Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure.

Non-compartmental analysis of telavancin microdialysis data indicated a sustained exposure in soft tissues and that unbound plasma concentrations were underestimated in vitro. The objective of the present evaluation was to develop a population pharmacokinetic model of telavancin to describe its plasma protein binding, its distribution into muscle, and subcutaneous tissue and to predict pharmacokinetic/-dynamic target attainment (PTA). Total plasma concentrations and microdialysate concentrations (plasma, subcutaneous, and muscle tissue) were available up to 24 h (plasma microdialysate, up to 8 h) post-dose from eight healthy subjects after a single intravenous infusion of 10 mg/kg telavancin. Population pharmacokinetic modeling and simulations were performed using NONMEM. A two-compartment model with saturable protein binding best described plasma concentrations. Plasma unbound fractions at steady state were 23, 15, and 11% at 100, 50, and 10% of the maximum predicted concentrations respectively. Distribution into muscle and subcutaneous tissue was non-linear and described appropriately by one additional compartment each. Based on total plasma concentrations, predicted median (95% confidence interval) values of AUC/MIC (MIC 0.125 mg/L, clinical breakpoint for MRSA) at steady state were 4009 [3421-4619] with a PTA of 96 [78-100] %. The fAUC/MIC in muscle was 496 [227-1232] with a PTA of 100 [98-100] %. The %fT>MIC was approximately 100% in plasma and interstitial space fluid of muscle and subcutaneous tissues up to an MIC of 0.25 mg/L. The model provided a new hypothesis on telavancin plasma protein binding in vivo. Proposed pharmacodynamic targets in plasma and muscle are achieved with currently approved doses of 10 mg/kg daily.

Current role of oxazolidinones and lipoglycopeptides in skin and soft tissue infections.

PURPOSE OF REVIEW: An increase of skin and soft tissue infections involving Staphylococcus aureus has been reported in community and hospital settings. Methicillin resistance in S. aureus is associated with treatment failure and increased mortality. Recently, new antimicrobials with enhanced activity against methicillin-resistant Staph. aureus have been approved for the treatment of skin and soft tissue infections. Among these, novel oxazolidinones and lipoglycopeptides represent options with favorable pharmacokinetic characteristics and safety profiles. RECENT FINDINGS: Newly approved compounds include tedizolid, characterized by the availability of both oral and intravenous formulation and once daily administration and dalbavancin, a long-acting antimicrobial allowing for weekly administration. These new molecules present advantages, such as enhanced activity against multidrug-resistant Gram-positive bacteria and favorable safety profiles. SUMMARY: We have reviewed the pharmacokinetic characteristics and the implications for use in skin and soft tissue infections of tedizolid and dalbavancin. Advantages associated with the use of these compounds include the possibility for early patient discharge, reduced hospital length of stay, and outpatient treatment, with potential impact on morbidity, mortality, and overall health-care costs.

Clinical Pharmacokinetics and Pharmacodynamics of Telavancin Compared with the Other Glycopeptides.

Telavancin was discovered by modifying the chemical structure of vancomycin and belongs to the group of lipoglycopeptides. It employs its antimicrobial potential through two distinct mechanisms of action: inhibition of bacterial cell wall synthesis and induction of bacterial membrane depolarization and permeabilization. In this article we review the clinically relevant pharmacokinetic and pharmacodynamic data of telavancin. For comparison, the pharmacokinetic and pharmacodynamic data of the other glycopeptides are presented. Although, in contrast to the newer lipoglycopeptides, telavancin demonstrates a relatively short half-life and rapid total clearance, its apparent volume of distribution (Vd) is almost identical to that of dalbavancin. The accumulation of telavancin after repeated dosing is only marginal, whereas the pharmacokinetic values of the other glycopeptides show much greater differences after administration of multiple doses. Despite its high plasma-protein binding of 90% and relatively low Vd of approximately 11 L, telavancin shows near complete equilibration of the free fraction in plasma with soft tissue. The ratio of the area under the plasma concentration-time curve from time zero to 24 h (AUC24) of unbound plasma concentrations to the minimal inhibitory concentration (MIC) required to inhibit growth of 90% of organisms (MIC90) of Staphylococcus aureus and S. epidermidis of telavancin are sufficiently high to achieve pharmacokinetic/pharmacodynamic targets indicative for optimal bacterial killing. Considering both the AUC24/MIC ratios of telavancin and the near complete equilibration of the free fraction in plasma with soft tissue, telavancin is an appropriate antimicrobial agent to treat soft tissue infections caused by Gram-positive pathogens. Although the penetration of telavancin into epithelial lining fluid (ELF) requires further investigations, the AUC24/MIC ratio for S. aureus indicates that bactericidal activity in the ELF could be expected.

Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects.

A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects (n = 32) received a single, weight-stratified, fixed dose of 500 mg (n = 4), 750 mg (n = 8), or 1,000 mg (n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC0-∞) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC0-∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.).

Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.