Review
The clinical positioning of telavancin in Europe

https://doi.org/10.1016/j.ijantimicag.2014.12.006Get rights and content

Highlights

  • Clinical experience with the lipoglycopeptide telavancin in Europe is limited.

  • Telavancin has potent in vitro activity against Gram-positive isolates, e.g. meticillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA).

  • Telavancin is non-inferior to vancomycin for nosocomial Gram-positive pneumonia.

  • Baseline moderate-to-severe renal impairment increases mortality risk of telavancin.

  • Where renal function permits, telavancin is an alternative to vancomycin or linezolid.

Abstract

Telavancin was the first marketed lipoglycopeptide. Although licensed in Europe in 2011 for the treatment of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus (MRSA), it did not become clinically available until March 2014. Given the limited clinical experience with telavancin in Europe, this review provides an overview of its antimicrobial and clinical activity as well as its position among today's antimicrobials, with particular focus on the implications of its licensing requirements. Telavancin has potent in vitro activity against isolates of Gram-positive pathogens, including MRSA and glycopeptide-intermediate S. aureus strains. In addition, at clinically attainable doses telavancin inhibits Gram-positive isolates of antibiotic-resistant strains from biofilm models. The in vitro potency of telavancin has been corroborated in the clinical setting. Comparative clinical studies of telavancin demonstrate non-inferiority compared with vancomycin in the treatment of hospital-acquired Gram-positive pneumonia, with high cure rates for telavancin-treated patients with monomicrobial S. aureus infection, including isolates with reduced vancomycin susceptibility. These studies also demonstrate an overall similar safety profile for telavancin and vancomycin, although importantly, patients with moderate-to-severe renal impairment at baseline are at greater risk for mortality with telavancin and this feature must be taken into account when selecting patients for its usage. In Europe, telavancin is a useful alternative for patients with difficult-to-treat, hospital-acquired MRSA pneumonia when there are very few alternatives. For example, it should be considered in such patients when vancomycin and linezolid are not suitable and where renal function permits.

Introduction

On 18 March 2014, the lipoglycopeptide antimicrobial telavancin (VIBATIV®) became available once again in Europe. This followed the original 2011 approval of telavancin for proven or suspected meticillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia, including ventilator-associated pneumonia [1]. However – and uniquely in this field – the positive opinion of the European Medicines Agency (EMA) was qualified by the statement that telavancin should be used only in situations where it is known or suspected that other alternatives are not suitable. Given that clinical experience with telavancin in Europe is limited and that the compound comes into clinical use with this significant caveat about its utilisation, this review is intended to provide an overview of telavancin's clinical positioning in today's anti-MRSA hospital antimicrobial armamentarium.

Section snippets

History of telavancin in Europe

Telavancin was the first marketed lipoglycopeptide. It is a semisynthetic derivative of vancomycin with structural alterations instigating potent activity against multiple Gram-positive organisms. Discovered in 2004, telavancin was designed to share the favourable distribution properties of its parent compound while maintaining potent activity against antimicrobial-resistant organisms, as evaluated in animal models [2].

Telavancin was jointly developed by Theravance, Inc. (South San Francisco,

Licensing of telavancin

Telavancin was approved and launched in the USA in 2009 for the treatment of adult patients with complicated SSSIs caused by susceptible Gram-positive bacteria, including both MRSA and meticillin-susceptible S. aureus (MSSA) [18]. Although approved in Canada in 2009 for the same indication as in the USA (complicated SSSI), telavancin has not been launched in this country [19]. In June 2013, licensing of telavancin in the USA was expanded to include the treatment of adult patients with

Antimicrobial properties of telavancin

Telavancin displays activity against a broad spectrum of Gram-positive organisms, including those with reduced susceptibility to vancomycin [2], [3], [24], [25], [26], [27], [28], [29], [30]; however, as with other glycopeptides, it does not have activity against Gram-negative organisms. Telavancin has a dual mechanism of action, targeting the bacterial cell wall and membrane. As with vancomycin, and oritavancin and dalbavancin (the other semisynthetic lipoglycopeptides), telavancin inhibits

Clinical experience with telavancin in its licensed indications

The pooled findings from two phase 3 clinical studies of telavancin for the treatment of patients with hospital-acquired, Gram-positive pneumonia [the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) studies; NCT00107952 and NCT00124020] have been described in detail previously [13]. Briefly, 1532 patients from 274 study sites in 38 countries were randomised and 1503 patients received at least one dose of telavancin (10 mg/kg q24h) or the comparator vancomycin [1 g

Metabolism

Telavancin is not extensively metabolised and has been shown to be metabolically stable. Its plasma protein binding is high at ca. 90%. This is primarily to serum albumin and is not affected by renal or hepatic impairment [23]. Telavancin is not a substrate for any of the seven recombinant human CYP450s examined (1A2, 2C9, 2C19, 2D6, 3A4, 3A5 and 4A11). In humans, telavancin is excreted largely unchanged in the urine [23], [60], [61]. Following intravenous administration of 14C-labelled

Clinical positioning of telavancin

Uniquely, telavancin has been introduced into the clinical arena with the specific intention that it will be used effectively only as a last resort and where renal function permits. Undoubtedly this will present challenges for clinicians since the frequency of its deployment will inevitably be low so that in many instances there will be no familiarity with, or recollection of, using the compound. In some last-resort situations, clinicians may well be faced with the conundrum of considering

Conclusions

MRSA remains a public health priority in Europe and, despite a decrease in the incidence of MRSA infections in recent years, the proportion of S. aureus isolates reported as MRSA in 2012 was ≥25% in 7 of 30 European countries that provided surveillance reports [70]. Treatment options for hospital-acquired and ventilator-associated pneumonia caused by MRSA are limited in Europe, with vancomycin and linezolid being the most widely used [66]. However, these treatments have limitations, including

Funding

None.

Competing interests

RM has provided consultancy services and/or has been a speaker for AstraZeneca, Astellas, Basilea, Bayer Healthcare, Clinigen Specialty Pharmaceuticals, Janssen, Johnson & Johnson, Novartis, Pfizer and Sumitomo; GC has provided consultancy services for Clinigen Specialty Pharmaceuticals; PC has provided consultancy services and/or has been a speaker for Novartis, Pfizer and Cubist; HML has provided consultancy services and/or has been a speaker for AstraZeneca, Astellas, Basilea, Bayer

Ethical approval

Not required.

Acknowledgments

Medical writing support was provided by Rhian Harper Owen, an independent medical writer, funded by Clinigen Specialty Pharmaceuticals, Burton-on-Trent, UK (the European distributors of telavancin). The concept for the paper was developed at an Advisory Board held and funded by Clinigen Specialty Pharmaceuticals and at which the authors participated. The authors received no payment in respect of this publication.

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