Natural glycopeptide antibiotics like vancomycin and teicoplanin have played a significant role in countering the threat posed by Gram-positive bacterial infections. The emergence of resistance to glycopeptides among enterococci and staphylococci has prompted the search for second-generation drugs of this class and semi-synthetic derivatives are currently under clinical trials. 

Figure 1. Structural formula of Oritavancin diphosphate

Antimicrobial resistance among Gram-positive organisms has been increasing steadily during the past several decades and the current development of antibiotics falls short of meeting the needs. Oritavancin (LY-333328 diphosphate), a promising novel second-generation semisynthetic lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides, which originally discovered by Eli Lilly Research Laboratories for use in the treatment of serious bacterial infection with resistant gram-positive pathogens. It has concentration-dependent activity against a variety of Gram-positive organisms specially methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate resistant Staphylococcus aureus (VISA), Streptococcus pneumoniae and vancomycin-resistant enterococcus. It is rapidly bactericidal against many species and in particular for enterococci where vancomycin and teicoplanin are only bacteriostatic even against susceptible strains. The pharmacokinetic profile of oritavancin has not been fully described; however, oritavancin has a long half-life of about 195.4 hours and is slowly eliminated by renal means. 

Oritavancin is not metabolized by the liver in animals. Oritavancin diphosphate will most probably be prescribed as a once-daily dose and it demonstrates concentration-dependent bactericidal activity. Various clinical studies of oritavancin diphosphate have shown good performance. 

Oritavancin diphosphate has demonstrated preliminary safety and efficacy in Phase I and II clinical trials. In a Phase III clinical trial, oritavancin diphosphate has achieved the primary efficacy end point in the treatment of complicated Gram-positive skin and skin-structure infections. To date, adverse events have been mild and limited; the most common being administration site complaints, headache, rhinitis, dry skin, pain, increases in liver transaminases and accumulation of free cholesterol and phospholipids in phagocytic (macrophages) and nonphagocytic (fibroblast) cells. 

Statistical differences in adverse events were oedema and tremor which were more common with the higher dose of oritavancin and pulmonary embolism/thrombosis. Oritavancin diphosphate appears to be a promising antimicrobial alternative to vancomycin (with additional activity against Staphylococcus and Enterococcus resistant to vancomycin) for the treatment of complicated Gram-positive skin and skin-structure infections. Additional clinical data are required to fully assess its use.

Despite the remarkable properties, the use of this potent agent should be restricted to severe infection caused by resistant or poorly sensitive Gram-positive organisms, to limit the risk of potential selection of resistance. Large clinical studies (including safety studies) will aid in positioning this compound in the arsenal of new antiGram-positive agents.

References

[1] Das B , Sarkar C , Schachter J . Review - Oritavancin – A new semisynthetic lipoglycopeptide agent to tackle the challenge of resistant gram positive pathogens[J]. Pakistan Journal of Pharmaceutical Sciences, 2013, 26(5):1045-1055.
[2] Atul K, Henry J M. Visual compatibility of oritavancin diphosphate with selected coadministered drugs during simulated Y?site administration[J]. Am J Health-Syst Pharm. 2010, 67:1640-1644.
[3] Dennis J, Cada,Danial E, Baker.Oritavancin diphosphate.[J].Hospital pharmacy,2014,49(11):1049-60.
[4] https://pubchem.ncbi.nlm.nih.gov/compound/53297457
[5] https://www.chemspider.com/Chemical-Structure.30791862.html?rid=8240164b-9e46-431b-87dc-7fea7f78c5e7