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.
Abstract
Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus ...guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400–600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.
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.
The delivery of personalized antimicrobial therapy is a critical component in the treatment of patients with invasive infections. Vancomycin, the drug of choice for infections due to ...methicillin-resistant Staphylococcus aureus, requires the use of therapeutic drug monitoring (TDM) for delivery of optimal therapy. Current guidance on vancomycin TDM includes the measurement of a trough concentration as a surrogate for achieving an AUC to minimum inhibitory concentration (MIC) by broth microdilution (AUC/MICBMD) ratio ≥400. Although trough-only monitoring has been widely integrated into clinical practice, there is a high degree of inter-individual variability between a measured trough concentration and the actual AUC value. The therapeutic discordance between AUC and trough may lead to suboptimal outcomes among patients with infections due to less susceptible pathogens or unnecessarily increase the probability of acute kidney injury (AKI) in others. Given the potentially narrow vancomycin AUC range for optimal effect and minimal AKI, clinicians need a “real-time” system to predict accurately the AUC with limited pharmacokinetic (PK) sampling. This article reviews two innovative approaches for calculating the vancomycin AUC in clinical practice based on one or two drug concentrations. One such approach involves the use of Bayesian computer software programs to estimate the “true” vancomycin AUC value with minimal PK sampling and provide AUC-guided dosing recommendations at the bedside. An alternative involves use of two concentrations (peak and trough) and simple analytic equations to estimate AUC values. Both approaches provide considerable improvements over the current trough-only concentration monitoring method.
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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.
Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel β-lactam/β-lactamase inhibitor combination with expanded microbiologic activity against carbapenem-resistant non-
(CR-NME) and ...difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibition of many Ambler class A and class C enzymes. It is currently approved for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) and those with complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alternative treatments are available. Given the number of recently approved β-lactams with expanded activity against highly resistant Gram-negative pathogens, this review summarizes the published literature on I/R, with a focus on its similar and distinguishing characteristics relative to those of other recently approved agents. Overall, available data support its use for the treatment of patients with HABP/VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R retains some activity against CR-NME and DTR P. aeruginosa isolates that are resistant to the newer β-lactams and vice versa, suggesting that susceptibility testing be performed for all the newer agents to determine optimal treatment options for patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD and clinical studies are warranted to determine the optimal role of I/R, alone and in combination, for the treatment of patients with highly resistant Gram-negative infections. Until further data are available, I/R is a potential treatment for patients with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the risks.
Fluoroquinolone antibiotics recently have gained increased national attention due to safety concerns. A well-described and serious adverse event associated with receipt of fluoroquinolones is ...tendinitis and tendon rupture. These tendon injuries can result in long-term sequelae, including chronic pain and mobility restrictions, and may warrant surgery. Due to the severity of these adverse events, a black box warning is included in the product labeling of all fluoroquinolones. In light of the mounting concerns surrounding fluoroquinolone-associated toxicities, the purpose of this clinical review is to provide a comprehensive summary of the risk of tendinopathy associated with levofloxacin, one of the most widely prescribed antibiotics in the United States, across in vitro, animal, and clinical studies, relative to other antibiotics. As part of this review, clinical presentation and onset, proposed mechanisms, patient-specific risk factors, and management of fluoroquinolone-induced tendon injury are summarized. Data were obtained from a comprehensive PubMed literature search and a review of U.S. Food and Drug Administration documents. Although tendinopathy is considered a fluoroquinolone class-wide toxicity, data from in vitro studies, animal studies, patient-level analyses, and large national and international surveillance reports suggest that levofloxacin, as well as its parent compound ofloxacin, possess higher propensities to cause tendon damage relative to other fluoroquinolones. Risk with ofloxacin and levofloxacin appears to be exposure dependent, with higher doses and longer durations being most commonly associated with tendinopathy. Other well-described patient risk factors for fluoroquinolone-associated tendinopathy include older age (older than 60 yrs), receipt of concomitant corticosteroid therapy, presence of renal dysfunction, and history of solid organ transplantation. Given widespread use of levofloxacin across patient care settings, knowledge of both patient- and drug-specific characteristics associated with increased risk of tendinitis and tendon rupture can promote safe use of levofloxacin and other fluoroquinolones.
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