RESUMEN
In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).
Asunto(s)
Bacteriemia , Sepsis , Adulto , Humanos , Bacteriemia/tratamiento farmacológico , Hospitales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Combinación de Medicamentos , CeftazidimaRESUMEN
Gram-negative antibiotic resistance continues to grow as a global problem due to the evolution and spread of ß-lactamases. The early ß-lactamase inhibitors (BLIs) are characterized by spectra limited to class A ß-lactamases and ineffective against carbapenemases and most extended spectrum ß-lactamases. In order to address this therapeutic need, newer BLIs were developed with the goal of treating carbapenemase producing, carbapenem resistant organisms (CRO), specifically targeting the Klebsiella pneumoniae carbapenemase (KPC). These BL/BLI combination drugs, avibactam/avibactam, meropenem/vaborbactam, and imipenem/relebactam, have proven to be indispensable tools in this effort. However, non-KPC mechanisms of resistance are rising in prevalence and increasingly challenging to treat. It is critical for clinicians to understand the unique spectra of these BL/BLIs with respect to non-KPC CRO. In Part 1of this 2-part series, we describe the non-KPC attributes of the newer BL/BLIs with a focus on utility against Enterobacterales and Pseudomonas aeruginosa.
Asunto(s)
Antibacterianos , Pseudomonas aeruginosa , Inhibidores de beta-Lactamasas , beta-Lactamasas , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , beta-Lactamasas/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Proteínas Bacterianas , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/enzimología , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pruebas de Sensibilidad Microbiana , beta-Lactamas/farmacología , beta-Lactamas/uso terapéutico , Meropenem/farmacología , Meropenem/uso terapéutico , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimologíaRESUMEN
We evaluated the in vitro activity of meropenem-vaborbactam plus aztreonam (MEV-ATM) against 140 metallo-ß-lactamase (MBL)-producing Klebsiella pneumoniae isolates. Among them, 25 isolates (17.9%) displayed minimum inhibitory concentrations (MIC) ≥ 8 µg/mL, while 112 (80.0%) had MIC ≤ 2 µg/mL. Genomic analysis and subsequent gene cloning experiments revealed OmpK36 134-135GD-insertion and increased carbapenemase gene (blaNDM-1 and blaOXA-48-like) copy numbers are the main factors responsible for MEV-ATM non-susceptibility. Notably, MEV-ATM is actively against aztreonam-avibactam-resistant mutants due to CMY-16 mutations.
Asunto(s)
Antibacterianos , Aztreonam , Ácidos Borónicos , Meropenem/farmacología , Aztreonam/farmacología , Antibacterianos/farmacología , Klebsiella pneumoniae/genética , beta-Lactamasas/genética , Combinación de Medicamentos , Pruebas de Sensibilidad Microbiana , Compuestos de Azabiciclo/farmacologíaRESUMEN
We characterized the molecular determinants of meropenem-vaborbactam (MV) non-susceptibility among non-metallo-ß-lactamase-producing KPC-Klebsiella pneumoniae (KPC-KP). Whole-genome sequencing was performed to identify mutations associated with MV non-susceptibility. Isolates with elevated MV MICs were found to have mutations encoding truncated or altered OmpK36 porins and increased blaKPC copy numbers. KPC-KP isolates with decreased susceptibility to MV were detected among a collection of isolates predating the availability of MV.
RESUMEN
Bacterial infections, including those caused by Pseudomonas aeruginosa, often lead to sepsis, necessitating effective antibiotic treatment like carbapenems. The key pharmacokinetic/pharmacodynamic (PK/PD) index correlated to carbapenem efficacy is the fraction time of unbound plasma concentration above the minimum inhibitory concentration (MIC) of the pathogen (%fT > MIC). While multiple targets exist, determining the most effective one for critically ill patients remains a matter of debate. This study evaluated meropenem's bactericidal potency and its ability to combat drug resistance in Pseudomonas aeruginosa under three representative PK/PD targets: 40% fT > MIC, 100% fT > MIC, and 100% fT > 4× MIC. The hollow fiber infection model (HFIM) was constructed, validated, and subsequently inoculated with a substantial Pseudomonas aeruginosa load (1 × 108 CFU/mL). Different meropenem regimens were administered to achieve the specified PK/PD targets. At specified intervals, samples were collected from the HFIM system and subjected to centrifugation. The resulting supernatant was utilized to determine drug concentrations, while the precipitates were used to track changes in both total and drug-resistant bacterial populations over time by the spread plate method. The HFIM accurately reproduced meropenem's pharmacokinetics in critically ill patients. All three PK/PD target groups exhibited a rapid bactericidal response within 6 h of the initial treatment. However, the 40% fT > MIC and 100% fT > MIC groups subsequently showed bacterial resurgence and resistance, whereas the 100% fT > 4× MIC group displayed sustained bactericidal activity with no evidence of drug resistance. The HFIM system revealed that maintaining 100% fT > 4× MIC offers a desirable microbiological response for critically ill patients, demonstrating strong bactericidal capacity and effective prevention of drug resistance.
Asunto(s)
Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Meropenem/uso terapéutico , Enfermedad Crítica , Antibacterianos/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.
Asunto(s)
Antibacterianos , Cefepima , Cefalosporinas , Meropenem , Pruebas de Sensibilidad Microbiana , Infecciones Urinarias , beta-Lactamasas , Humanos , Meropenem/uso terapéutico , Meropenem/farmacología , Cefepima/uso terapéutico , Cefepima/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Cefalosporinas/uso terapéutico , Cefalosporinas/farmacología , beta-Lactamasas/genética , Adulto , Femenino , Masculino , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Persona de Mediana Edad , Método Doble Ciego , Proteínas Bacterianas/genética , Genotipo , Fenotipo , Anciano , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Resultado del Tratamiento , Ácidos Borínicos , Ácidos CarboxílicosRESUMEN
ANT3310 is a novel broad-spectrum diazabicyclooctane serine ß-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii (n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) (n = 252) or Klebsiella pneumoniae carbapenemase (KPC) (n = 180) carbapenemases, and Pseudomonas aeruginosa (n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii. This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other ß-lactam/ß-lactamase combinations.
Asunto(s)
Acinetobacter baumannii , Inhibidores de beta-Lactamasas , Humanos , Animales , Ratones , Meropenem/farmacología , Inhibidores de beta-Lactamasas/farmacología , Lactamas , Antibacterianos/farmacología , beta-Lactamasas , Carbapenémicos/farmacología , Compuestos de Azabiciclo/farmacología , Combinación de Medicamentos , Pruebas de Sensibilidad MicrobianaRESUMEN
Phage-antibiotic combination treatment is a novel noteworthy drug delivery method in anti-infection. In the current study, we have isolated a new phage, pB23, against carbapenem-resistant Acinetobacter baumannii 2023. Synergistic antibacterial effect between phage pB23 and meropenem combination could be more stable, using moderate doses of phage (multiplicity of infection ranging from 0.1 to 1,000) based on results of in vitro antibacterial activity. Phage pB23 and meropenem combination could effectively clear mature biofilms and prevent biofilm formation of carbapenem-resistant Acinetobacter baumannii in vitro. Phage pB23 and meropenem combination also has good synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii in different growth phases under static culture conditions. The pig skin explant model shows that phage pB23 and meropenem combination has a synergistic effect to remove bacteria from wounds ex vivo. Phage pB23 and meropenem combination also exhibited a synergistic antibacterial effect in vivo using a zebrafish infection mode. The potential promotion of phage proliferation by meropenem and the sensitivity recovery of phage-resistant bacteria to meropenem might elucidate the mechanism of the synergistic antimicrobial activity. In summary, our study illustrates that phage pB23 and meropenem combination could produce synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii under static growth conditions. This study also demonstrates that phage-antibiotic combination will become an effective strategy to enhance antibacterial activity of individual drug and provide a new idea of the drug development for the treatment of infections due to carbapenem-resistant Acinetobacter baumannii and other multidrug-resistant bacteria.
RESUMEN
Antimicrobial resistance (AMR) in Acinetobacter baumannii is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of A. baumannii do not display growth well in in vivo models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of A. baumannii AB5075. This strain has a chromosomally encoded oxa-23 that was deleted (Δoxa-23), then plasmids expressing oxa-23, oxa-24/40, oxa-58, imp-1, vim-2, and ndm-1 were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (fT > MIC). AB5075 and the AB5075Δoxa-23 mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases oxa-24/40 and oxa-58 had an MIC of 64 mg/L. The metallo-ß-lactamases imp-1, vim-2, and ndm-1 had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed in vivo growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying fT > MIC of the transformants and was readily described by an inhibitory sigmoid Emax relationship. Stasis was achieved with a fT > MIC of 0.36. These A. baumannii transformants are invaluable new tools for the assessment of anti-Acinetobacter compounds and provide a new pathway for AMR preparedness.
RESUMEN
Standard dosing could fail to achieve adequate systemic concentrations in ICU children or may lead to toxicity in children with acute kidney injury. The population pharmacokinetic analysis was used to simultaneously analyze all available data (plasma, prefilter, postfilter, effluent, and urine concentrations) and provide the pharmacokinetic characteristics of meropenem. The probability of target fT > MIC attainment, avoiding toxic levels, during the entire dosing interval was estimated by simulation of different intermittent and continuous infusions in the studied population. A total of 16 critically ill children treated with meropenem were included, with 7 of them undergoing continuous kidney replacement therapy (CKRT). Only 33% of children without CKRT achieved 90% of the time when the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) for an MIC of 2 mg/L. In dose simulations, only continuous infusions (60-120 mg/kg in a 24-h infusion) reached the objective in patients <30 kg. In patients undergoing CKRT, the currently used schedule (40 mg/kg/12 h from day 2 in a short infusion of 30 min) was clearly insufficient in patients <30 kg. Keeping the dose to 40 mg/kg q8h without applying renal adjustment and extended infusions (40 mg/kg in 3- or 4-h infusion every 12 h) was sufficient to reach 90% fT > MIC (>2 mg/L) in patients >10 kg. In patients <10 kg, only continuous infusions reached the objective. In patients >30 kg, 60 mg/kg in a 24-h infusion is sufficient and avoids toxicity. This population model could help with an individualized dosing approach that needs to be adopted in critically ill pediatric patients. Critically ill patients subjected to or not to CKRT may benefit from the administration of meropenem in an extended or continuous infusion.
RESUMEN
Introduction. Bacterial keratitis, particularly caused by Pseudomonas aeruginosa, is challenging to treat because of multi-drug tolerance, often associated with the formation of biofilms. Antibiotics in development are typically evaluated against planktonic bacteria in a culture medium, which may not accurately represent the complexity of infections in vivo.Hypothesis/Gap Statement. Developing a reliable, economic ex vivo keratitis model that replicates some complexity of tissue infections could facilitate a deeper understanding of antibiotic efficacy, thus aiding in the optimization of treatment strategies for bacterial keratitis.Methodology. Here we investigated the efficacy of three commonly used antibiotics (gentamicin, ciprofloxacin and meropenem) against Pseudomonas aeruginosa cytotoxic strain PA14 and invasive strain PA01 using an ex vivo porcine keratitis model.Results. Both strains of P. aeruginosa were susceptible to the MIC of the three tested antibiotics. However, significantly higher concentrations were necessary to inhibit bacterial growth in the minimum biofilm eradication concentration (MBEC) assay, with both strains tolerating concentrations greater than 512 mg l-1 of meropenem. When MIC and higher concentrations than MBEC (1024 mg l-1) of antibiotics were applied, ciprofloxacin exhibited the highest potency against both P. aeruginosa strains, followed by meropenem, while gentamicin showed the least potency. Despite this, none of the antibiotic concentrations used effectively cleared the infection, even after 18 h of continuous exposure.Conclusions. Further exploration of antibiotic concentrations and aligning dosing with clinical studies to validate the model is needed. Nonetheless, our ex vivo porcine keratitis model could be a valuable tool for assessing antibiotic efficacy.
Asunto(s)
Antibacterianos , Biopelículas , Ciprofloxacina , Modelos Animales de Enfermedad , Queratitis , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Antibacterianos/farmacología , Porcinos , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Biopelículas/efectos de los fármacos , Queratitis/microbiología , Queratitis/tratamiento farmacológico , Ciprofloxacina/farmacología , Gentamicinas/farmacología , Meropenem/farmacologíaRESUMEN
Campylobacter fetus is known to cause human disease, particularly in elderly and immunocompromised hosts. There are limited published data for antimicrobial susceptibility patterns with this organism, and no interpretive criteria are available. We reviewed antimicrobial susceptibilities of C. fetus isolates tested at a tertiary care center and reference laboratory over an 11-year period. C. fetus isolates from patients treated at Mayo Clinic and those sent as referrals for identification and susceptibility were included. Antimicrobial susceptibility testing was performed using agar dilution for ciprofloxacin, doxycycline, erythromycin, gentamicin, meropenem, and tetracycline. Geographic distribution, culture source, organism minimal inhibitory concentration (MIC) distributions, and MIC50 and MIC90 were examined. Excluding duplicates, 105 unique isolates were identified from 110 positive cultures. Blood cultures represented the most common source, followed by body fluids, skin and soft tissue, and central nervous system. Gentamicin and meropenem had favorable MIC50 and MIC90 of 1 µg/mL. Ciprofloxacin demonstrated an MIC50 of 1 µg/mL; however, the MIC90 was >2 µg/mL. Erythromycin demonstrated MIC50 and MIC90 of 2 µg/mL. Tetracycline and doxycycline were tested on a limited number of isolates and showed a wide range of MICs. Gentamicin and meropenem demonstrated favorable MICs in C. fetus isolates. These may represent therapeutic options for consideration in serious C. fetus infections, pending susceptibility results. Ciprofloxacin, which showed variable results, may be more appropriate for use only after susceptibility testing. C. fetus interpretive criteria are needed to aid clinicians in selection of both empiric and definitive therapies. IMPORTANCE: Our findings contribute to the scant literature on Campylobacter fetus antimicrobial susceptibility test results. We used a reference test method of agar dilution and provide MICs for a large number of organisms and antimicrobial agents.
Asunto(s)
Antiinfecciosos , Campylobacter , Humanos , Anciano , Campylobacter fetus , Doxiciclina/farmacología , Meropenem , Agar , Antibacterianos/farmacología , Ciprofloxacina/farmacología , Eritromicina/farmacología , Tetraciclina , Gentamicinas/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Rapid phenotypic detection assays, including Carba NP and its variants, are widely applied for clinical diagnosis of carbapenemase-producing Enterobacterales (CPE). However, these tests are based on the acidification of the pH indicator during carbapenem hydrolysis, which limits test sensitivity and speed, especially for the detection of CPE producing low-activity carbapenem (e.g., OXA-48 variants). Herein, we developed a novel rapid and sensitive CPE detection method (Carba PBP) that could measure substrate (meropenem) consumption based on penicillin-binding protein (PBP). Meropenem-specific PBP was used to develop a competitive lateral flow assay (LFA) for meropenem identification. For the detection of carbapenemase activity, meropenem concentration was optimized using a checkerboard assay. The performance of Carba PBP was evaluated and compared with that of Carba NP using a panel of 94 clinical strains characterized by whole-genome sequencing and carbapenem susceptibility test. The limit of detection of PBP-based LFA for meropenem identification was 7 ng mL-1. Using 10 ng mL-1 meropenem as the substrate, Carba PBP and Carba NP could detect 10 ng mL-1 carbapenemase within 25 min and 1,280 ng mL-1 CPE in 2 h, respectively. The sensitivity and specificity were 100% (75/75) and 100% (19/19) for Carba PBP and 85.3% (64/75) and 100% (19/19) for Carba NP, respectively. When compared with Carba NP, Carba PBP showed superior performance in detecting all the tested CPE strains (including OXA-48-like variants) within 25 min and presented two orders of magnitude higher analytical sensitivity, demonstrating potential for clinical diagnosis of CPE. IMPORTANCE This study successfully achieved the goal of carbapenemase activity detection with both high sensitivity and convenience, offering a convenient lateral flow assay for clinical diagnosis of carbapenemase-producing Enterobacterales.
Asunto(s)
Proteínas Bacterianas , beta-Lactamasas , Humanos , Proteínas de Unión a las Penicilinas/genética , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , beta-Lactamasas/metabolismo , Carbapenémicos/farmacología , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Recognition of seasonal trends in bacterial infection and drug resistance rates may enhance diagnosis, direct therapeutic strategies, and inform preventive measures. Limited data exist on the seasonal variability of Acinetobacter baumannii. We investigated the seasonality of A. baumannii, the correlation between temperature and meropenem resistance, and the impact of temperature on this bacterium. RESULTS: Meropenem resistance rates increased with lower temperatures, peaking in winter/colder months. Nonresistant strain detection exhibited temperature-dependent seasonality, rising in summer/warmer months and declining in winter/colder months. In contrast, resistant strains showed no seasonality. Variations in meropenem-resistant and nonresistant bacterial resilience to temperature changes were observed. Nonresistant strains displayed growth advantages at temperatures ≥ 25 °C, whereas meropenem-resistant A. baumannii with ß-lactamase OXA-23 exhibited greater resistance to low-temperature (4 °C) stress. Furthermore, at 4 °C, A. baumannii upregulated carbapenem resistance-related genes (adeJ, oxa-51, and oxa-23) and increased meropenem stress tolerance. CONCLUSIONS: Meropenem resistance rates in A. baumannii display seasonality and are negatively correlated with local temperature, with rates peaking in winter, possibly linked to the differential adaptation of resistant and nonresistant isolates to temperature fluctuations. Furthermore, due to significant resistance rate variations between quarters, compiling monthly or quarterly reports might enhance comprehension of antibiotic resistance trends. Consequently, this could assist in formulating strategies to control and prevent resistance within healthcare facilities.
Asunto(s)
Acinetobacter baumannii , Antibacterianos , Meropenem , Pruebas de Sensibilidad Microbiana , Estaciones del Año , Temperatura , beta-Lactamasas , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/genética , Meropenem/farmacología , Antibacterianos/farmacología , beta-Lactamasas/genética , Adaptación Fisiológica/genética , Farmacorresistencia Bacteriana/genética , Humanos , Infecciones por Acinetobacter/microbiología , Proteínas Bacterianas/genéticaRESUMEN
AIMS: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients. METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months). CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).
RESUMEN
The purpose of this study was to evaluate the MBT-ASTRA to determine susceptibility to ceftazidime/avibactam (CZA) and meropenem (MEM) of Enterobacterales directly from positive blood cultures (BC). Bacterial suspension was incubated with antibiotic and analyzed by MALDI-TOF MS. The relative growth was calculated and cutoff values were determined to categorize isolates as "S," "I," and "R." Klebsiella spp. with CZA 20/8 mg/L and 1.5-h incubation presented 1 (5.9%) major discrepancy and 96.3% category agreement; other species required 2.5 h for 100% category agreement. For MEM, 4 mg/L and 1.5h were necessary, demonstrating 2 (6.67%) minor discrepancies and 93.3% categorical agreement.
Asunto(s)
Cultivo de Sangre , Ceftazidima , Humanos , Ceftazidima/farmacología , Meropenem/farmacología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Antibacterianos/farmacología , Combinación de Medicamentos , Pruebas de Sensibilidad Microbiana , beta-LactamasasRESUMEN
PURPOSE: Real-world experience with meropenem/vaborbactam (M/V) is limited. Our aim is to report a clinical experience of M/V in the treatment of resistant Gram-negative bacilli. METHODS: This is a prospective observational study including patients hospitalized in the University Hospital of Pisa (March 2021-Jan 2023) with infections by both extended-spectrum ß-lactamases (ESBL)-producing Enterobacterales and carbapenem-resistant Klebsiella pneumoniae (Kp) treated with M/V. The primary outcome measure was clinical success, defined as a composite of survival, resolution of signs and symptoms and absence of microbiological failure at day 30 from infection onset. A multivariable regression analysis was performed to identify factors associated with clinical failure. Odds ratio (OR) with 95% confidence intervals (CI) was calculated. RESULTS: A total of 104 patients who received M/V were included: 24/104 (23.1%) infections were caused by ESBL non-hypervirulent Enterobacterales, 17/104 (16.3%) by ESBL-producing hypervirulent Klebsiella pneumoniae (hvKp) and 63/104 (60.6%) by CRE. The most common infections were bloodstream infections, followed by urinary tract infections, hospital-acquired pneumonia, intra-abdominal infections and others. Septic shock occurred in 16/104 (15.4%) patients. Clinical success was achieved in 77% of patients, and 30-day mortality rate was 15.4%. In patients with KPC-producing Kp infections, clinical success and 30-day mortality rates were 82% and 11.5%, respectively. On multivariable analysis, SOFA score (OR 1.32, 95% CI 1.02-1.7, p=0.032) was independently associated with clinical failure, while source control (OR 0.16, 95% CI 0.03-0.89, p=0.036) was protective. CONCLUSIONS: M/V is a promising therapeutic option against infections caused by difficult-to-treat ESBL-producing Enterobacterales and CR-Kp.
RESUMEN
BACKGROUND: In Japan, carbapenem-resistant Enterobacterales (CRE) infections were incorporated into the National Epidemiological Surveillance of Infectious Diseases (NESID) in 2014, necessitating mandatory reporting of all CRE infections cases. Subsequently, pathogen surveillance was initiated in 2017, which involved the collection and analysis of CRE isolates from reported cases to assess carbapenemase gene possession. In this surveillance, CRE is defined as (i) minimum inhibitory concentration (MIC) of meropenem ≥2 mg/L (MEPM criteria) or (ii) MIC of imipenem ≥2 mg/L and MIC of cefmetazole ≥64 mg/L (IPM criteria). This study examined whether the current definition of CRE surveillance captures cases with a clinical and public health burden. METHODS: CRE isolates from reported cases were collected from the public health laboratories of local governments, which are responsible for pathogen surveillance. Antimicrobial susceptibility tests were conducted on these isolates to assess compliance with the NESID CRE definition. The NESID data between April 2017 and March 2018 were obtained and analyzed using antimicrobial susceptibility test results. RESULTS: In total, 1681 CRE cases were identified during the study period, and pathogen surveillance data were available for 740 (44.0%) cases. Klebsiella aerogenes and Enterobacter cloacae complex were the dominant species, followed by Klebsiella pneumoniae and Escherichia coli. The rate of carbapenemase gene positivity was 26.5% (196/740), and 93.4% (183/196) of these isolates were of the IMP type. Meanwhile, 315 isolates were subjected to antimicrobial susceptibility testing. Among them, 169 (53.7%) fulfilled only the IPM criteria (IPM criteria-only group) which were susceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-only group and MEPM criteria group significantly differed in terms of carbapenemase gene positivity (0% vs. 67.8%), multidrug resistance rates (1.2% vs. 65.8%), and mortality rates (1.8% vs 6.9%). CONCLUSION: The identification of CRE cases based solely on imipenem resistance has had a limited impact on clinical management. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public health burden. This emphasis will enable the efficient allocation of limited health and public health resources and preservation of newly developed antimicrobials.
Asunto(s)
Antiinfecciosos , Imipenem , Humanos , Meropenem/farmacología , Imipenem/farmacología , Vigilancia en Salud Pública , Proteínas Bacterianas/genética , beta-Lactamasas/genética , Cefmetazol , Escherichia coli , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacologíaRESUMEN
BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.
Asunto(s)
Puntuaciones en la Disfunción de Órganos , Sepsis , Humanos , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Meropenem , Pronóstico , Antibacterianos , Servicio de Urgencia en Hospital , Mortalidad Hospitalaria , Curva ROC , Estudios RetrospectivosRESUMEN
AIMS: Antibiotic management of infections caused by Acinetobacter baumannii often fails due to antibiotic resistance (especially to carbapenems) and biofilm-forming strains. Thus, the objective here was to evaluate in vitro the antibacterial and antibiofilm activity of biogenic silver nanoparticle (Bio-AgNP) combined with meropenem, against multidrug-resistant isolates of A. baumannii. METHODS AND RESULTS: In this study, A. baumannii ATCC® 19606™ and four carbapenem-resistant A. baumannii (Ab) strains were used. The antibacterial activity of Bio-AgNP and meropenem was evaluated through broth microdilution. The effect of the Bio-AgNP association with meropenem was determined by the checkboard method. Also, the time-kill assay and the integrity of the bacterial cell membrane were evaluated. Furthermore, the antibiofilm activity of Bio-AgNP and meropenem alone and in combination was determined. Bio-AgNP has antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration ranging from 0.46 to 1.87 µg ml-1. The combination of Bio-AgNP and meropenem showed a synergistic and additive effect against Ab strains, and Bio-AgNP was able to reduce the MIC of meropenem from 4- to 8-fold. Considering the time-kill of the cell, meropenem and Bio-AgNP when used in combination reduced bacterial load to undetectable levels within 10 min to 24 h after treatment. Protein leakage was observed in all treatments evaluated. When combined, meropenem/Bio-AgNP presents biofilm inhibition for Ab2 isolate and ATCC® 19606™, with 21% and 19%, and disrupts the biofilm from 22% to 50%, respectively. The increase in nonviable cells in the biofilm can be observed after treatment with Bio-AgNP and meropenem in carbapenem-resistant A. baumannii strains. CONCLUSIONS: The combination of Bio-AgNP with meropenem can be a therapeutic option in the treatment of infections caused by carbapenem-resistant A. baumannii.