http://sgc.anlis.gob.ar/handle/123456789/4 INEI 2026-04-22T22:08:29Z http://sgc.anlis.gob.ar/handle/123456789/2737 Title: A mechanism-based pharmacokinetic/pharmacodynamic analysis of polymyxin B-based combination therapy against carbapenem-resistant Klebsiella pneumoniae isolates with diverse phenotypic and genotypic resistance mechanisms Authors: Mahadevan, Ramya; Garcia, Estefany; Sharma, Rajnikant; Qiu, Hongqiang; Elsheikh, Ahmed; Parambi, Robert; Saad Abboud, Cely; Pasteran, Fernando; Ramirez, Maria Soledad; Kaye, Keith S; Bonomo, Robert A; Rao, Gauri G. Abstract: Increased resistance to β-lactams/β-lactamase inhibitors by mutations in β-lactamase genes, porins, and efflux pumps complicates the management of carbapenem-resistant Klebsiella pneumoniae (CRKP). Polymyxin B (PMB)-based combination therapy is the best alternative treatment for middle and low-income countries that cannot access the latest medicines. It is crucial to know both phenotypic and genotypic characteristics of a pathogen to understand the killing effect of each drug and its combinations. Hence, our objective was to incorporate mechanistic insights gained from resistance mechanisms of each isolate to develop a mechanism-based pharmacokinetic/pharmacodynamic model. Six clinical CRKP isolates with diverse genotypic resistance expressing blaKPC, blaNDM, porin, and mgrB mutations were used for static concentration time kill (SCTK) assays to evaluate the rate and extent of killing by monotherapy, double and triple combinations using PMB (0.5-64 mg/L), meropenem (10-120 mg/L), and fosfomycin (75-500 mg/L). Isolate BRKP28 expressed non-functional MgrB (a regulatory protein) and high-level phenotypic resistance (PMB MIC: >128 mg/L). In line with the observed resistance, the model estimated that BRKP28 had a reduced maximum killing rate constant for PMB (3.61 h⁻¹) relative to other isolates. The mechanistic synergy of PMB, due to outer membrane disruption, was incorporated into three isolates with porin mutations. PMB demonstrated 83%-88% mechanistic synergy with meropenem and 81%-98% with fosfomycin. The model further estimated that a very low concentration of PMB (0.49-0.64 mg/L) was sufficient to achieve 50% of the maximum synergy. Simulations using population pharmacokinetic models showed that combination therapy of PMB (1 mg/kg q12h) and fosfomycin (8 g q8h) achieved >73% reduction in area under the bacterial load-versus-time curve across four isolates. The triple combination therapy achieved a 67.7% reduction in non-carbapenamase producing isolate. These findings demonstrates that a low PMB dosing regimen (1 mg/kg q12h) can produce synergistic effects in combination therapy and may be effective in managing infections caused by CRKP, including PMB resistant isolates. Description: Fil: Mahadevan, Ramya. Titus Family Department of Clinical Practice, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA. Fil: García, Estefany. Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Fil: Sharma, Rajnikant. Titus Family Department of Clinical Practice, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA. Fil: Qiu, Hongqiang. Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China; College of Pharmacy, Fujian Medical University, Fuzhou, People's Republic of China. Fil: Elsheikh, Ahmed. Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Fil: Parambi, Robert. Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Fil: Saad Abboud, Cely. Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil. Fil: Pasteran, Fernando. Antimicrobianos, Instituto Nacional de Enfermedades Infecciosas, Antimicrobial Service of the National Institute of Infectious Diseases (ANLIS Dr. Carlos G. Malbrán), Buenos Aires, Argentina. Fil: Ramirez, María Soledad. Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA. Fil: Kaye, Keith S. Division of Allergy, Immunology and Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. Fil: Bonomo, Robert A. Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA; Geriatric Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Education and Clinical Center, Cleveland, Ohio, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Departments of Pharmacology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Fil: Rao, Gauri G. Titus Family Department of Clinical Practice, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA; Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 2025-12-19T00:00:00Z http://sgc.anlis.gob.ar/handle/123456789/2736 Title: Carbapenem-Resistant Gram-Negative Bacilli Bacteremia in Argentina (EMBARCAR): Findings From a Prospective, Multicenter Cohort Study Authors: Balbuena, Juan Pablo; Córdova, Ezequiel; Mykietiuk, Analia; Farina, Javier; Gañete, Marcelo; Scapellato, Pablo G.; Lespada, María Inés; Nannini, Esteban; Contreras, Rosa; Cunto, Eleonora; Barcelona, Laura; Pasteran, Fernando; Salgueira, Claudia; Hojman, Martin; Blanco, Miriam; Cox Fernandez, William E; Lopez Alegre, Horacio; Ezcurra, Cecilia; Godoy, Dario; Biglia, Maria A; Lopez Furst, Maria J; Mendez, Gustavo; Aguirre Rios, Maria F; Messina, Oscar; Ciappina, Antonella; Pálizas, Fernando; Altclas, Javier; Gaudenzi, Giuliano; Cardone, Romina; Sánchez-Cunto, Milagro; Ruiz, Mariquena; Perez,Gabriel; Sanchez, Cesar; Stryjewski,Martin E Abstract: Background: Bloodstream infections (BSIs) caused by carbapenem-resistant gram-negative bacilli (CR-GNB) are difficult-to-treat infections associated with high mortality. Outcomes of BSI due to CR-GNB may vary in different countries. Methods: Prospective observational, multicenter study, including consecutive hospitalized index patients aged ≥18 years, with a positive blood culture for CR-GNB, between July 2020 and March 2022 in Argentina. Among patients with Klebsiella pneumoniae BSIs, logistic regressions adjusted by propensity score (PS) were used to identify variables associated with 30-day mortality. Results: Overall, 466 patients with CR-GNB BSIs were included. The mean age was 56.7 (SD ±16) years and most patients (75%) were in critical care units. The median INCREMENT-CPE mortality score was 10 (IQR, 6-12). Most common micro-organisms were K pneumoniae (53%) and Acinetobacter baumannii (25%). Among Enterobacterales, resistance mechanisms included K pneumoniae carbapenemase (KPC) in 50%, metallo-beta-lactamase carbapenemase (MBL) in 48%, OXA carbapenemase in 6%, and a combination of carbapenemases in 5% of patients. Overall, 30-day mortality was 52%. Among patients with BSI due to K pneumoniae, the PS-adjusted multivariate analysis showed that an INCREMENT-CPE score ≥8 points (odds ratio [OR], 3.48; 95% CI, 1.53, 7.93) was associated with increased 30-day mortality. In contrast, the use of regimens including ceftazidime-avibactam alone or in combination with aztreonam was associated with decreased 30-day mortality (OR, .20; 95% CI, .09, .47). Conclusions: BSIs due to CR-GNB are associated with high mortality rates in Argentina. Among patients with CR-K pneumoniae bacteremia the use of ceftazidime-avibactam alone or in combination with aztreonam was associated with a reduction in mortality. 2025-12-24T00:00:00Z http://sgc.anlis.gob.ar/handle/123456789/2734 Title: Glyphosate resistance as a potential driver for the dissemination of multidrug-resistant clinical strains Authors: Knecht, Camila A; Prack McCormick, Barbara; Álvarez, Verónica E.; Gonzales Machuca, Adrián; Buzzola, Fernanda; Fuchs, Julio; Salgado, Pablo; Campos, Josefina; Müller, Jochen A.; Quiroga, María Paula; Centrón, Daniela Abstract: The rise of antimicrobial resistance (AMR) constitutes a serious threat to global health. Environmental bacterial communities are a key reservoir of AMR genes (ARGs) that can spread to clinical pathogens. Biocides, which include broadspectrum herbicides, can co-select for ARGs, posing a potential driver for AMR spread. Glyphosate, the world’s most widely used herbicide with known bactericidal properties, targets the shikimate pathway and may thus exert selective pressure favoring resistant bacteria, potentially elevating clinical AMR risk from a One Health perspective. We assessed glyphosate resistance in multidrug-resistant (MDR) species isolated from nosocomial infections. Furthermore, we investigated the relationship between glyphosate-resistant environmental species and clinically relevant MDR pathogens using whole-genome sequencing of environmental and clinical strains. Multidrug-resistant species from hospital-acquired infections exhibited high levels of glyphosate resistance. We established a link between glyphosate-resistant environmental species and typically MDR species common in nosocomial settings. Genomic analysis revealed that glyphosate resistance is partially independent of mutations in the target enzyme (5-enolpyruvylshikimate-3-phosphate synthase), suggesting the contribution of alternative mechanisms, such as efflux pumps. Our findings indicate that glyphosate exposure could favor the prevalence of bacteria associated with nosocomial infections and the rise of MDR clinical strains. This suggests that intensive glyphosate use may accelerate the dissemination of AMR. Consequently, the AMR dimension should be incorporated into the environmental risk assessment of biocidal products that are not used as antimicrobial agents. Description: English, 13 pages 2026-03-24T00:00:00Z http://sgc.anlis.gob.ar/handle/123456789/2719 Title: Burden and serotype distribution of invasive Pneumococcal disease among high-risk patients from Latin America and the Caribbean: A systematic review and meta-analysis Authors: Bardach, Ariel; Ruvinsky, Silvina; Ciapponi, Agustin; Alconada, Tomás; Brizuela, Martín; Voto, Carla; Roel, Macarena; Gagetti, Paula Abstract: Invasive pneumococcal diseases (IPD), caused by Streptococcus pneumoniae , entail significant morbidity and mortality, especially in high-risk populations. In Latin America and the Caribbean (LAC) data are scarce. Objective: To estimate the disease burden, serotype distribution, and healthcare resource use among high- risk children and adults with IPD in LAC. Methods: We conducted a systematic review following PRISMA guidelines and a preregistered protocol (PROSPERO CRD42025629682). We searched CENTRAL, PubMed, Embase, LILACS, EconLIT, Global Health, CINAHL, SciELO, surveillance networks, and grey literature sources (Jan 20 0 0-Dec 2024). Results: Search yielded 6227 records, 181 studies were included, representing 63,671 IPD cases from 20 LAC countries. Pneumonia accounted for 52% of IPD cases, followed by meningitis 22% and bacteremia 20%. Median incidence was 13.13 cases per 10 0,0 0 0 persons per year, global case fatality rate was 17%, in meningitis 23% and in adults ≥60 years was 35%. In 36% of patients ICU admission was required. Post- PCV introduction, vaccine serotypes declined while nonvaccine serotypes increased, particularly among children < 5 years, with variability across LAC countries. Conclusion: This review highlights the burden and patterns of IPD serotypes among high-risk populations in LAC. Optimized vaccination strategies and continuous surveillance are required. ©2025 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases 2025-11-21T00:00:00Z