FormalPara Key Points

Review of case studies of off-label use of oritavancin for osteomyelitis has shown clinical success against Gram-positive pathogens in osteomyelitis, and it should be considered an effective treatment option.

Oritavancin could offer a more patient-friendly treatment option as it can be administered intravenously (IV) once a week compared to daily IV treatment for multiple consecutive days or oral tablets, thus reducing impact on daily activities, and potentially reducing the length of hospitalization or avoiding it.

Future studies are needed to explore outpatient use of oritavancin for osteomyelitis treatment, the possible pharmacoeconomic benefits and patient impact.

1 Introduction

Osteomyelitis is an infectious, inflammatory disease of the bone that remains difficult to treat, typically requiring a prolonged course of intravenous (IV) antibiotics [1]. 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) [2]. 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) [2]. 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 [6] 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 [8]. Acute osteomyelitis is defined as infection occurring before the development of sequestra, which usually occurs within 2 weeks of initial disease onset [9]. 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 [7]. 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 [18].

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 [23]. 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 [22]. 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 [27].

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 [37]. Specifically, against enterococci, oritavancin is only approved for vancomycin-susceptible Enterococcus faecalis [30]. 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.

2 Methods

This was a comprehensive literature review of microbiologically positive patients who received oritavancin for the treatment of acute or chronic osteomyelitis. Searches of PubMed and Google Scholar for papers, case reports, or other available data were conducted using the following search terms: “osteomyelitis” and “oritavancin”; “osteomyelitis” AND “oritavancin” AND “off-label”; osteomyelitis AND oritavancin AND off-label AND multiple dose. This search identified 17 resources in PubMed and in Google Scholar 73 additional (not duplicate) resources. These were reviewed and reduced to only resources that included cases of osteomyelitis and treatment with single or multiple doses of oritavancin. Reports were included if patients had a microbiologically confirmed osteomyelitis infection and were treated with oritavancin. A total of 38 cases were retrieved for analysis; 20 from seven published papers and 18 from the Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME) registry. From the 38 cases, 23 had microbiologically confirmed osteomyelitis infections and were included in the final review.

Both “clinical cure” and “clinical success” were used interchangeably throughout the analyzed literature and had the same definition: resolution of clinical signs and symptoms of infections, wound closure, resolution of fever, normalization of white blood cell count, no additional infection-related hospital admission, surgical debridement or amputation, no need for additional antibiotic therapy for the indication for which oritavancin was initially administered. Clinical “cure” or “success” are identified within the tables; however, we consider them under the same definition as clinical cure. Clinical improvement was defined as recovery from infection with need for additional Gram-positive therapy after completion of oritavancin treatment. Clinical failure was defined as inadequate resolution or progressive worsening of infection, and need for continued or alternative Gram-positive therapy at completion of oritavancin therapy, or loss at follow-up.

3 Results

Seven papers and cases from the CHROME registry were used for our analysis, which included 23 patients with microbiologically confirmed infections who received oritavancin for the treatment of osteomyelitis. These chart reviews and case studies reported administration of oritavancin, but not why it was selected by the clinician. However, clinical status of the patient, anatomic location of the infection, patient availability for follow-up, safety of other available treatments, and relevant co-morbidities would have been considered. Patients who received only one or two doses of oritavancin were still included because they were deemed to either exhibit clinical improvement or were a clinical success (Tables 1, 2, 3, 4, 5). The median age was 50 years (range 26–98 years), and 54% (13/23) were female. The most common co-morbidities were diabetes mellitus and hypertension. Osteomyelitis was confirmed in patients by either nuclear bone scans or by MRI. A total of 14 patients (56%) had documentation of antimicrobial treatment prior to administration of oritavancin, and one patient received concurrent doxycycline. All patients received at least one 1200 mg dose of oritavancin, and the majority (22) of patients received one 1200 mg dose followed by at least two further 1200 mg doses over a varied timeline (Tables 1, 2, 3, 4, 5).

Table 1 Patients receiving oritavancin to treat culture-positive osteomyelitis—results per pathogen, methicillin-resistant Staphylococcus aureus
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Table 2 Patients receiving oritavancin to treat culture-positive osteomyelitis—results per pathogen, methicillin-sensitive Staphylococcus aureus
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Table 3 Patients receiving oritavancin to treat culture-positive osteomyelitis—results per pathogen, vancomycin-resistant Enterococcus (daptomycin non-susceptible)
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Table 4 Patients receiving oritavancin to treat culture-positive osteomyelitis—results per pathogen, group A Streptococcus pyogenes
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Table 5 Summary of the real-world experience using oritavancin for microbiologically positive osteomyelitis
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The most common pathogen was MRSA, which was isolated in 48% (n = 11) of patients. Overall, clinical cure was achieved in 65% of patients (n = 15/23); however, clinical improvement was also demonstrated among patients—when combined, the overall rates of clinical success increased to 87% (n = 20/23).

Three clinical failures were documented. One osteomyelitis patient with confirmed MRSA, E. faecalis, and E. coli, who had received trimethoprim/sulfamethoxazole (TMP/SMX) therapy prior to one 1200 mg dose of oritavancin, was considered a treatment failure, and was then switched to ciprofloxacin and doxycycline. The second patient had a confirmed osteomyelitis MRSA infection, and oritavancin was given at two doses of 1200 mg every 9 days, which was switched to doxycycline after failure. The third patient was an active intravenous drug user (IVDU), and over a period of 71 days experienced multiple treatment failures. Initially administered vancomycin and cefazolin, once osteomyelitis infection was confirmed as MSSA this was reduced to just cefazolin; on day 8 of treatment, one 1200 mg dose of oritavancin was given and the patient was discharged on oral clindamycin. This patient then returned on day 50 of treatment, reporting non-adherence to clindamycin, and cephalexin was given for 1 month. At day 71 the patient presented with recurrent and worsening infection and eventually was discharged on TMP/SMX and rifampin for 3 months. Two months later the patient returned and a small aortic valve vegetation was identified alongside osteomyelitis; cefazolin was initiated followed by chronic suppressive therapy with cephalexin. All treatment failure cases received a regimen of only one or two doses of oritavancin, which is inconsistent with osteomyelitis treatment guidelines, which suggest 4–6 weeks of antimicrobial treatment [47].

All patients were included in the safety analysis. Oritavancin was well tolerated with adverse events (AEs) reported in only two cases (8.7%). One patient developed a moderate, infusion-related reaction during the second dose of oritavancin; the infusion was stopped and the patient was sent to the emergency department (ED) for observation and switched to linezolid. The second patient, who received only two oritavancin doses, was found to have anemia and leukopenia, and was transitioned to doxycycline for an additional 10 days. Clinical improvement was demonstrated in both patients prior to terminating oritavancin therapy due to AEs.

4 Discussion

Osteomyelitis remains a difficult to treat infection with significant treatment challenges, commonly requiring both surgical debridement and concomitant antibiotic therapy with agents active against the bone-infecting pathogen. MRSA is responsible for the majority of cases of osteomyelitis, which can persist and/or recur in up to 40% of patients [48]. While vancomycin remains the most frequently selected antibiotic for the treatment of osteomyelitis [16], vancomycin use is associated with increased rates of failure and recurrence, likely due to its poor penetration into bone and biofilm formations, as well as the occurrence of vancomycin-intermediate S. aureus (VISA), heterogenous VISA (hVISA), and S. aureus isolates with increasing minimum inhibitory concentrations (MICs) [49, 50]. Antimicrobial selection needs to consider whether the agent achieves adequate bone penetration, with bioavailable bone concentrations exceeding the pathogen MIC. Anatomical location of infected bone, as well as vascularity, which may be compromised, affects achievable bone concentrations. Oritavancin has been shown to rapidly penetrate osseous tissues in rabbit tibia models and drug levels are maintained for greater than 168 h. The active ratio of oritavancin in bone is still unknown; in this animal model, bone penetration, defined as the tissue to serum AUC0-168 ratio into bone matrix and bone marrow, was 1.7 and 3.1, respectively, which is higher than that of linezolid, vancomycin, teicoplanin, and dalbavancin [33]. One caveat to note is that the concentrations of oritavancin obtained in the rabbit study by Lehoux (and those of the cited comparators) represent total drug concentrations, and the active fraction of each drug in bone remains to be described [33]. Therefore, the PK/PD relationship of oritavancin in bone and other tissues should be interpreted with caution. These data provided the stimulus for using single and multiple oritavancin dosing in patients with osteomyelitis. Clinical outcomes of oritavancin treatment for osteomyelitis caused by MRSA, MSSA, VRE, and S. pyogenes from the analyzed case reports and data are collated in Tables 1, 2, 3, 4. Oritavancin has been shown to be efficacious in a wide range of Gram-positive bone infections, with a 1200 mg dose (occasionally, a continued 800 mg dose) administered once a week for 4–8 weeks, with few adverse events. In this review, we chronicled the efficacy, safety, and clinical outcomes of 23 pathogen culture-positive patients with osteomyelitis who were treated with oritavancin in published case reports and also from the CHROME registry. Bone biopsy and tissue culture are the gold standard of osteomyelitis diagnosis; however, the use of these methods can be challenging due to their invasive nature. Thus, in the reviewed case reports, real-world diagnostic methods were made using bone scans or MRI. Real-world evidence regarding oritavancin shows high rates of clinical success with both single or multiple doses to treat osteomyelitis, and is well tolerated with minimal adverse events, without need for therapeutic drug monitoring (Table 5). In ABSSSIs, recent studies have demonstrated the potential opportunity for oritavancin to facilitate early discharge for patients, as the IV infusions are once per week, and it has also been administered in the ED to avoid hospitalization of patients for IV treatment [51]. While certainly promising, these findings are limited by the number of case reports and the unique circumstances of each case, as well as the potential influence of prior or concomitant antimicrobial therapy to successful outcomes; thus, future analysis is needed. Additionally, these data may be useful in identifying the optimal dosing frequency, which remains to be established, and we suggest each regimen should be adapted for the management of individual patients.

5 Conclusion

We reported on 23 microbiologically positive patients who received oritavancin, either in single or multiple doses, for the treatment of osteomyelitis. Few adverse events were noted, and they were generally mild and reversible. Oritavancin treatment for osteomyelitis was generally safe, effective, and well tolerated, and was able to facilitate outpatient therapy. The clinical success in these patients suggests that use of oritavancin, given at 1200 mg or 800 mg in multiple doses, can be beneficial for the treatment of osteomyelitis. The long half-life of oritavancin lends itself to a convenient treatment for patients, as a once-per-week IV infusion, and may reduce the need for central line placement, which could have a positive impact on a patient’s quality of life. Future studies to evaluate the potential pharmacoeconomic benefits of oritavancin for osteomyelitis treatment, as well as the impact of infrequent IV infusions in the OPAT setting on patients’ lives and productivity, should be explored. Clinicians should consider the use of oritavancin in the treatment of those patients with osteomyelitis as a safe and efficacious option.