Efficacy of telavancin, a lipoglycopeptide antibiotic, in experimental models of Gram-positive infection

Abstract

Telavancin is a parenteral lipoglycopeptide antibiotic with a dual mechanism of action contributing to bactericidal activity against multidrug-resistant Gram-positive pathogens. It has been approved for the treatment of complicated skin and skin structure infections due to susceptible Gram-positive bacteria and hospital-acquired/ventilator-associated bacterial pneumonia due to Staphylococcus aureus when other alternatives are unsuitable. Telavancin has been demonstrated to be efficacious in multiple animal models of soft tissue, cardiac, systemic, lung, bone, brain and device-associated infections involving clinically relevant Gram-positive pathogens, including methicillin-resistant S. aureus, glycopeptide-intermediate S. aureus, heterogeneous vancomycin-intermediate S. aureus and daptomycin non-susceptible methicillin-resistant S. aureus. The AUC_0–24h/MIC ratio is the primary pharmacodynamically-linked pharmacokinetic parameter. The preclinical data for telavancin supports further investigative clinical evaluation of its efficacy in additional serious infections caused by susceptible Gram-positive pathogens.

Keywords::

• bacteremia
• endocarditis
• Gram-positive bacteria
• methicillin-resistant Staphylococcus aureus
• osteomyelitis
• pneumonia
• skin diseases
• Staphylococcus aureus
• telavancin
• vancomycin resistance

Financial & competing interests disclosure

SS Hegde and JW Janc are employees of Theravance Biopharma US, Inc., and hold equity securities of the parent company Theravance Biopharma, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Manuscript editing and formatting assistance was provided by E Howard, formerly with Envision Scientific Solutions, funded by Theravance Biopharma Antibiotics, Inc.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Gram-positive infections are associated with significant morbidity and mortality.

• Infections caused by Gram-positive pathogens with decreased susceptibility to available therapies, particularly methicillin-resistant Staphylococcus aureus (MRSA), are contributing to a major public health crisis.

• Animal models of infection including those for skin/soft tissue and wound infections, bloodstream infections, pneumonia, osteomyelitis, endocarditis and device-related infections have been exploited with great predictive power to guide the development of novel antibacterials.

• Telavancin is a parenteral lipoglycopeptide antibiotic shown to be efficacious in multiple animal models of soft tissue, cardiac, systemic, lung, bone, brain and device-associated infections involving clinically relevant Gram-positive pathogens, including MRSA, glycopeptide-intermediate S. aureus, heterogeneous vancomycin-intermediate S. aureus and daptomycin non-susceptible MRSA.

• Telavancin is approved in the USA for the treatment of adult patients with complicated skin and skin-structure infections caused by susceptible isolates of Gram-positive pathogens and for the treatment of adult patients with hospital-acquired bacterial pneumonia (including ventilator-associated bacterial pneumonia) caused by susceptible strains of S. aureus when alternative treatments are not suitable [5]. Telavancin is approved in Europe for the treatment of nosocomial pneumonia caused by MRSA when other alternatives are unsuitable [6] and in Canada for the treatment of complicated skin and skin-structure infections caused by susceptible isolates of Gram-positive pathogens [7].

• The efficacy profile in additional in vivo models of infection for telavancin supports its further evaluation in indications beyond skin and lung infections, particularly bacteremia and osteomyelitis.

Notes

¹The MIC testing methodology and corresponding FDA-approved breakpoints for telavancin have recently been revised and are published in the CLSI M100-S24 guidelines [28] and telavancin product insert [5].