Among hospitalized adults who received vancomycin for their skin and skin structure infection (SSSI), patients who experienced acute kidney injury (AKI) had considerably higher 30-day readmission ...rates. Nearly half of the observed 30-day readmissions were due to non-SSSI-related reasons, which is consistent with the persistent organ dysfunction observed among patients with AKI.
Vancomycin: We Can't Get There From Here Patel, Nimish; Pai, Manjunath P.; Rodvold, Keith A. ...
Clinical infectious diseases,
04/2011, Letnik:
52, Številka:
8
Journal Article
Recenzirano
Background. We sought to characterize the pharmacodynamic profile of the more intensive vancomycin dosing regimens currently used in response to the recent vancomycin guidelines. Methods. A series of ...Monte Carlo simulations was performed for vancomycin regimens ranging from .5 g intravenous (IV) Q12H to 2 g IV Q12H. The probability of achieving an AUC/MIC ratio ≥ 400 for each dosing regimen was calculated for minimum inhibitory concentrations (MICs) from .5 to 2 mg/L. The risk of nephrotoxicity for each regimen was derived from a previously published vancomycin trough-nephrotoxicity logistic regression function. Restricted analyses were performed that only included subjects with troughs between 15 and 20 mg/L. Results. At a MIC of 2 mg/L, even the most aggressive dosing regimen considered (2 g every 12 h) only yielded a probability of target attainment (PTA) of 57% while generating a nephrotoxicity probability upward of 35%. At a MIC of 1 mg/L, ≥3 g per day provided PTA in excess of 80% but were associated with unacceptable risks of nephrotoxicity. In the restricted analyses of subjects with troughs between 15 and 20 mg/L, all regimens produced a PTA of 100% at MICs ≤1 mg/L. The PTA was variable among the regimens at a MIC of 2 mg/L and was highly dependent on the total daily dose administered. Conclusions. This study indicates that vancomycin may not be useful for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC values > 1 mg/L where PTA is questionable. Since an AUC/MIC ratio ≥ 400 is target associated with efficacy, one should consider incorporating computation of AUC when monitoring vancomycin.
Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such ...as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan-specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm(3)) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm(3) (-5.9%), <112,500 cells/mm(3) (-2.4%), and <100,000 cells/mm(3) (-1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.).
Abstract
Background
Empirical models to predict β-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill ...patients; however, no such models exist for patients with cystic fibrosis (CF).
Objectives
To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin.
Methods
A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis–Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions.
Results
Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27–32) years, 51.4 (49.9–55.8) kg, 162.6 (160.0–165.1) cm and 0.6 (0.5–0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin.
Conclusions
A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.
Infections caused by methicillin‐resistant Staphylococcus aureus (MRSA) are a major public concern. Hospital‐acquired MRSA rates have steadily increased over the past 25 years, and the bacterial ...strain is making inroads to the community. The morbidity and mortality burden of MRSA infection is compounded by delayed or inappropriate antibiotic treatment, taking a toll on health care resources that are already stretched thin. Vancomycin has historically been the drug of choice for this pathogen because its broad spectrum can address the multidrug resistance of most MRSA infections. Despite its sustained in vitro microbiologic inhibitory activity, researchers are beginning to question the continued utility of vancomycin for MRSA infections. Evidence against vancomycin is most notable with regard to nosocomial pneumonia and skin and soft tissue infections. In addition, because vancomycin must be administered intravenously, patients typically require prolonged hospitalization, which further increases the cost of MRSA treatment and exposes patients to additional nosocomial infections. Recent studies have shown that antibiotics with good bioavailability, such as linezolid, can be given orally to facilitate early hospital discharge, thus alleviating the economic burden of MRSA infections. Several agents have been developed over the past decade that have excellent in vitro activity against MRSA. Further studies are needed to determine if these drugs can better eradicate MRSA than vancomycin and remedy the adverse outcomes frequently observed with this organism.
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.
To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly obese and nonobese subjects.
We performed a nonparametric population ...pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and nonobese kidney function-matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (C
), minimum concentrations (C
), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500-mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin C
target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens.
No significant differences were observed in clearance, volume of distribution at steady state, or terminal half-life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, C
, and C
values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a C
target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage.
Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.
Abstract The recent emergence and spread of infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are concerning because carbapenems have represented a last line of defense against ...resistant strains of gram-negative pathogens. Existing therapies against CRE include tigecycline, the recently approved drug ceftazidime-avibactam, and older drugs not widely used in recent years, such as colistin, fosfomycin, and aminoglycosides. Best practices for use of the available drugs are not well defined. New therapeutic options with activity against CRE offer the opportunity to enhance our current approach to managing patients with infections due to CRE. The purpose of this report is to review the evolving epidemiology and treatment of infections due to CRE. As part of the treatment overview, this manuscript will discuss supportive data for antibiotics currently being used in the treatment of infections due to CRE, as well as those recently approved and in late-stage development.
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