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.

Treatment of osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections with dalbavancin and oritavancin: A systematic review.

BACKGROUND: There is increasing interest in the use of oritavancin and dalbavancin for complicated Gram-positive infections as an alternative to in-hospital intravenous or outpatient antimicrobial therapy. OBJECTIVE: To evaluate the efficacy and safety of long-acting lipoglycopeptides (laLGPs) in patients with osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections. METHODS: A systematic literature search was performed using 'dalbavancin' and 'oritavancin' as search terms. For inclusion in this review, studies had to include at least one human subject treated for an indication other than acute bacterial skin and skin structure infections. The primary outcome for this review was clinical success as defined by each individual study, and patients were stratified by type of infection. RESULTS: In total, 38 studies (18 randomized controlled trials/case series and 20 case reports) met the inclusion criteria. The most common off-label indication for oritavancin and dalbavancin was osteoarticular infection, with a median success rate of 73% [interquartile range (IQR) 58-85%] among the 14 studies with more than one patient. The success rate for endocarditis and cardiac-device-related infections was 68% (IQR 56-86%) among nine studies, and the success rate for catheter-related bloodstream infection was 75% (IQR 59-90%) among seven studies. Among the 16 studies of almost 700 patients receiving laLGPs, there were 98 reports of adverse events, resulting in 13% of treated patients reporting an event. CONCLUSIONS: This review provides evidence that laLGPs are safe and efficacious for osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections. Further research is needed to confirm these results.

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.

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.

On- and off-label utilization of dalbavancin and oritavancin for Gram-positive infections.

BACKGROUND: Long-acting lipoglycopeptides (laLGPs) are FDA approved only for acute bacterial skin and skin structure infections (ABSSSIs). However, these antibiotics show promise for off-label use, reductions in hospital length of stay (LOS) and healthcare cost savings. OBJECTIVES: To assess the effectiveness, safety, impact on LOS and estimated cost savings from laLGP treatment for Gram-positive infections. METHODS: Retrospective cohort of adult patients who received at least one dose of laLGPs at the University of Colorado Health system. Descriptive statistics were utilized for analysis. RESULTS: Of 59 patients screened, 56 were included: mean age 47 years, 59% male and 30% injection drug users/polysubstance abusers (dalbavancin, 71%; oritavancin, 25%; both, 4%). Most common indications for laLGP: ABSSSIs (36%), osteomyelitis (27%) and endocarditis (9%). Most common isolated pathogens: MSSA and MRSA (25% and 19%, respectively), Enterococcus faecalis (11%) and CoNS (11%). Previous antibiotics were administered for a median of 13 days (IQR = 7.0-24.5 days) and laLGPs for a median of one dose (IQR = 1-2 doses). Ten (18%) patients were lost to follow-up. Clinical failure was found in 7/47 (15%) cases with adequate follow-up. Mild adverse effects occurred in six (11%) patients. Projected reduction in hospital LOS and health-system costs were 514 days (9.18 days/person average) and $963456.72 ($17204.58/person average), respectively. CONCLUSIONS: Prospective trials are needed to validate the use of these antibiotics for Gram-positive infections in practice, with the hope that they will reduce hospital LOS and the need for daily antibiotic infusions to provide alternative options for patients not qualifying for outpatient parenteral antimicrobial therapy.

Telavancin-associated acute kidney injury
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Telavancin is a lipoglycopeptide semi-synthetic derivative of vancomycin used for select infections caused by Gram-positive bacteria including Staphylococcus aureus. Human clinical trials suggest that telavancin is potentially nephrotoxic, however there is no histopathologic description of acute kidney injury (AKI) in humans. An animal model has recently characterized the histologic changes associated with telavancin-induced AKI as proximal tubular injury with numerous phagolysosomes. We present a case of a 47-year-old man with methicillin-resistant Staphylococcus aureus bacteremia treated with telavancin, who developed AKI after 5 weeks of intravenous therapy. Acute tubular injury with lysosomal proliferation and acute interstitial nephritis were observed on kidney biopsy. To our knowledge, this is the first reported case of AKI due to telavancin that has documented kidney histopathology.
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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.

Time Course and Extent of Renal Function Changes in Patients Receiving Treatment for Staphylococcal Pneumonias: An Analysis Comparing Telavancin and Vancomycin from the ATTAIN Trials.

STUDY OBJECTIVE: Telavancin and vancomycin are both approved for treatment of hospital-acquired and ventilator-associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of this study was to assess renal function changes by performing renal shift table analyses of telavancin- and vancomycin-treated patients in phase III trials. DESIGN: Retrospective, descriptive analysis of data from the safety population from the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials. PATIENTS: A total of 1503 adults with hospital-acquired or ventilator-associated bacterial pneumonia primarily caused by gram-positive pathogens and who received telavancin (n = 751) or vancomycin (n = 752). MEASUREMENTS AND MAIN RESULTS: Decline or improvement in creatinine clearance (CrCl) across seven defined categories (≤30, >30-40, >40-50, >50-60, >60-70, >70-80, and >80 ml/min) was classified as negative or positive shifts, respectively. The number of categories crossed (either positive or negative) determined the grade of shift (of a potential grades 1-6, with crossing from one category to the next adjacent category defined as a grade 1 shift) at specific time points compared with baseline: day 4, day 7, and end of therapy (EOT). Approximately 77%-91.6% of patients had either no change or improvement of CrCl across all time points for both treatments. Negative shifts were consistent for telavancin (day 4, 19.3%; day 7, 19.0%; EOT, 23.0%) but increased over time for vancomycin (day 4, 8.4%; day 7, 12.3%; EOT, 19.3%). A significantly lower proportion of patients receiving vancomycin showed renal function decline on day 4 and day 7. At EOT, negative shift rates were similar between treatments (treatment difference 3.6% [95% CI -0.7 to 7.9]). At day 7 and EOT, a higher percentage of vancomycin-treated patients experienced high-grade negative shifts relative to telavancin (day 7, vancomycin 2.8% vs telavancin 1.9%; EOT, vancomycin 4.7% vs telavancin 4.1%), though differences were not statistically significant. CONCLUSION: Use of shift tables revealed differences in timing of renal function changes in patients receiving telavancin and vancomycin. Telavancin-related declines in renal function were similar at day 4 and day 7, with a slight increase by EOT. This differed from vancomycin, which caused a steady increase in the percentage of patients with renal function decline over time. A significant difference in negative renal shifts between treatments occurred at day 4 and day 7 and favored vancomycin; however, the difference was minimal and not significant at EOT.

Multiple-Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections.

OBJECTIVE: Oritavancin is a lipoglycopeptide antibiotic approved for use in acute bacterial skin and skin structure infections as a single 1200-mg parenteral dose. Because of oritavancin's long half-life and broad gram-positive activity, interest in its use for other infections is high. METHODS: This study is a retrospective cohort evaluation of patients receiving oritavancin at a single academic medical center. All patients receiving more than one dose of oritavancin were included. Patients were excluded if therapy was interrupted by more than 14 days. Efficacy, defined a priori as clinical success, improvement, or failure, and adverse drug effect outcomes were collected. RESULTS: Seventeen patients received multiple oritavancin doses (range 2-18 doses) for the treatment of complicated infections including osteomyelitis, surgical site infection, intravascular infections, and pneumonia. All patients achieved clinical success or improvement with oritavancin. Four patients (24%) had an adverse event requiring oritavancin discontinuation that reversed rapidly. CONCLUSIONS: Off-label oritavancin use may be a safe and effective alternative to daily antibiotic infusions to treat complicated infectious disease processes. This study is limited by small sample size and retrospective design, but it provides information on using oritavancin in these complex gram-positive infections.