Osteomyelitis is an infectious, inflammatory disease of the bone that remains difficult to treat, typically requiring a prolonged course of intravenous (IV) antibiotics . The incidence of osteomyelitis has been reported to be as high as 21.8 cases per 100,000 person-years, and was higher for men than for women and increased with age (p < 0.001) . Over a 40-year period, annual osteomyelitis incidence rates have increased from 11.4 cases to 24.4 per 100,000 person-years (p < 0.001) . Osteomyelitis occurs when microorganisms invade previously healthy bone, leading to an inflammatory response and concomitant destruction of the bone, which are the hallmarks of osteomyelitis [3,4,5]. Antibiotics poorly penetrate dead bone and infected fluids; surgical treatment with debridement of the necrotic bone accompanied by the identification of the infectious etiology, via surgical sampling or needle aspiration, allows for the optimization of antibiotic therapy [5, 6]. There are two major classification schemes for osteomyelitis [6, 7]: The Lew and Waldvogel  system classifies osteomyelitis by duration of disease—either acute or chronic, as well as infection mechanism—hematogenous or contiguous infection. Histopathology of osteomyelitis rather than duration of illness is used to categorize whether osteomyelitis is chronic or acute . Acute osteomyelitis is defined as infection occurring before the development of sequestra, which usually occurs within 2 weeks of initial disease onset . Chronic osteomyelitis is defined as longstanding infection that evolves over months or even years, characterized by the persistence of microorganisms, low-grade inflammation, and the presence of dead bone and fistulous tracts [4, 6]. Clinical signs persisting for longer than 10 days are associated with the development of necrotic bone and chronic osteomyelitis. Chronic osteomyelitis may also present as a recurrent or intermittent disease, with periods of dormancy of variable duration [10, 11]. Additionally, osteomyelitis classification is divided into one of two categories (defined by physiologic mechanism): contiguous dissemination (trauma, surgery, or prosthetic hardware), or via hematogenous seeding. Contiguous osteomyelitis is further subdivided into whether or not there is vascular insufficiency [3, 6]. The gold standard for diagnosing osteomyelitis is bone biopsy and tissue culture; however, these invasive procedures often prove prohibitive—indeed chronic osteomyelitis remains challenging to diagnose, and clinicians use a combination of clinical symptoms, laboratory, radiographic, and microbiological findings to do so.
The Cierny-Mader scheme classifies osteomyelitis by anatomic stages and patient health status, in order to provide patient management guidance. Stages 1–4 describe anatomic location and progression, and host health status categories by local and systemic factors that affect immune surveillance, metabolism, and bone vascularity [7, 10].
While other causative pathogens have been identified in osteomyelitis, Staphylococcus aureus, in particular methicillin-resistant S. aureus (MRSA), is among the most common. MRSA has advantageous features for bone infection; an array of virulence factors (including the production and release of cytotoxins), enhanced pathogenesis, and biofilm formation, while concomitantly impairing host/immune response . Co-morbidities impairing peripheral blood flow, including diabetes mellitus, may make osteomyelitis in these patients even more difficult to treat [5, 6].
Osteomyelitis treatment usually includes the use of prolonged, high-dose, IV antibiotics [1, 12,13,14,15,16]. However, this tactic must be balanced against antimicrobial stewardship to avoid resistance, as well as the risks associated with IV catheters, and costs accompanying agents themselves [12, 17]. There is a paucity of randomized, clinical trials to suggest the use of a single antibiotic or combination of agents for osteomyelitis in adults, and the optimal route and duration of antibiotics with osteomyelitis remains ill-defined due to limited prospective clinical trials. Most experts in the USA recommend 4–6 weeks of IV antibiotic therapy for osteomyelitis [1, 12,13,14,15]. Once the patient is stable for discharge, treatment can be continued, either administered via outpatient parenteral antibiotic therapy (OPAT) with substantial vascular access, such as a peripherally inserted central catheter (PICC), or transition to a suitable oral alternative .
Vancomycin is usually the core of IV therapy, particularly for MRSA infections. However, vancomycin use is challenging because of the weight-based dosing, dosing frequency, the necessity of single and multiple daily doses, the need for therapeutic drug-level monitoring and for vascular access, and toxicities associated with its use [16, 19, 20]. Other antibiotic therapies available have adverse events that can develop with prolonged use, or limit their usage in certain populations. Development of neutropenia and thrombocytopenia is associated with extended use (> 14 days) of ceftaroline or linezolid, respectively [21, 22], and linezolid treatment for > 28 days can cause lactic acidosis and optic neuritis . Additionally, linezolid patients concurrently taking selected serotonin reuptake inhibitors can develop serotonin toxicity, and concurrent monoamine oxidase inhibitor use has been associated with hypoglycemia [24,25,26]. Daptomycin can cause elevated creatinine phosphokinase (CPK), myopathies, or eosinophilic pneumonia . Delafloxacin is an effective agent that requires a loading dose—it also has a better safety profile than other fluoroquinolones; however, the fluoroquinolone warning issued by the US Food and Drug Administration (FDA) is still applicable .
In addition, many antibiotics, including vancomycin, often have difficulty penetrating biofilm formations and most fail to penetrate bone. When long-term treatment courses are necessary, availability of antibiotics with longer dosing intervals, fewer toxicities, and minimal to no requirement for monitoring therapeutic drug levels, would be preferred.
Oritavancin is a long-acting, semi-synthetic, second-generation lipoglycopeptide approved by the FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) [28,29,30]. The pharmacokinetic/pharmacodynamic (PK/PD) data showed that administration of a large, single 1200 mg dose of oritavancin was safe, well tolerated, and optimizes concentration-dependent killing against several Gram-positive organisms, resulting in more effective and pronounced bactericidality as compared with the smaller, originally traditional doses and dosing schemes of oritavancin [31, 32]. The large volume of distribution of oritavancin and penetration into bone are favorable for exploring its use in osteomyelitis [31,32,33]. Oritavancin demonstrates potent in vitro activity against most Gram-positive organisms, most notably Staphylococcus, Streptococcus, and Enterococcus species [32, 34,35,36]. The in vitro bactericidal activity of oritavancin against stationary-phase S. aureus cells, and sterilization of biofilms, is a particularly appealing feature when treating osteomyelitis with or without the addition of prosthetic devices and hardware . Specifically, against enterococci, oritavancin is only approved for vancomycin-susceptible Enterococcus faecalis . However, oritavancin also has activity against other Enterococcus species, including vanA-producing vancomycin-resistant Enterococcus faecium (VRE) [36, 38].
Oritavancin has favorable PK/PD, achieves wide distribution and penetration, and has potent in vitro activity against common osteomyelitis-causing pathogens. Additionally, a PICC is not necessary. These features make oritavancin a potentially useful option for the treatment osteomyelitis, although the physiological complexity, severity, and recurrence of these infections will likely require more than a single dose. The use of oritavancin in the off-label treatment of osteomyelitis is currently restricted to a series of case reports, which show that multiple doses of oritavancin are safe and effective in the treatment of osteomyelitis caused by VRE, MSSA, and MRSA [39,40,41,42,43,44,45,46]. We present the reported outcomes of multiple-dose oritavancin therapy in patients with osteomyelitis.