Telavancin Dose Research Articles

Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

Evaluation of telavancin-loaded bone cement: Elution, eluate activity, and mechanical properties

Prosthetic joint infection (PJI) is the most common reason for early revision of total joint replacements. In these applications, antibiotic-loaded bone cement (ALBC) is widely used both as a prophylaxis and treatment/management for PJI. However, over time, the bacterial strains most frequently associated with PJI have become resistant to the antibiotics commonly used in ALBC's such as gentamicin and vancomycin. The present study was an in vitro evaluation of telavancin-loaded Palacos R and Simplex P cements, with different amounts of the antibiotic added to 40 g of cement powder: 0.125, 0.25, 0.5, 1.0, and 2.0 g.Telavancin elution was measured from each cement over 60 days. The efficacy of the eluted telavancin in eliminating four bacterial strains associated with PJI (MSSA, MRSA, and S. epidermidis) was determined. Mechanical tests, four-point bend, compression, and fracture toughness, were performed.In this in vitro study, the higher doses of telavancin increased telavancin release, and Palacos exhibited better elution than did Simplex. Similarly, the addition of 2 g of telavancin to the Palacos increased the efficacy of the ALBC for preventing bacterial colonization and biofilm formation. However, the mechanical performance of the bone cement containing telavancin was significantly reduced after wet curing, with flexural and compressive strength of the cements weakening. Moreover, Palacos that contained telavancin resulted in higher fracture toughness than did Simplex. Therefore, incorporating telavancin into Palacos for use in total joint replacement surgery demonstrated better performance than Simplex but further study is needed to improve the detrimental effects on mechanical properties.

Real-World Clinical Use and Outcomes of Telavancin for the Treatment of Bone and Joint Infections: Results from the Telavancin Observational Use Registry (TOUR™).

BackgroundAdditional antibiotic options are needed to treat bone and joint infections caused by penicillin-resistant Gram-positive pathogens.ObjectiveThis subanalysis of the Telavancin Observational Use Registry (TOUR™) aimed to record real-world telavancin usage patterns in patients with bone and joint infections treated with telavancin.MethodsTOUR was a multicenter observational-use registry study conducted at 45 US sites between January 2015 and March 2017. Patient characteristics, infection type, infecting pathogen(s), previous treatment, telavancin dosing and duration, clinical response, and adverse event data were collected by retrospective medical chart reviews. As such, inclusion/exclusion criteria were limited, and any patient receiving at least one dose of telavancin at the discretion of the treating physician was eligible. Patients were assessed as either positive clinical response, failed treatment, or indeterminate outcome.ResultsOf the 1063 patients enrolled in TOUR, 27.4% (291/1063) were patients with bone and joint infections including osteomyelitis (with or without prosthetic material), acute septic arthritis, and prosthetic joint infections. Most of these patients had osteomyelitis without prosthetic material (191/291; 66.0%). Among patients assessed at the end of treatment, 211/268 (78.7%) achieved a positive clinical response, 26/268 (9.7%) failed treatment, and 31/268 (11.6%) had an indeterminate outcome. The most frequent pathogen was methicillin-resistant Staphylococcus aureus (110/291; 37.8%). The median (interquartile range [IQR as Q1, Q3]) telavancin dose was 750.0 mg (IQR, 750, 750 mg) or 8.2 mg/kg (IQR, 6.8, 9.7 mg/kg) administered for a median of 26 days (IQR, 12, 42 days). These assessments were recorded in the registry ≥ 30 days after the last dose of telavancin was administered.ConclusionsReal-world data from the TOUR study show that clinicians are using once-daily telavancin with positive clinical outcomes for the treatment of bone and joint infections caused by Gram-positive pathogens.Clinical Trial RegistrationThis trial was registered with ClinicalTrials.gov (NCT02288234) on 11 November, 2014.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00255-6.

Clinical Outcomes for Telavancin for Salvage Therapy in Methicillin-resistant Staphylococcus Aureus Bacteremia

Background Little evidence exists for the use of telavancin in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia as salvage therapy. This study aims to evaluate the efficacy and safety of telavancin as salvage therapy in the treatment of MRSA bacteremia. Methods Electronic medical charts of patients who received telavancin for the treatment of MRSA bacteremia at an academic, tertiary care medical center in the United States between January 1, 2015, and May 31, 2019, were reviewed for clinical cure, reinfection, prior antibiotic use, source of infection, microbiological culture clearance, patient mortality, and adverse effects. The primary outcome was clinical cure. Results Thirty-eight charts were identified, and 11 met inclusion criteria for this analysis. Vancomycin or daptomycin was given for an average of 5.4 and 2.6 days, respectively, before the initiation of telavancin. The average telavancin dose used was 7.5 mg/kg. All patients achieved clinical cure, and there were no instances of 60-day mortality. Two patients experienced reinfection: 1 patient after 268 days and another after 467 days. Four patients experienced either QTc prolongation or acute renal failure. Conclusions The use of telavancin in MRSA bacteremia demonstrated microbiological cure, clinical cure, and minimal reinfection in the reviewed patient population. Telavancin may be a potential treatment option for patients with MRSA bacteremia as salvage therapy.

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

PurposeU.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.MethodsThe 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).ResultsThe 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.ConclusionThe 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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00228-020-03072-y.

Clinical Experience with Telavancin for the Treatment of Patients with Bacteremia and Endocarditis: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BackgroundBacteremia and endocarditis caused by Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), are challenging to treat and are associated with high morbidity and mortality. Telavancin is a lipoglycopeptide antibacterial active against susceptible Gram-positive pathogens, including MRSA.ObjectiveThis registry study assessed the real-world use and clinical outcomes of telavancin in patients with bacteremia or endocarditis enrolled in the Telavancin Observation Use Registry (TOUR™).MethodsThe subset of patients enrolled in TOUR who were diagnosed with endocarditis and/or bacteremia with a known or unknown primary source (N = 151) were analyzed. Data including demographics, infection type, baseline pathogens, prior or concomitant antimicrobial therapy, dosing regimen, clinical response, treatment-emergent adverse events (TEAEs) of interest, and mortality were collected by retrospective medical chart review.ResultsTelavancin was primarily used as a second-line or greater therapy (n = 132, 87.4%). MRSA was present in 87 (57.6%) patients. Median telavancin dose was 740.6 mg (interquartile range (IQR) 206.0 mg) and median duration of therapy was 9.0 days (IQR 24.0 days). Of the 132/151 (87.4%) patients with an available assessment at the end of telavancin therapy, a positive clinical response was achieved in 98/132 (74.2%), while 14/132 (10.6%) failed therapy and 20/132 (15.2%) had an indeterminant outcome. TEAEs occurred in 24 (15.9%) patients. The most frequent TEAE was renal failure (n = 12, 7.9%); seven of these patients were receiving concomitant nephrotoxic medications. There was no change in creatinine clearance for 67/89 (75.3%) patients with values recorded at the beginning and the end of telavancin therapy.ConclusionsIn real-world clinical practice, overall positive clinical outcomes are observed in patients with bacteremia or endocarditis treated with telavancin, including in those patients infected with MRSA or another S. aureus pathogen. Telavancin may be an alternative treatment option for these patients.Trial RegistrationThis trial was registered with clinicaltrials.gov (NCT02288234) on 11 November 2014.Electronic supplementary materialThe online version of this article (10.1007/s40801-020-00191-x) contains supplementary material, which is available to authorized users.

Clinical Experience with Telavancin: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BackgroundTelavancin—a lipoglycopeptide antibacterial agent active against Gram-positive pathogens including methicillin-sensitive and -resistant Staphylococcus aureus (MRSA)—is approved in the USA for once-daily intravenous use. This registry study captured patient characteristics, prescribing patterns, and treatment outcomes associated with telavancin use in real-world clinical practice.ObjectiveThis prospective, multicenter, observational study will characterize current real-world practice patterns for the use of telavancin in the USA by describing demographic and clinical conditions, examining the process of care and rationale for use, and describing the clinical effectiveness and selected safety outcomes among patients treated with telavancin.MethodsThe Telavancin Observational Use Registry (TOUR™) is an observational multicenter registry study. Clinical data—including patient demographics, pathogens, telavancin dosing and treatment duration, and adverse events—along with investigators’ assessments of outcome, were collected through retrospective medical chart review.ResultsData from 1063 patients were collected from 45 US sites. Of these patients, 29.4% were ≥ 65 years of age [mean age ± standard deviation, 55.2 ± 15.4 years; median age (interquartile range), 57.0 (46.0–66.0)], 53.4% were male, and 83.4% were White. The primary infections in these patients included complicated skin and skin-structure infection (48.7%), bone and joint infections (27.4%), bacteremia and endocarditis (14.2%), and lower respiratory tract infections (8.5%). The predominant pathogen identified was MRSA (37.7%). The mean telavancin dose and duration of treatment were 741.7 ± 194.3 mg and 17 ± 17 days, respectively. Of the 964 (90.7%) patients for whom an end-of-treatment assessment was available, 77.7% had a positive clinical response, 10.1% failed treatment, and 12.2% had indeterminate outcomes.ConclusionsReal-world data collected from the TOUR study show once-daily telavancin is being used for the treatment of a variety of Gram-positive infections with generally positive clinical outcomes.Electronic supplementary materialThe online version of this article (10.1007/s40801-019-00165-8) contains supplementary material, which is available to authorized users.

1555. Risk of Developing Acute Kidney Injury in Patients Receiving Piperacillin–Tazobactam and Vancomycin Compared with Those on Piperacillin–Tazobactam and Telavancin

BackgroundThe combination of piperacillin–tazobactam (PIP-TAZO) and vancomycin is associated with an increased frequency of acute kidney injury (AKI) in patients when compared with either agent alone. Like vancomycin, telavancin is also used for gram-positive infections and has been reported to cause AKI, but there is a paucity of data regarding the development of AKI with the combination of PIP-TAZO and telavancin. The purpose of this study was to compare the incidence of AKI in patients receiving PIP-TAZO with concomitant vancomycin or telavancin.MethodsThis retrospective cohort study included patients admitted between November 2016 and March 2019 who received at least 2 days of either vancomycin or telavancin in combination with PIP-TAZO. Patients were excluded if they had a baseline calculated creatinine clearance of less than 20 milliliters per minute or were receiving renal replacement therapy. Any cases of AKI were defined as a serum creatinine increase of 0.3 milligrams per deciliter (mg/dL) or an increase in creatinine of 1.5 times baseline when observed within 7 days of the studied antibiotic combinations. Statistical analysis was performed to compare baseline characteristics and the development of AKI between the two groups.ResultsNinety-four patients with an average age of 55 years met the inclusion criteria. Forty-seven patients were included in both treatment arms. There were no statistically significant differences observed between study group baseline characteristics. All patients received PIP-TAZO 3.375 grams every 8 hours as a 4-hour infusion and the average telavancin dose was 7.5 mg/kg. Seventeen of 94 (18%) patients developed AKI, 8(17%) in the vancomycin and PIP-TAZO group and 9 (19%) in the telavancin and PIP-TAZO group (P = 1.0). No patients required dialysis.ConclusionThe development of AKI appears to be similar when comparing vancomycin and PIP-TAZO to telavancin and PIP-TAZO in our population. It is noteworthy that PIP-TAZO was given as an extended infusion and telavancin dosing was lower than the manufacturer recommendations in this evaluation. Additional studies are warranted to further examine the occurrence of AKI with these antibiotic combinations.Disclosures All authors: No reported disclosures.

Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus.

The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.

Efficacy of Telavancin Alone and in Combination with Ampicillin in a Rat Model of Enterococcus faecalis Endocarditis.

We first assessed telavancin (TLV) pharmacokinetics in rats after a single subcutaneous dose of 35 mg/kg of body weight. The pharmacokinetic data were used to predict a TLV dose that simulates human exposure, and the efficacy of TLV was then evaluated using a TLV dose of 21 mg/kg every 12 h against Enterococcus faecalis OG1RF (TLV MIC of 0.06 μg/ml) in a rat endocarditis model with an indwelling catheter. Therapy was given for 3 days with TLV, daptomycin (DAP), or ampicillin (AMP) monotherapy and with combinations of TLV plus AMP, AMP plus gentamicin (GEN), and AMP plus ceftriaxone (CRO); rats were sacrificed 24 h after the last dose. Antibiotics were given to simulate clinically relevant concentrations or as used in other studies. TLV treatment resulted in a significant decrease in bacterial burden (CFU per gram) in vegetations from 6.0 log10 at time 0 to 3.1 log10 after 3 days of therapy. Bacterial burdens in vegetations were also significantly lower in the TLV-treated rats than in the AMP (P = 0.0009)- and AMP-plus-GEN (P = 0.035)-treated rats but were not significantly different from that of the AMP-plus-CRO-treated rats. Bacterial burdens from vegetations in TLV monotherapy and TLV-plus-AMP-and-DAP groups were similar to each other (P ≥ 0.05). Our data suggest that further study of TLV as a therapeutic alternative for deep-seated infections caused by vancomycin-susceptible E. faecalis is warranted.

Outpatient treatment of osteomyelitis with telavancin

Telavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens including Staphylococcus aureus, the most frequent cause of osteomyelitis. Treatment is often challenging due to needs for surgical intervention along with prolonged administration of intravenous antimicrobials, frequently in an outpatient setting. This was a retrospective analysis of the efficacy and safety of telavancin for treatment of osteomyelitis provided as outpatient parenteral antimicrobial therapy (OPAT) in physician office infusion centres. Medical records of 60 patients receiving telavancin for osteomyelitis in 22 physician office infusion centres from 2010 to 2011 and 2013 to 2015 were reviewed. Of these, 60% were treated without hospitalisation, 37% had orthopaedic hardware and 56% had concurrent infections. Staphylococcus aureus was the most common pathogen (78%), primarily methicillin-resistant. The median duration of telavancin treatment in the outpatient setting was 21 days (range 3–105 days). Telavancin was used as first-line therapy in 32% of cases, following prior antibiotic failure in 47% and due to intolerance to previous agents in 22%, predominantly daptomycin or vancomycin. The telavancin dose was 10 mg/kg/day, adjusted for renal function in 25% of patients. The majority of patients self-administered telavancin at home via an elastomeric infusion pump. Overall clinical success was 73%. No significant differences in outcomes were observed with the presence of hardware, concurrent infection, concomitant therapies or type of osteomyelitis. Telavancin-associated adverse events occurred in 57%, with discontinuation in three patients (5%). These data demonstrate the effective and safe OPAT use of telavancin, providing an alternative for successful treatment of patients with osteomyelitis.

Evaluation of telavancin dose capping in a large community hospital

BackgroundTelavancin is a bactericidal lipoglycopeptide treat susceptible Gram-positive pathogens including Methicillin-resistant Staphylococcus aureus. Pharmacokinetic studies have shown that obese patients have increased exposure to telavancin compared with non-obese patients. Dose capping of 750 mg was utilized in selected patients with the purpose of minimizing toxicity and decreasing costs without compromising efficacy.MethodsRetrospective case series includes adult patients admitted from 2010–2016 who received at least three doses of telavancin. Data collection includes patient demographics, telavancin dosing, antibiotic indication, length of stay, laboratory and microbiological data, and case mix index (CMI). The primary outcome is to assess the efficacy of capping telavancin doses at 750 mg compared with non-capped doses. Secondary outcomes include safety and financial outcomes, as well as readmission rates.Results333 patients were evaluated with 164 meeting the inclusion criteria. Seventy-three patients in the capped group vs. 91 in the non-capped group. Most common infections included ABSSI, pneumonia and bacteremia. Mean weight 110 kg in capped vs. 108 kg in noncapped, mean age 52 vs. 58, male 63% vs. 70%, fever resolution 83% vs. 60%, CMI 3.19 vs. 3.43 Six patients (8.2%) in the capped group were readmitted and 6 (8.5%) needed additional antibiotics compared with 12 (13.2%) and 9 (9.9%) in the non-capped group, respectively. Seven (9.6%) patients in the capped group experienced nephrotoxicity compared with 21 (23.1%) in the non-capped group (P = 0.04). The capped group experienced 7 (9.6%) incidents of mortality vs. 28 (30.8%) in the non-capped group (P = 0.001). When doses were capped, approximately $1,400 was saved per patient.ConclusionThe use of a capped 750 mg telavancin dose in adult patients appears to be an alternative dosing scheme that maintains efficacy and safety as well as being associated with reduced cost. Additional pharmacokinetic and clinical studies are needed to further investigate the use of capped dosing of telavancin to support the findings of this retrospective case series.Disclosures All authors: No reported disclosures.

Kidney injury associated with telavancin dosing regimen in an animal model.

The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.

Impact of telavancin on prothrombin time and activated partial thromboplastin time as determined using point-of-care coagulometers

Telavancin is approved in the United States, Canada, and Europe (At the time of submission, the telavancin European marketing authorization for nosocomial pneumonia was suspended until Theravance provides evidence of a new European Medicines Agency approved supplier) as an antibiotic to treat certain Gram-positive bacterial skin infections. Telavancin has been shown to prolong plasmatic prothrombin (PT) and activated partial thromboplastin (aPTT) clotting times in clinical diagnostic lab-based assays. In this study, we evaluated the potential for telavancin to prolong whole blood PT/International Normalized Ratio (INR) and aPTT tests on point-of-care (POC) instruments. Whole blood collected from 8 healthy subjects was supplemented with telavancin to final concentrations of 0, 10, 20, and 100μg/ml. Final concentrations were selected to match trough, twice trough, and peak plasma levels following the approved 10mg/kg dose. Four widely employed POC coagulation instruments were chosen to be representative of the POC platforms currently in use.. These systems were the Roche Coaguchek XS, the Abbott iSTAT, the ITC Hemochron SIG+, and the Alere INRatio2 POC devices. The PT/INR measured by the Coaguchek XS showed the greatest sensitivity to the presence of telavancin. The PT/INR measured by the Hemochron SIG+ and iSTAT were sensitive to telavancin but to a lesser extent. The INRatio2 was the least sensitive to the presence of telavancin when testing the whole blood PT/INR. Only the Hemochron SIG+ device was capable of measuring aPTT and showed a concentration-dependent increase in aPTT. This study supports the current recommendation that PT and aPTT monitoring be conducted immediately to the next dose of telavancin when coagulation parameters are tested using POC instrumentation.

Case Report: Artificial Elevation of Prothrombin Time by Telavancin

Methicillin-resistant Staphylococcus aureus infections are a well-documented risk of surgery and are becoming increasingly difficult to treat owing to continued acquired resistance. A new antibiotic for treatment of Staphylococcus aureus is telavancin. A patient at our institution was prescribed telavancin for multiple spinal abscesses before spinal surgery. Routine preoperative testing revealed an international normalized ratio (INR) of 2.05 with no clear cause. Careful review of the patient's medication history and prescriber information revealed that telavancin may interfere with prothrombin time (PT/INR) testing. In vitro testing by our laboratory confirmed an association between telavancin dose and an increase in PT/INR. An alternative reagent for PT/INR testing unaffected by telavancin dose revealed a PT/INR of 0.97. Telavancin interacts with artificial phospholipid surfaces used to monitor coagulation while having no actual effect on coagulation. All physicians, especially orthopaedic surgeons, should be aware of the effects of telavancin and ensure proper measures are taken to acquire the true INR by switching the reagent used to test PT/INR or ensuring the PT/INR is drawn before telavancin dosing.

Acute renal insufficiency during telavancin therapy in clinical practice

To describe the tolerance to long-term telavancin therapy among inpatients as it relates to nephrotoxicity. Retrospective cohort study of adult patients who received telavancin at the Barnes-Jewish Hospital from 1 September 2009 to 1 December 2010. Patients who received less than three doses of telavancin, were on haemodialysis prior to telavancin administration or died within 48 h of initial telavancin administration were excluded. Twenty-one patients received telavancin and met the inclusion criteria. Seven of 21 patients (33%) developed acute renal insufficiency during therapy. Patients who developed acute renal insufficiency had a mean glomerular filtration rate reduction of 56 mL/min/1.73 m(2). In the univariate analysis, high body mass index (P=0.025), use of intravenous contrast dye (P=0.017) and prior serum vancomycin trough levels >20 mg/L (P=0.017) were associated with developing acute renal insufficiency. Two patients required haemodialysis; two had persistent renal insufficiency. Supratherapeutic vancomycin trough levels, high body mass index and receipt of intravenous contrast dye prior to telavancin therapy were associated with acute renal insufficiency.

Detection of vancomycin levels in patients receiving telavancin but not vancomycin

Sir, Telavancin is a lipoglycopeptide antibiotic with a chemical structure closely related to the glycopeptide antibiotic vancomycin. Telavancin has excellent in vitro activity against methicillinresistant staphylococci and, in the trials which led to its approval for the treatment of skin and soft tissue infections, it was shown to be non-inferior to vancomycin. 1 Renal toxicity is the principal significant adverse effect of telavancin. 2 A standard dose of 10 mg/kg daily is recommended in patients with normal renal function and monitoring of serum or plasma levels is neither recommended nor available commercially. 2 It is not known if telavancin serum levels correlate with the efficacy or renal toxicity of this antibiotic. Perhaps due to a lack of therapeutic superiority data and concerns about renal toxicity, telavancin has yet to be widely used in clinical practice. Recently, a patient receiving the standard dose of telavancin for a staphylococcal infection was demonstrated to have an apparent detectable serum vancomycin level (after the level was inadvertently ordered by a house officer). This serendipitous finding led us to check vancomycin levels in several other patients with normal renal function who were receiving standard doses of telavancin. No patients had received vancomycin. Trough levels were obtained immediately prior to a dose of telavancin and peak levels were obtained 1 h after the infusion was completed. The vancomycin serum levels were determined by a particle-enhanced turbidometric inhibition immunoassay method (Synchron LX System, Beckman Coulter, Inc., Brea, CA, USA). The results are shown in Table 1. Wespeculatethatif aconsistent correlationcanbeestablished between serum vancomycin and telavancin levels in patients treated with telavancin, a commercially available vancomycin serum level assay can then be used to monitor telavancin therapy, in place of an unavailable telavancin assay, in order to establish possible correlation between telavancin levels and its clinical efficacy and/or renal toxicity. Although telavancin plasma assays were apparently done as part of approval studies, we had no access to a telavancin assay to attempt to establish the correlation. 3 If the manufacturer of telavancin or an independent investigator is able to perform telavancin assays, they may choose to perform such a study.

Effects of telavancin on coagulation test results

The lipoglycopeptide antibiotic, telavancin, may interfere with some laboratory coagulation tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT). To evaluate the effects of telavancin on PT and aPTT assays in common use. Pooled normal human plasma was spiked with telavancin 10, 20, 100 or 200 μg/ml (equivalent to trough, 2 × trough, peak and 2 × peak clinical plasma concentrations, respectively) or diluent control (0.9% sodium chloride). Samples were analysed using 16 PT reagents and seven aPTT reagents. Telavancin 200 μg/ml (corresponding to 2 × peak clinical plasma concentration), produced significant PT prolongation (> 9% difference vs. diluent control) with all the 16 PT reagents (range 12% to > 600%). At lower telavancin concentrations, PT prolongation was dose-dependent and varied among reagents, but appeared greatest with preparations containing recombinant tissue factor. With telavancin 10 μg/ml (equivalent to trough), PT prolongation was 10% with HemosIL(®) PT-Fibrinogen Recombinant, while ranging from 5% to -1% with all other reagents. Significant (> 34% difference vs. baseline) and dose-dependent aPTT prolongation was observed with all the seven reagents in samples spiked with telavancin 100 or 200 μg/ml (range 65-142% at 200 μg/ml). aPTT reagents containing a silica activator appeared to be more sensitive to telavancin interference. Telavancin 10 μg/ml was not associated with increased aPTT with any of the reagents tested. Telavancin has the potential to prolong both PT and aPTT in vitro. It is recommended that samples for PT or aPTT be obtained just prior to a telavancin dose (trough).

An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic

Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram-positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function.Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t1/2]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values.Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half-lives between 1.2 and 2.4 h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys.Application of the simple allometric equation (Y = aWb) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl × BW = aWb) resulted in a good correlation between predicted and observed values of Cl, AUC, and t1/2 in humans.These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans.

Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log(10) CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.