Explore the vast range of titles available.

Background. Data suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity. Methods. A retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were ⩾18 years old, (2) had an absolute neutrophil count of ⩾1000 cells/mm3, (3) received vancomycin for >48 h, (4) had ⩾1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of <2.0 mg/dL. Patients were excluded if they (1) had a diagnosis of cystic fibrosis, (2) received intravenous contrast dye within 7 days of starting vancomycin or during therapy, or (3) required vasopressor support during therapy. Demographics, comorbid conditions, and treatment data were collected. The highest observed vancomycin trough value within 96 h of initiation of vancomycin therapy and the estimated vancomycin AUC were analyzed as measures of vancomycin exposure. The vancomycin AUC value from 0 to 24 h at steady state (in units of mg × h/L) for each patient was estimated by use of the maximum a posteriori probability Bayesian procedure in ADAPT II. Nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dL or 50%, whichever was greater, following initiation of vancomycin therapy. Logistic and Cox proportional hazards regression models identified the vancomycin pharmacodynamic index that best describes the relationship between vancomycin exposure and toxicity. Results. During the study period, 166 patients met the inclusion criteria. Both initial vancomycin trough values and 0–24-h at steady state AUC values were associated with nephrotoxicity in the bivariate analyses. However, the vancomycin trough value, modeled as a continuous variable, was the only vancomycin exposure variable associated with nephrotoxicity in the multivariate analyses. Conclusions. The results indicate that a vancomycin exposure-toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association.

New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Shionogi.

Background.Piperacillin-tazobactam is frequently used to treat Pseudomonas aeruginosa infections in critically ill patients. In an effort to improve clinical outcomes, an extended-infusion dosing scheme for piperacillin-tazobactam therapy was devised using a Monte Carlo simulation and was adopted into clinical practice at Albany Medical Center (Albany, New York). This study evaluates the clinical implications of extended infusion of piperacillin-tazobactam therapy for critically ill patients with P. aeruginosa infection. Methods.We performed a cohort study of patients who received piperacillin-tazobactam therapy for a P. aeruginosa infection that was susceptible to piperacillin-tazobactam during the period January 2000–June 2004. Prior to February 2002, all patients received intermittent infusions of piperacillin-tazobactam (3.375 g intravenously for 30 min every 4 or 6 h); after this time, all patients received extended infusions of piperacillin-tazobactam (3.375 g intravenously for 4 h every 8 h). Data on demographic characteristics, disease severity, and microbiology were collected, and outcomes were compared between groups. Results.A total of 194 patients comprised the 2 study groups: 102 patients received extended infusions of piperacillin-tazobactam, and 92 patients received intermittent infusions of piperacillin-tazobactam. No differences in baseline clinical characteristics were noted between the 2 groups. Among patients with Acute Physiological and Chronic Health Evaluation-II scores ⩾17, 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2% vs. 31.6%, respectively; P = .04), and median duration of hospital stay after collection of samples for culture was significantly shorter for patients who received extended-infusion therapy than for patients who received intermittent-infusion therapy (21 days vs. 38 days; P = .02). Conclusions.These results indicate that extended-infusion piperacillin-tazobactam therapy is a suitable alternative to intermittent-infusion piperacillin-tazobactam therapy, and they strongly suggest that improved outcomes may be realized by administering extended-infusion piperacillin-tazobactam therapy to critically ill patients with P. aeruginosa infection.

Background Epidemiological data for United States (US) hospitals regarding the burden of Acinetobacter baumannii and carbapenem-resistant A. baumannii (CRAB) are scarce; thus, this study aimed to describe the incidence of A. baumannii and CRAB across US hospitals between January 1, 2018 and December 31, 2022. Methods This was a retrospective cohort study of hospitalized patients with microbiology data from the PINC AI™ Database. Incidence rates of A. baumannii and CRAB (January 1, 2018 – December 31, 2022) were determined across US hospitals in each census region. Incidence rates of A. baumannii and CRAB were determined at the hospitalization encounter and individual levels. Presence of CRAB was based on non-susceptibility to either doripenem, imipenem, or meropenem. Patient demographics, comorbidities, outcomes, including in-hospital mortality, were compared between patients with CRAB and carbapenem-susceptible A. baumannii (CSAB) at the hospitalization encounter level. Results During the study period, 7,270 hospitalization encounters with ≥ 1 A. baumannii clinical cultures were identified. The overall A. baumannii incidence rate was 1.19 cases per 100 hospitalization encounters and 1.33 cases per 100 unique patients. For CRAB, a total of 2,708 hospitalization encounters were identified, and incidence rate was 0.44 cases per 100 hospitalization encounters. The West South Central, East North Central, and East South Central regions had the highest CRAB incidence rates (0.78, 0.67, and 0.63 cases per 100 hospitalization encounters, respectively). Compared with CSAB, patients with CRAB had significantly more positive cultures with A. baumannii (20.9% vs. 10.0%, respectively, P  < 0.0001) and higher prevalence of other Gram-negative pathogens in any clinical culture site within ± 3 days of the index A. baumannii clinical culture (47.2% vs. 42.9%, respectively, P  = 0.0004). Patients with CRAB had higher incidences of in-hospital mortality vs. patients with CSAB (20.5% vs. 11.3%, respectively, P  < 0.0001). Conclusions Presence of A. baumannii was identified on a clinical culture in 1% of adult hospitalizations in this multicenter US study. Over a third of A. baumannii hospitalization encounters were CRAB, with the highest incidence rates per 100 hospitalization encounters observed in the most central US regions. Clinicians should consider A. baumannii as a potential pathogen in patients in regions with an increasing incidence rate of A. baumannii .

Background. Contemporary vancomycin dosing schemes are designed to achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio of ≥400. However, scant clinical data exist to support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs. Methods. A cohort study of hospitalized, adult, nondialysis patients with methicillin-resistant Staphylococcus aureus bloodstream infections treated with vancomycin was performed to quantitatively evaluate the relationship between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure profile for day 1 and 2 of therapy for each patient based on their dosing schedule and collected concentrations. Classification and Regression Tree (CART) analysis was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure. Failure was defined as 30-day mortality, bacteremia was ≥7 days, or recurrence. Results. During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART-derived day 1 and 2 thresholds for AUC/MIC by broth microdilution and AUC/MIC by Etest. In the multivariate analyses, all risk ratios were approximately 0.5 for all CART-derived AUC/MIC exposure thresholds, indicating that achievement of CART-derived AUC/MIC exposure thresholds was associated with a 2-fold decrease in failure. Conclusions. These findings establish the critical importance of daily AUC/MIC ratios during the first 2 days of therapy. As with all observational studies, these findings should be interpreted cautiously and validated in a multicenter randomized trial before adoption into practice.

We aimed to determine if available evidence from a previously conducted systematic literature review was sufficient to conduct a robust network meta-analysis (NMA) using the International Society for Pharmacoeconomics and Outcomes Research Good Practice Task Force NMA study questionnaire to evaluate suitability, relevance, and credibility of available randomized-controlled trials (RCT) of antibacterial therapies for treatment of patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). We assessed feasibility and reliability of an NMA for a connected network of RCTs, and then relevance and credibility of the connected network for informing decision-making. This previously conducted systematic literature review using Cochrane dual-reviewer methodology, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and PICOTS (population, interventions, comparators, outcomes, timing, and setting) criteria identified 25 citations between 2001 and 2018; 18 were unique RCTs. Trial design characteristics, outcome definitions, assessment time points, and analyses populations varied across studies. Using “clinical response,” an efficacy end point to health technology assessment agencies, we assessed potential network credibility, which collapsed from the overall data set to four studies and five interventions. This did not include closed loop(s) needed to assess consistency. Of the studies reporting clinical response, >70% of patients were ventilated at baseline with mean Acute Physiologic Assessment and Chronic Health Evaluation II scores from 14.7 to 17.5. Pseudomonas aeruginosa (range, 18.4–64.1%) and Klebsiella spp. (range, 1.6–49%) were the most common causative pathogens. We identified relevant RCTs for most standard-of-care agents approved for HABP/VABP, which provided a comprehensive evidence base. In summary, our appraisal of available evidence for the clinical response outcome among adult patients with HABP/VABP does not support the conduct of a scientifically robust and clinically meaningful NMA. Although this data is vital to registration, there are significant limitations in these trials for health technology assessments, payor decisions, guidelines, and protocol decisions.

The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration. Ceftazidime–avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate. Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime–avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments. Ceftazidime–avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.

Background Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described. Methods A systematic literature review and meta-analysis was performed to examine this relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections. Results Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting [C& SR]), there was an increased risk of mortality (odds ratio [OR], 1.60 [95% CI, 1.25–2.50]). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 [95% CI, 1.27–2.44]). Conclusions Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli .

Background We developed a clinical bedside tool to simultaneously estimate the probabilities of third-generation cephalosporin-resistant Enterobacteriaceae (3GC-R), carbapenem-resistant Enterobacteriaceae (CRE), and multidrug-resistant Pseudomonas aeruginosa (MDRP) among hospitalized adult patients with Gram-negative infections. Methods Data were obtained from a retrospective observational study of the Premier Hospital that included hospitalized adult patients with a complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP), or bloodstream infection (BSI) due to Gram-negative bacteria between 2011 and 2015. Risk factors for 3GC-R, CRE, and MDRP were ascertained by multivariate logistic regression, and separate models were developed for patients with community-acquired versus hospital-acquired infections for each resistance phenotype ( N  = 6). Models were converted to a singular user-friendly interface to estimate the probabilities of a patient having an infection due to 3GC-R, CRE, or MDRP when ≥ 1 risk factor was present. Results Overall, 124,068 patients contributed to the dataset. Percentages of patients admitted for cUTI, cIAI, HAP/VAP, and BSI were 61.6, 4.6, 16.5, and 26.4%, respectively (some patients contributed > 1 infection type). Resistant infection rates were 1.90% for CRE, 12.09% for 3GC-R, and 3.91% for MDRP. A greater percentage of the resistant infections were community-acquired relative to hospital-acquired (CRE, 1.30% vs 0.62% of 1.90%; 3GC-R, 9.27% vs 3.42% of 12.09%; MDRP, 2.39% vs 1.59% of 3.91%). The most important predictors of having an 3GC-R, CRE or MDRP infection were prior number of antibiotics; infection site; infection during the previous 3 months; and hospital prevalence of 3GC-R, CRE, or MDRP. To enable application of the six predictive multivariate logistic regression models to real-world clinical practice, we developed a user-friendly interface that estimates the risk of 3GC-R, CRE, and MDRP simultaneously in a given patient with a Gram-negative infection based on their risk (Additional file 1). Conclusions We developed a clinical prediction tool to estimate the probabilities of 3GC-R, CRE, and MDRP among hospitalized adult patients with confirmed community- and hospital-acquired Gram-negative infections. Our predictive model has been implemented as a user-friendly bedside tool for use by clinicians/healthcare professionals to predict the probability of resistant infections in individual patients, to guide early appropriate therapy.

Acinetobacter meningitis is becoming an increasingly common clinical entity, especially in the postneurosurgical setting, with mortality from this infection exceeding 15%. Infectious Diseases Society of America guidelines for therapy of postneurosurgical meningitis recommend either ceftazidime or cefepime as empirical coverage against Gram-negative pathogens. However, assessment of the pharmacodynamics of these cephalosporins in cerebrospinal fluid suggests that recommended doses will achieve pharmacodynamic targets against fewer than 10% of contemporary acinetobacter isolates. Thus, these antibiotics are poor options for suspected acinetobacter meningitis. From in vitro and pharmacodynamic perspectives, intravenous meropenem plus intraventricular administration of an aminoglycoside may represent a superior, albeit imperfect, regimen for suspected acinetobacter meningitis. For cases of meningitis due to carbapenem-resistant acinetobacter, use of tigecycline is not recommended on pharmacodynamic grounds. The greatest clinical experience rests with use of polymyxins, although an intravenous polymyxin alone is inadvisable. Combination with an intraventricularly administered antibiotic plus removal of infected neurosurgical hardware appears the therapeutic strategy most likely to succeed in this situation. Unfortunately, limited development of new antibiotics plus the growing threat of multidrug-resistant acinetobacter is likely to increase the problems posed by acinetobacter meningitis in the future.