Oritavancin: an update

Oritavancin is a new antibacterial lipoglycopeptide that has been approved in the USA (2014) and in Europe (2015) for the treatment of acute bacterial skin and skin structure infections in adults. Oritavancin has a rapid bactericidal effect through its inhibition of bacterial cell wall biosynthesis and disruption of bacterial membrane integrity. Its main characteristic is the exceptionally long terminal half-life which allows for a single-dose regimen. Recently, we comprehensively reviewed oritavancin [1] and we are now providing an update including the most recent literature.

Two recent studies from Canada as well as the USA and Europe examined the antimicrobial activity of oritavancin against contemporary isolates. Susceptibility rates of >99% were found for methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Streptococcus spp. and Enterococcus spp. with an in vitro activity at least equivalent to or even more potent than vancomycin, daptomycin, linezolid or tigecycline [2,3]. Notably, in the Canadian study only 5 of 3408 isolates of S. aureus were considered nonsusceptible with a minimal inhibitory concentration (MIC) of 0.25 mg/l, which is one doubling dilution above the CLSI-approved susceptibility breakpoint (CLSI susceptibility breakpoint ≤0.12) [2,4]. Among the 2569 streptococci isolates from Europe, 11 were considered oritavancin resistant with an MIC of 0.5 mg/l (EUCAST resistance breakpoint for streptococci: 0.25 mg/l) [3, 5].

We previously speculated that the rapid bactericidal activity of oritavancin may be of benefit when treating infections where biofilms play a role, such as antibiotic lock therapy in patients with catheter-related infections [1]. Biofilms are a challenge to antibiotic therapy, since they consist of nondividing or slow-dividing bacteria which may be less amenable to drug action. Furthermore, penetration of the drug through the biofilm may be a limiting factor. An in vitro model, where time-kill assays were performed on nondividing bacteria from stationary cultures, showed better bactericidal activity for oritavancin than dalbavancin or vancomycin [6]. In contrast, data from an in vitro model of catheter-related infection did not demonstrate any effect on S. aureus biofilm viability with oritavancin, whereas a strong effect was seen with telavancin and dalbavancin [7]. Further animal studies are needed to resolve whether methodological hurdles, such as the binding to plasticware, are responsible for this negative result.

The worrisome increase of vancomycin-resistant Enterococcus faecium (VRE) infections calls for additional treatment options. Oritavancin shows good in vitro activity against vancomycin-susceptible and vancomycin-resistant enterococci. Interestingly, oritavancin is active against enterococci displaying the VanA phenotype (vancomycin MIC > 4 mg/l and teicoplanin MIC > 8 mg/l) and enterococci with VanB phenotype (vancomycin MIC >4 mg/l and teicoplanin MIC ≤ 8 mg/l). This is in contrast to dalbavancin and telavancin, which are only active against the VanB phenotype [2,8,9]. It is important to note, however, that the safety and efficacy of oritavancin in treating enterococcal infections, except for acute bacterial skin and skin structure infections, has not been established.

Although the emergence of isolates resistant to oritavancin has so far not been reported in the clinical setting, it is possible to generate nonsusceptible isolates in vitro. One study reports enterococci isolates with stably elevated MIC (up to 32-fold elevated) by serial passaging over 20 days. Interestingly, cross-resistance between oritavancin and vancomycin, daptomycin, linezolid or rifampicin has not been observed in these isolates [10].

Oritavancin, as well as daptomycin, shows a rapid bactericidal activity against S. aureus [11] and VRE [9]. Whether this rapid effect results in a clinical advantage is currently unclear. However, when high inocula of VRE are tested in vitro, oritavancin displayed a more potent killing than daptomycin. This is in contrast to S. aureus where both drugs have similar effects with high inocula [11].

Longer treatment durations could influence the ability of the drug to clear infections. An in vitro pharmacokinetic/pharmacodynamic model suggests that a single dose of oritavancin may not be sufficient against VRE isolates with reduced daptomycin susceptibility and thus several doses are needed [12]. How to best treat enterococcal infections and whether there is a clinical benefit in high-inoculum infections, such as osteomyelitis, remains to be shown in further animal studies and ultimately in clinical trials.

A difficulty encountered in clinical practice is that treatment with oritavancin can transiently affect results of laboratory diagnostic tests, especially coagulation parameters. This is attributed to interaction with phospholipid-containing laboratory agents. For example, the international normalized ratio can be falsely increased in some assays, whereas the activated partial thromboplastin time can be increased in all testing systems available until now. Diagnostic tests for thrombin time and activated protein C resistance are not affected. Further research is needed to categorize which tests can be safely conducted during oritavancin therapy [13].

Presumably, a key driver for the clinical development of oritavancin was the promise of a drug that would permit the discharge of patients and save costs associated with hospitalization. In a retrospective chart review of 118 patients with acute bacterial skin and skin structure infection in the USA, a comparable clinical effectiveness was observed between a multidose standard of care therapy and a single dose of oritavancin therapy [14]. As expected, oritavancin resulted in significant cost savings ($2139 USD per patient).

Since its introduction to the market, little progress has been made regarding the use of oritavancin. In the clinical trial register, clinicaltrials.gov, there are two small prospective clinical trials listed that have not yet been published. Both address multiple dosing in healthy subjects (NCT02470702) and in patients with acute bacterial skin and skin structure infection (NCT02925416). Another study addresses safety and tolerability of oritavancin in the pediatric population (NCT02134301).

Nevertheless, there are further key questions that remain unresolved. Future efforts need to address the role of oritavancin in treating biofilm-associated infections and treating infections with enterococci (esp. VRE). Most importantly, further randomized controlled clinical trials are needed.