The efficacy of telavancin in comparison with linezolid on endotracheal tube biofilm in pigs with methicillin-resistant Staphylococcus aureus pneumonia.

BACKGROUND: The effect of systemic treatment of ventilator-associated pneumonia (VAP) with telavancin, a semisynthetic lipoglycopeptide with good penetration in vitro biofilms, has not been tested in vivo during mechanical ventilation. This study examined the efficacy of telavancin compared with linezolid against endotracheal tube (ETT) biofilms in a porcine model of methicillin-resistant Staphylococcus aureus (MRSA) VAP. METHODS: VAP was induced in 18 pigs by instilling 107 colony-forming units (CFU/mL) of an MRSA strain susceptible to telavancin and linezolid into each pulmonary lobe. Randomization into three groups was done at pneumonia diagnosis: control (IV glucose 0.5% solution q24); linezolid (10 mg/kg q12) and telavancin groups (22.5 mg/kg q24). After 72 h of MV, data regarding bronchoalveolar lavage (BAL), tracheal aspirate (TA), ETT MRSA biofilm load and thickness measured by scanning electron microscopy were obtained. RESULTS: All 18 pigs completed the study. MRSA was isolated in 100% of ETTs from the control and linezolid groups and in 67% from the telavancin group. Telavancin treatment presented a lower MRSA load compared to the control and linezolid treatments (telavancin median [interquartile range (IQR)] = 1.94 [0.00-5.45], linezolid 3.99 [3.22-4.68] and control 4.93 [4.41-5.15], P = 0.236). Telavancin treatment also resulted in the lowest biofilm thickness according to the SEM (4.04 [2.09-6.00], P < 0.001). We found a positive correlation between ETT and BAL load (rho = 0.511, P = 0.045). CONCLUSIONS: In our VAP model, systemic telavancin treatment reduced ETT MRSA occurrence, load, and biofilm thickness. Our findings may have a bearing on ICU patients' clinical outcomes.

Statistical distribution of micro and macro pores in acrylic bone cement- effect of amount of antibiotic content.

Aseptic loosening due to mechanical failure of bone cement is considered to be a leading cause of revision of joint replacement systems. Detailed quantified information on the number, size and distribution pattern of pores can help to obtain a deeper understanding of the bone cement's fatigue behavior. The objective of this study was to provide statistical descriptions for the pore distribution characteristics of laboratory bone cement specimens with different amounts of antibiotic contents. For four groups of bone cement (Palacos) specimens, containing 0.3, 0.6, 1.2 and 2.4 wt/wt% of telavancin antibiotic, seven samples per group were micro computed tomography scanned (38.97 µm voxel size). The images were first preprocessed in Mimics and then analyzed in Dragonfly, with the level of threshold being set such that single-pixel pores become visible. The normalized pore volume data of the specimens were then used to extract the logarithmic histograms of the pore densities for antibiotic groups, as well as their three-parameter Weibull probability density functions. Statistical comparison of the pore distribution data of the antibiotic groups using the Mann-Whitney non-parametric test revealed a significantly larger porosity (p < 0.05) in groups with larger added antibiotic contents (2.4 and 0.6 wt/wt% vs 0.3 wt/wt%). Further analysis revealed that this effect was associated with the significantly larger frequency of micropores of 0.1-0.5 mm diameter (p < 0.05) in groups with larger antibiotic content (2.4 wt/wt% vs and 0.6 and 0.3 wt/wt%), implying that the elution of the added antibiotic produces micropores in this diameter range mainly. Based on this observation and the fatigue test results in the literature, it was suggested that micropore clusters have a detrimental effect on the mechanical properties of bone cement and play a major role in initiating fatigue cracks in highly antibiotic added specimens.

National surveillance of antimicrobial susceptibilities to ceftaroline, dalbavancin, telavancin, tedizolid, eravacycline, omadacycline, and other comparator antibiotics, and genetic characteristics of bacteremic Staphylococcus aureus isolates in adults: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) program in 2020.

Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive infections and is associated with community-acquired infections (CAIs) and hospital-associated infections (HAIs). In 2020, 315 S. aureus isolates, including 145 methicillin-susceptible S. aureus (MSSA) and 170 MRSA, mainly associated with bacteremia and mostly CAIs, were collected from 16 hospitals in different regions of Taiwan. Minimum inhibitory concentrations (MICs) were determined using the Sensititre™ complete automated AST system. Staphylococcal cassette chromosome mec (SCCmec) types were analysed using multiplex polymerase chain reaction. The median age of patients infected with MRSA was significantly higher than that of patients infected with MSSA (72.5 years vs. 67.0 years, P=0.027). MIC50/MIC90 values of eravacycline and omadacycline were 0.06/0.12, and 0.25/0.5, respectively. Of the MRSA isolates, 4.1% presented susceptible dose-dependence to ceftaroline, most of which (85.7%) were HAI- and Panton-Valentine leukocidin (PVL)-negative. Among the MRSA isolates, 7.1% were not susceptible to telavancin and tedizolid (mainly type IV, PVL-negative, and CAI), 0.6% were not susceptible to daptomycin (type III, PVL-negative, and HAI), and 1.8% were not susceptible to quinupristin/dalfopristin (three isolates were type III, IV, and VT, respectively, and all were PVL-negative), but all were susceptible to dalbavancin. In conclusion, patients with bacteremia caused by MRSA were older than those with bacteremia caused by MSSA, SCCmec type IV was more predominant in CAI than in HAI, and MRSA isolates not susceptible to novel anti-MRSA antimicrobials belonged to types II, III, or IV. Further studies that include comprehensive demographics and more detailed descriptions of other antimicrobial-resistant genes are urgently needed.

Antibacterial activity of recently approved antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) strains: A systematic review and meta-analysis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infections are considered an important public health problem, and treatment options are limited. Accordingly, in this meta-analysis, we analyzed published studies to survey in vitro activity of recently approved antibiotics against MRSA isolates. METHODS: We searched electronic databases; PubMed, Scopus, and Web of Science to identify relevant studies (until November 30, 2020) that have focused on the in vitro activity of telavancin, dalbavancin, oritavancin, and tedizolid against MRSA isolates. Statistical analyses were conducted using STATA software (version 14.0). RESULTS: Thirty-eight studies were included in this meta-analysis. Overall in vitro activity of tedizolid on 12,204 MRSA isolates was 0.250 and 0.5 µg/mL for MIC50 and MIC90, (minimum inhibitory concentration at which 50% and 90% of isolates were inhibited, respectively), respectively. The overall antibacterial activity of dalbavancin on 28539 MRSA isolates was 0.060 and 0.120 µg/mL for MIC50 and MIC90, respectively. The overall antibacterial activity of oritavancin on 420 MRSA isolates was 0.045 and 0.120 µg/mL for MIC50 and MIC90, respectively. The overall antibacterial activity of telavancin on 7353 MRSA isolates was 0.032 and 0.060 µg/mL for MIC50 and MIC90, respectively. The pooled prevalence of tedizolid, telavancin, and dalbavancin susceptibility was 100% (95% CI: 100-100). CONCLUSION: Telavancin, dalbavancin, oritavancin, and tedizolid had potent in vitro activity against MRSA isolates. The low MICs and high susceptibility rates of these antibiotics recommend a hopeful direction to introduce useful antibiotics in treating MRSA infections in the future.

Evaluation of a Capped Dosing Telavancin Regimen Compared to Standard Dosing at a Large Community Teaching Hospital.

Telavancin, a lipoglycopeptide antibiotic, is traditionally dosed at 10 mg/kg based on total body weight but is associated with toxicities that limit its use. This study supports the use of a capped dosing regimen of 750 mg in obese patients, which is associated with equal efficacy and fewer adverse effects compared to traditional dosing.

Application of physiologically based pharmacokinetic modeling to predict the pharmacokinetics of telavancin in obesity with renal impairment.

PURPOSE: U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function. METHODS: The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI). RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf was predicted to increase 1.07-fold in mild RI, 1.23-fold in moderate RI, 1.41-fold in severe RI, and 1.57-fold in end-stage renal disease (ESRD), compared with that in obese HAP with normal renal function. The PBPK model combined with Monte Carlo simulations (MCS) suggested that dose adjustment based on a 750-mg-fixed dose could achieve effectiveness with reduced risk of toxicity, compared with current TBW-based dosing recommendations. CONCLUSION: The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.

Evaluating the Rapid Emergence of Daptomycin Resistance in Corynebacterium: a Multicenter Study.

Members of the genus Corynebacterium are increasingly recognized as pathobionts and can be very resistant to antimicrobial agents. Previous studies have demonstrated that Corynebacterium striatum can rapidly develop high-level daptomycin resistance (HLDR) (MIC, ≥256 µg/ml). Here, we conducted a multicenter study to assay for this in vitro phenotype in diverse Corynebacterium species. Corynebacterium clinical isolates (n = 157) from four medical centers were evaluated. MIC values to daptomycin, vancomycin, and telavancin were determined before and after overnight exposure to daptomycin to identify isolates able to rapidly develop daptomycin nonsusceptibility. To investigate assay reproducibility, 18 isolates were evaluated at three study sites. In addition, the stability of daptomycin nonsusceptibility was tested using repeated subculture without selective pressure. The impact of different medium brands was also investigated. Daptomycin nonsusceptibility emerged in 12 of 23 species evaluated in this study (C. afermentans, C. amycolatum, C. aurimucosum, C. bovis, C. jeikeium, C. macginleyi, C. pseudodiphtheriticum, C. resistens, C. simulans, C. striatum, C. tuberculostearicum, and C. ulcerans) and was detected in 50 of 157 (31.8%) isolates tested. All isolates displayed low (susceptible) MIC values to vancomycin and telavancin before and after daptomycin exposure. Repeated subculture demonstrated that 2 of 9 isolates (22.2%) exhibiting HLDR reverted to a susceptible phenotype. Of 30 isolates tested on three medium brands, 13 (43.3%) had differences in daptomycin MIC values between brands. Multiple Corynebacterium species can rapidly develop daptomycin nonsusceptibility, including HLDR, after a short daptomycin exposure period.

Efficacy of Telavancin in Comparison to Linezolid in a Porcine Model of Severe Methicillin-Resistant Staphylococcus aureus Pneumonia.

Current guidelines recommend vancomycin and linezolid as first-line agents against methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Telavancin is a potential new therapeutic alternative, specifically in monomicrobial MRSA pneumonia. This study compared the efficacies of telavancin versus linezolid in a porcine model of severe MRSA pneumonia. In 18 mechanically ventilated pigs (32.11 ± 1.18 kg), 75 ml of 106 CFU/ml of MRSA was administered into each pulmonary lobe. After the onset of pneumonia, pigs were randomized into three groups: a control group, a group receiving 22.5 mg/kg of body weight every 24 h (q24h) of telavancin, and a group receiving 10 mg/kg q12h of linezolid intravenously. Tracheal aspirate and bronchoalveolar lavage (BAL) fluids were cultured every 24 h. After 48 h of treatment, tissue samples were collected from the ventral and dorsal sections of each lobe. Microbiological and histopathological analyses were performed. Lung tissue concentrations differed among the groups (P = 0.019), with the lowest MRSA lung burden in the telavancin group (P < 0.05 versus the control). MRSA was detected in 46.7%, 40.0%, and 21.7% of the lung tissue samples from the control, linezolid, and telavancin groups, respectively (P < 0.001). MRSA concentrations differed among the groups in tracheal aspirate fluid (P = 0.011) but not in BAL fluid. Furthermore, there was no increased risk of kidney injury during telavancin use. Thus, telavancin has higher bactericidal efficacy than linezolid during the first 48 h of treatment in a porcine model of severe MRSA pneumonia. However, studies are needed to confirm the benefits of telavancin in treating MRSA nosocomial pneumonia.

Dalbavancin and telavancin in the treatment of infective endocarditis: a literature review.

Glycopeptides have an established role in the management of infective endocarditis, and feature in current treatment guidelines. Newer lipoglycopeptide agents (dalbavancin, telavancin and oritavancin), which are analogues of glycopeptides with structural modifications giving rise to added novel mechanisms of antimicrobial activity, are approved for the treatment of Gram-positive skin and skin structure infections, and also for nosocomial pneumonia (only telavancin has approval for the latter indication). Recent evidence has also emerged to support their use in the treatment of bone and joint infections. This article reviews the current literature on dalbavancin and telavancin in the treatment of infective endocarditis, a condition for which the role of these agents is yet to be established.

Glycopeptide Hypersensitivity and Adverse Reactions.

Glycopeptides, such as vancomycin and teicoplanin, are primarily used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, such as cellulitis, endocarditis, meningitis, pneumonia, and septicemia, and are some of the most commonly prescribed parenteral antimicrobials. Parenteral glycopeptides are first-line therapy for severe MRSA infections; however, oral vancomycin is used as a first-line treatment of Clostridioides difficile infections. Also, we currently have the longer-acting lipoglycopeptides, such as dalbavancin, oritavancin, and telavancin to our armamentarium for the treatment of MRSA infections. Lastly, vancomycin is often used as an alternative treatment for patients with ß-lactam hypersensitivity. Common adverse effects associated with glycopeptide use include nephrotoxicity, ototoxicity, and Redman Syndrome (RMS). The RMS is often mistaken for a true allergy; however, it is a histamine-related infusion reaction rather than a true immunoglobulin E (IgE)-mediated allergic reaction. Although hypersensitivity to glycopeptides is rare, both immune-mediated and delayed reactions have been reported in the literature. We describe the various types of glycopeptide hypersensitivity reactions associated with glycopeptides and lipoglycopeptides, including IgE-mediated reactions, RMS, and linear immunoglobulin A bullous dermatosis, as well as describe cross-reactivity with other glycopeptides.

Antimicrobial Activity of Telavancin Tested In Vitro Against a Global Collection of Gram-Positive Pathogens, Including Multidrug-Resistant Isolates (2015-2017).

This study evaluated the in vitro antimicrobial activity of telavancin against a large collection of Gram-positive pathogens of clinical importance, which were collected worldwide from 2015 through 2017, including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, Enterococcus spp., ß-hemolytic streptococci (BHS), Streptococcus pneumoniae, and viridans group streptococci (VGS). This report completes 7 years of continuous surveillance data for telavancin using the approved reference method for in vitro testing methodology that includes the addition of polysorbate 80. For isolates collected from 2015 through 2017, telavancin exhibited potent activity against the following species and groups that have Clinical and Laboratory Standards Institute (CLSI)-approved interpretive criteria: MRSA (MIC90 value, 0.06 µg/mL; 100% susceptible), vancomycin-susceptible Enterococcus faecalis (MIC90 value, 0.25 µg/mL; 99.9% susceptible), BHS (MIC90 value, 0.03 µg/mL; 100% susceptible), and VGS (MIC90 value, 0.03 µg/mL; 99.0% susceptible). Importantly, telavancin maintained excellent antimicrobial activity against multidrug-resistant subsets of these pathogen groups and against ceftaroline-nonsusceptible (telavancin MIC90 value, 0.06 µg/mL; 100% susceptible) and ceftaroline-resistant (telavancin MIC90 value, 0.12 µg/mL; 100% susceptible) S. aureus isolates.

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.).

Telavancin in Hospital-Acquired and Ventilator-Associated Pneumonia (HAP/VAP) Caused by Staphylococcus aureus: Post Hoc Analysis of 2 Randomized, Controlled Trials.

INTRODUCTION: The efficacy and safety of telavancin versus vancomycin in microbiologically evaluable patients with hospital-acquired or ventilator-associated pneumonia (HAP/VAP) caused by Staphylococcus aureus with vancomycin minimum inhibitory concentration (MIC) ≥ 1.0 µg/mL was analyzed using data derived from previously reported Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials. METHODS: This post hoc subgroup analysis of two randomized, double-blind, comparator-controlled, parallel-group phase 3 trials conducted at 274 sites in 38 countries included 194 microbiologically evaluable patients with HAP/VAP caused by monomicrobial S. aureus with vancomycin MIC ≥ 1.0 µg/mL. Patients received intravenous telavancin (10 mg/kg every 24 h) or intravenous vancomycin (1 g every 12 h with site-specific modifications) for 7-21 days. Efficacy was assessed by clinical cure, defined as improvement or non-progression of radiographic findings at end of treatment and resolution of pneumonia signs and symptoms at follow-up/test-of-cure visits, and survival 28 days post-randomization. Safety was assessed from categorical shifts in creatinine clearance during therapy and adverse events (AEs). RESULTS: Clinical cure rates were numerically greater following telavancin versus vancomycin treatment overall (85.4% vs. 74.3%; treatment difference [95% confidence interval (CI)], 11.1% [- 0.002%, 22.2%]) and in patients aged ≥ 65 years (81.6% vs. 66.2%; treatment difference [95% CI], 15.5% [- 0.9%, 30.2%]) patients with VAP (92.3% vs. 47.6%; treatment difference [95% CI], 44.7% [18.1%, 64.9%]), and patients with baseline Acute Physiology And Chronic Health Evaluation II score ≥ 20 (71.4% vs. 55.6%; treatment difference [95% CI], 15.9% [- 11.7%, 40.5%]). Renal function declined in 7 (7.9%) patients receiving telavancin and 6 (5.7%) patients receiving vancomycin. Survival proportion was numerically higher (85.2% vs. 80.2%; treatment difference [95% CI], 5.0% [- 5.8%, 15.8%]) and AEs were comparable in patients treated with telavancin versus vancomycin. CONCLUSION: Telavancin is an alternative to vancomycin for HAP/VAP caused by S. aureus with vancomycin MIC ≥ 1 µg/mL. FUNDING: Theravance Biopharma R&D, Inc., South San Francisco, CA, USA.

Evaluation of telavancin susceptibility in isolates of Staphylococcus aureus with reduced susceptibility to vancomycin.

Historically, vancomycin has been considered a primary therapeutic option for treating infections with Staphylococcus aureus, but isolates with reduced vancomycin susceptibility (SA-RVS) (MIC ≥ 4 µg/mL) have emerged. Telavancin, a semisynthetic lipoglycopeptide, is an alternative treatment option for S. aureus, but data examining telavancin activity against SA-RVS are limited. In the present study, we characterize 300 isolates of S. aureus isolates (50 vancomycin-susceptible (VSSA) isolates and 250 SA-RVS isolates) from a large tertiary care, academic medical center, 51.8% of which were methicillin resistant (MRSA). Sixteen (6.4%) SA-RVS isolates were non-susceptible to telavancin, whereas all VSSA isolates were susceptible. Additionally, 3.6% of SA-RVS isolates were non-susceptible to daptomycin, with three (1.2%) isolates testing non-susceptible to both telavancin and daptomycin. When tested against other classes of antimicrobials, there were no statistical differences in susceptibility of VSSA and SA-RVS isolates, except for the fluoroquinolones (ciprofloxacin and moxifloxacin). Molecular characterization of the isolates showed that SCCmec types II and IV together represented over half of the SA-RVS isolates; 12.0% of the VSSA isolates were SCCmec type II. Using RepPCR, we detected 16 distinct strain types in this isolate collection, and tst-1 (gene encoding the Staphylococcus toxic shock syndrome super-antigen) carriage was low (5.4%). Overall, we show that in addition to reduced vancomycin susceptibility, a small, but clinically significant, proportion of SA-RVS isolates also demonstrate reduced susceptibility to both telavancin and daptomycin.

Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms.

Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci, enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality and healthcare costs. In recent years, only a small number of novel antibiotics effective against Gram-positive bacteria has been approved. This review will discuss the current evidence for novel branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin, tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action, pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented. As for any emerging antibiotic agent, resistance is likely to develop against these highly effective antibiotics. Only through appropriate dosing, utilization and careful resistance development monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future.

Real-world use of telavancin in the treatment of osteomyelitis.

This is a retrospective analysis of patients with osteomyelitis who received telavancin at some time during their treatment course. The primary outcome was the percent of patients cured or improved at the end of telavancin therapy (EOTT). The secondary outcome was the percent of patients cured or improved three months after discontinuation of telavancin therapy. There were 32 cases of osteomyelitis with methicillin-resistant Staphylococcus aureus identified in 17 (56.7%), methicillin-sensitive Staphylococcus aureus 2(6.6%), coagulase negative staphylococci 6 (20.0%) and other pathogens, 5 (16.7%). At EOTT, 87.5% of patients had their osteomyelitis cured and 94.6% had the infection cured at three months after telavancin was completed. The most common adverse events associated with telavancin were gastrointestinal in nature (nausea (25.8%), vomiting (9.7%) and diarrhea (3.2%)) followed by metallic taste (6.5%). A favorable outcome was achieved for many patients receiving the antimicrobial regimen that included telavancin for the treatment of osteomyelitis.

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.

In vitro activity of telavancin against Staphylococcus aureus causing pneumonia or skin and skin structure infections with concomitant bloodstream infections in United States hospitals (2012-2016).

Pneumonia and skin and skin structure infections (SSSIs) caused by S. aureus can lead to serious bloodstream infections (BSIs). This study reports on potent telavancin in vitro activity (MIC90, 0.06 µg/mL; 100% susceptible) against 674 US S. aureus causing pneumonia or SSSI with associated BSI in hospitalized patients during 2012-2016.

VISA-Daptomycin non-susceptible Staphylococcus aureus frequently demonstrate non-susceptibility to Telavancin.

Telavancin was evaluated against S. aureus isolates with reduced susceptibility to other antimicrobial agents using two broth microdilution methods and Etest® strips. The three methods provided comparable results. Differences in telavancin susceptibility versus non-susceptibility were noted mainly in the VISA-daptomycin non-susceptible group of isolates. In this group the percent susceptibility was 38% for the Etest® method and 50% and 54% for the 2 broth microdilution methods. All differences in susceptibility were within one 2-fold dilution.

Use of telavancin in adolescent patients with cystic fibrosis and prior intolerance to vancomycin: A case series.

The most common pathogen in pediatric cystic fibrosis (CF) patients is Staphylococcus aureus, and drug-resistant species are associated with negative outcomes. Methicillin-resistant Staphylococcus aureus (MRSA) is notoriously hard to treat because many antibiotics are not FDA approved for children and drug allergies or intolerances can prohibit the use of others. Telavancin is currently indicated for hospital-acquired pneumonia and ventilator-associated pneumonia caused by MRSA, but it has not been studied in patients with CF or in pediatrics. As a semi-synthetic derivative of vancomycin, it is unknown if cross-reactivity with telavancin occurs in patients with vancomycin hypersensitivity or intolerance. In this case series, we describe three adolescent patients with CF and previous intolerance to vancomycin who received telavancin for bronchopulmonary exacerbations.