Ahorita-que? The New Gram Positive Antibiotic, Oritavancin

Vancomycin is the work-horse antibiotic every person reaches for. It is a glycopeptide that covers a wide range of gram positive bacteria, with its niche being in its coverage of methicillin-resistant staphylococcus aureus and Enterococcus spp. It is bacteriostatic, with dosing issues and highly nephrotoxic, however it is ubiquitous throughout any hospital in the United States. I honestly think people think this is the only antibiotic that exists. The problem here, of course, is the high risk of resistance to vancomycin developing. Other types of antibiotics exist, such as TMP-SMX, linezolid, and daptomycin which all work via different mechanisms of action. One of the newer toys that we have is oritavancin. 

Oritavancin is a semisynthetic lipoglycopeptide in the same class as telavancin and dalbavancin and related to the one and only, vancomycin (as you can see based on the suffix -cin, 1). They all contain a common heptapeptide core, which allows them to inhibit cell wall synthesis and transpeptidation by binding to the C-terminal D-Ala-D-Ala end of the growing chain. While the core structure is the same as in vancomycin, there are structural changes to the side chains that allows oritavancin to have improved activity against Enterococci and VRE by giving it additional mechanisms of action on top of cell wall synthesis inhibition (1,2):

There is a lot going on there, but lets blow up up the structure to see the other mechanisms (1,2):

1. It is able to bind to the D-Ala-D-Lac end of the growing cell wall, which is a common resistance organism in Enterococci spp harboring the VanA gene
2. It forms homodimers prior to binding to the D-Ala-D-Ala/D-Lac end, increasing the binding affinity
3. It anchors itself against the cell wall, allowing concentration dependent membrane depolarization

In terms of pharmacokinetics, it has a high degree of protein binding and large volume of distribution, resulting in a half-life of around 393 hours (3). As a result, many of the studies on oritavancin evaluate a single dose, which lasts for the entire treatment duration without any downsides. It is rapidly bactericidal in a concentration dependent manner, with the Cmax:MIC ratio being the pharmacodynamic parameter that best describes its activity. For instance, a Cmax:MIC ratio of 4 is sufficient to produce bactericidal activity in vitro against a standard (10⁵) inoculum of MRSA. Given the long plasma half-life, the time above MIC and the AUC to MIC ratio are also highly correlated with its activity. 

Spectrum of Activity

It should be noted that oritavancin, like other MRSA agents with broad spectrum of activity, was approved for skin and soft tissue infections, an indication no one really uses it for. Indeed, ID folks will pull out things like tedizolid and daptomycin for severe invasive disease and not for cellulitis. I mention this because you are more than likely going to encounter oritavancin as a last resort rather than a first line agent. Due to this, I find susceptibility studies helpful. 

In one cohort of 886 gram-positive bacteria, oritavancin was able to inhibit all strains of MRSA, MRCoNS, beta-hemolytic streptococci, VRE, and almost all strains of S. pyogenes (4):

Another study evaluated the in vitro activity of oritavancin against over 9000 S. aureus isolates from the US and Europe (5). Oritavancin demonstrated potent activity and inhibited all MSSA strains, along with MRSA. Notably, the MIC was significantly higher in strains of MRSA with Daptomycin MIC of 1 to 4 and vancomycin MIC of 2, although it still inhibited these isolates (threshold used here for inhibition <0.5ug/mL):

Oritavancin also displayed potent activity against vancomycin-susceptible and vanB-carrying E. faecalis and E. faecium isolates. MIC was higher in those carrying vanA, however it still inhibited these strains (6):

A larger study of over 15,000 gram positive pathogens causing bloodstream infections found that over 99.5% of staphylococcus aureus isolates were susceptible, while 96-99% of E. faecalis samples being susceptible at any given point (7). High susceptibility rates were also observed for E. faecium isolates that displayed VanA (97.7%) and VanB (100%) resistance:

The one exception is E. faecalis that had high vancomycin MIC and vanA phenotypes, however remained below the susceptibility breakpoint. A few points to note here:

1. The broad spectrum of activity
2. MIC to vancomycin and daptomycin may give you a clue with regards to resistance to oritavancin and potentially, higher odds of failure (think of vancomycin “creep” phenomena).
3. vanA phenotype may become a major mechanism contributing to resistance 

Oritavancin SSTI

The major data with regards to its use in the clinical arena comes from studies regarding SSTI. The landmark SOLO 1 trial was an international, randomized, double blind study comparing a single dose oritavancin vs vancomycin for 7-10 days in SSTI (8). Primary endpoint was a composite of cessation of spreading/reduction in the size of the lesion, absence of fever, and absence of need for rescue antibiotic. 968 patients were randomized, with oritavancin showing non-inferiority with vancomycin in the primary outcome:

This held true even when accounting for the different pathogens involved:

The second part, the SOLO II, was a similarly designed trial (9). 1019 patients were randomized in a 1:1 fashion, with 97% growing gram positive pathogens. When looking at the primary end composite endpoint, oritavancin was non-inferior to vancomycin (80% vs 82.9%, respectively):

Notably, those with major cutaneous abscess had lower response when treated with oritavancin (81% for oritavancin vs 89.9% for vancomycin), however all achieved a reduction of >20% in the size of the lesion. Further, when breaking down the clinical response per pathogen, both treatments were comparable:

In the subgroup of 792 patients of the SOLO trials (10) who were treated as outpatients, primary endpoint was not statistically different between groups (80.4% for oritavancin vs 77.5% for vancomycin, difference 2.9%, 95% CI -2.8 to 8.5). 

Oritavancin in Severe disease

In the above data, we can gather that oritavancin is as good as vancomycin for cellulitis. But you know no one will use it for such a simple outpatient disease. The niche I have seen is those complicated gram positive infections, typically endocarditis, where resistance precludes the use of other antibiotics or those who you would not think they would be a candidate for outpatient parenteral antibiotic therapy i.e. OPAT. Usually, these are folks who use IV drugs. Yet data for its use in these types of infections is limited to case series. For instance, a retrospective study of 19 patients who received more than one dose of oritavancin showed that all had either improvement or treatment success, with the types of infection ranging from endovascular graft infection with S. lugdunensis, E. faecium hepatic abscess, vertebral osteomyelitis and surgical site infections (11). 

A case series of 5 patients with endocarditis also demonstrated its utility with 3 cures achieved (12):

A review of 23 patients with osteomyelitis found that clinical cure was achieved in 65% of patients, with overall clinical success being achieved in 20/23 patients evaluated (13). In a review of 24 cases of severe gram positive infections in IVDU, clinical cure was achieved in 79% (14). 3 patients were deemed failures, with one being due to non-adherence to the second dose. A review of 440 patients who received oritavancin found clinical success was achieved in 88.1% of patients, including 10/11 of those with bone/joint infection and 7 out of 8 with osteomyelitis (15). One case series describes 10 patients with invasive infections who received oritavancin, with 7 achieving clinical cure following therapy. Most patients had MSSA bacteremia in this series (16). 

References:

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11. Schulz LT, Dworkin E, Dela-Pena J, Rose WE. Multiple-Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections. Pharmacotherapy. 2018 Jan;38(1):152-159. doi: 10.1002/phar.2057. Epub 2017 Dec 11. PMID: 29121395.
12. Terrero Salcedo DA, El-Herte R, Granada M (2018) Oritavancin for the Treatment of Infective Endocarditis due to Gram-positive Organism. Ann Case Rep: ACRT-202. DOI: 10.29011/2574-7754/100102
13. Scoble PJ, Reilly J, Tillotson GS. Real-World Use of Oritavancin for the Treatment of Osteomyelitis. Drugs Real World Outcomes. 2020 Jun;7(Suppl 1):46-54. doi: 10.1007/s40801-020-00194-8. PMID: 32588387; PMCID: PMC7334326.
14. Ahiskali A, Rhodes H. Oritavancin for the treatment of complicated gram-positive infection in persons who inject drugs. BMC Pharmacol Toxicol. 2020 Oct 28;21(1):73. doi: 10.1186/s40360-020-00452-z. PMID: 33115540; PMCID: PMC7594421.
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