CORR Insights®: Can Oritavancin Be Used for Treatment and/or Suppressive Antimicrobial Therapy of Bone and Joint Infections Caused by Vancomycin-resistant Enterococcus faecium?

Where Are We Now?

Most of what we do as surgeons is only possible by the grace of reliable antibiotic prophylaxis. Although vancomycin-resistant Enterococcus (VRE) bone and joint infections are rare, they are difficult to treat, and the transmissible vancomycin-resistance genes expressed by these organisms raise the specter of increasingly common bacterial resistance to one of our most commonly used prophylactic antibiotics. We need to develop effective treatments to control these resistant organisms.

Two of the better-known antibiotic agents that are effective against VRE are linezolid and daptomycin. Linezolid (Zyvox, Pfizer) is an oxazolidone antibiotic that inhibits the initiation of protein synthesis. Specifically, it interferes with the binding of N-formylmethionyl-tRNA to the ribosome. Linezolid has the advantage of absolute oral bioavailability and is relatively safe when administered for a short period of time, but after 10 to 14 days, serious side effects including myelosuppression and immune-mediated thrombocytopenia occur in more than 30% of patients [7]. Despite the bacteriostatic mechanism of action and 100% oral bioavailability of linezolid, these side effects limit its use for extended treatment or suppressive therapy.

Daptomycin (Cubicin, Novartis) is a lipopeptide antibiotic that disrupts bacterial cell membrane function. Specifically, daptoycin molecules integrate into the cell membrane in a phosphatidylglycerol-dependent fashion and then aggregate, forming ion channels that allow rapid depolarization that result in cell death. Daptomycin is generally well tolerated, but hepatotoxicity and nephrotoxicity can occur, as can myopathy and rhabdomyolysis, with about 10% of patients developing serum creatinine kinase levels greater than 500 U/L [8]. Daptomycin is only available intravenously and is typically dosed daily, so treatment often necessitates placement of a peripherally inserted central catheter (PICC line); these aspects also limit the use of daptomycin chronic bacterial suppressive therapy.

Because of the problems with those medications, we need to be open-minded to alternatives. Oritavancin (Orbactiv, Melinta Therapeutics) is a semisynthetic glucopeptide antibiotic. In a manner similar to vancomycin and all other glycopeptide and lipoglycopeptide antibiotics, oritavancin inhibits transglycosylation; specifically it exhibits a bactericidal action by binding to the D-alanyl-D-alanine C-termini of growing peptidoglycan chains, thus disrupting cell wall formation. But unlike vancomycin, oritavancin also interrupts transpeptidation via secondary binding to pentaglycyl (Asp/Asn) bridging segments of peptidoglycans. Additionally, the structure of oritavancin includes a hydrophobic 4’-chlorobiphenylmethyl substituent on the disaccharide sugar that interacts with and disrupts existing cell membranes resulting in depolarization, permeabilization, and concentration-dependent rapid cell death [18]. Importantly, oritavancin also binds strongly to plasma proteins and has a high protein binding capacity, affording an amazing half-life of up to 16 days. This unique property has helped secure FDA approval for single-dose treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria (1200 mg administered as a single dose by intravenous [IV] infusion over 3 hours) [5].

In this issue of Clinical Orthopaedics and Related Research®, Krsak et al. [11] present a small heterogenous case series of patients with VRE bone and joint infections who were treated with oritavancin with some success and few side effects. Based on these discoveries, surgeons might prefer oritavancin for outpatient parenteral antibiotic therapy after surgical treatment of VRE osteomyelitis, and they might also consider oritavancin or other long-acting glycopeptide antibiotics for treating challenging infections in tricky situations.

Where Do We Need To Go?

As wonderful as it is to know that there is a drug that is effective against an otherwise difficult-to-treat organism such as VRE, some readers may be astounded to learn that there is an antibiotic agent available that is effective against gram-positive organisms for up to 2 weeks after a single dose. What is more, oritavancin is not the only such agent. Dalbavancin (Dalvance, AbbVie) is a semisynthetic lipoglycopeptide that also disrupts transglycosylation and transpeptidation of peptidoglycan cell walls in gram-positive bacteria and has a prolonged half-life of more than 14 days. Dalbavancin is also active against VRE strains expressing vanC and vanB resistance genes, but not those expressing vanA [1]. Could the prolonged activity of a single dose of either of these antibiotics afford advantages for the treatment of some of our patients?

Overt industry funding of primary research by pharmaceutical companies is not particularly common in orthopaedic surgery, and astute readers may note that three of 11 study authors disclosed personal payments from the maker of oritavancin during the study period, and two of the other authors are actually employees of that company; but before anyone declares this to be a disqualifying bias, it should be noted that vanA is the most common resistant gene expressed by VRE worldwide [12, 17], and dalbavancin is simply not effective against those organisms. Among these two agents, oritavancin clearly has an advantage in the treatment of most extant VRE strains, but for the treatment, suppression, or perhaps prophylaxis of gram-positive organisms generally, it remains unclear which of these agents is most advantageous. Could further study compare the effectiveness and risk profiles of these agents?

How Do We Get There?

It is important to note that neither oritavancin nor dalbavancin are FDA approved for the treatment of or suppressive antimicrobial therapy for bone and joint infections; as such, their use for these indications remains off label. The work of Krsak et al. [11] in this month’s CORR® is nonetheless an important proof-of-concept paper on a topic that matters, and readers should conclude that bone and joint infections can or could be successfully treated with oritavancin, but future studies are necessary to better characterize adverse effects and to determine the precise likelihood of treatment success.

Some of those studies are beginning to appear. A retrospective review from the Downtown Dublin Wound Center showed that multidose oritavancin could be used to treat and cure chronic osteomyelitis. Authors concluded that given its unique characteristics and half-life, oritavancin could be especially useful when treatment options are limited by patient complexities or barriers to their ability to access healthcare services [4]. Another study has demonstrated that a methicillin-resistant Staphylococcus aureus (MRSA) prosthetic joint infection has been successfully suppressed for more than 2 years with outpatient parenteral antibiotic therapy with weekly oritavancin infusions [3]. And although RCT trials are rare in orthopaedic research, in this topic a well-designed RCT may be on the horizon. A retrospective comparison between dalbavancin and oritavancin already has been performed [13], and based on a comparison of adverse reactions between those drugs, the advantage may be with dalbavancin. A lower likelihood of adverse reactions increases the likelihood of treatment adherence and may enhance suitability for long-term treatment or suppressive therapy. Long-term treatment or suppressive therapy that could be administered once or twice weekly via peripheral IVs at infusion centers could present an important paradigm shift from daily infusions via central catheters, and this could both reduce complications and enhance adherence. This advance may come to fruition in the near term.

Further out on the not-too-distant horizon, the future of next-generation molecular diagnostic tests is meeting with artificial intelligence–powered decision tools and the vast information available in the portable EMR cloud. Imagine “empiric” therapy that instantaneously accounts for granular, patient-specific characteristics. Imagine firstline providers simply dictating an “antibiotic” order and then being presented with an evidence-based choice that accounts for known culture and molecular diagnostic data, prior therapies, patient allergies, demographic factors, and the local antibiogram to arrive at an “optimized empiric” therapy. The future may be fast approaching. Although many surgeons are routinely dumping powdered vancomycin into surgical fields [14], the best evidence suggests that this practice is not effective [6, 15]. We need a better approach. Selective extended antibiotic prophylaxis may be beneficial to some high-risk patients [9]. Single-dose long-acting antibiotics could enhance adherence and improve outcomes for some of our most challenging cases.

Read This Next

• Controversies surrounding antibiotic prophylaxis in orthopaedic surgery are all but settled. This review summarizes some key evidence regarding some controversial topics [2].

• Could single-dose long-acting antibiotics close the rift between orthopaedic subspecialty societies and the CDC, which in 2017 recommended that “additional prophylactic antimicrobial agent doses should not be administered after the surgical incision is closed in the operating room” [10]?

• And how might this be reconciled with the apparently clear superiority of first-generation cephalosporins? From the Mayo Clinic, an award-winning article extols the virtues of the tried-and-true cefazolin and encourages surgeons to approach cefazolin allergy with some skepticism [16].