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The in vitro susceptibility testing interpretive criteria (STIC) for TZP against Enterobacterales were recently updated by the Food and Drug Administration (FDA), Clinical & Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). The United States Committee on Antimicrobial Susceptibility Testing (USCAST) also recently reviewed TZP STIC for Enterobacterales and arrived at different STIC for Enterobacterales and herein we explain our recommendations and rationale behind them. Based on our review of the available data, USCAST does not recommend TZP STIC for certain Enterobacterales species that have a moderate to high likelihood of clinically significant AmpC production (E. cloacae, C. freundii, and K. aerogenes only) or for third-generation cephalosporin-non-susceptible (3GC-NS) Enterobacterales. USCAST recommends a TZP susceptibility breakpoint of ≤ 16/4 mg/L for third-generation cephalosporin-susceptible (3GC-S) Enterobacterales but only endorses the use of extended infusion TZP regimens for patients with infections due to these pathogens.
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Among consecutive patients with multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia we found those treated with ceftazidime-avibactam were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with ceftolozane-tazobactam (40% vs. 10%; P=0.002). Ceftazidime-avibactam resistance was associated with new mutations in ampC and efflux regulatory pathways.
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We report identification of 5 patients with infections caused by NDM-5-producing E. coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane ß-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.
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OBJECTIVES: To assess risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR) and extended-ß-lactam-resistant P. aeruginosa (EBR) infection/colonization, and to develop and compare tools for predicting isolation of CR and EBR from clinical cultures. METHODS: This retrospective study analysed hospitalized patients with positive P. aeruginosa cultures between 2015 and 2021. Two case-control analyses were performed to identify risk factors and develop scoring tools for distinguishing patients with CR versus carbapenem-susceptible (CS) P. aeruginosa and EBR versus CS P. aeruginosa. The performance of institutionally derived scores, externally derived scores and the presence/absence of key risk factors to predict CR and EBR were then compared. RESULTS: A total of 2379 patients were included. Of these, 8.3% had a positive culture for CR, 5.0% for EBR and 86.7% for CS P. aeruginosa. There was substantial overlap in risk factors for CR and EBR. Institutional risk scores demonstrated modestly higher area under the ROC curve values than external scores for predicting CR (0.67 versus 0.58) and EBR (0.76 versus 0.70). Assessing the presence/absence of ≥1 of the two strongest predictors (prior carbapenem use or CR isolation within 90â days) was slightly inferior to scoring tools for predicting CR, and comparable for predicting EBR. CONCLUSIONS: Clinicians concerned about CR in P. aeruginosa should consider the likelihood of EBR when making treatment decisions. A simple approach of assessing recent history of CR isolation or carbapenem usage performed similarly to more complex scoring tools and offers a more pragmatic way of identifying patients who require coverage for resistant P. aeruginosa.
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Antibacterianos , Carbapenémicos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Resistencia betalactámica , Humanos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/tratamiento farmacológico , Estudios Retrospectivos , Carbapenémicos/farmacología , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Antibacterianos/farmacología , Anciano , Estudios de Casos y Controles , Adulto , Pruebas de Sensibilidad Microbiana , beta-Lactamas/farmacologíaRESUMEN
BACKGROUND: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. OBJECTIVES: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. RESULTS: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. CONCLUSIONS: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.
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Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Fosfomicina , Infecciones por Bacterias Gramnegativas , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Humanos , Fosfomicina/farmacocinética , Fosfomicina/administración & dosificación , Fosfomicina/farmacología , Fosfomicina/efectos adversos , Femenino , Masculino , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Persona de Mediana Edad , Anciano , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Adulto , Klebsiella pneumoniae/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Anciano de 80 o más Años , Administración Intravenosa , Método de Montecarlo , Espectrometría de Masas en Tándem , Bacterias Gramnegativas/efectos de los fármacosRESUMEN
Observational data published over the past decade have suggested that concomitant receipt of piperacillin-tazobactam with vancomycin significantly increases the risk for vancomycin-associated acute kidney injury. Importantly, however, there is significant controversy surrounding this association, and debate continues about the veracity of the risk. Given this ongoing debate, the recently published "Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial" is of tremendous interest to the infectious diseases community. In ACORN, the authors conclude that there was no association between receipt of cefepime or piperacillin-tazobactam and the primary outcome of acute kidney injury or death by day 14, despite the fact that >75% of the population received concomitant vancomycin. In this perspective, we provide a brief history on the controversy, provide a critical analysis of the ACORN findings, and ultimately discuss how these data help inform the ongoing debate.
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Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.
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Antiinfecciosos , Neumonía Asociada a la Atención Médica , Neumonía Bacteriana , Infecciones por Pseudomonas , Humanos , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Neumonía Asociada a la Atención Médica/tratamiento farmacológico , Hospitales , Meropenem/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Pseudomonas aeruginosa , Infecciones por Pseudomonas/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
In the past decade, the prevalence of multidrug-resistant gram-negative (MDR-GN) bacterial infections has increased significantly, leading to higher rates of morbidity and mortality. Treating these infections poses numerous challenges, particularly when selecting appropriate empiric therapy for critically ill patients for whom the margin for error is low. Fortunately, the availability of new therapies has improved the treatment landscape, offering safer and more effective options. However, there remains a need to establish and implement optimal clinical and therapeutic approaches for managing these infections. Here, we review strategies for identifying patients at risk for MDR-GN infections, propose a framework for the choice of empiric and definitive treatment, and explore effective multidisciplinary approaches to managing patients in the hospital while ensuring a safe transition to outpatient settings.
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Antibacterianos , Infecciones por Bacterias Gramnegativas , Humanos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , HospitalesRESUMEN
BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).
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Infections caused by extensively drug-resistant Pseudomonas aeruginosa are difficult to treat due to limited effective treatment options. In this issue, a patient with a corneal infection caused by a Verona integron-encoded metallo-ß-lactamase (VIM)- and Guiana extended-spectrum ß-lactamase (GES)-coproducing P. aeruginosa strain associated with the recent artificial tears-related outbreak in the United States is described. This resistance genotype/phenotype further compromises therapeutic options, and this report provides insights into diagnostic and treatment approaches for clinicians dealing with infections due to this highly resistant P. aeruginosa.
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Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Pseudomonas aeruginosa/genética , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/epidemiología , beta-Lactamasas/genética , beta-Lactamasas/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVES: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients. METHODS: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA). RESULTS: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower. DISCUSSION: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.
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Hemodiafiltración , Polimixina B , Humanos , Polimixina B/uso terapéutico , Antibacterianos , Hemodiafiltración/métodos , Cromatografía Liquida , Estudios Prospectivos , Creatinina , Espectrometría de Masas en Tándem , Enfermedad Crítica , Pruebas de Sensibilidad MicrobianaRESUMEN
Background: Administration of doses via an extended infusion (EI) is an important strategy to optimize beta-lactams. Available data on the impact of EI on outcomes largely focus on clinical cure or mortality in critically ill patients or those with resistant pathogens. The potential benefits of EI extend beyond these populations and outcomes, and further study is warranted. Methods: This was a retrospective cohort study of adult patients who received cefepime, piperacillin/tazobactam, or meropenem for Gram-negative bacteremia via EI or intermittent infusion. Patients were matched 1:1 based on study drug, sepsis severity, intensive care unit (ICU) status, bacteremia source, and pathogen. Outcomes assessed included time to clinical stabilization, rates of treatment failure, mortality, recurrence, and length of stay (LOS). Results: Two hundred sixty-eight patients were included. Baseline characteristics were similar between groups. Forty-two percent of patients were in the ICU at infection onset and the most common pathogen was Escherichia coli (41%). After adjusting for residual differences between groups, receipt of EI was independently associated with shorter time to clinical stability (adjusted odds ratio, 0.32; 95% confidence interval, .22-.47), time to defervescence, and time to white blood cell count normalization. Furthermore, EI was associated with a lower incidence of treatment failure, decreased recurrence of bacteremia, and shorter LOS. There was no difference in mortality. These findings were consistent regardless of patient location (ICU vs ward), baseline renal function, source of bacteremia, or study drug received. Conclusions: These findings suggest that EI beta-lactams are an important stewardship strategy to improve clinical outcomes in patients with Gram-negative bacteremia.
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Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections. Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine- and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases-the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections.
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Recommended antimicrobial treatment durations for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa have evolved over the past few decades. In this Viewpoint, we provide a narrative review of landmark trials investigating antimicrobial treatment durations for VAP caused by P. aeruginosa, and appraise iterations of expert consensus guidelines based on these data. We highlight strengths and weaknesses of existing data on this topic and provide recommendations for future avenues of study.
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Neumonía Asociada al Ventilador , Humanos , Neumonía Asociada al Ventilador/tratamiento farmacológico , Antibacterianos/uso terapéutico , Pseudomonas aeruginosa , Esquema de MedicaciónRESUMEN
Although pharmacists are key members of the healthcare team, they are currently ineligible to independently prescribe the oral coronavirus disease 2019 (COVID-19) antivirals. We report the roles pharmacists have undertaken during the COVID-19 pandemic and provide evidence for the support of independent oral COVID-19 antiviral prescribing.
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Importance: Some experts have cautioned that national and health system emphasis on rapid administration of antimicrobials for sepsis may increase overall antimicrobial use even among patients without sepsis. Objective: To assess whether temporal changes in antimicrobial timing for sepsis are associated with increasing antimicrobial use, days of therapy, or broadness of antimicrobial coverage among all hospitalized patients at risk for sepsis. Design, Setting, and Participants: This is an observational cohort study of hospitalized patients at 152 hospitals in 2 health care systems during 2013 to 2018, admitted via the emergency department with 2 or more systemic inflammatory response syndrome (SIRS) criteria. Data analysis was performed from June 10, 2021, to March 22, 2022. Exposures: Hospital-level temporal trends in time to first antimicrobial administration. Outcomes: Antimicrobial outcomes included antimicrobial use, days of therapy, and broadness of antibacterial coverage. Clinical outcomes included in-hospital mortality, 30-day mortality, length of hospitalization, and new multidrug-resistant (MDR) organism culture positivity. Results: Among 1â¯559â¯523 patients admitted to the hospital via the emergency department with 2 or more SIRS criteria (1â¯269â¯998 male patients [81.4%]; median [IQR] age, 67 [59-77] years), 273â¯255 (17.5%) met objective criteria for sepsis. In multivariable models adjusted for patient characteristics, the adjusted median (IQR) time to first antimicrobial administration to patients with sepsis decreased by 37 minutes, from 4.7 (4.1-5.3) hours in 2013 to 3.9 (3.6-4.4) hours in 2018, although the slope of decrease varied across hospitals. During the same period, antimicrobial use within 48 hours, days of antimicrobial therapy, and receipt of broad-spectrum coverage decreased among the broader cohort of patients with SIRS. In-hospital mortality, 30-day mortality, length of hospitalization, new MDR culture positivity, and new MDR blood culture positivity decreased over the study period among both patients with sepsis and those with SIRS. When examining hospital-specific trends, decreases in antimicrobial use, days of therapy, and broadness of antibacterial coverage for patients with SIRS did not differ by hospital antimicrobial timing trend for sepsis. Overall, there was no evidence that accelerating antimicrobial timing for sepsis was associated with increasing antimicrobial use or impaired antimicrobial stewardship. Conclusions and Relevance: In this multihospital cohort study, the time to first antimicrobial for sepsis decreased over time, but this trend was not associated with increasing antimicrobial use, days of therapy, or broadness of antimicrobial coverage among the broader population at-risk for sepsis, which suggests that shortening the time to antibiotics for sepsis is feasible without leading to indiscriminate antimicrobial use.