Oritavancin has been studied in a variety of animal models to determine its tissue and bone penetration and therefore potential role against Gram-positive organisms causing invasive diseases including meningitis, endocarditis, and osteomyelitis [
30,
36‐
39]. When studied against VSE and both VanA- and VanB-mediated VRE endocarditis in rabbits, oritavancin displayed heterogeneous distribution throughout the cardiac vegetations [
39]. In those rabbits with aortic endocarditis, twice-daily oritavancin was the only glycopeptide antibiotic tested that displayed significant activity regardless of the phenotype of enterococcal strains. When compared against vancomycin in rabbits with MRSA left-sided endocarditis, once-daily oritavancin was determined to be equally effective in both clearing the bacteremia and in reducing bacterial counts in the vegetations and tissues [
36]. In a rabbit model of meningitis caused by
Streptococcus pneumoniae, a single dose of oritavancin was shown to reduce bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as continuous infusion ceftriaxone [
37]. Maximum concentrations of oritavancin in the CSF were reached several hours after administration, and although the estimated CSF penetration was relatively low at 1–5%, the highly active in vivo activity resulted in reduced bacterial titers, decreased inflammatory markers, and sterilization of the CSF. However, the tolerability of such high doses needed to penetrate into the CSF is still to be determined in humans. Oritavancin has also been studied in rabbits to determine the differential distribution from serum to bone tissue [
40]. Following a 5 min infusion, oritavancin serum concentrations were greater than or equal to 10 mg/L for at least 24 h, which is several times higher than the MIC
90 for
S. aureus (0.06 mg/L) and
S. pneumoniae (≤0.008 mg/L). Additionally, bone concentrations remained above the MIC
90 for
S. aureus for over 168 h following a single 20 mg/kg dose.
Clinical Trials
Clinical trials presented here are related to the registration of oritavancin with a novel therapeutic dosing scheme and earlier trials utilizing different dosing regimens were not included. To evaluate the non-inferiority of front-loaded oritavancin dosing regimens compared to infrequent dosing in complicated skin and skin structure infections (cSSSI), a phase II, multicenter, randomized, double-blind, parallel, active-comparator study was completed.(33) The single or infrequent doses for the treatment of complicated skin and skin structure infections (SIMPLIFI; ClinicalTrials.gov identifier, NCT00514527) study included adult patients with a cSSSI either suspected or proven to be caused by a Gram-positive pathogen. To meet the definition of cSSSI for the purposes of this study, patients were required to have one or more of the following: infection required surgical intervention within 48 h of enrollment; infection suspected or confirmed to involve deep subcutaneous tissue (excluding fascia or muscle layers); significant underlying disease present to complicate treatment, including diabetes, bacteremia, cellulitis with ≥3% of total body surface area, corticosteroid therapy, cirrhosis, burn, radiation therapy, or known immune suppression. There were three oritavancin treatment groups for comparison including daily (200 mg daily for 3–7 days), infrequent (800 mg on day 1 with an optional 400 mg on day 5), and single-dose (1200 mg as one-time dose) groups. The primary objective of the study was the clinical response in the clinically evaluable (CE) and intention-to-treat (ITT) populations at test of cure (TOC) on days 21–29, decided by the investigator, as cure, improvement, failure, or indeterminate based on clinical signs and symptoms.
A total of 302 patients were included in the ITT population (100 in the daily group, 103 in the infrequent group, and 99 in the single-dose group), of which 228 were included in the CE population [
33]. Demographics and baseline characteristics were similar among all treatment groups, with 37.7% of patients having major abscesses, 31.8% wound infections, and 30.5% cellulitis. The most commonly isolated pathogen was
S. aureus (87.6%), 49% being MRSA, with other Gram-positive organisms isolated including
Streptococcus pyogenes (5.7%),
Streptococcus agalactiae (3.8%), and
E. faecalis (3.8%). The oritavancin MIC
90 for all
S. aureus isolated was 0.12 mg/L, and the overall range of MICs for
S. aureus was 0.008–0.5 mg/L. There was no difference in the primary outcome of clinical cure/improvement in the ITT population, occurring in 72.4%, 78.2%, and 81.8% in the daily, infrequent, and single-dose groups, respectively [90% confidence interval (CI), −1.7 to 17.8 for comparison of 1200 and 200 mg groups; 90% CI, −5.8 to 14.6 for comparison of 800 and 200 mg groups]. Similarly, when evaluating the results for only those with
S. aureus isolated (both MRSA and MSSA), cure rates were similar among groups with 67.4% for the daily group, 79.5% for the infrequent group, and 78.9% for the single-dose group. Over half of the patients in the study experienced an adverse event (56%, 61.2%, and 55.6% in the daily, infrequent, and single-dose groups, respectively), of which the majority were considered to be mild or moderate in severity (85.7%) and unrelated to study medication (58.0%). Based on these phase II study results, oritavancin is considered safe, effective, and well tolerated as a 1200 mg single dose for the treatment of cSSSI caused by Gram-positive organisms, including MRSA.
Two pivotal double-blind, randomized phase III studies, SOLO I and II (ClinicalTrials.gov identifiers, NCT01252719 and NCT01252732, respectively), were completed to assess the clinical efficacy and safety of the previously studied 1200 mg single dose of oritavancin in acute bacterial skin and skin structure infections (ABSSSIs) [
42,
43]. These studies included patients 18 years or older with ABSSSIs thought or proven to be caused by a Gram-positive organism with a lesion surrounded by erythema, edema, or an induration of at least 75 cm
2. Patients were either given oritavancin 1200 mg as a single dose, or vancomycin 1000 mg or 15 mg/kg dosed twice daily for 7–10 days. The primary outcome was a composite endpoint of the following three criteria: cessation of spreading or reduction in lesion size, absence of fever, and no need for a rescue antibiotic at 48–72 h. Non-inferiority of oritavancin against vancomycin was defined by a 10% non-inferiority margin at the 1-sided α level of 0.025, with a primary efficacy outcome rate assumed to be 75%. Key secondary outcomes were investigator-assessed clinical cure at the post-therapy evaluation (PTE) and a reduction in lesion size of 20% or more at the early clinical evaluation (ECE). There were no significant differences in demographics or baseline characteristics between groups or between studies. The majority of patients in SOLO I had cellulitis (51.2% and 48.6% for oritavancin and vancomycin, respectively) and abscesses (29.5% and 29.4%, respectively) while the patients in SOLO II were more evenly split among wound (38.0% and 35.1%, respectively), cellulitis (28.6% and 33.3%, respectively), and abscesses (33.4% and 31.7%). The median lesion area at baseline was 248.0 versus 225.6 cm
2, and 287.8 versus 308.8 cm
2 in the oritavancin versus vancomycin in SOLO I and SOLO II, respectively. A positive culture occurred in 61.1% and 60.5% in the oritavancin and vancomycin groups in SOLO I, and 69.8% and 70.1% in the oritavancin and vancomycin groups in SOLO II. The most common pathogen isolated from the infection site in both studies was
S. aureus and MRSA, isolated in 201 and 204 patients in SOLO I and SOLO II, respectively. Of note, there were few patients included in these studies with positive blood cultures as baseline. For SOLO I, there were 18 and 9 patients compared to SOLO II with 6 and 10 patients with positive blood cultures in the oritavancin and vancomycin groups, respectively.
Oritavancin met the predetermined non-inferiority criteria against vancomycin in the modified ITT (mITT) population with 82.3% of patients in the oritavancin group versus 78.9% in the vancomycin group (absolute difference 3.4, 95% CI, −1.6 to 8.4) and 80.1% in the oritavancin group versus 82.9% in the vancomycin group (absolute difference −2.7, 95% CI, −7.5 to 2.0) meeting the primary composite endpoint in SOLO I and SOLO II, respectively. Additionally, when evaluating the clinical cure at PTE [79.6% vs. 80.0%; absolute difference −0.4 (95% CI, −5.5 to 4.7) and 82.7% vs. 80.5%; absolute difference 2.2 (95% CI, −2.6 to 7.0) for oritavancin vs. vancomycin in SOLO I and SOLO II, respectively] and reduction in lesion size of 20% or more at ECE [86.9% vs. 82.9%; absolute difference 4.1 (95% CI, −0.5 to 8.6) and 85.9% vs. 85.3%; absolute difference 0.6 (95% CI, −3.7 to 5.0) for oritavancin vs. vancomycin in SOLO I and SOLO II, respectively], oritavancin also met the predetermined non-inferiority margin of less than a 10% difference. In those patients with isolated MRSA in the microbiological ITT (MicroITT) population, the primary efficacy endpoint occurred in 80.8% of those on oritavancin versus 80.0% of those on vancomycin [absolute difference 0.8 (95% CI, −10.1 to 11.7)] in SOLO I, and 82.0% of those on oritavancin versus 81.2% of those on vancomycin [absolute difference 0.8 (95% CI, −9.9 to 11.5)] in SOLO II, again showing similar efficacy between groups in both studies.
Treatment-emergent adverse events (TEAEs) occurred similarly between groups with 63.8% versus 60.0% and 50.9% versus 50.2% of patients reporting at least one adverse event in the oritavancin versus vancomycin groups in SOLO I and SOLO II, respectively. However, these TEAEs were generally considered to be mild in severity and only 5.8% in the oritavancin group versus 3.8% in the vancomycin group in SOLO I and 3.6% in the oritavancin group versus 2.6% in the vancomycin group in SOLO II reported discontinuation of study drug due to adverse events. Additionally, in SOLO II, 5 cases of osteomyelitis were reported as an adverse event in the oritavancin group compared to 0 cases in the vancomycin group, and in SOLO I, one case of osteomyelitis was reported in each group. It was noted that the 5 events in SOLO II occurred within the first 9 days of initiating the study medication and the authors suggest that the osteomyelitis was likely present at the time of enrollment, but missed by the investigators. Based on this data, osteomyelitis is listed as a warning for oritavancin, and it is recommended to monitor patients for signs and symptoms of osteomyelitis and to initiate appropriate alternative therapy if it is suspected [
19]. Of note, due to the extended half-life of oritavancin, safety effects were evaluated at the 60 day follow-up assessment and the investigators failed to identify any prolonged or delayed adverse events in the oritavancin group [
42,
43]. Therefore, based on the SOLO I and SOLO II studies, oritavancin is considered a safe and effective single-dose alternative to traditional therapies for ABSSSIs caused by Gram-positive organisms.
In addition to the completed ABSSSI studies, a new trial on the ClinicalTrials.gov registry and results database is currently recruiting for a pediatric study looking to evaluate oritavancin for suspected or confirmed bacterial infections in children (ClinicalTrials.gov identifier, NCT0213430). Furthermore, a safety, tolerability and pharmacokinetics study of a new oritavancin formulation with an adjusted infusion time, concentration, and reconstitution/administration solution is also recruiting at this time (ClinicalTrials.gov identifier, NCT02471690).