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Klebsiella pneumoniaeisolates that produce carbapenemases (KPCs) are rapidly disseminating worldwide. To determine their genetic background, we investigated 16 blaKPC-2-harboring K. pneumoniae isolates from 5 countries. The isolates were multidrug resistant, possessed the blaKPC-2 gene, and differed by additional Beta-lactamase content. They harbored a naturally chromosome-encoded bla gene (blaSHV-1 [12.5%], blaSHV-11 [68.7%], or blaOKP-AVB [18.8%]) and several acquired and plasmid-encoded genes (blaTEM-1 [81.3%], blaCTX-M-2 [31.3%], blaCTX-M-12 [12.5%], blaCTX-M-15 [18.7%], and blaOXA-9 [37.5%]). The blaKPC-2 gene was always associated with 1 of the Tn4401 isoforms (a, b, or c). Tn4401 was inserted on different-sized plasmids that belonged to different incompatibility groups. Several blaKPC-containing K. pneumoniae clones were found: 9 different pulsotypes with 1 major (sequence type 258) and 7 minor distinct allelic profiles. Different clones harboring different plasmids but having identical genetic structure, Tn4401, could be at the origin of the worldwide spread of this emerging resistance gene. [ABSTRACT FROM AUTHOR]

Study Objectives: Pleural tuberculosis (TB) is a diagnostic challenge because of its nonspecific clinical presentation and paucibacillary nature. The inefficiency of conventional laboratory methods and the reliance on pleural biopsy have motivated the evaluation of alternative diagnostic strategies. We have evaluated polymerase chain reaction (PCR) directed to the IS6110 sequence of Mycobacterium tuberculosis, the determination of adenosine deaminase (ADA) activity, and measurement of interferon (IFN)-gamma levels in pleural fluid in the diagnosis of pleural TB.Patients: ADA activity, IFN-gamma levels, and PCR were evaluated in 140 cases of pleural effusion, 42 with confirmed pleural TB, 19 with probable pleural TB, 70 with a nontuberculous etiology, and 9 having an undetermined etiology.Results: ADA activity, IFN-gamma levels, and PCR were 88%, 85.7%, and 73.8% sensitive, respectively, and 85.7%, 97.1%, and 90% specific, respectively, for pleural TB that had been confirmed by either culture or pleural biopsy specimens. The combination of PCR, IFN-gamma measurement, and ADA activity determination allowed the selective increase of sensitivity and specificity for probable and confirmed cases compared to individual methods. Positive and negative predictive values for these individual or combined methods were maintained over a wide range of prevalence of pleural TB in the patient population presenting with pleural effusions. Fever and younger age were associated with tuberculous pleural effusion (p < 0. 0001), while blood in sputum and older age were associated with malignant etiology (p < 0.008).Conclusions: These clinical variables together with the use of ADA activity determination, PCR, and measurement of IFN-gamma levels provide the basis for the rapid and efficient diagnosis of pleural TB in different clinical settings. [ABSTRACT FROM AUTHOR]

Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM&#95;001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Biomass is a key element in biofuels which can be defined as a fuel produced through contemporary biological processes, and its increased use can support the EU's aims of reducing greenhouse gas emissions. Information on the nature and the quality of the biomass or biofuel is important in order to support the optimization of their combustion with respect to realizing higher efficiencies and lower emissions during energy production. Three reference materials were produced by a collaborative approach among national metrology institutes and designated institutes within the scope of the EMPIR project: BIOFMET. The project was aimed to establish advanced traceable measurement standards for the determination of the calorific value, impurities, and other parameters such as density, kinematic viscosity, moisture, and ash. This paper presents the sampling and processing methodology, homogeneity, stability, characterization campaign, the assignment of property values, and their associated uncertainties in compliance with ISO 17034 for biofuel reference materials: biodiesel, wood pellet powder, and wood pellet. Parameters of interest in biodiesel reference material-UME BIOFMET CRM 01 are gross calorific value (GCV), density, viscosity, and mass fractions of Ca, K, Mg, Na, P, and S elements. Parameters to be certified in wood pellet powder reference material-UME BIOFMET CRM 02 are GCV, moisture, ash, and mass fractions of Al, Cr, K, Mg, Mn, Ni, S, and Zn elements. Parameters to be certified in the wood pellet reference material-UME BIOFMET CRM 03 are GCV and moisture. The homogeneity and stability of the materials were assessed in accordance with ISO 33405. The materials were characterized by interlaboratory comparison studies among competent metrology institute and designated institute laboratories. Assigned values and uncertainties of the certified values were calculated in accordance with ISO 33405, and uncertainties include characterization, homogeneity, and stability components. The developed CRMs are intended to be used for the development and validation of measurement procedures for the determination and quality control/assurance purposes of the quality parameters for biofuels. It should be emphasized that the UME BIOFMET CRM 01-Biodiesel CRM is the first biodiesel reference material certified for calorific value. Among the developed wood CRMs, the pellet form, UME BIOFMET CRM 03, was found to be more stable than the powder one, UME BIOFMET CRM 02, for the moisture parameter. Sixfold lower relative uncertainty value for short-term stability at 45 °C and twofold lower relative uncertainty value for long-term stability at 22 °C were obtained for the moisture parameter of the CRM in pellet form compared to the CRM in powder form., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Antimicrobial resistance (AMR) is positioning as one of the most relevant threats to global public health and threatens the effective treatment of an ever-growing number of bacterial infections in various healthcare settings, particularly in acute care and surgical units, as well as in the community. Among multidrug-resistant (MDR) gram-negative bacteria (MDRGNB), Enterobacterales , Pseudomonas aeruginosa, and Acinetobacter baumannii require special attention, since they account for most of the mortality associated with bacterial infections and are often MDR. It is clear that there is an important global variation in antibiotic resistance profiles among MDRGNB species. Extended-spectrum β-lactamase-producing Enterobacterales , carbapenem-resistant Enterobacterales , DTR- P. aeruginosa , and MDR- A. baumannii are the focus of this review. Here, we summarize a series of relevant studies on risk factors associated with colonization and infection with these MDRGNB. Likewise, we offer a comparative overview of those studies providing scoring systems to predict the risk of infection with these MDR pathogens, and their pros and cons. Despite the variable accuracy of published risk factors for predicting colonization or infection with MDRGNB, these scores are valuable tools that may help anticipate colonization and infection among those colonized. More importantly, they may help reduce unnecessary use of broad-spectrum antimicrobials and guiding the selection of an optimal treatment., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered as potential competing interests. M.V.V. and C.J.P have received honoraria and research grants from MSD, Pfizer, bioMérieux, West and GPC pharma. S.S.K has received honoraria for participating in advisory boards and as a speaker from MSD, Pfizer, GSK, and Menarini. P.K has received honoraria for participating in an advisory board from Pfizer and as a speaker from bioMérieux, MSD and Pfizer. The other authors declare no competing financial interest. All authors, except J.C.G.B, C.J.P, N.R.A, and L.W.A received an honorarium from Pfizer to attend a steering committee meeting to discuss their regional perspective on MDR gram-negative infections and AMS strategies. The output of these discussions was used to create to a framework for this manuscript prior to its development., (© The Author(s) 2024.)

Resistance to ceftazidime-avibactam (CZA) due to Klebsiella pneumoniae carbapenemase (KPC) variants is increasing worldwide. We characterized two CZA-resistant clinical Klebsiella pneumoniae strains by antimicrobial susceptibility test, conjugation assays, and WGS. Isolates belonged to ST258 and ST45, and produced a KPC-31 and a novel variant KPC-197, respectively. The novel KPC variant presents a deletion of two amino acids on the Ω-loop (del&#95;168-169&#95;EL) and an insertion of two amino acids in position 274 (Ins&#95;274&#95;DS). Continued surveillance of KPC variants conferring CZA resistance in Colombia is warranted., Importance: Latin America and the Caribbean is an endemic region for carbapenemases. Increasingly high rates of Klebsiella pneumoniae carbapenemase (KPC) have established ceftazidime-avibactam (CZA) as an essential antimicrobial for the treatment of infections due to MDR Gram-negative pathogens. Although other countries in the region have reported the emergence of CZA-resistant KPC variants, this is the first description of such enzymes in Colombia. This finding warrants active surveillance, as dissemination of these variants could have devastating public health consequences., Competing Interests: C.P. and M.V.V. have received consulting fees and/or research grants from Merck Sharp and Dohme, Pfizer, WEST, and bioMérieux. All other authors declare no competing interests.

This work evaluated the insecticidal, antifeedant and AChE inhibitory activity of compounds with eudesmane skeleton. The insecticidal activity was tested against larvae of Drosophila melanogaster and Cydia pomonella, the compounds 3 and 4 were the most active (LC 50 of 104.2 and 106.7 μM; 82.0 and 84.4 μM, respectively). Likewise, the mentioned compounds were those that showed the highest acetylcholinesterase inhibitory activity, with IC 50 of 0.26 ± 0.016 and 0.77 ± 0.016 μM, respectively. Enzyme kinetic studies, as well as molecular docking, show that the compounds would be non-competitive inhibitors of the enzyme. The antifeedant activity on Plodia interpunctella larvae showed an antifeedant index (AI) of 99% at 72 h for compounds 16, 27 and 20. The QSAR studies show that the properties associated with the polarity of the compounds would be responsible for the biological activities found., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic exposure to potentially toxic elements (PTEs) such as cadmium (Cd) leads to male reproductive toxicity through the generation of oxidative stress. Spirulina Arthrospira maxima (AM) is a cyanobacterium that has been consumed since ancient times for its high nutritional value, and in recent years for its antiviral, hepatoprotective, hypoglycemic, anticancer, and antioxidant effects, among others. This study aimed to evaluate the effects of AM against the damage to reproductive health induced by Cd. A total of 48 10-week-old sexually experienced male Wistar rats were distributed in five groups ( n = 8): control; vehicle (tween-water); cadmium chloride (CdCl 2 ) 5 mg/kg; and three doses of AM (100, 200 and 400 mg/kg) + CdCl 2 5 mg/kg. All treatments were orally administered once a day for 36 consecutive days. At the end, sexual behavior was evaluated, and semen, testicle, and blood samples were obtained to analyze sperm quality, enzymatic activity, and testosterone levels, respectively. Rats exposed to Cd showed a decrease in sexual behavior, as well as in the quality of reproductive health, and an increase in oxidative stress; while rats exposed simultaneously to AM + Cd showed an improvement in all this parameters. Based on our results, we believe that the mechanism by which AM exerts its effect could be attributed to the presence of phycobiliproteins. These compounds are responsible for exerting an antioxidant effect and chelating effect on elements such as Cd.

Introduction: Antimicrobial resistance surveillance is a fundamental tool for the development, improvement, and adjustment of antimicrobial stewardship programs, therapeutic guidelines, and universal precautions to limit the cross-transmission of resistant bacteria between patients. Since the beginning of 2020, the SARS-CoV-2 pandemic profoundly challenged the health system and, according to some reports, increased the rates of antimicrobial resistance., Objective: To describe the behavior of antimicrobial resistance of the most frequent bacterial pathogens in twenty Colombian hospitals from January 2018 to December 2021., Materials and Methods: We conducted a descriptive study based on the microbiological information recorded from January 2018 to December 2021 in twenty levels III and IV health institutions in twelve Colombian cities. We identified the species of the ten most frequent bacteria along with their resistance profile to the antibiotic markers after analyzing the data through WHONET., Results: We found no statistically significant changes in most pathogens’ resistance profiles from January 2018 to December 2021. Only Pseudomonas aeruginosa had a statistically significant increase in its resistance profile, particularly to piperacillin/tazobactam and carbapenems., Conclusions: The changes in antimicrobial resistance in these four years were not statistically significant except for P. aeruginosa to piperacillin/tazobactam and carbapenems.

Antimicrobial resistance is one of the major global health threats. Antimicrobial stewardship (AMS) has been set as a priority within international action plans to combat this issue. The region of Latin America and the Caribbean are recognized for their high antimicrobial resistance rates; nevertheless, a low number of studies describing implemented interventions for this topic have been published. This review aims to provide an overview of the status of AMS in our region, focusing on the main progress achieved and describing the different published efforts made by countries towards the implementation of antimicrobial stewardship programs (ASP). Common areas of intervention included were (a) education approaches, (b) antimicrobial guideline implementation and monitoring, (c) diagnostic stewardship, (d) technological tools: electronic clinical decision support systems in AMS, (e) pharmacy-driven protocols and collaborative practice agreements, and (f) economic impact. The search demonstrated the varied interventions implemented in diverse healthcare settings; the results accentuate their influence on antimicrobial consumption, antimicrobial resistance, clinical outcomes, and direct economic impact. The integration of multiple strategies within each hospital was highlighted as an essential key to ASP success. Even though the literature found demonstrated clear progress, there is still a special need for strengthening leadership from the top down, defining goals based on needs, and gaining support through policy and financing in LAC.

Background: Studies have shown that more than 50% of the antibiotics used in hospitals are unnecessary or inappropriate and, that antimicrobial resistance may cost up to 20 billion USD in excess medical costs each year. On the other hand, Antimicrobial Stewardship Programs (ASP) significantly reduce inappropriate antimicrobial use, emergence of antimicrobial resistance, healthcare associated infections, and costs in hospital settings., Objective: To evaluate the development of ASP and antibiotic savings in 7 Latin American hospitals using standardized quantitative indicators in all the participating health care institutions., Methods: An interventional study was conducted, where pre- and post- evaluations were performed using a standardized score tool adapted from the Joint Commission International accreditation standards and, the Colombian Institute of Technical Standards and Certification. We evaluated ASP from 7 Latin American hospitals between 2019 and 2020. A pre-intervention evaluation was done in each hospital to quantify the degree of development of the ASP (ASP Development score). Based on these results, tailored on-site training was implemented in each hospital, followed by a post-intervention evaluation to quantify improvement of ASP-development indicators. In addition, monetary savings in antimicrobials derived from the ASP intervention were estimated., Results: In the pre-intervention evaluation, the average ASP development score for the 7 institutions was 65.8% (40-94.3%). The items with the lowest development score were those related to monitoring and communicating the ASP progress and success. For the post-intervention evaluation, 2 institutions couldn't participate due to the pressure imposed by the COVID-19 pandemic. For the remaining 5/7 hospitals, the average ASP development score was 82.3% with an increase of 12.0% when compared to the pre-intervention measurement of the same institutions (average pre-intervention score 70.3% (48.2%-94.3%) The items with a significant increase were key performance indicators, AMS education and training of the prescribers. Three of the seven (3/7) hospitals reported antibiotic monetary savings associated to the ASP intervention., Conclusions: The use of the tool described shown to be useful to evaluate specific areas of ASP-development that were lacking and tailor interventions for the participating hospitals, consequently, it helped improve ASP-development in the institutions that underwent pre- intervention and post-intervention analysis. In addition, the strategies showed monetary savings on antimicrobial costs when measured., (© 2023. The Author(s).)

Despite technological advancements in infectious disease rapid diagnostic tests (RDTs) and use to direct therapy at the per-patient level, RDT utilisation in antimicrobial stewardship programmes (ASPs) is variable across low-to-middle income and high-income countries. Key insights from a panel of seven infectious disease experts from Colombia, Japan, Nigeria, Thailand, the UK, and the USA, combined with evidence from a literature review, were used to assess the value of RDTs in ASPs. From this, a value framework is proposed which aims to define the benefits of RDT use in ASPs, separate from per-patient benefits. Expert insights highlight that, to realise the value of RDTs within ASPs, effective implementation is key; actionable advice for choosing an RDT is proposed. Experts advocate the inclusion of RDTs in the World Health Organization Model List of essential in vitro diagnostics and in iterative development of national action plans., (© 2023. The Author(s).)

The treatment of splenic marginal zone lymphoma is debated: splenectomy (the old standard-of-care) is better than chemotherapy but maybe not better than rituximab-containing treatment. We examined all 358 patients diagnosed with splenic marginal zone lymphoma in Sweden 2000-2020. The median overall survival was 11.0 years. The median age was 73 years; 61% were women. Age was the only independently prognostic clinical characteristic. Eighty-six patients were started on wait-and-watch, 90 rituximab monotherapy, 47 rituximab-chemotherapy, 88 splenectomy, 37 chemotherapy, and 10 both systemic therapy and splenectomy. Overall survival was inferior in patients treated with chemotherapy, but equal in patients treated with rituximab, rituximab-chemotherapy and splenectomy. Patients treated with both systemic therapy and splenectomy showed good outcome, suggesting that surgery can be safely reserved for nonresponders. After adjustment for age, survival did not differ between patients started on wait-and-watch and those treated with splenectomy or rituximab-containing therapy. Over time, rituximab use and survival increased in patients ≥73 years. This is, to our knowledge, the largest population-based study of splenic marginal zone lymphoma patients treated with upfront rituximab. We conclude that wait-and-watch remains the most reasonable option in asymptomatic splenic marginal zone lymphoma patients. Symptomatic patients should be offered single-agent rituximab in first line., Competing Interests: HRJ and BEW planned the study. HRJ and BEW analyzed data and wrote the manuscript. KS, OL, MH, MVS, MO, IT, AJ, and BEW contributed to the registry and data interpretation. All authors participated in the final version of the manuscript.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Ceftazidime-avibactam (CZA) is the combination of a third-generation cephalosporin and a new non-β-lactam β-lactamase inhibitor capable of inactivating class A, C, and some D β-lactamases. From a collection of 2,727 clinical isolates of Enterobacterales ( n = 2,235) and P. aeruginosa ( n = 492) that were collected between 2016 and 2017 from five Latin American countries, we investigated the molecular resistance mechanisms to CZA of 127 (18/2,235 [0.8%] Enterobacterales and 109/492 [22.1%] P. aeruginosa). First, by qPCR for the presence of genes encoding KPC, NDM, VIM, IMP, OXA-48-like, and SPM-1 carbapenemases, and second, by whole-genome sequencing (WGS). From the CZA-resistant isolates, MBL-encoding genes were detected in all 18 Enterobacterales and 42/109 P. aeruginosa isolates, explaining their resistant phenotype. Resistant isolates that yielded a negative qPCR result for any of the MBL encoding genes were subjected to WGS. The WGS analysis of the 67 remaining P. aeruginosa isolates showed mutations in genes previously associated with reduced susceptibility to CZA, such as those involved in the MexAB-OprM efflux pump and AmpC (PDC) hyperproduction, PoxB ( bla OXA-50-like ), FtsI (PBP3), DacB (PBP4), and OprD. The results presented here offer a snapshot of the molecular epidemiological landscape for CZA resistance before the introduction of this antibiotic into the Latin American market. Therefore, these results serve as a valuable comparison tool to trace the evolution of the resistance to CZA in this carbapenemase-endemic geographical region. IMPORTANCE In this manuscript, we determine the molecular mechanisms of ceftazidime-avibactam resistance in Enterobacterales and P. aeruginosa isolates from five Latin American countries. Our results reveal a low rate of resistance to ceftazidime-avibactam among Enterobacterales ; in contrast, resistance in P. aeruginosa has proven to be more complex, as it might involve multiple known and possibly unknown resistance mechanisms.

We report the presence of the mcr-1 gene among 880 Escherichia coli clinical isolates collected in 13 hospitals from 12 Colombian cities between 2016 and 2019. Seven (0.8%) isolates were colistin resistant (MIC ≥ 4 µg/mL). These colistin-resistant isolates were screened for the presence of the mcr-1 gene; five carried the gene. These five isolates were subjected to whole genome sequencing (WGS) to identify additional resistomes and their ST. In addition, antimicrobial susceptibility testing revealed that all E. coli isolates carrying mcr-1 were susceptible to third generation-cephalosporin and carbapenems, except one, which carried an extended-spectrum β-lactamase (CTX-M-55), along with the fosfomycin resistance encoding gene, fosA . WGS indicated that these isolates belonged to four distinct sequence types (ST58, ST46, ST393, and a newly described ST14315) and to phylogroups B1, A, and D. In this geographic region, the spread of mcr-1 in E. coli is low and has not been inserted into high-risk clones such as ST131, which has been present in the country longer.

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA., Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality., Findings: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses., Interpretation: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms., Funding: National Institutes of Health., Competing Interests: Declaration of interests All authors report funding support from the Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. Additionally, during the conduct of this study, and outside of the submitted work, the authors report the following disclosures. KSK reports consulting fees paid directly to him by Merck, Shionogi, Qpex, and Micrux. JG-D reports grants and contracts paid to her institution from NIH, BARDA, Janssen Research & Development LLC, Pfizer, BioNTech SE, GCAR, Hoffman La-Roche, I-Mab Bioppharma, Rebiotix, Target Health, LLC OBO Lilly USA, GlaxoSmithKline, Summit Limited, Cidara Therapeutics, Merck Sharp & Dohme, Seres Therapeutics; and Infectious Diseases Society of America Research Committee participation paid to her directly. SSK reports speaker and advisory board payments from Pfizer, Astellas, Novartis, Merck, and Gilead. JMO reports speaker payments from Pfizer, MSD, and Biotoscana; and board participation on the Chair Ethics Committee. SLV-B reports personal fees from Pfizer, Biotoscana, and MSD; meeting support from MSD and Pfizer; and data safety monitoring board participation with MSD and GlaxoSmithKline. PT reports honoraria payments to his institution from Aj Biologics and bioMérieux. GW reports payment to his institution from Allergan for contracted activities. LMA reports grants and contracts paid to her institution from Rainmakers/CDC multisystem inflammatory syndrome in adults with SARS-CoV-2, and Regeneron study co-investigator; consulting and honoraria paid directly to them from Medscape for CME lectures, and Ferring Pharmaceuticals for advisory board participation; and volunteer work as the director of the IDSA Board of Directors. KO reports payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; meeting support from Pfizer, MSD, and Gilead; and expert testimony support from Pfizer, bioMérieux, and MSD. MES reports speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; consultancy for Basilea; and data safety monitoring board participation with Fulcrum Therapeutics. JMM reports grants from Pfizer, MSD, and bioMérieux, the National Fund for Scientific and Technological Development; and the Agencia Nacional de Investigation y Desarrollo Millennium Science Initiative/Millennium Initiative for Collaborative Research on Bacterial Resistance, Government of Chile. DLP reports grants and contracts paid to his institution from Merck, Pfizer, and Shionogi; consulting and honoraria payments to him by Merck, Shionogi, QPex, Spero Therapeutics, Sumitomo, Pfizer, and bioMérieux; meeting support from Shionogi; and board and committee participation with Symvivo, and AMR action fund. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. RAB reports grants and contracts, paid to his institution, by VenatoRx, Wockhardt, and Merck; payments made to him by Pfizer to moderate meeting sessions; patents with Case Western Reserve University on the development of boronic acid transition state inhibitors for β-lactamases (WO2022187362A1, US9949995B2, and US20170252326A1); and payment for participation on a data safety monitoring board, safety oversight committee support, and Logistics Associate for DMID-CROMS (contractor) with Technical Resources International. MVV reports contracts, consulting fees, and honoraria payments from Pfizer and MSD; consulting fees from West Quimica Colombia; and honoraria from bioMérieux. RP reports grants from BioFire Diagnostics, ContraFect, and TenNor Therapeutics; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Day Zero Diagnostics, Torus Biosystems, Mammoth Biosciences, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix and CARB-X; has a patent on Bordetella pertussis and parapertussis PCR issued (US8507201B2), a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic; US7076117B2), and a patent on an anti-biofilm substance issued (US8802414B2); receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course. CAA reports the grants and contracts paid to his institution from NIH and NIAID, MeMed Diagnostics, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; payments to him for UpToDate royalties, reimbursement of meeting attendance, and speaking from Infectious Diseases Society of America, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, bioMérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, Brazilian Society for Infectious Diseases, reviewer participation as part of the NIH grant Review Study Sections, travel expenses from the Infectious Disease Society of America (IDSA) Board of Directors, and for Editor in Chief for Antimicrobial Agents and Chemotherapy; non-paid participation with WHO Antibacterial Pipeline Advisory Group; and participation on the IDSA Board of Directors. HFC reports participation on a Merck data safety monitoring board for molnupiravir paid directly to him, stock ownership in Moderna and Merck, and a position as expert witness for Lilly and Nexus Pharmaceuticals. VGF reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from Infectious Diseases of America; pending patent for a host gene expression signature diagnostic for sepsis (US9850539B2); and stock options with Valanbio and ArcBio. YD reports grants from Entasis, Asahi Kasei Pharma, Shionogi, and Kanto Chemical paid to his institution; consulting fees paid directly to him from Meiji Seika Pharma, Shionogi, Gilead, MSD, Chugai, and bioMérieux; and speaker payments from MSD, Shionogi, AstraZeneca, Teijin Healthcare, Gilead, FujiFilm Toyama Chemical, bioMerieux, HU Frontier, and Eiken Chemical paid to him. DvD reports grants and contracts from the NIH and Merck paid to his institution outside of the published work; and consultancy for Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, and Karius. MJS reports contract payments to his institution from Merck, Allergan, BioFire Diagnostics, Affinity Biosensors, and SNIPRBiome; personal consulting fees from Shionogi; and data and safety monitoring board participation for Spero Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Identify molecular mechanisms responsible for the in vitro non-susceptibility to ceftolozane/tazobactam (TOL) in a group of 158 clinical isolates of Pseudomonas aeruginosa from five Latin American countries collected before the introduction of TOL into the clinical practice., Methods: Clinical isolates of P. aeruginosa ( n  = 504) were collected between January 2016 and October 2017 from 20 hospitals located in Argentina, Brazil, Chile, Colombia, and Mexico. Minimum inhibitory concentrations (MICs) to TOL were determined by standard broth microdilution and interpreted according to CLSI breakpoints. Initially, production of carbapenemases in TOL non-susceptible isolates was assessed by Rapidec® followed by qPCR to detect bla KPC , bla NDM-1 , bla VIM , and bla IMP . Illumina® WGS was performed for isolates in which non-susceptibility to TOL was not mediated by carbapenemases., Results: A total of 158 (31.3%) isolates were non-susceptible to TOL. In 74 (46.8%) of these isolates, non-susceptibility to TOL was explained by the production of at least one carbapenemase. WGS revealed that some isolates carried ESBLs, mutated bla PDC and ampD , associated with decreased susceptibility to TOL., Conclusion: Substitutions found in PDC and carbapenemase production were the most common presumed mechanisms of resistance to TOL detected in this study. This study shows that epidemiological surveillance is warranted to monitor the emergence of novel mechanisms of resistance to TOL that might compromise its clinical utility., Competing Interests: CH-G is currently employed by MSD. JMu received funding from FONDECYT #1211947 from the Agencia Nacional de Investigation y Desarrollo (ANID), Government of Chile. MV have received consulting fees from MSD, Pfizer; WEST, and BioMérieux, none of which had any involvement in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mojica, De La Cadena, Ríos, García-Betancur, Díaz, Reyes, Hernández-Gómez, Radice, Gales, Castañeda Méndez, Munita, Pallares, Martínez and Villegas.)

Background: Evidence shows limited adherence to antimicrobial stewardship (AMS) principles., Objectives: To identify educational gaps and systemic barriers obstructing adherence to AMS principles., Methods: A mixed-methods study combining a thematic analysis of qualitative interviews (January-February 2021) and inferential analysis of quantitative surveys (May-June 2021) was conducted. Participants from France, the USA, Mexico and India were purposively sampled from online panels of healthcare professionals to include infectious disease physicians, infection control specialists, clinical microbiologists, pharmacologists or pharmacists expected to apply AMS principles in their practice setting (e.g. clinic, academic-affiliated or community-based hospital). A gap analysis framework guided this study., Results: The final sample included 383 participants ( n  = 33 interviews; n  = 350 surveys). Mixed-methods findings indicated suboptimal knowledge and skills amongst participants to facilitate personal and collective application of AMS principles. Survey data indicated a gap in ideal versus current knowledge of AMS protocols, especially amongst pharmacologists (Δ0.95/4.00, P  < 0.001). Gaps in ideal versus current skill levels were also measured and were highest amongst infectious control specialists (Δ1.15/4.00, P  < 0.001), for convincing hospital executives to allocate resources to AMS programmes. Already existing systemic barriers (e.g. insufficient dedicated time/funding/training) were perceived as being aggravated during the COVID-19 pandemic (72% of survey participants agreed). Reported gaps were highest in India and France., Conclusions: The educational needs of professionals and countries included in this study can inform future continuous professional development activities in AMS. Additional funding should be considered to address perceived systemic barriers. Local assessments are warranted to validate results and suitability of interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

The term difficult-to-treat resistance has been recently coined to identify Gram-negative bacteria exhibiting resistance to all fluoroquinolones and all β-lactam categories, including carbapenems. Such bacteria are posing serious challenges to clinicians trying to identify the best therapeutic option for any given patient. Delayed appropriate therapy has been associated with worse outcomes including increase in length of stay, increase in total in-hospital costs and ∼20% increase in the risk of in-hospital mortality. In addition, time to appropriate antibiotic therapy has been shown to be an independent predictor of 30 day mortality in patients with resistant organisms. Improving and anticipating aetiological diagnosis through optimizing not only the identification of phenotypic resistance to antibiotic classes/agents, but also the identification of specific resistance mechanisms, would have a major impact on reducing the frequency and duration of inappropriate early antibiotic therapy. In light of these considerations, the present paper reviews the increasing need for rapid diagnosis of bacterial infections and efficient laboratory workflows to confirm diagnoses and facilitate prompt de-escalation to targeted therapy, in line with antimicrobial stewardship principles. Rapid diagnostic tests currently available and future perspectives for their use are discussed. Early appropriate diagnostics and treatment of MDR Gram-negative infections require a multidisciplinary approach that includes multiple different diagnostic methods and further consensus of algorithms, protocols and guidelines to select the optimal antibiotic therapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Multidrug-resistant (MDR) Gram-negative bacteria (GNB) pose a critical threat to global healthcare, worsening outcomes and increasing mortality among infected patients. Carbapenemase- and extended-spectrum β-lactamase-producing Enterobacterales, as well as carbapenemase-producing Pseudomonas and Acinetobacter spp., are common MDR pathogens. New antibiotics and combinations have been developed to address this threat. Clinical trial findings support several combinations, notably ceftazidime-avibactam (CZA, a cephalosporin-β-lactamase inhibitor combination), which is effective in treating complicated urinary tract infections (cUTI), complicated intra-abdominal infections and hospital-acquired and ventilator-associated pneumonia caused by GNBs. Other clinically effective combinations include meropenem-vaborbactam (MVB), ceftolozane-tazobactam (C/T) and imipenem-relebactam (I-R). Cefiderocol is a recent siderophore β-lactam antibiotic that is useful against cUTIs caused by carbapenem-resistant Enterobacterales (CRE) and is stable against many β-lactamases. Carbapenem-resistant Enterobacterales are a genetically heterogeneous group that vary in different world regions and are a substantial cause of infections, among which Klebsiella pneumoniae are the most common. Susceptible CRE infections can be treated with fluoroquinolones, aminoglycosides or fosfomycin, but alternatives include CZA, MVB, I-R, cefiderocol, tigecycline and eravacycline. Multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are increasingly common pathogens producing a range of different carbapenemases, and infections are challenging to treat, often requiring novel antibiotics or combinations. Currently, no single agent can treat all MDR-GNB infections, but new β-lactam-β-lactamase inhibitor combinations are often effective for different infection sites and, when used appropriately, have the potential to improve outcomes. This article reviews clinical studies investigating novel β-lactam approaches for treatment of MDR-GNB infections., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Ceftolozane/tazobactam (C/T) is a combination of an antipseudomonal oxyiminoaminothiazolyl cephalosporin with potent in vitro activity against Pseudomonas aeruginosa and tazobactam, a known β-lactamase inhibitor. The aim of this study was to evaluate the activity of C/T against clinical isolates of P. aeruginosa and Enterobacterales collected from five Latin American countries between 2016 and 2017, before its clinical use in Latin America, and to compare it with the activity of other available broad-spectrum antimicrobial agents., Methods: a total of 2760 clinical isolates (508 P. aeruginosa and 2252 Enterobacterales ) were consecutively collected from 20 hospitals and susceptibility to C/T and comparator agents was tested and interpreted following the current guidelines., Results: according to the CLSI breakpoints, 68.1% (346/508) of P. aeruginosa and 83.9% (1889/2252) of Enterobacterales isolates were susceptible to C/T. Overall, C/T demonstrated higher in vitro activity than currently available cephalosporins, piperacillin/tazobactam and carbapenems when tested against P. aeruginosa , and its performance in vitro was comparable to fosfomycin. When tested against Enterobacterales , it showed higher activity than cephalosporins and piperacillin/tazobactam, and similar activity to ertapenem., Conclusions: these results show that C/T is an active β-lactam agent against clinical isolates of P. aeruginosa and Enterobacterales .

Resilience is having the ability to respond to adversity proactively and resourcefully. The coronavirus disease 2019 (COVID-19) pandemic's profound impact on antimicrobial stewardship programs (ASP) requires clinicians to call on their own resilience to manage the demands of the pandemic and the disruption of ASP activities. This article provides examples of ASP resilience from pharmacists and physicians from seven countries with different resources and approaches to ASP-The United States, The United Kingdom, Canada, Nigeria, Lebanon, South Africa, and Colombia. The lessons learned pertain to providing ASP clinical services in the context of a global pandemic, developing new ASP paradigms in the face of COVID-19, leveraging technology to extend the reach of ASP, and conducting international collaborative ASP research remotely. This article serves as an example of how resilience and global collaboration is sustaining our ASPs by sharing new "how to" do antimicrobial stewardship practices during the COVID-19 pandemic., Competing Interests: Debra A. Goff; Timothy P. Gauthier; Bradley J. Langford; Pavel Prusakov; Ubaka Chukwuemka M; Benedict C. Nwomeh; Khalid A. Yunis; Therese Saad; Maria Virginia Villegas; Diane Ashiru‐Oredope and Pablo J. Sanchez: see conflict of interest disclosure form submitted with manuscript. Andrew Morris, Philip Howard, Dena van den Bergh, and Nela Martinez have no relevant conflicts of interest., (© 2022 The Authors. JACCP: Journal of the American College of Clinical Pharmacy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Background: Antimicrobial stewardship programs (ASPs) have become a fundamental pillar in optimizing antimicrobial usage, improving patient care, and reducing antimicrobial resistance (AMR). Herein we evaluated the impact of an ASP on antimicrobial consumption and AMR in Colombia., Methods: We designed a retrospective observational study and measured trends in antibiotic consumption and AMR before and after the implementation of an ASP using interrupted time series analysis over a 4-year period (24 months before and 24 months after ASP implementation)., Results: ASPs were implemented according to the available resources in each of the institutions. Before ASP implementation, there was a trend toward an increase in the antibiotic consumption of all measured antimicrobials selected. Afterward, an overall decrease in antibiotic consumption was observed. The use of ertapenem and meropenem decreased in hospital wards, while a decrease in the use of ceftriaxone, cefepime, piperacillin/tazobactam, meropenem, and vancomycin was observed in intensive care units. After ASP implementation, the trend toward an increase of oxacillin-resistant Staphylococcus aureus, ceftriaxone-resistant Escherichia coli, and meropenem-resistant Pseudomonas aeruginosa was reversed., Conclusions: In our study, we showed that ASPs are a key strategy in tackling the emerging threat of AMR and have a positive impact on antibiotic consumption and resistance., (© 2022. The Author(s).)

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries., Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete., Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96)., Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions., Funding: The National Institutes of Health., Competing Interests: Declaration of interests MW, ME, LC, YY, ZL, SS, EC, LL, SSK, HG, KM, LK, SDR, SHM, CM, JR, MVV, CH, RA, KB, BCF, BNK, and RAB report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. BMH reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), during the conduct of this study, and a grants from the NIH and the NIAID (K01AI148593–01), outside the submitted work. JMM reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and grants from Pfizer, MSD, and bioMerieux, outside the submitted work. KO reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; and meeting support from Pfizer, MSD, and Gilead, outside the submitted work. GW reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), and from Allergan. MJS reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; contracts payments, to his institution, from Merck, Allergan, BioFire Diagnostics, and Affinity Biosensors; personal consulting fees from Achaogen and Shionogi; and board participation for Spero Therapeutics, outside the submitted work. SLV-B reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and personal fees from MSD and Biotoscana, outside the submitted work. MES reports grants from the NIH during the conduct of the study; speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; and consultancy for Basilea, outside the submitted work. CL reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and salary support from the National Institute of General Medical Sciences of the NIH (award number T32GM086330) outside the submitted work. DLP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants and contracts with MERCK, Pfizer, and Shionogi; consulting fees from Merck, Shionogi, and Qpex; payments and financial support from Sumitomo, Merck, Pfizer, bioMerieux, and Shionogi; and board participation for Symvivo, outside the submitted work. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Cardinal Health, Microbiotix, Stryker, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, the International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, Osaka University, and the National Cerebral and Cardiovascular Center of Japan; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Novartis, Amgen, Teva, Vir, Shire, Alexion, Gilead, Tracon, Rakuten, Abbvie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation, outside the submitted work. YD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants from Janssen, Pfizer, MSD, Shionogi, Astellas, and Kanto Chemical, outside the submitted work; and personal fees from Janssen, MSD, Entasis, VenatoRx, AstraZeneca, Gilead, FUJIFILM Toyama Chemical, bioMerieux, and Meiji Seika Pharma, outside the submitted work. RP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; reports grants from Merck, ContraFect, TenNor Therapeutics, and Shionogi; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix; has a patent on Bordetella pertussis (parapertussis) PCR issued, a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an anti-biofilm substance issued; receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course, outside the submitted work. HFC reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; personal fees from Merck; and stock ownership from Moderna, outside the submitted work. VGF reports personal Fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, and Aridis; grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; royalties from UpToDate; and stock options in Valanbio. CAA is employed at the University of Texas Health Science Center in Houston, TX, USA; declares money paid to the University of Texas as part of a grant from Merck, MeMed Diagnostics, Entasis Therapeutics, and the ARLG of the NIH and the NIAID (UM1AI104681); reports royalties paid as personal fees from UptoDate (Harrison Principles of Internal Medicine and Mandell Principles and Practice of Infectious Diseases); reports personal fees from the NIH and the NIAID for being a study section member and grant reviewer; reports an editor-in-chief stipend from the American Society for Microbiology for Antimicrobial Agents and Chemotherapy; reports reimbursement for travel to Infectious Disease Week and Infectious Disease programme committee meetings as Infectious Disease chair from the Infectious Disease Society of America; and reports reimbursement for traveling to the American Society for Microbiology Microbe conference from the American Society for Microbiology. DvD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; is a consultant for Actavis, Tetraphase, Sanofi Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, and Utility; receives an editor's stipend from the British Society for Antimicrobial Chemotherapy; and reports grants from the NIH, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) is a global challenge. However, detection efforts can be laborious because numerous mechanisms produce carbapenem resistance. A minimum inhibitory concentration-based algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) was proposed to identify the isolates most likely to harbor a carbapenemase; however, prospective validation in geographies displaying genotypic diversity and varied carbapenemase prevalence is warranted., Methods: CRPA isolates were collected during the Enhancing Rational Antimicrobials for P. aeruginosa (ERACE-PA) global surveillance program from 17 sites in 12 countries. Isolates underwent susceptibility testing following local standards to ceftazidime, cefepime, and ceftolozane/tazobactam. Isolates underwent initial phenotypic carbapenemase screening followed by molecular testing if positive. The primary algorithm criteria were applied, and results were compared with phenotypic carbapenemase results to assess the performance of the algorithm. A secondary criterion, the algorithm criterion or imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible, was assessed., Results: A total of 807 CRPA were assessed, and 464 isolates met the algorithm criteria described above. Overall, testing was reduced by 43% compared with testing all CRPA. Carbapenemase-positive isolates missed by the algorithm were largely driven by Guiana extended spectrum (GES). Addition of the criterion of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible decreased the number of CP-CRPA missed by the algorithm (21 vs 40 isolates, respectively), reducing number of isolates tested by 39%., Conclusions: Application of the initial algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) performed well in a global cohort, with 33% phenotypically carbapenemase-positive isolates. The addition of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible reduced the number of phenotypically carbapenemase-positive isolates missed and may be useful in areas with a prominence of GES., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The cephalosporin-β-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019-2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC 50/90 was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC 50/90 values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies., (© 2021. The Author(s).)

The Basset-Boussinesq-Oseen (BBO) equation correctly describes the nonuniform motion of a spherical particle at a low Reynolds number. It contains an integral term with a singular kernel which accounts for the diffusion of vorticity around the particle throughout its entire history. However, if there are any departures in either rigidity or shape from a solid sphere, besides the integral force with a singular kernel, the Basset history force, we should add a second history force with a non-singular kernel, related to the shape or composition of the particle. In this work, we introduce a fractional generalized Basset-Boussinesq-Oseen equation which includes both history terms as fractional derivatives. Using the Laplace transform, an integral representation of the solution is obtained. For a driven single particle, the solution shows that memory effects persist indefinitely under rather general driving conditions., (© 2021. The Author(s), under exclusive licence to EDP Sciences, SIF and Springer-Verlag GmbH Germany, part of Springer Nature.)

The present study evaluated the in vitro potency of ceftazidime and cefepime among carbapenem-resistant Pseudomonas aeruginosa isolates collected as part of a global surveillance program and assessed the pharmacodynamic implications using previously published population pharmacokinetics. When susceptible, MICs resulted at the high end of distribution for both ceftazidime and cefepime, thus 6 g/day was required to achieve optimal pharmacodynamic profiles. These findings should be considered in the clinic and for the application of CLSI susceptibility breakpoints.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen with an increase in the frequency of infections caused by multidrug resistant (MDR) and extensively drug resistant (XDR) strains, limiting the available therapeutic options. The most troublesome resistance is the acquisition and production of carbapenemases such as Verona integron-encoded metallo-β-lactamases (VIM), the most frequent and widespread, and the Klebsiella pneumoniae carbapenemases (KPC), which has continuously spread in the last decade. Its dissemination is linked to their location on mobile genetic elements (MGEs). In Colombia, VIM and KPC have been increasing in its frequency showing major successful dissemination. In this article, we molecularly characterized and analyzed the genetic context of bla VIM and bla KPC in carbapenem-resistant P. aeruginosa (CRPA) isolates from infected and colonized patients in two tertiary-care hospitals, one in Medellín and the other in a municipality close to Medellín, both areas with high carbapenemase endemicity in Colombia (2013-2015). Using whole-genome sequencing (WGS), we identified a remarkable variety of genetic backgrounds in these MDR P. aeruginosa isolates carrying bla KPC- 2 and bla VIM- 2 . There were a diversity of class 1 integron and variations in the gene cassettes associated to bla VIM- 2 , as well as a possible event of spread of bla KPC- 2 mediated by a plasmid that contained part of Tn 4401 b in one infection case. The dissemination of bla VIM- 2 and bla KPC- 2 in P. aeruginosa in this area in Colombia has been strongly influenced by successful international clones, carrying these genes and additional determinants of resistance on MGEs, accompanied by gene rearrangement under an antimicrobial selection pressure. These findings emphasize the need to implement control strategies based on rational antibiotic use., Competing Interests: MV has received grant support from the Merck Inc., Pfizer, and WestQuímica. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rada, De La Cadena, Agudelo, Pallares, Restrepo, Correa, Villegas and Capataz.)

The genus Raoultella was established in 2001. Species of Raoultella and Klebsiella share many ecological, biochemical, clinical, and microbiological features. Given the shortcomings of available technology for species identification in the clinical microbiology laboratory, are practically indistinguishable. Since the late 2000s there has been an increase in case reports of human Raoultella infections. Therefore, several authors are postulating that Raoultella spp. are rare and/or emerging pathogens. Conclusions: Raoultella spp. are very similar to Klebsiella spp . The epidemiology and the clinical relevance of the human Raoultella spp. infections is uncertain and further studies are required. The previous difficulties in the identification of Raoultella spp. and the introduction of more precise identification techniques may explain the recent increase in the number of case reports. Raoultella spp. might be rather underdiagnosed than rare or emerging pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Appel, Quijano-Martínez, De La Cadena, Mojica and Villegas.)

ESBLs are a group of plasmid-mediated, diverse, complex and rapidly evolving enzymes that pose a therapeutic challenge today in hospital- and community-acquired infections. Thirty-six years after the first report, diagnostic and therapeutic approaches for ESBLs are still the subject of controversy. Detection of these enzymes is recommended for epidemiological purposes and facilitates targeted therapy, necessary for antimicrobial stewardship. On the other hand, ESBLs are not confined to specific species, phenotypic detection methods have pitfalls, and concerns exist about the accuracy of antimicrobial susceptibility testing systems to rely on MIC values for cephalosporins and β-lactam combination agents. In this issue, we present a PRO/CON debate on ESBL testing for ceftriaxone-non-susceptible Enterobacterales., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Polymyxin resistance in Klebsiella pneumoniae has been attributed to mutations in mgrB , phoPQ , pmrAB , and crrAB and to the presence of mcr plasmid-mediated genes. Herein, we describe the molecular characteristics of 24 polymyxin- and carbapenem-resistant K. pneumoniae isolates recovered from six Colombian cities between 2009 and 2019. Minimum inhibitory concentrations (MICs) to polymyxin were confirmed by broth microdilution, and whole-genome sequencing was performed to determine sequence type, resistome, and mutations in the genes related to polymyxin resistance, as well the presence of mcr . The results showed high-level resistance to polymyxin (MICs ≥ 4 μg/mL). bla KPC-3 was present in the majority of isolates (17/24; 71%), followed by bla KPC-2 (6/24; 25%) and bla NDM-1 (1/24; 4%). Most isolates belonged to the CG258 (17/24; 71%) and presented amino acid substitutions in PmrB (22/24; 92%) and CrrB (15/24; 63%); mutations in mgrB occurred in only five isolates (21%). Additional mutations in pmrA , crrA , and phoPQ nor any of the mcr resistance genes were identified. In conclusion, we found clonal dissemination of polymyxin and carbapenem-resistant K. pneumoniae isolates in Colombia, mainly associated with CG258 and bla KPC-3 . Surveillance of this multidrug-resistant clone is warranted due to the limited therapeutic options for the treatment of carbapenem-resistant K. pneumoniae infections.

Introduction: Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined., Methods: We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256)., Results: IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56-3.04; I 2  = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24-2.47; I 2  = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70-4.16; I 2  = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36-3.59; I 2  = 58%)., Conclusion: Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.

Introduction: Anal cancer is a rare pathology which has increased over the last few decades, and, therefore, gained importance for the quality of life of affected individuals. Thus, a review has been conducted in the Colombian coffee region (Departments of Caldas, Quindío y Risaralda) describing its behaviour and clinical-epidemiological profile., Materials and Methods: Descriptive review of 437 patients of Western SAS Oncologists between January 2000 and December 2019 with a diagnosis of anal cancer., Results: 62% of cases presented in women with a median age of 62 years, 30% in the sixth decade; centred at 65% in three main cities designated as capitals (Manizales, Pereira and Armenia); 62% as localised disease, with 40% stage II-A and 6% as initial metastasis; 29% presented positive ganglia, particularly N1a; squamous cell or epidermoid histology in 90%; 16% poorly differentiated; 5% related to Human Immunodeficiency Virus infection; localisation in the medial area of the anal canal in 63% of cases; 83% completed treatment, and 92% of them received chemotherapy/radiation therapy with 87% based on the Nigro protocol; finally, 11% presented with relapse in the liver in 10% of cases and 55% local., Conclusion: Four hundred and thirty-seven patients evaluated over 20 years with follow up at median 34.13 months (standard deviation 41.75) with median survival at later ages decreasing to 62% in patients older than 80 years, and differences in survival in localised disease at 78% in comparison to 46% in advanced metastasis. Finally, the overall 5-year survival rate is 69% with a median survival of 191 months in the study., Competing Interests: The authors declare no conflicts of interest of any kind in the collection, analysis of information or the results from an academic, labour or economic point of view., (© the authors; licensee ecancermedicalscience.)

Introduction: Carbapenemases are β-lactamases able to hydrolyze a wide range of β-lactam antibiotics, including carbapenems. Carbapenemase production in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp., with and without the co-expression of other β-lactamases is a serious public health threat. Carbapenemases belong to three main classes according to the Ambler classification: class A, class B, and class D., Areas Covered: Carbapenemase-bearing pathogens are endemic in Latin America. In this review, we update the status of carbapenemases in Latin America and the Caribbean., Expert Opinion: Understanding the current epidemiology of carbapenemases in Latin America and the Caribbean is of critical importance to improve infection control policies limiting the dissemination of multi-drug-resistant pathogens and in implementing appropriate antimicrobial therapy.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The dissemination of the uropathogenic O25b-ST131 Escherichia coli clone constitutes a threat to public health. We aimed to determine the circulation of E. coli strains belonging to O25b:H4-B2-ST131 and the H 30-Rx epidemic subclone causing hospital and community-acquired urinary tract infections (UTI) in Colombia., Methods: Twenty-six nonduplicate, CTX-M group-1-producing isolates causing UTI in the hospital and community were selected for this study., Results: Twenty-two E. coli isolates harboring CTX-M-15, one CTX-M-3, and three CTX-M-55 were identified. Multilocus Sequence Typing (MLST) showed a variety of sequence types (STs), among which, ST131, ST405, and ST648 were reported as epidemic clones. All the E. coli ST131 sequences carried CTX-M-15, from which 80% belonged to the O25b:H4-B2 and H 30-Rx pandemic subclones and were associated with virulence factors iss , iha , and sat . E. coli isolates (23/26) were resistant to ciprofloxacin and associated with amino acid substitutions in quinolone resistance-determining regions (QRDR). We detected two carbapenem-resistant E. coli isolates, one coproducing CTX-M-15, KPC-2, and NDM-1 while the other presented mutations in ompC . Additionally, one isolate harbored the gene mcr-1 ., Conclusions: Our study revealed the circulation of the E. coli ST131, O25b:H4-B2- H 30-Rx subclone, harboring CTX-M-15, QRDR mutations, and other resistant genes. The association of the H 30-Rx subclone with sepsis and rapid dissemination warrants attention from the public health and infections control.

Carbapenem-resistant Enterobacterales (CRE) pose a significant threat to global public health. The most important mechanism for carbapenem resistance is the production of carbapenemases. Klebsiella pneumoniae carbapenemase (KPC) represents one of the main carbapenemases worldwide. Complex mechanisms of bla KPC dissemination have been reported in Colombia, a country with a high endemicity of carbapenem resistance. Here, we characterized the dynamics of dissemination of bla KPC gene among CRE infecting and colonizing patients in three hospitals localized in a highly endemic area of Colombia (2013 and 2015). We identified the genomic characteristics of KPC-producing Enterobacterales recovered from patients infected/colonized and reconstructed the dynamics of dissemination of bla KPC-2 using both short and long read sequencing. We found that spread of bla KPC-2 among Enterobacterales in the participating hospitals was due to intra- and interspecies horizontal gene transfer (HGT) mediated by promiscuous plasmids associated with transposable elements that was originated from a multispecies outbreak of KPC-producing Enterobacterales in a neonatal intensive care unit. The plasmids were detected in isolates recovered in other units within the same hospital and nearby hospitals. The gene "epidemic" was driven by IncN-pST15-type plasmids carrying a novel Tn 4401 b structure and non-Tn 4401 elements (NTE KPC ) in Klebsiella spp., Escherichia coli , Enterobacter spp., and Citrobacter spp. Of note, mcr-9 was found to coexist with bla KPC-2 in species of the Enterobacter cloacae complex. Our findings suggest that the main mechanism for dissemination of bla KPC-2 is HGT mediated by highly transferable plasmids among species of Enterobacterales in infected/colonized patients, presenting a major challenge for public health interventions in developing countries such as Colombia., (Copyright © 2020 American Society for Microbiology.)

Objectives: This study aimed to evaluate the susceptibility of clinical isolates of Enterobacterales and Pseudomonas aeruginosa to fosfomycin and to determine the concordance of disk diffusion (DD) and broth microdilution (BMD) with agar dilution (AD) for fosfomycin susceptibility testing., Methods: The activity of fosfomycin against 225 clinical isolates of Escherichia coli (n = 64), Klebsiella pneumoniae (n = 68), Enterobacter spp. (n = 28) and P. aeruginosa (n = 65) was tested by AD, DD and BMD. For DD, results were recorded considering and not considering colonies growing within the inhibition halo as recommended by the CLSI and EUCAST, respectively. Escherichia coli breakpoints were used for all Enterobacterales. Results were reported as categorical agreement (CA), major error (ME; false-resistant), very major error (VME; false-susceptible) and minor error (any other discrepancies)., Results: Fosfomycin susceptibility of all tested species was >90% by AD. Following CLSI guidelines, DD was the only method reaching ≥90% CA with AD for E. coli and K. pneumoniae, albeit yielding 6% ME. Neither DD nor BMD achieved acceptable CA percentages for Enterobacter spp. Following EUCAST guidelines, none of the methods had CA ≥ 90%. For Enterobacterales, the best performance of DD is achieved when read as indicated by EUCAST but interpreted according the CLSI breakpoints (>97% CA; 0% VME; ≤2% ME). For P. aeruginosa, BMD yielded the best results (89% CA; 0% VME; 11% ME)., Conclusion: Neither DD or BMD provide accurate results owing to unacceptable ME and VME percentages even when performed as intended by the guidelines., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the sensitivity and specificity of the Allplex™ Entero-DR, a quantitative PCR-based method, for the detection of β-lactamase-encoding genes and vancomycin-resistance determinants in 156 previously characterized Gram-negative bacilli and Enterococcus spp. from bacterial cultures., Result: The method had 100% sensitivity and between 92 and 100% of specificity for identifying bla KPC , bla VIM , bla IMP , bla NDM , bla OXA-48-like , bla CTX-M and vanA. In nine isolates, unspecific amplifications were detected. The Ct of these false positives was above 33. The Ct of the correctly identified bla and van genes did not surpass 28 and 30, respectively. None of the clinical isolates included as negative controls yielded any amplification. Therefore, the Allplex™ Entero-DR assay is a highly accurate test for the detection of important antibiotic resistance determinants. With this assay, reliable results can be obtained within 3 h. However, according to our data, samples with Ct values greater than 33 should be considered with caution.

Tuberculous meningitis (TBM) is a medical emergency: it is the most severe, lethal and disabling clinical form of tuberculosis. We report the case of a 44-year-old woman who had undergone a clandestine abortion six weeks before admission. One week later, she had abnormal vaginal discharge. Three weeks prior to admission, headache, hyperpyrexia and mental alteration were added. At admission, a transvaginal ultrasound showed abnormalities of the uterine cavity. Sepsis and endometritis were diagnosed, and a hysterectomy was scheduled. During preoperative evaluation, meningeal signs were found. The first lumbar puncture (LP) showed a lymphomononuclear pleocytosis, hypoglycorrhachia and hyperproteinorrachia. After five days treatment with ceftriaxone, vancomycin and dexamethasone, only partial recovery occurred. A second LP showed AFB and PCR confirmed Mycobacterium tuberculosis. The histopathology of endometrial biopsy confirmed endometrial tuberculosis. Therapeutic response to anti-tuberculous treatment and corticosteroids was excellent. No other cause of immunosuppression apart from pregnancy was found. To the best of our knowledge, this is the first report of TBM secondary to endometrial tuberculosis and highlights an unusual clinical scenario in which severe and disseminated forms of TB could be present. TBM during and after pregnancy is rare, but compared with TBM in non-pregnant women, it has a poorer prognosis. Early diagnosis and treatment can be lifesaving in this life-threatening disease.

Background : High rates of resistance to third-generation cephalosporins and carbapenems in Enterobacterales have been reported in Latin America. Ceftazidime/avibactam (CZA) is the combination of a third-generation cephalosporin and a non-β-lactam β-lactamase inhibitor, which has shown activity against isolates producing class A, C and D β-lactamases. Herein, we evaluated the activity of CZA and comparators against clinical isolates of Enterobacterales in Latin America. Methods : The activity of CZA and comparators was evaluated against clinical isolates of Enterobacterales from Argentina, Brazil, Chile, Colombia and Mexico that were collected between January 2016 and October 2017. One specific phenotypic subset was evaluated. A carbapenem non-susceptible (CNS) phenotype was defined as any isolate displaying a minimum inhibitory concentration (MIC) ≥1 mg/L for ertapenem. Results : CZA was active against 95.8% of all isolates and 77.5% of CNS isolates. Fosfomycin (FOS) and tigecycline (TGC) were the second most active antibiotics with 93.4% of Enterobacterales being susceptible. Conclusions : The results of this study underline the potential therapeutic role of CZA in Latin America.

Introduction: The carbapenem inactivation method (CIM) is a cost-effective assay for detecting carbapenemases. However, its interpretation is unclear for Pseudomonas spp. We evaluate its accuracy when meropenem is changed to imipenem., Methods: We analyzed 266 P. aeruginosa isolates. The CIM method consists of: resuspend bacterial colonies (a full 10μL loop) in 400μL water, in which a 10μg disk of meropenem/imipenem is immersed. After 2h of incubation (35°C), remove the disk, place it onto a Mueller-Hinton agar plate previously inoculated with Escherichia coli (ATCC 25922), and incubate at 35 ̊C between 18-24 h. Interpretation criteria (mm of inhibition zone): ≤19mm, positive; ≥25mm negative; 20-24mm, undetermined., Results: Imipenem improves the sensitivity and specificity of CIM when compared to meropenem (99.4% and 98.9%, vs. 91.9% and 94.7%, respectively)., Conclusions: The accuracy of CIM for carbapenemase detection in P. aeruginosa is increased with the use of imipenem., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)

Background: Antimicrobial resistance (AMR) is a global threat to public health. Antibiotic stewardship programs (AMSP) promote the proper use of antimicrobials, improve clinical and economic outcomes, and helps containing the AMR., Aim: To evaluate the diagnostic phase of the AMS programs and early implementation of AMS at three high complexity hospitals that belong to the social security system in Peru., Methods: A quasi-experimental multicenter study was implemented. The construction of the AMSP, microbiological baselines, antimicrobial consumption and consensus on AMS activities were evaluated at the diagnosis and early implementation periods of the AMSP., Results: Following implementation, hospitals doubled their score of resources and processes available for the AMS program from 6.75 to 13.75. The prevalence of extended spectrum beta-lactamase producing enterobacteria was 50-60% while Pseudomonas aeruginosa averaged 69% resistance to carbapenems. The defined daily dose (DDD) of ceftriaxone was 13.63, vancomycin 7.35 and meropenem 6.73 in average. Hospitals A and C decreased the use of antimicrobials (30-50%)., Discussion: The implementation of the AMSP in the three hospitals was achieved through diverse strategies designed by multidisciplinary teams, which in addition to its articulation, reduce the consumption of broad spectrum antimicrobials at an early stage.

Background: Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown., Methods: To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements., Results: We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape., Conclusion: We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.

Background: Recent studies suggest that sustained use of generic antibiotics may be associated with clinical failure and emergence of antibacterial resistance. The present study was designed to determine the clinical outcome between the use of generic meropenem (GM) and brand-name meropenem (BNM). Additionally, this study evaluated the economic impact of GM and BNM to determine if the former represents a cost-effective alternative to the latter., Methods: Patients treated between January 2011 and May 2014 received GM while patients treated between June 2014 and March 2017 received BNM. Mortality was compared between groups. Total infection cost was defined by the cost of antimicrobial consumption, length of stay, and laboratory and imaging exams until infection resolution., Findings: A total of 168 patients were included; survival rate for the 68 patients treated with GM was 38% compared to 59% in the patients treated with BNM. Multivariate analysis showed that the variables most strongly-associated with mortality were cardiovascular disease (OR 18.18, 95% CI 1.25-262.3, p = 0.033) and treatment with generic meropenem (OR 18.45, 95% CI 1.45-232.32, p = 0.024). On the other hand, total infection cost did not show a significant difference between groups (BNM $10,771 vs. GM $11,343; p = 0.91)., Interpretation: The present study suggests that patients treated with GM have a risk of death 18 times higher compared to those treated with BNM. Furthermore, economic analysis shows that GM is not more cost effective than BNM., Summary: More studies measuring clinical outcomes are needed to confirm the clinical equivalence of brand-name versus generic antibiotics, not only for meropenem but also for other molecules., (Copyright © 2019 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)