Key points from the evidence

The content of this evidence summary was up-to-date in July 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Telavancin (Vibativ; Clinigen Healthcare Limited) is a lipoglycopeptide antibacterial agent, the first of a new class of antibiotics. It has been granted a marketing authorisation for the 'treatment of adults with nosocomial pneumonia including ventilator-associated pneumonia, known or suspected to be caused by methicillin-resistant Staphylococcus aureus (MRSA). Telavancin should only be used in situations where it is known or suspected that other alternatives are not suitable.' Two non-inferiority studies compared intravenous (IV) telavancin with IV vancomycin in patients with hospital-acquired pneumonia suspected to be due to Gram-positive pathogens. For the 2 individual studies and the pooled analysis telavancin was shown to be non-inferior to vancomycin for cure rates at follow-up assessment 7 to 14 days after the end of treatment. Telavancin has a risk of nephrotoxicity and increases the risk of mortality in patients with pre-existing acute renal failure.

Effectiveness

  • Two non-inferiority studies have shown that 7 to 21 days of intravenous (IV) telavancin 10 mg per kg every 24 hours is non-inferior to IV vancomycin 1 g every 12 hours in patients with hospital-acquired pneumonia suspected to be due to Gram-positive pathogens. In the all-treated population, cure rates 7 to 14 days after the end of treatment were 58.9% with telavancin and 59.5% with vancomycin (n=1503; pooled analysis of 2 RCTs).

  • Telavancin was not shown to be superior to vancomycin for the pooled analysis of cure rates for participants with confirmed MRSA (secondary outcome). For this subgroup (n=293) cure rates were 74.8% with telavancin and 74.7% with vancomycin.

Safety

  • The European public assessment report (EPAR) for telavancin concluded that the safety profile of telavancin was inferior to that of vancomycin.

  • The summary of product characteristics (SPC) includes a number of warnings and precautions that reflect the risk minimisation measures recommended by the Committee for Medicinal Products for Human Use.

  • Telavancin has a risk of nephrotoxicity and increases the risk of mortality in patients with pre-existing acute renal failure. The SPC lists acute renal failure as a common adverse reaction (between 1 in 10 and 1 in 100).

  • Telavancin is contraindicated in pregnancy (potential risk of teratogenicity).

  • The SPC states that there is a risk of QTc prolongation with telavancin.

Patient factors

  • Telavancin should be given as an intravenous infusion over 60 minutes. The SPC warns that there is a risk of infusion‑related reactions including red man syndrome-like reactions.

Resource implications

  • The cost of telavancin is anticipated to be £258 for a 250 mg vial and £645 for a 750 mg vial. Based on this price the treatment cost for a patient of 75 kg treated at a dose of 10 mg per kg every 24 hours would range from £4515 for 7 days to £9030 for 14 days of treatment.

  • Vancomycin at a dose of 1 g IV every 12 hours costs £225.54 for 7 days and £451.08 for 14 days of treatment.

  • Linezolid at a dose of 600 mg twice a day (given IV or orally) costs £623 for 7 days and £1246 for 14 days of treatment.

Introduction and current guidance

Hospital-acquired pneumonia is defined as pneumonia that occurs 48 hours or more after hospital admission and is not incubating at hospital admission. Early-onset (occurring within 4 days of admission) hospital-acquired pneumonia is usually caused by the same bacteria and viruses as community-acquired pneumonia and has a good prognosis. Late‑onset (starting 5 days or more after admission) hospital-acquired pneumonia has a worse prognosis and is usually caused by micro-organisms that are acquired from the hospital environment. MRSA, Pseudomonas aeruginosa and other non-pseudomonal Gram‑negative bacteria are the most common causes. NICE is currently developing a clinical guideline on pneumonia, which will cover both community- and hospital-acquired pneumonia in adults.

Full text of Introduction and current guidance.

Product overview

Telavancin is a lipoglycopeptide antibacterial agent, the first of a new class of antibiotics. Telavancin was granted a marketing authorisation from the European Medicines Agency in 2011 for 'the treatment of adults with nosocomial pneumonia including ventilator‑associated pneumonia, known or suspected to be caused by methicillin-resistant Staphylococcus aureus (MRSA)'. The marketing authorisation states that 'telavancin should only be used in situations where it is known or suspected that other alternatives are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents'. The antimicrobial resistance page of the Public Health England website provides guidance to the NHS on this topic. Telavancin is active against Gram‑positive bacteria only. In mixed infections where Gram‑negative or certain types of anaerobic bacteria are suspected, telavancin should be given with the appropriate antibacterial agent(s) (summary of product characteristics).

Full text of Product overview.

Evidence review

  • This evidence summary is based on a pooled analysis of 2 identically designed randomised controlled trials (RCTs) (Rubinstein et al. 2011). The 2 studies were conducted in patients with hospital-acquired pneumonia suspected to be due to Gram‑positive pathogens. The studies compared intravenous (IV) telavancin (10 mg per kg every 24 hours) with IV vancomycin (1 g every 12 hours) for 7 to 21 days for the primary outcome of clinical response at follow-up or test-of-cure visit. The studies were designed to show that telavancin was non-inferior to vancomycin.

  • For the individual 2 studies and the pooled analysis telavancin was shown to be non‑inferior to vancomycin for cure rates at follow-up assessment 7 to 14 days after the end of treatment. In the pooled all-treated population (n=1503) cure rates were 58.9% (441/749) with telavancin compared with 59.5% (449/754) with vancomycin. In the pooled clinically evaluable population (n=654) cure rates were 82.4% (257/312) with telavancin compared with 80.7% (276/342) with vancomycin.

  • Telavancin was not shown to be superior to vancomycin for the pooled analysis of cure rates for participants with confirmed MRSA (secondary outcome). In participants with confirmed MRSA, cure rates were 74.8% (104/139) with telavancin compared with 74.7% (115/154) with vancomycin.

  • A post-hoc analysis of Rubinstein et al. (2011) (Torres et al. 2014) excluded people with severe renal impairment and pre-existing acute renal failure at baseline. Clinical cure rates in the all-treated and clinically evaluable populations were similar for telavancin and vancomycin and similar to the rates reported by Rubinstein et al. (2011).

  • A second post-hoc analysis of Rubinstein et al. (2011) (Corey et al. 2014) investigated 28-day all-cause mortality in a subgroup of the all-treated population (n=1289). Overall 28-day survival rates were similar in the telavancin group (76%) and vancomycin group (77%). However, survival rates were lower in the telavancin group for patients with moderate to severe or severe renal impairment.

  • The European public assessment report for telavancin (EPAR) concluded that the safety profile of telavancin was inferior to that of vancomycin. Despite telavancin having a non‑favourable benefit/risk balance in the overall patient population, the Committee for Medicinal Products for Human Use (CHMP) acknowledged that for patients with nosocomial pneumonia due to Gram-positive pathogens and who cannot receive commonly used antibacterial agents (for example, because of hypersensitivity or MRSA) there are limited treatment options for this life-threatening infection. The CHMP therefore considered that the benefit/risk balance of telavancin was favourable for treating nosocomial pneumonia, including ventilator-associated pneumonia, known or suspected to be caused by MRSA, exclusively in situations where it is known or suspected that other alternatives are not suitable. However they recommended a number of risk minimisation measures which are reflected in the summary of product characteristics (SPC).

  • An application for a marketing authorisation for complicated skin and soft tissue infections was also submitted for telavancin. However, the CHMP considered the benefit/risk balance for this indication to be negative. Therefore, the EPAR states that telavancin should not be used for this or any other indications not approved.

  • Telavancin has a risk of nephrotoxicity and increases the risk of mortality in patients with pre-existing acute renal failure. The SPC lists acute renal failure as a common adverse reaction (between 1 in 10 and 1 in 100) and states that telavancin is contraindicated in patients with acute renal failure and in patients with severe renal impairment (creatinine clearance less than 30 ml/min, including patients undergoing haemodialysis). Patients with a creatinine clearance of 30 to 50 ml/min should have the dose reduced to 7.5 mg per kg every 24 hours. All patients receiving telavancin should have their renal function monitored daily for at least the first 3 to 5 days of treatment and every 48 to 72 hours thereafter.

  • Telavancin is contraindicated in pregnancy (potential risk of teratogenicity). The summary of product characteristics states that the pregnancy status of women of childbearing potential has to be established before treatment is given.

  • The manufacturer of telavancin sent a direct healthcare professional communication letter in June 2014 highlighting important safety concerns associated with the use of telavancin. The letter which is available on the MHRA website highlights the risks of nephrotoxicity, QTc prolongation, reproductive toxicity and off-label use and outlines how to manage these safety concerns in order to minimise the risk to the patient.

  • The most common adverse reactions (occurring in more than 1% of patients) reported in the summary of product characteristics are fungal infection, insomnia, dysgeusia, headache, dizziness, nausea, constipation, diarrhoea, vomiting, increased alanine aminotransferase and increased aspartate aminotransferase, pruritus, rash, acute renal failure, increased blood creatinine, urine abnormality (foamy urine), fatigue and chills.

Full text of Evidence review.

Context

Alternative treatment options for hospital-acquired pneumonia caused by MRSA include intravenous (IV) vancomycin and (IV or oral) linezolid.

Full text of Context

Estimated impact for the NHS

Telavancin has a very narrow approved indication. It has been granted a marketing authorisation for the 'treatment of adults with nosocomial pneumonia including ventilator‑associated pneumonia, known or suspected to be caused by MRSA. Telavancin should only be used in situations where it is known or suspected that other alternatives are not suitable.'

As stated in the approved indication, consideration should be given to official guidance on the appropriate use of antibacterial agents.

The manufacturer considers that telavancin is a treatment reserved for use only when other treatments such as intravenous (IV) vancomycin and linezolid (IV or oral) are inappropriate or have failed and is, therefore, a third-line treatment option for adults with hospital-acquired pneumonia known or suspected to be caused by MRSA (Clinigen Healthcare Limited: personal communication March and May 2014).

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.