Digital Features for this Adis Drug Q&A can be found at https://doi.org/10.6084/m9.figshare.17118950.

FormalPara Adis evaluation of the new IV formulation of oritavancin (KIMYRSA™) in the management of ABSSSIs

Has better diluent compatibility, full dose in a single vial, a shorter infusion time and a lower infusion volume than the original IV formulation.

Similar pharmacokinetic profile to that of the original IV formulation.

Generally well tolerated with no new safety signals.

What is the rationale for developing a new intravenous (IV) formulation of oritavancin?

Acute bacterial skin and skin structure infections (ABSSSIs) are heterogeneous bacterial infections that can range from mild local infections to life-threatening systemic infections, and include wound infection, cellulitis/erysipelas and major cutaneous abscesses [1, 2]. The most common causative pathogens for ABSSSIs are gram-positive bacteria, such as Staphylococcus aureus [including methicillin-resistant S. aureus (MRSA)] and Streptococcus pyogenes [1, 2].

With many antibacterial agents being available for the treatment of ABSSSIs, the choice of appropriate antibacterial therapy is based on several factors, including site of infection, causative pathogen, local antibacterial resistance patterns, drug characteristics (e.g. potential drug-drug interactions, efficacy and safety profiles, cost and ability for easy transition at discharge) and patient characteristics (e.g. presence of comorbidities) [1,2,3,4]. Vancomycin, linezolid, ceftaroline, daptomycin and clindamycin are among the recommended first-line parenteral antibacterial therapy in the 2014 Infectious Diseases Society of America practice guidelines for skin and soft tissue infections [4].

Many patients with ABSSSIs, including those with minimal comorbidity and mild or no systemic signs of infection, are hospitalized for several days solely to receive multi-dose and multi-day parenteral antibacterial therapy, which poses a significant financial burden on healthcare systems [5,6,7]. Based on any comorbidities and infection severity, hospitalized patients receiving multi-dose and multi-day parenteral antibacterial therapy may transition to outpatient parenteral or oral antibacterial therapy (OPAT) [7, 8]. However, transitioning patients to OPAT may not overcome the limitations of multiple drug administrations, dosage adjustment, therapeutic drug monitoring and treatment non-adherence, which can lead to poor clinical outcomes [8].

In an attempt to decrease healthcare costs and improve clinical outcomes, single-dose antibacterial treatments, such as oritavancin and dalbavancin, have been developed as an alternative to multi-dose and multi-day antibacterial treatment for ABSSSIs [3, 9]. Oritavancin, a long-acting lipoglycopeptide, is the first single-dose intravenous (IV) antibacterial therapy approved in the USA for the treatment of adult patients with ABSSSI caused by, or suspected to be caused by, susceptible gram-positive microorganisms [10, 11]. The originally approved IV formulation of oritavancin (ORBACTIV®) is prepared from three separate vials using dextrose 5% in sterile water for dilution, and infused over 3 h with an infusion volume of 1 L [11]. A newly developed IV formulation of oritavancin (KIMYRSA™) includes the solubilizer hydroxypropyl-β-cyclodextrin (HPβCD); it can be prepared from a single vial, and has a better diluent compatibility, a shorter infusion time of 1 h and a smaller infusion volume of 250 mL than the originally approved IV formulation [10, 12]. Table 1 provides a summary of the prescribing information of the new IV formulation of oritavancin in the USA [10]. Consult local prescribing information for further details.

Table 1 Summary of the prescribing information of the new intravenous formulation of oritavancin (KIMYRSA™) in acute bacterial skin and skin structure infections in the USA [10]
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What are the antibacterial effects of oritavancin?

Oritavancin, a semi-synthetic lipoglycopeptide analogue of vancomycin, has multiple mechanisms of action where it inhibits the transglycosylation (polymerization) and transpeptidation (crosslinking) steps of bacterial cell wall biosynthesis by binding to the step peptide of peptidoglycan precursors and peptide bridging segments of the cell wall, respectively [13]. Additionally, oritavancin disrupts bacterial membrane integrity, leading to the depolarization and increased permeability, and cell death [13, 14].

Oritavancin has demonstrated antibacterial activity, both in vitro and in clinical infections, against clinically relevant isolates of gram-positive bacteria associated with ABSSSIs [10]. In the US prescribing information, specified pathogens are Staphylococcus aureus [including methicillin-susceptible S. aureus (MSSA) and MRSA isolates], Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus pyogenes, Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin-susceptible isolates only) [10]. CLSI identified minimum inhibitory concentration (MIC) breakpoints for susceptibility of oritavancin against specified microorganisms are: S. aureus including MRSA (≤ 0.12 μg/mL); Streptococcus species (≤ 0.25 μg/mL); vancomycin-susceptible E. faecalis (≤ 0.12 μg/mL) [15].

Oritavancin was tested against gram-positive clinical isolates collected worldwide, or in the USA and/or Europe as part of the 1997–2016 SENTRY antimicrobial surveillance program [16,17,18,19,20]. Oritavancin exhibited potent in vitro activity against S. aureus including MSSA (n = 79,287; 99.7–99.9% susceptible) [17,18,19,20]; viridans group streptococci (VGS) including the S. anginosus group (n = 2293; 100%) [19, 20]; β-haemolytic streptococci (BHS) including S. agalactiae, S. dysgalactiae and S. pyogenes (n = 5212; 99.4–99.7%) [19, 20]; and E. faecalis (n = 5714; 99.5–99.9%) [19, 20], with oritavancin MIC values required to inhibit 90% of isolates (MIC90) being 0.03–0.06 μg/mL against S. aureus, 0.06 μg/mL against VGS and E. faecalis, and 0.12–0.25 μg/mL against BHS [17,18,19,20]. Oritavancin also exhibited potent in vitro activity against gram-positive pathogens exhibiting resistance to ≥ 1 clinically relevant antibacterial drugs, including MRSA (n = 46,373; 99.6–99.9%) [17, 20] and vancomycin-resistant enterococci isolates (n = 7615; 92.2–98.3%) when using the breakpoint for vancomycin-susceptible E. faecalis [16]; MIC90 values against respective isolates were 0.06 μg/mL and 0.06–0.12 μg/mL. Overall, in vitro activity of oritavancin was consistent over time and comparable between the isolates collected in the USA and Europe [16,17,18,19,20].

In vitro, oritavancin exhibits synergistic bactericidal activity when used in combination with gentamicin, moxifloxacin or rifampicin against isolates of MSSA, with gentamicin or linezolid against isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous VISA and vancomycin-resistant S. aureus (VRSA), and with rifampin against isolates of VRSA [10]. No in vitro antagonism has been demonstrated between oritavancin and gentamicin, moxifloxacin, linezolid or rifampin [10].

In vitro, oritavancin demonstrated a concentration-dependent bactericidal activity against S. aureus, S. pyogenes and E. faecalis [10]. Moreover, in in vitro time-kill kinetics studies, oritavancin exerted sustained bactericidal activity (≥ 3-log kill relative to starting inoculum) against isolates of MSSA, MRSA, and vancomycin-susceptible and vancomycin-resistant enterococci in a concentration-dependent manner [21, 22]. Relative to other evaluated antibacterial agents (i.e. ceftaroline, daptomycin, dalbavancin, linezolid, tedizolid, telavancin and vancomycin), oritavancin exhibited the most rapid bactericidal activity against MSSA and MRSA isolates [22]. Oritavancin also exhibited potent in vitro activity against biofilms of MSSA, MRSA and VRSA, and increased the permeability of stationary phase cells in a concentration-dependent manner [12]. The antibacterial efficacy of oritavancin appeared to correlate with the area under the concentration-time curve (AUC)/MIC ratio [10].

There was no evidence of resistance to oritavancin in clinical studies but in vitro, the emergence of S. aureus and E. faecalis strains resistant to oritavancin has been observed in serial passage studies [10].

What is the pharmacokinetic profile of oritavancin?

Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg, with the mean population-predicted concentration time profile displaying a multi-exponential decline with a long terminal half-life [10, 11]. It is extensively distributed into tissues and is ≈ 85% bound to human plasma proteins. Following a single dose of oritavancin 800 mg in healthy individuals, oritavancin exposure in skin blister fluid is ≈ 20%. Oritavancin is slowly excreted unchanged, with less than 1% and 5% of the dose recovered in faeces and urine, respectively. In a population pharmacokinetic analysis, oritavancin has a total volume of distribution of ≈ 87.6 L and clearance of 0.445 L/h; the terminal half-life is ≈ 245 h. The pharmacokinetics of oritavancin are not affected to any clinically relevant extent by age, weight, gender, race or mild to moderate renal or hepatic impairment [10, 11].

The pharmacokinetic similarity between the new and original IV formulations of oritavancin was demonstrated in a randomized, open-label, phase 1 pharmacokinetic study where eligible patients with ABSSSIs were randomized to receive a single-dose of IV oritavancin 1200 mg in 250 mL of 0.9% sodium chloride over a 1 h infusion (i.e. new IV formulation), or in 1000 mL of dextrose 5% in sterile water over a 3 h infusion (i.e. original IV formulation) [12, 23]. Following administration of a single-dose IV oritavancin 1200 mg, the mean AUC from time zero to 72 h and 168 h was similar between the two IV formulations, with the mean peak concentration and time to reach maximum concentration being higher and faster with the new 1 h infused IV formulation due to the shorter infusion time (Table 2) [12].

Table 2 The mean pharmacokinetic properties of the two intravenous formulations of oritavancin in patients with acute bacterial skin and skin structure infections [12, 23]
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What is the overall clinical profile of oritavancin?

The efficacy and safety of oritavancin for the treatment of ABSSSIs are well established with the original 3 h infused IV formulation [24,25,26,27,28,29] and has been extensively reviewed previously [30,31,32]. There are no specific clinical studies designed to assess the efficacy of the new IV formulation of oritavancin for the treatment of ABSSSIs.

In two identically designed, randomized, double-blind, noninferiority phase 3 SOLO I and SOLO II trials (n = 1987), the efficacy of a single-dose regimen of IV oritavancin 1200 mg infused over 3 h was compared to a 7–10 days regimen of IV vancomycin 1 g or 15 mg/kg twice daily in patients with ABSSSIs [25, 26]. In each trial, oritavancin was noninferior to vancomycin in terms of the clinical response rate (SOLO I 82.3% vs 78.9%; SOLO II 80.1% vs 82.9%, primary endpoint in both trials), the investigator-assessed clinical cure rate (79.6% vs 80.0%; 82.7% vs 80.5%) and the proportion of patients achieving a ≥ 20% reduction in lesion size (86.9% vs 82.9%; 85.9% vs 85.3%) [25, 26]. In subgroup analyses, some of which were post-hoc, the primary and secondary efficacy endpoints were generally similar between the treatment groups regardless of treatment setting (inpatient or outpatient), disease severity, infection type, lesion type, baseline pathogen, geographic region, age, sex, race, weight or baseline kidney or liver function [24,25,26,27, 29].

In the SOLO I and II trials, oritavancin was generally well tolerated and exhibited a safety profile similar to that of vancomycin [28]. In patients treated with oritavancin or vancomycin, the incidence of any-grade adverse events (AEs), serious AEs and treatment discontinuation due to AEs was similar between the treatment groups (55.3%, 5.8% and 3.7% vs 56.9%, 5.9% and 4.2%). Most AEs were of mild to moderate severity and the most common AEs (≥ 3% incidence) with oritavancin included nausea (9.9% vs 10.5% with vancomycin), headache (7.1% vs 6.7%), vomiting (4.6% vs 4.7%), cellulitis (3.8% vs 3.3%), diarrhoea (3.7% vs 3.3%), constipation (3.4% vs 3.9%), infusion site extravasation (3.4% vs 3.4%), pyrexia (3.1% vs 3.2%) and pruritus (3.0% vs 7.4%). The most commonly reported serious AEs with oritavancin were cellulitis (1.1%) and osteomyelitis (0.4%), which were also the most common AEs leading to discontinuation of oritavancin (0.4% and 0.3%, respectively). The incidences of infections and infestations, abscesses or cellulitis, and hepatic and cardiac AEs were slightly higher with oritavancin than with vancomycin; however, more than 80% of these AEs were of mild to moderate severity [28].

Real-world experience in 112 patients with a confirmed or suspected gram-positive infection further supported the clinical benefits of oritavancin demonstrated in the SOLO I and II trials [33]. Oritavancin was associated with high positive clinical response (92.8%) and microbial eradication rate (90.0%), with <  5% of patients hospitalized for worsening or recurrence of the index infection within 28 days of oritavancin treatment. The tolerability profile of oritavancin was consistent to that observed in the SOLO I and II trials [33].

The tolerability profile of the new IV formulation of oritavancin was similar to that of the original IV formulation and revealed no new safety signals in the phase 1 pharmacokinetic study [12]. In this study, diarrhoea, chills, pyrexia, pruritus, infection and headache occurred in ≥ 2 patients (at least 4% of patients) receiving the new IV formulation of oritavancin. No kidney-related AEs were reported for any of the patients treated with the new formulation of oritavancin and there was no evidence that oritavancin with HPβCD was associated with increased renal toxicity [12]. Positive antiglobulin tests were reported in 2% (1/50) and 9.6% (5/52) of patients receiving the new and original IV formulations of oritavancin, respectively; positive indirect antiglobulin tests have the potential to interfere with cross-matching before blood transfusion [10, 12]. There were no reports of haemolysis in patients who had positive indirect or direct antiglobulin tests [10, 12].

What is the current clinical position of the new IV formulation of oritavancin?

With the majority of standard-of-care IV antibacterial treatment regimens for ABSSSIs requiring multi-dose and multi-day administration, IV oritavancin provides an effective single-dose regimen for ABSSSIs that can facilitate outpatient treatment and eliminate the need for unnecessary hospitalization, especially for patients with mild to moderate disease severity and minimal comorbidity [12]. The new IV formulation of oritavancin, which has a similar pharmacokinetic profile to that of the original IV formulation, is a convenient, effective treatment option for patients with ABSSSIs. Relative to the original IV formulation, the new IV formulation of oritavancin requires only a single vial during preparation, and has better diluent compatibility, a lower infusion volume and a shorter infusion time, thereby potentially improving patient convenience and optimizing the use of clinical resources.

The antibacterial activity, as well as efficacy and safety profiles of oritavancin for the treatment of ABSSSIs are well established with the original IV formulation. Oritavancin exhibits potent in vitro antibacterial activity against gram-positive bacteria associated with ABSSSI, including MRSA, and has noninferior efficacy and a similar tolerability profile to that of vancomycin. In addition, the new IV formulation of oritavancin revealed no new safety signals in the phase 1 pharmacokinetic study in patients with ABSSSIs.

Results of systematic reviews and meta-analyses comparing the efficacy of newer glycopeptides to standard care for ABSSSIs have indicated that a single-dose 3-h infusion oritavancin is less costly and has comparable efficacy and safety [34]. To improve patient clinical outcomes and resource utilization, several centres in the USA have implemented oritavancin as part of a multidisciplinary treatment program for ABSSSIs [12]. Indeed, real-world studies have suggested potential clinical and economic benefits associated with the single-dose IV oritavancin regimen in patients with ABSSSIs where the treatment reduced disease progression rates [6], infection sequelae from ABSSSI treatment failures [35], 30-day hospital readmission rates [6, 35, 36] and/or length of hospital stays without affecting readmission rates [5, 6]. Furthermore, pharmacoeconomic analyses (from the hospital perspective) of oritavancin versus vancomycin in patients with confirmed or suspected gram-positive ABSSSIs and risk of MRSA in the USA indicate that oritavancin is associated with substantial healthcare cost savings by lowering drug administration burden and reducing hospital admissions [37, 38]. Although these studies have been conducted with the original 3 h infused IV formulation of oritavancin, similar clinical and economic benefits are expected with the new 1 h infused IV formulation of oritavancin [12].

Additional studies in real-world settings assessing the economic benefits between single-dose 1-h infusion oritavancin and daily injections or oral antibiotic therapies in ABSSSIs would be of interest.