Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?

We are rapidly approaching a crisis in antibiotic resistance, particularly among Gram-negative pathogens. This, coupled with the slow development of novel antimicrobial agents, underscores the exigency of redeploying existing antimicrobial agents in innovative ways. One therapeutic approach that was heavily studied in the 1980s but abandoned over time is dual beta-lactam therapy.

Relationship between time to clinical response and outcomes among Pneumonia Outcomes Research Team (PORT) risk class III and IV hospitalized patients with community-acquired pneumonia who received ceftriaxone and azithromycin.

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP.

Pharmacokinetics and pharmacodynamics of once-daily administration of intravenous tobramycin in adult patients with cystic fibrosis hospitalized for an acute pulmonary exacerbation.

The serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation.

Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with cystic fibrosis-related acute pulmonary exacerbations.

Objectives: Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agent's pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations.

Daptomycin pharmacokinetics and pharmacodynamics in a pooled sample of patients receiving thrice-weekly hemodialysis.

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG.

The utility of acute physiology and chronic health evaluation II scores for prediction of mortality among intensive care unit (ICU) and non-ICU patients with methicillin-resistant Staphylococcus aureus bacteremia.

Objective: Bloodstream infections due to methicillin-resistant Staphylococcus aureus (MRSA) have been associated with significant risk of in-hospital mortality. The acute physiology and chronic health evaluation (APACHE) II score was developed and validated for use among intensive care unit (ICU) patients, but its utility among non-ICU patients is unknown. The aim of this study was to determine the ability of APACHE II to predict death at multiple time points among ICU and non-ICU patients with MRSA bacteremia.

Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data.

Objectives And Methods: The present study's objective was to evaluate serotonin toxicity with concomitant use of linezolid or comparators and serotonergic agents from 20 Phase III and IV comparator-controlled clinical studies on treatment of various Gram-positive infections. All reported adverse events were evaluated for serotonin toxicity using exact and surrogate terms consistent with Sternbach Criteria and Hunter Serotonin Toxicity Criteria.

Results: Baseline demographics and co-morbidities were similar between linezolid and comparator groups.

Predictors of agr dysfunction in methicillin-resistant Staphylococcus aureus (MRSA) isolates among patients with MRSA bloodstream infections.

Despite emerging evidence that dysfunction in the accessory gene regulator (agr) locus is associated with deleterious outcomes among patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections, factors predictive of agr dysfunction have not been evaluated. This study describes the epidemiology of agr dysfunction, identifies predictors of agr dysfunction in MRSA isolates among those with MRSA bloodstream infections, and describes the relationship between agr dysfunction and other microbiologic phenotypes. A cross-sectional study of patients with MRSA bloodstream infections at two institutions in upstate New York was performed.

Penetration of vancomycin into epithelial lining fluid in healthy volunteers.

Although vancomycin is often regarded as an agent that concentrates poorly in the lower respiratory tract, as determined from concentrations in epithelial lining fluid (ELF), few data are available. This study sought to determine the profile of vancomycin exposure in the ELF relative to plasma. Population modeling and Monte Carlo simulation were employed to estimate the penetration of vancomycin into ELF.

Refining vancomycin protein binding estimates: identification of clinical factors that influence protein binding.

While current data indicate only free (unbound) drug is pharmacologically active and is most predictive of response, pharmacodynamic studies of vancomycin have been limited to measurement of total concentrations. The protein binding of vancomycin is thought to be approximately 50%, but considerable variability surrounds this estimate. The present study sought to determine the extent of vancomycin protein binding, to identify factors that modulate its binding, and to create and validate a prediction tool to estimate the extent of protein binding based on individual clinical factors.

Use of pharmacodynamic principles to inform β-lactam dosing: "S" does not always mean success.

Dose optimization is one of the key strategies for enhancing antimicrobial stewardship. There have been tremendous strides in our understanding of antibiotic exposure-response relationships over the past 25 years. For many antibiotics, the "pharmacodynamic" or the exposure variable associated with outcome has been identified.