Mechanism of Action

Telavancin is an antibacterial drug.

Pharmacodynamics

The antimicrobial activity of telavancin appears to best correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. An exposure-response analysis of 2 cSSSI clinical trials supports the dose of 10 mg/kg every 24 hours.

Cardiac Electrophysiology

The effect of telavancin on cardiac repolarization was assessed in a randomized, double-blind, multiple-dose, positive-controlled, and placebo-controlled, parallel study (n=160). Healthy subjects received VIBATIV (telavancin for injection) 7.5 mg/kg, VIBATIV (telavancin for injection) 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from VIBATIV (telavancin for injection) 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebo-corrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for VIBATIV (telavancin for injection) 10 mg/kg and 22 msec for the positive control (Table 5). By 1 hour after infusion the maximum QTc prolongation was 6-9 msec for VIBATIV (telavancin for injection) and 15 msec for the positive control.

Table 5 : Mean and Maximum QTcF Changes from Baseline Relative to Placebo

ECGs were performed prior to and during the treatment period in patients receiving VIBATIV (telavancin for injection) 10 mg/kg in 3 studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with VIBATIV (telavancin for injection) and 164 of 1033 (16%) allocated to vancomycin received concomitant medications known to prolong the QTc interval and are known to be associated with definite or possible risk of torsades de pointes. The incidence of QTc prolongation > 60 msec was 1.5% (15 patients) in the VIBATIV (telavancin for injection) group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 VIBATIV (telavancin for injection) patients received concomitant medications known to prolong the QTc interval and definitely or possibly associated with a risk of torsades de pointes, compared with 1 of the 6 patients who received vancomycin. A similar number of patients in each treatment group ( < 1%) who did not receive a concomitant medication known to prolong the QTc interval experienced a prolongation > 60 msec from baseline. In a separate analysis, 1 patient in the VIBATIV (telavancin for injection) group and 2 patients in the vancomycin group experienced QTc > 500 msec. No cardiac adverse events were ascribed to prolongation of the QTc interval.

Pharmacokinetics

The mean pharmacokinetic parameters of telavancin (10mg/kg) after a single and multiple 60-minute intravenous infusions (10 mg/kg every 24 hours) are summarized in Table 6.

Table 6: Pharmacokinetic Parameters of Telavancin in Healthy Adults, 10 mg/kg

In healthy young adults, the pharmacokinetics of telavancin administered intravenously were linear following single doses from 5 to 12.5 mg/kg and multiple doses from 7.5 to 15 mg/kg administered once-daily for up to 7 days. Steady-state concentrations were achieved by the third daily dose.

Distribution

Telavancin binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The mean binding is approximately 90% and is not affected by renal or hepatic impairment.

Concentrations of telavancin in skin blister fluid were 40% of those in plasma (AUC_0-24hr ratio) after 3 daily doses of 7.5 mg/kg VIBATIV (telavancin for injection) in healthy young adults.

Metabolism

No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11. The clearance of telavancin is not expected to be altered by inhibitors of any of these enzymes.

In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for < 10% of the radioactivity in urine and < 2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.

Excretion

Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and < 1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.

Specific Populations

Geriatric Patients

The impact of age on the pharmacokinetics of telavancin was evaluated in healthy young (range 21-42 years) and elderly (range 65-83 years) subjects. The mean CrCl of elderly subjects was 66 mL/min. Age alone did not have a clinically meaningful impact on the pharmacokinetics of telavancin [see Use in Specific Populations].

Pediatric Patients

The pharmacokinetics of telavancin in patients less than 18 years of age have not been studied.

Gender

The impact of gender on the pharmacokinetics of telavancin was evaluated in healthy male (n=8) and female (n=8) subjects. The pharmacokinetics of telavancin were similar in males and females. No dosage adjustment is recommended based on gender.

Renal Impairment

The pharmacokinetics of telavancin were evaluated in subjects with normal and subjects with varying degrees of renal impairment following administration of a single dose of telavancin 7.5 mg/kg (n=28). The mean AUC_0-∞- values were approximately 13%, 29%, and 118% higher for subjects with CrCl > 50 to 80 mL/min, CrCl 30 to 50 mL/min, and CrCl ≤ 30 mL/min, respectively, compared to subjects with normal renal function. Dosage adjustment is required in patients with CrCl ≤ 50 mL/min [see DOSAGE AND ADMINISTRATION].

Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:

CrCl = [140 – age (years)] x ideal body weight (kg)* /[72 x serum creatinine (mg/dL)] {x 0.85 for female patients}

*Use actual body weight if < ideal body weight (IBW)
IBW (male) = 50 kg + 0.9 kg/cm over 152 cm height
IBW (female) = 45.5 kg + 0.9 kg/cm over 152 cm height

Following administration of a single dose of VIBATIV (telavancin for injection) 7.5 mg/kg to subjects with end-stage renal disease, approximately 5.9% of the administered dose of telavancin was recovered in the dialysate following 4 hours of hemodialysis. The effects of peritoneal dialysis have not been studied.

Following a single intravenous dose of VIBATIV (telavancin for injection) 7.5 mg/kg, the clearance of hydroxypropyl-beta-cyclodextrin was reduced in subjects with renal impairment, resulting in a higher exposure to hydroxypropyl-beta-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, the mean clearance values were 38%, 59%, and 82% lower, respectively, compared to subjects with normal renal function. Multiple infusions of VIBATIV (telavancin for injection) may result in accumulation of hydroxypropyl-beta-cyclodextrin.

Hepatic Impairment

The pharmacokinetics of telavancin were not altered in subjects with moderate hepatic impairment (n= 8, Child-Pugh B) compared to healthy subjects with normal hepatic function matched for gender, age, and weight. The pharmacokinetics of telavancin have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Drug Interactions

In Vitro

The inhibitory activity of telavancin against the following CYP 450 enzymes was evaluated in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, and 3A4/5. Telavancin inhibited CYP 3A4/5 at potentially clinically relevant concentrations. Upon further evaluation in a Phase 1 clinical trial, telavancin was found not to inhibit the metabolism of midazolam, a sensitive CYP3A substrate (see below).

Midazolam

The impact of telavancin on the pharmacokinetics of midazolam (CYP 3A4/5 substrate) was evaluated in 16 healthy adult subjects following administration of a single dose of VIBATIV (telavancin for injection) 10 mg/kg, intravenous midazolam 1 mg, and both. The results showed that telavancin had no impact on the pharmacokinetics of midazolam and midazolam had no effect on the pharmacokinetics of telavancin. Therefore, telavancin is unlikely to alter the pharmacokinetics of drugs metabolized by the CYP450 system to a clinically significant degree.

Aztreonam

The impact of telavancin on the pharmacokinetics of aztreonam was evaluated in 11 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, aztreonam 2 gm, and both. Telavancin had no impact on the pharmacokinetics of aztreonam and aztreonam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or aztreonam is recommended when both drugs are coadministered.

Piperacillin-tazobactam

The impact of telavancin on the pharmacokinetics of piperacillin-tazobactam was evaluated in 12 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, piperacillin-tazobactam 4.5 g, and both. Telavancin had no impact on the pharmacokinetics of piperacillin-tazobactam and piperacillin-tazobactam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or piperacillin-tazobactam is recommended when both drugs are coadministered.

Microbiology

Telavancin is a semisynthetic, lipoglycopeptide antibiotic. Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive organisms in vitro, as demonstrated by time-kill assays and MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. In vitro studies demonstrated a telavancin post-antibiotic effect ranging from 1 to 6 hours against S. aureus and other Gram-positive pathogens.

Although telavancin is approximately 90% protein bound, the presence of human serum or human serum albumin has minimal impact on the in vitro activity of telavancin against staphylococci, streptococci, and vancomycin-susceptible enterococci.

Mechanism of Action

Telavancin inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan. Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Interactions with Other Antibacterials

In vitro investigations demonstrated no antagonism between telavancin and amikacin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, rifampin, and trimethoprim/sulfamethoxazole, when tested in various combinations against telavancin susceptible staphylococci, streptococci, and enterococci. This information is not available for other bacteria.

Cross-Resistance

Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. There is no known cross-resistance between telavancin and other classes of antibiotics.

Antibacterial Activity

Telavancin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections as described in the Indications and Usage section [see INDICATIONS AND USAGE]:

Facultative Gram-Positive Microorganisms

Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus pyogenes
Enterococcus faecalis (vancomycin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

Greater than 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the telavancin-susceptible breakpoint for organisms of similar genus shown in Table 7. The safety and effectiveness of telavancin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Facultative Gram-Positive Microorganisms

Enterococcus faecium (vancomycin-susceptible isolates only)
Staphylococcus haemolyticus
Streptococcus dysgalactaie subsp. equisimilis
Staphylococcus epidermidis

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution technique

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure [see References]. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of telavancin powder. The MIC values should be interpreted according to the criteria provided in Table 7.

Diffusion technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations [see References]. This procedure uses paper disks impregnated with 30 mcg of telavancin to test the susceptibility of microorganisms to telavancin. The disk diffusion interpretive criteria are provided in Table 7.

Table 7 : Susceptibility Interpretive Criteria for Telavancin

A report of “susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor the performance of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard telavancin powder should provide the range of values noted in Table 8.

Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.

Table 8 : Acceptable Quality Control Ranges for Telavancin to be used in Validation of Susceptibility Test Results

Animal Toxicology and/or Pharmacology

Two-week administration of telavancin in rats produced minimal renal tubular vacuolization with no changes in BUN or creatinine. These effects were not seen in studies conducted in dogs for similar duration. Four weeks of treatment resulted in reversible elevations in BUN and/or creatinine in association with renal tubular degeneration that further progressed following 13 weeks of treatment.

These effects occurred at exposures (based on AUCs) that were similar to those measured in clinical trials.

The potential effects of continuous venovenous hemofiltration (CVVH) on the clearance of telavancin were examined in an in vitro model using bovine blood. Telavancin was cleared by CVVH and the clearance of telavancin increased with increasing ultrafiltration rate [see OVERDOSAGE].

Clinical Trials

Complicated Skin and Skin Structure Infections

Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) were enrolled in two randomized, multinational, multicenter, double-blinded trials (Trial 1 and Trial 2) comparing VIBATIV (telavancin for injection) (10 mg/kg IV every 24 hours) with vancomycin (1 g IV every 12 hours) for 7 to 14 days. Vancomycin dosages could be adjusted per site-specific practice. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. These trials were identical in design, enrolling approximately 69% of their patients from the United States.

The trials enrolled adult patients with cSSSI with suspected or confirmed MRSA as the primary cause of infection. The all-treated efficacy (ATe) population included all patients who received any amount of study medication according to their randomized treatment group and were evaluated for efficacy. The clinically evaluable population (CE) included patients in the ATe population with sufficient adherence to the protocol.

The ATe population consisted of 1,794 patients. Of these, 1,410 (78.6%) patients were clinically evaluable (CE). Patients with demographic and baseline characteristics were well-balanced between treatment groups and are presented in Table 9.

Table 9 : Baseline Infection Types in Patients in Trials 1 and 2 – ATe Population

The primary efficacy endpoints in both trials was the clinical cure rates at a follow-up (Test of Cure) visit in the ATe and CE populations. Clinical cure rates in Trials 1 and 2 are displayed for the ATe and CE population in Table 10.

Table 10: Clinical Cure at Test-of-Cure in Trials 1 and 2 - ATe and CE Populations

The cure rates by pathogen for the microbiologically evaluable (ME) population are presented in Table 11.

Table 11 : Clinical Cure Rates at the Test-of-Cure for the Most Common Pathogens in Trials 1 and 2 – ME Population¹

In the two cSSSI trials, clinical cure rates were similar across gender and race. Clinical cure rates in the telavancin clinically evaluable (CE) population were lower in patients 65 years of age compared to those < 65 years of age. A decrease of this magnitude was not observed in the vancomycin CE population. Clinical cure rates in the telavancin CE population < 65 years of age were 503/581 (86.6%) and in those 65 years were 88/122 (72.1%). In the vancomycin CE population clinical cure rates in patients < 65 years of age were 492/570 (86.3%) and in those 65 years was 111/137 (82.0%). Clinical cure rates in the telavancin-treated patients were lower in patients with baseline CrCl 50 mL/min compared to those with CrCl > 50 mL/min. A decrease of this magnitude was not observed in the vancomycin-treated patients [see WARNINGS AND PRECAUTIONS].

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 8th ed., CLSI document M7-A8, CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA. 19087-1898, 2009.

2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests, Approved Standard – 10th ed. CLSI document M2-A10; CLSI, Wayne, PA. 19087-1898, 2009.

3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing - 19th Informational Supplement. CLSI document M100-S19, CLSI, Wayne, PA. 19087-1898, 2009.

Last reviewed on RxList: 9/17/2009
This monograph has been modified to include the generic and brand name in many instances.