Hospital-acquired pneumonia caused by methicillin-resistant Staphylococcus aureus: telavancin

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.