Another anti-MRSA agent making its way to the market

There has been an intensified focus on the emergence of methicillin-resistant Staphlococcus aureus, both community-acquired and hospital-acquired strains, throughout the past 10 years. Staph aureus is associated with human disease ranging from non-invasive skin and soft tissue infections to invasive infections of the bone, cardiovascular system, blood and lungs.

S. aureus quickly mounts resistance to antibiotics. Shortly after the introduction of penicillin to the market in the 1940s, resistant strains of S. aureus were isolated. The response was research and the development of methicillin in 1960s. Remarkably, methicillin-resistant S. aureus (MRSA) was quickly noted in 1961. Vancomycin had been discovered in the 1950s but was rarely used due to its toxicity profile. The increasing prevalence of MRSA led to the reformulation of vancomycin in the 1970s and its place in therapy as the drug of choice for MRSA infections was established. Hospital-acquired MRSA was first identified in 1968. Since then, MRSA rates have risen to nearly 60% in intensive care units as noted in 2004 by Klevens et al.

Market research and development also surged to find new anti-MRSA agents. Linezolid (Zyvox, Pharmacia and Upjohn), daptomycin (Cubicin, Cubist) and quinupristin/dalfopristin (Synercid, King) have made their way to the market to treat some types of MRSA infections. The newest agent, telavancin (Vibativ, Astellas, Theravance) has been approved to treat adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of gram-positive infections, including MRSA.

Telavancin

Telavancin is a novel lipoglycopeptide with rapidly acting batericidal activity. It is a semi-synthetic derivative of vancomycin. It is highly active against multi-drug resistant gram positive bacteria, like MRSA, vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA).

Telavancin exerts its concentration- dependent, bactericidal activity uniquely by having multiple mechanisms of action. It can bind to the bacterial membrane, disrupting membrane barrier function by interference of peptidoglycan polymerization and cross-linking, causing loss in bacterial cell viability. Telavancin also inhibits transglycosylase activity (binding to the D -Ala-D -Ala terminal) ultimately leading to inhibition of cell wall synthesis. It is thought it has higher affinity for D -Ala-D –Ala giving it a 10-fold greater potency toward inhibition of peptidoglycan synthesis.

On Sept. 14, 2009, Theravance Inc. announced that FDA approved marketing of telavancin for injection for the treatment of complicated skin and skin-structure infections. It will be indicated for the treatment of skin infections caused by susceptible pathogens. The recommended starting dose is 10 mg/kg intravenously every 24 hours. Telavancin will require infusion over at least 60 minutes to avoid the infusion related reaction of Red man’s syndrome.

Telavancin displays linear and predictable pharmacokinetics. Studied doses ranged from 7.5-15 mg/kg/day and resulted in serum drug concentrations of 96.7-202.5 microgram/mL, respectively. Elimination half-life (t _) has been observed at seven to nine hours, which will allow for convenient once-daily dosing. Telavancin will be predominately excreted via renal elimination with 60% to 70% unchanged in the urine. Dose reductions for patients with moderate to severe renal dysfunction will be required.

A pharmacokinetic debate circles around the substantially higher plasma protein binding of this drug. Plasma protein binding is 93% vs. 50% for telavancin and vancomycin, respectively. It is suspected that only unbound drug is able to have antimicrobial effects on susceptible pathogens. If telavancin is so highly protein bound, it is thought less drug exists at the site of infection. Time-kill experiments have evaluated the MIC changes of Staphylococcus spp. in the presence and absence of serum and found a two-fold increase in MIC of telavancin. Telavancin maintained bactericidal activity despite this increase, which suggests the mechanism of action is independent of protein binding. The clinical effect of this controversy is not yet known.

Telavancin, like other concentration dependent killing antibiotics, has postantibiotic effect (PAE). PAE was estimated at four to six hours against Staph spp., including MSSA, MRSA and VISA. Vancomycin has a PAE of only one hour. In pharmacokinetic/pharmacodynamic modeling, AUC to MIC ratio was the most predictive of telavancin efficacy. The lowest maximum concentration resulting in no growth at 24 hours was 5 mg/L (AUC/MIC ration of 50) and equivalent to a dose of 10 mg/kg once daily.

The treatment of cSSSI is the only labeled approval for telavancin by the FDA. Several studies led to the approval for this particular indication. The FAST and FAST2 Studies were phase 2 trials conducted to evaluate the treatment of cSSSIs. Both FAST and FAST2 assessed the data on safety and efficacy of telavancin at doses of 7.5 mg/kg once daily and 10 mg/kg once daily, respectively. Each was conducted as a randomized, double-blind, active-controlled multicenter trial. FAST evaluated adult cSSSI infections (n=167) who received one of the following: telavancin 7.5 mg/kg once daily, vancomycin 1 gm every 12 hours and/or nafcillin 2 gm every six hours, oxacillin 2 gm every six hours, or cloxacillin 0.5-1 gm every six hours (dose adjustments were allowed per site standard practice). FAST 2 used 10 mg/kg once daily of telavancin compared with the same agents in FAST (n=195). The results in both studies were similar and demonstrated comparable cure rates to the other agents, no statistical difference was found. The most substantial weakness of these studies is the initial dosing of vancomycin at 1 gm IV every 12 hours. There are sufficient data now to suggest when treating

S. aureus (MSSA and MRSA) infections, a standard 1 gm dose for most patient with normal renal function will not achieve goal trough levels.

Phase 3 trials

Two phase 3 trials have been conducted (ATLAS I and II). ATLAS I and II were identical randomized, double-blind multicenter trials. Telavancin 10 mg/kg once daily was compared to vancomycin 1 gm every 12 hours. In ATLAS I (n=1867), cure rates were similar between the two groups; 88.3% cure (90.6% cure for evaluated MRSA) and 87.1% cure (84.4% cure for evaluated MRSA). No statistical difference was shown. ALTAS II was a retrospective sub-study of telavancin versus vancomycin for treatment of cSSSI associated with surgical procedures. The subset (n=194) of the original patients of ATLAS I was evaluated for clinical efficacy and microbiological efficacy at test-of-cure (7-14 days at completion of therapy). The results of this study did not demonstrate statistical difference between the groups. The authors concluded that telavancin was at least equivalent to vancomycin for the treatment of cSSSI, associated with a surgical site.

While telavancin studies showed the drug to be safe and effective, telavancin did report significantly more serious adverse effects. Its package insert will include a black box warning for fetal risk. It is encouraged that women of childbearing potential should receive a serum pregnancy test prior to administration of telavancin. Adverse developmental outcomes have been observed in three animal models at clinically relevant doses, raising a concern for similar outcomes in humans. Other major adverse events noted were: increased nephrotoxicity, including a decreased efficacy with moderate to severe baseline renal impairment, infusion related reaction (Red man’s syndrome), QTc prolongation, and coagulation test interferences. Other non-serious adverse drug reactions reported at ≥ 2% were rigors, generalized pruritis, nausea/vomiting, diarrhea and abdominal pain. Nausea/vomiting rates were noted to be much higher in the telavancin group compared to vancomycin (27%/14% vs. 15%/7%).

Serious adverse effects

An increase in serum creatinine (1.5 times baseline) occurred more often in the telavancin treated group compared with vancomycin treated group (15% vs. 7%). In a subgroup analysis of pooled cSSSI studies, clinical cure rates in the telavancin-treated patient were lower in patients with baseline CrCl < 50 mL/min compared to those with CrCl ≤ 50 mL/min. This effect has not been noted in vancomycin treated patients and this should be clinically considered when selecting this agent when treating a serious gram-positive skin infection.

Infusion related reaction (Red man’s Syndrome)

This adverse effect was observed in patients receiving multiple different doses of telavancin. It is common in the glycopeptides class of antimicrobial agents and can be avoided by prolonging the infusion to 60 minutes.

QTc prolongation

Prolongation of the QTc interval was seen in healthy volunteers receiving doses of 7.5 mg/kg and 15 mg/kg of telavancin. Extreme caution is warranted for patients who are taking drugs known to prolong the QT interval as well as those patients with long QT syndrome, uncompensated heart failure or severe left ventricle hypertrophy. Pharmacists will need to conduct drug profile reviews on these patients for other medication that may prolong QTc and physicians will need to monitor patients closely for cardiac abnormalities/changes.

The focus of health care organizations to control and effectively treat serious infections caused by pathogenic gram-positive organisms (including MRSA, VISA, and VRSA) will continue to intensify. Full knowledge of antimicrobial agents available to treat these infections and their drug profiles is essential to caring for patients. Telavancin is another agent to add to our arsenal for cSSSI. Telavancin’s initial studies for efficacy are promising but the adverse drug effect profiles are concerning. As history has proven, S. aureus is extremely adaptive and quickly mounts resistance. Telavancin’s place in therapy will be for treatment failures with other first line gram-positive antimicrobials and in the future for increasing resistance of gram-positive pathogens.

Kimberly Boeser, PharmD, is the Infectious Disease Clinical Pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.