hybrid WGS. The impact of VIM-1 production on cefiderocol resistance in the ECC background was examined at microbiological, molecular, biochemical, and atomic levels. Antimicrobial susceptibility testing yielded 83.3% susceptible isolates and MIC50/90 values of 1/4 mg/L. Decreased susceptibility to cefiderocol was mainly associated with isolates producing VIM-1, with cefiderocol MICs 2- to 4-fold higher than for isolates carrying other types of carbapenemases. E. cloacae and Escherichia coli VIM-1 transformants displayed significantly enhanced cefiderocol MICs. Biochemical assays with purified VIM-1 protein revealed low but detectable cefiderocol hydrolysis. Simulation studies revealed how cefiderocol is anchored to the VIM-1 active site. Additional molecular assays and WGS data analysis highlighted the implication of SHV-12 coproduction and suggested the inactivation of the FcuA-like siderophore receptor as further contributors to the higher cefiderocol MICs. Our findings warn of the potential of the VIM-1 carbapenemase to at least partly limit the activity of cefiderocol in the ECC. This effect is probably enhanced due to combination with additional mechanisms, such as ESBL production and siderophore inactivation, and indicates the need for active surveillance to extend the life span of this promising cephalosporin.
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Anti-Infecciosos , Enterobacteriáceas Resistentes a Carbapenêmicos , Enterobacter cloacae , Carbapenêmicos/farmacologia , Sideróforos/farmacologia , Cefalosporinas/farmacologia , beta-Lactamases/metabolismo , Testes de Sensibilidade Microbiana , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , CefiderocolRESUMO
MALDI-TOF MS is considered to be an important tool for the future development of rapid microbiological techniques. We propose the application of MALDI-TOF MS as a dual technique for the identification of bacteria and the detection of resistance, with no extra hands-on procedures. We have developed a machine learning approach that uses the random forest algorithm for the direct prediction of carbapenemase-producing Klebsiella pneumoniae (CPK) isolates, based on the spectra of complete cells. For this purpose, we used a database of 4,547 mass spectra profiles, including 715 unduplicated clinical isolates that are represented by 324 CPK with 37 different ST. The impact of the culture medium was determinant in the CPK prediction, being that the isolates were tested and cultured in the same media, compared to the isolates used to build the model (blood agar). The proposed method has an accuracy of 97.83% for the prediction of CPK and an accuracy of 95.24% for the prediction of OXA-48 or KPC carriage. For the CPK prediction, the RF algorithm yielded a value of 1.00 for both the area under the receiver operating characteristic curve and the area under the precision-recall curve. The contribution of individual mass peaks to the CPK prediction was determined using Shapley values, which revealed that the complete proteome, rather than a series of mass peaks or potential biomarkers (as previously suggested), is responsible for the algorithm-based classification. Thus, the use of the full spectrum, as proposed here, with a pattern-matching analytical algorithm produced the best outcome. The use of MALDI-TOF MS coupled with machine learning algorithm processing enabled the identification of CPK isolates within only a few minutes, thereby reducing the time to detection of resistance.
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Enterobacteriáceas Resistentes a Carbapenêmicos , Infecções por Klebsiella , Humanos , Klebsiella pneumoniae , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Infecções por Klebsiella/diagnóstico , Infecções por Klebsiella/microbiologia , Aprendizado de MáquinaRESUMO
OBJECTIVES: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. METHODS: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on ß-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. RESULTS: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC ß-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. CONCLUSIONS: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new ß-lactam/ß-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.
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Ceftazidima , Infecções por Pseudomonas , Humanos , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Cefalosporinase , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Tazobactam/farmacologia , Combinação de Medicamentos , Imipenem/farmacologia , Imipenem/uso terapêutico , Pseudomonas aeruginosa/genética , Testes de Sensibilidade MicrobianaRESUMO
Metallo-ß-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all ß-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine ß-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel ß-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. ß-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum ß-lactamases and class C ß-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.
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Aztreonam , Inibidores de beta-Lactamases , Aztreonam/farmacologia , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , beta-Lactamases/genética , Espanha , Compostos Azabicíclicos/farmacologia , Testes de Sensibilidade Microbiana , Combinação de MedicamentosRESUMO
This case report describes an 80-year-old patient's right-sided hemicranial headache, right-sided tongue hemiatrophy with fasciculations and deviation, right side of the tongue on protrusion, and mild dysarthria.
Assuntos
Pirofosfato de Cálcio , Doenças do Nervo Hipoglosso , Humanos , Doenças do Nervo Hipoglosso/diagnóstico por imagem , Doenças do Nervo Hipoglosso/etiologia , Difosfatos , Língua/inervaçãoRESUMO
Introducción: la sostenibilidad ambiental es una de las metas del milenio establecidas por la Asamblea General de las Naciones Unidas. La minimización de residuos, la producción más limpia, la ecoeficiencia y la prevención de la contaminación contribuyen a su cumplimiento. En el sector de la salud, la Producción Más Limpia se enfoca en la prevención de la contaminación, y en la eliminación de desechos peligrosos, infecciosos y químicos y de emisiones o vertimientos dentro de la institución; se fundamenta en buenas prácticas durante la prestación de servicios, en la sustitución de insumos con características peligrosas, en cambios en los procedimientos y en mejoramiento tecnológico. Objetivo: proponer opciones de Producción Más Limpia en la Universidad de Ciencias Médicas de Matanzas. Materiales y métodos: se desarrolló una investigación de tipo cualitativa, descriptiva y documental. La búsqueda se realizó en la base de datos SciELO y en Google Académico, en el período 2016-2020. Resultados: se identificaron cinco opciones de Producción Más Limpia con resultados satisfactorios que contribuyen a la sostenibilidad ambiental de la Universidad. Conclusiones: la introducción de nuevas tecnologías, la sustitución de sustancias contaminantes, el desarrollo energético y la separación correcta de los residuos, son opciones de Producción Más Limpia que favorecen el desarrollo sostenible.
Introduction: environmental sustainability is one of the millennium goals set by the United Nations General Assembly. Waste minimization, cleaner production, eco-efficiency and pollution prevention contribute to its compliance. In the health sector, Cleaner Production focuses on the prevention of pollution, the disposal of hazardous, infectious and chemical wastes and emissions or discharges within the institution; it is based on good practices during the provision of services, on the replacement of inputs with hazardous characteristics, on changes in procedures and on technological improvement. Objective: to propose Cleaner Production options at Matanzas University of Medical Sciences. Materials and methods: a qualitative, descriptive and documentary research was developed. The search was carried out in the SciELO database and in Google Scholar, in the period 2016-2020. Results: five Cleaner Production options were identified with satisfactory results that contribute to the environmental sustainability of the University. Conclusions: the introduction of new technologies, the replacement of pollutants, energy development and the correct separation of waste are Cleaner Production options that favor sustainable development.