Dose Of Oritavancin Research Articles

Experience with expanded use of oritavancin in a tertiary hospital: indications, tolerability and outcomes.

Oritavancin is a lipoglycopeptide antibacterial agent used to treat infections caused by Gram-positive organisms. It is FDA-approved for the treatment of acute bacterial skin and soft tissue infections (ABSSIs) but is increasingly being used off-label to treat invasive bacterial infections such as osteomyelitis, prosthetic joint infection and infective endocarditis. This study describes the clinical outcomes and adverse reactions related to oritavancin. This was a retrospective study conducted over a 5 year period at a tertiary care medical centre. Ninety-five adult patients were included in this study and were followed for 1 year after the last dose of oritavancin. The most common indication for oritavancin at our institution was osteomyelitis, followed by ABSSI. Other indications were vertebral infection, hardware-associated infection, bacteraemia and infective endocarditis. Fourteen percent (13/95) of patients developed an adverse reaction to oritavancin during the study period. Cure with no recurrence up to 1 year after the last dose of oritavancin was achieved in 74% (53/71) of patients, and the treatment failure rate was 19% (14/71 patients). Oritavancin is an effective agent that can be used to treat invasive Gram-positive bacterial infections other than ABSSI. Adverse events requiring drug discontinuation were common.

Oritavancin vs Standard of Care for Treatment of Nonendovascular Gram-Positive Bloodstream Infections.

Data is limited comparing oritavancin (ORT) to the standard-of-care (SOC) for the treatment gram-positive blood stream infections (BSI). This was a retrospective study of all patients in the Veteran's Affairs Health Care System treated with at least 1 dose of oritavancin or at least 5 days of vancomycin, daptomycin, ceftaroline, ampicillin, ampicillin-sulbactam, nafcillin, oxacillin, or cefazolin for a documented gram-positive BSI from 1 January 2015 to 30 June 2021. Patients with polymicrobial blood cultures or positive cultures from other sites were included if the organisms were sensitive to the incident antimicrobial; no concomitant antimicrobials could be used once the incident agent was started. Individuals were also excluded if they were diagnosed with endocarditis, had a neutrophil count 96-hours of treatment before the incident antimicrobial was started.The primary composite outcome was clinical failure, defined as all-cause mortality within 30-days from the end of therapy, or blood cultures positive for the incident organisms ≥72 hours after administration of the first dose and ≤30 days after the administration of the final dose of the study antimicrobial, or any drug or line-related readmissions within 30-days of hospital discharge. Two hundred-forty patients were identified for screening with 96 meeting criteria (27 in ORT and 69 in SOC groups). Baseline characteristics were generally balanced between groups except more patients in the ORT group received >96-hours of treatment before the incident antimicrobial was started (70.3% (19/27) vs 13.04% 9/69); P < .001). The pathogen most prevalent was methicillin susceptible Staphylococcus aureus (MSSA) (ORT 33.3% (9/27) vs SOC 46.4% (32/69)). Clinical failure occurred in 7.4% (2/27) in the ORT group and 17.4% (12/69) in SOC (P = .34). No components of the primary outcome were significantly different between groups, but AKI did occur more commonly in the SOC group (27.5% (19/69) vs 3.7% (1/27); P = .01). ORT appears to be a safe and effective option when directly compared to the SOC for non-endocarditis BSIs.

1845. Oritavancin Compared to the Standard-of-Care for the Treatment of Gram-positive Blood Stream Infections

Abstract Background Data is limited comparing oritavancin (ORT) to the standard-of-care (SOC) for the treatment gram-positive blood stream infections (BSI). Methods This was a retrospective study of all patients in the Veteran’s Affairs Health Care System treated with at least 1 dose of oritavancin or at least 5 days of vancomycin, daptomycin, ceftaroline, ampicillin, ampicillin-sulbactam, nafcillin, oxacillin, or cefazolin for a documented gram-positive BSI from 1 January 2015 to 30 June 2021. Patients with polymicrobial blood cultures or positive cultures from other sites were included if the organisms were sensitive to the incident antimicrobial; no concomitant antimicrobials could be used once the incident agent was started. Individuals were also excluded if they were diagnosed with endocarditis, had a neutrophil count &amp;lt; 500 cells/mm3, or had a diagnosis of Human Immunodeficiency Virus (HIV) on their problem list. The primary composite outcome was clinical failure, defined as all-cause mortality within 30-days from the end of therapy, or blood cultures positive for the incident organisms ≥72 hours after administration of the first dose and ≤30 days after the administration of the final dose of the study antimicrobial, or any drug or line-related readmissions within 30-days of hospital discharge. Secondary outcomes included all-cause 30-day readmission and rates of acute kidney injury (AKI). Results Two hundred-forty patients were identified for screening with 96 meeting criteria (27 in ORT and 69 in SOC groups). Baseline characteristics were generally balanced between groups except more patients in the ORT group received &amp;gt; 96-hours of treatment before the incident antimicrobial was started (70.3% (19/27) vs. 13.04% (9/69); p&amp;lt;0.001). The pathogen most prevalent was methicillin-susceptible Staphylococcus aureus (MSSA) (ORT 33.3% (9/27) vs. SOC 46.4% (32/69)). Clinical failure occurred in 7.4% (2/27) in the ORT group and 17.4% (12/69) in SOC (p=0.34). No components of the primary outcome were significantly different between groups, but AKI did occur more commonly in the SOC group (27.5% (19/69) vs. 3.7% (1/27); p=0.01). Conclusion ORT appears to be a safe and effective option when directly compared to the SOC for non-endocarditis BSIs. Disclosures Ryan P. Moenster, Pharm.D., FIDSA, Melinta Therapeutics: Grant/Research Support|Melinta Therapeutics: Honoraria.

Oritavancin for the treatment of complicated gram-positive infection in persons who inject drugs

BackgroundTreatment of complicated infections in persons who inject drugs (PWID) and patients experiencing homelessness poses a unique challenge to clinicians. Long-acting lipoglycopeptide antibiotics, such as oritavancin, may facilitate extended courses of outpatient intravenous therapy while avoiding the need for central lines, improving compliance and thus increasing the chance of clinical cure.MethodsRetrospective chart review of adult PWID who received at least one dose of oritavancin for a gram-positive infection between 1/1/17 and 6/30/19 at a large safety net hospital.ResultsTwenty three PWID received 24 courses of at least one dose of oritavancin for a gram-positive infection; 16 were experiencing homelessness at the time of diagnosis. Methicillin resistant Staphylococcus aureus (MRSA) was the most common infecting pathogen and bone or joint the most frequent infection site. Nineteen encounters resulted in clinical cure, including 5 whose conditions improved despite non-adherence to their prescribed regimen. Three patients experienced a non-favorable outcome. Two patients experienced mild adverse drug reactions that did not interfere with therapy; no patients died while on therapy.ConclusionOritavancin may be a clinically effective treatment option for the management of complicated gram-positive infections in PWID and patients experiencing homelessness. Further studies should be performed to validate these results.

Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: A Two-Year, Multicenter, Retrospective Study.

BackgroundAcute osteomyelitis is typically caused by Gram-positive pathogens, commonly antibiotic-resistant Staphylococcus species. Standard antibiotic treatment is challenging due to required multiple daily doses, therapeutic drug monitoring, and parenteral administration for at least 4 weeks. Oritavancin is a long-acting lipoglycopeptide antibiotic approved as a single 1200 mg dose for the treatment of adult patients with acute bacterial skin and skin structure infections.ObjectiveTo characterize the real-world use, efficacy, and safety of oritavancin in adult patients with acute osteomyelitis.MethodsThis was a 2-year, multicenter, retrospective, descriptive study of patients treated for acute osteomyelitis with weekly doses of oritavancin. End of therapy evaluation (ETE) was defined as evaluation at 7–10 days after the last dose of oritavancin, and post-therapy assessment (PTE) was at 3 months and 6 months. At ETE and PTE, patients were interviewed via telephone for clinical outcomes, using a standard questionnaire. Electronic medical record review was also conducted.Results134 patients were treated with oritavancin for acute osteomyelitis across 20 different Metro Infectious Disease Consultants infusion centers in six states. Of total positive cultures, 71.9% (92/128) were methicillin-resistant Staphylococcus aureus (MRSA) from deep wounds, bone, or joint culture; an additional nine (6.7%) of 134 patients presented with concomitant MRSA bacteremia. Oritavancin was administered via intravenous catheter; patients received an initial treatment of 1200 mg and then 800 mg weekly thereafter for a total number of doses of four (n = 118) or five (n = 16). 118 patients (88.1%) of the baseline 134 patients achieved clinical success at the ETE timepoint. 130 patients were available for PTE at 3 months and 6 months. Overall, relapse or persistent infection was diagnosed in 13/134 (9.7%) patients. Nine (6.7%) of 134 patients were admitted to the hospital during the follow-up period but none for osteomyelitis. Adverse events were reported in five (3.7%) patients including hypoglycemia-related symptoms (three patients), tachycardia (one patient), and tachycardia with chest pain (one patient). None of these patients were hospitalized due to adverse events, and all patients eventually finished their treatment regimens.ConclusionThis is the largest real-world clinical study of adult patients treated with oritavancin for acute osteomyelitis. Use of oritavancin for acute osteomyelitis infection resulted in a high rate of positive clinical outcomes and a low incidence of adverse events, thereby providing potential for a convenient, effective, and safe therapeutic option. Future prospective and comparative studies are needed to validate these findings.

Clinical Outcomes and Economic Impact of Oritavancin for Gram-Positive Infections: A Single Academic Medical Center Health System Experience.

BackgroundVancomycin treatment of complicated Gram-positive infections is associated with laboratory monitoring, nephrotoxicity, and multiple daily dosing. Oritavancin, a lipoglycopeptide antibiotic with a once-weekly dosing strategy and similar but slightly broader spectrum of activity, presents several opportunities over vancomycin to improve compliance and convenience for the patient. Minimal real-world clinical and acquisition cost data in the inpatient setting and clinical data surrounding multiple dosing in the outpatient setting have limited oritavancin use despite its potential logistic advantages.ObjectivesWe describe inpatient and outpatient oritavancin administration, clinical outcomes, and economic impact.MethodsThis was a single-center, retrospective case series of patients treated with at least one dose of oritavancin between May 2015 and September 2017 at an academic medical center in the USA. A simplified cost-avoidance analysis was conducted assuming the patient had a national health insurance plan and focused on hospital days prevented.ResultsSeventy-five patients received oritavancin during the study period. The most common use of oritavancin was in patients with acute bacterial skin and skin structure infections (ABSSSI), defined as cellulitis, abscess or non-surgical wounds (n = 25, 33%), followed by surgical wound infections (n = 12, 16%) and osteomyelitis or septic arthritis (n = 10, 13%). Clinical cure or improvement was achieved in 68 patients (93.2%), while five patients (6.8%) failed treatment; adverse reactions were reported in nine patients (12%). Thirty-five patients received oritavancin as inpatients; 20 patients (57%) had at least one hospital day avoided due to inpatient oritavancin administration resulting in a total cost avoidance of US$343,654.ConclusionIn this series of 75 patients with Gram-positive infections, oritavancin treatment resulted in clinical cure or improvement in most patients, and was generally well tolerated. Inpatient administration may avoid costs and outpatient administration is a reasonable consideration for patients in which prolonged antibiotic therapy is necessary.

A Two-Dose Oritavancin Regimen Using Pharmacokinetic Estimation Analysis.

BackgroundAntibiotics for the treatment of complicated, multidrug-resistant Gram-positive infections are limited, especially when prolonged treatment is necessary. Oritavancin is approved for the treatment of serious skin infections as a 1200 mg single-dose regimen, but case reports describe supplemental doses given at weekly intervals ranging from 800 mg to 1200 mg. ObjectiveThis study determined population pharmacokinetic estimates for a 1200 mg single dose with and without an 800 mg dose 1 week apart.MethodsA simulated oritavancin 1200 mg dose was infused over 3 h followed 7 days later by a simulated 800 mg dose infused over 3 h for pharmacokinetic estimation.ResultsThe oritavancin dosing displayed predictable linear pharmacokinetics and therapeutic concentrations. The total and free oritavancin concentrations remained above the susceptibility breakpoint (0.12 mg/L) for 8 weeks and 4.6 weeks, respectively, with the two-dose regimen. This was significantly greater than the single-dose regimen. This regimen also results in a greater area under the drug concentration–time curve (AUC) above the susceptibility breakpoint compared to the single-dose regimen (p < 0.001), and it maintains a high AUC:minimum inhibitory concentration (MIC) ratio against organisms with MICs up to 0.25 mg/L.ConclusionThese results along with the observational clinical reports of success and safety with this dosing scheme of 1200 mg followed by 800 mg 7 days later provide evidence for further evaluation of this approach when prolonged oritavancin treatment may be indicated.

The CHROME Study, a Real-world Experience of Single- and Multiple-Dose Oritavancin for Treatment of Gram-Positive Infections.

BackgroundOritavancin (ORI) is a long-acting lipoglycopeptide indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused or suspected to be caused by susceptible Gram-positive (GP) pathogens.MethodsData collected from a retrospective observational program (2014–2017), Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME), describe the utilization, outcomes, and adverse events (AEs) associated with ORI in 440 patients treated at 26 US sites for ABSSSI and other GP infections.ResultsClinical success in evaluable patients receiving at least 1 dose of oritavancin was 88.1% (386/438). In a subgroup of patients who received ORI for skin and soft tissue infections (n = 401) and bacteremia (n = 7), clinical success was achieved in 89.0% and 100%, respectively. A cohort of 32 patients received 2–10 ORI doses separated by no more than 14 days for complicated GP infections. Clinical success was observed in 30 of 32 patients (93.8%), including 10 of 11 (90.9%) patients with bone and joint infections and 7 of 8 (87.5%) patients with osteomyelitis. In the safety evaluable population, the overall rate of AEs was 6.6%.ConclusionsWe describe results from a real-world program that includes the largest multicenter, retrospective, observational study in patients who received at least 1 dose of ORI for the treatment of GP infections. This study confirms that ORI is an effective, well-tolerated antibiotic used in single and multiple doses for the treatment of ABSSSIs and complicated GP infections.

Treatment of chronic osteomyelitis with multidose oritavancin: A case series and literature review

Osteomyelitis remains difficult to treat, typically requiring a prolonged course of intravenous (i.v.) antibiotics. The optimal route and duration of antibiotics remains ill-defined due to limited prospective clinical trials. Oritavancin is a long-acting, semisynthetic lipoglycopeptide antibiotic with rapid concentration-dependent bactericidal activity against many Gram-positive organisms. Favourable pharmacokinetics makes oritavancin an appealing alternative to currently available antibiotics requiring daily infusion to decrease the risk of vascular access complications associated with outpatient antimicrobial therapy. The purpose of this study was to report the outcomes of nine patients with chronic osteomyelitis receiving multidose oritavancin. Using electronic medical records, patients aged ≥18 years treated with i.v. oritavancin between September 2015 and April 2018 at Downtown Dublin Wound Center, a hospital-owned outpatient wound care clinic and infusion centre affiliated with Meadows Regional Health System in Dublin, GA, were identified. Of 12 cases reviewed, 9 patients received at least two doses of i.v. oritavancin for the treatment of chronic osteomyelitis. All nine patients experienced clinical cure at 6-month follow-up after the last dose of oritavancin. Multidose oritavancin was found to be a safe and efficacious option for chronic osteomyelitis when treatment options are limited by patient complexities or barriers in their ability to access healthcare services.

A Real-world Patient Registry for Oritavancin Demonstrates Efficacy and Safety Consistent With the Phase 3 SOLO Program.

BackgroundOritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed.MethodsData collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice.ResultsData for 112 patients from 8 sites were collected. All patients received a single 1200-mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported.ConclusionsClinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials.

Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

Multiple-Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections.

Oritavancin is a lipoglycopeptide antibiotic approved for use in acute bacterial skin and skin structure infections as a single 1200-mg parenteral dose. Because of oritavancin's long half-life and broad gram-positive activity, interest in its use for other infections is high. This study is a retrospective cohort evaluation of patients receiving oritavancin at a single academic medical center. All patients receiving more than one dose of oritavancin were included. Patients were excluded if therapy was interrupted by more than 14 days. Efficacy, defined a priori as clinical success, improvement, or failure, and adverse drug effect outcomes were collected. Seventeen patients received multiple oritavancin doses (range 2-18 doses) for the treatment of complicated infections including osteomyelitis, surgical site infection, intravascular infections, and pneumonia. All patients achieved clinical success or improvement with oritavancin. Four patients (24%) had an adverse event requiring oritavancin discontinuation that reversed rapidly. Off-label oritavancin use may be a safe and effective alternative to daily antibiotic infusions to treat complicated infectious disease processes. This study is limited by small sample size and retrospective design, but it provides information on using oritavancin in these complex gram-positive infections.

Comparative Pharmacodynamics of Single-Dose Oritavancin and Daily High-Dose Daptomycin Regimens against Vancomycin-Resistant Enterococcus faecium Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Infection.

There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus

Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The phase 3 studies SOLO I and SOLO II demonstrated comparable efficacy and safety of a single dose of oritavancin compared with 7–10 days of twice-daily vancomycin in adults with acute bacterial skin and skin-structure infections (ABSSSIs). The present analysis assessed clinical responses by pathogen at 48–72 h and at study days 14–24 in SOLO patients within the pooled data set. Of the 1959 patients in the pooled SOLO studies, 1067 had at least one baseline Gram-positive pathogen and 405 had MRSA. Clinical response rates were similar for oritavancin- and vancomycin-treated patients by pathogen, including Staphylococcus aureus with or without the Panton–Valentine leukocidin (pvl) gene and from different clonal complexes, and were similar for pathogens within each treatment group. Oritavancin exhibited potent in vitro activity against all baseline pathogens, with MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of 0.12 µg/mL for Staphylococcus aureus, 0.25 µg/mL for Streptococcus pyogenes and 0.06 µg/mL for Enterococcus faecalis. Whereas both oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus, oritavancin provides a single-dose alternative to 7–10 days of twice-daily vancomycin to treat ABSSSIs.

Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin.

The purpose of this study was to measure oritavancin's electrocardiographic effects at a supratherapeutic dose of 1600 mg given intravenously (IV) over 3 hours. A cohort of 150 healthy volunteers were randomized to receive placebo, oritavancin, or oral moxifloxacin 400 mg in a parallel designed thorough QT study. A supratherapeutic mean maximum oritavancin concentration (Cmax ) of 232 μg/mL was achieved. There was no significant effect on baseline and placebo corrected (dd) QTcF, QRS, or heart rate; ddPR was slightly increased at most time points, with a maximum mean change of 7.7 milliseconds 1 hour after infusion. Linear PK-PD modeling predicted a 3.2-millisecond change in the PR interval for the Cmax (138 μg/mL) observed in pivotal phase 3 studies after 1200 mg of oritavancin. Moxifloxacin produced the expected increase in ddQTcF, validating assay sensitivity. At plasma concentrations above the clinical exposures of oritavancin, no clinically or statistically significant effect on QTcF, QRS, or heart rate was observed. The increase in PR is considered clinically insignificant, given the rapid decline in initial plasma concentration of oritavancin after infusion and the expected lower Cmax in patients. A therapeutic 1200-mg single dose of oritavancin is not anticipated to cause any clinically significant effect on cardiac electrophysiology.

252 Efficacy Outcomes by Lesion Type in Studies of a Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin

252 Efficacy Outcomes by Lesion Type in Studies of a Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin

99 A Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin: Lesion Size Reduction in Phase 3 Studies of Acute Bacterial Skin and Skin Infections

99 A Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin: Lesion Size Reduction in Phase 3 Studies of Acute Bacterial Skin and Skin Infections

Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections

BackgroundOritavancin is a lipoglycopeptide with bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and prolonged half-life allow for single-dose treatment.MethodsWe conducted a randomized, double-blind trial in which adults with acute bacterial skin and skin-structure infections received either a single intravenous dose of 1200 mg of oritavancin or a regimen of intravenous vancomycin twice daily for 7 to 10 days. Three efficacy end points were tested for noninferiority. The primary composite end point was defined as cessation of spreading or reduction in lesion size, absence of fever, and no need for administration of a rescue antibiotic 48 to 72 hours after administration of oritavancin. Secondary end points were clinical cure 7 to 14 days after the end of treatment, as determined by a study investigator, and a reduction in lesion size of 20% or more 48 to 72 hours after administration of oritavancin.ResultsThe modified intention-to-treat population comprised 475 patients who received oritavancin and 479 patients who received vancomycin. All three efficacy end points met the prespecified noninferiority margin of 10 percentage points for oritavancin versus vancomycin: primary end point, 82.3% versus 78.9% (95% confidence interval [CI] for the difference, −1.6 to 8.4 percentage points); investigator-assessed clinical cure, 79.6% versus 80.0% (95% CI for the difference, −5.5 to 4.7 percentage points); and proportion of patients with a reduction in lesion area of 20% or more, 86.9% versus 82.9% (95% CI for the difference, −0.5 to 8.6 percentage points). Efficacy outcomes measured according to type of pathogen, including methicillin-resistant Staphylococcus aureus, were similar in the two treatment groups. The overall frequency of adverse events was also similar, although nausea was more common among those treated with oritavancin.ConclusionsA single dose of oritavancin was noninferior to twice-daily vancomycin administered for 7 to 10 days for the treatment of acute bacterial skin and skin-structure infections caused by gram-positive pathogens. (Funded by the Medicines Company; SOLO I ClinicalTrials.gov number, NCT01252719.)

Pharmacodynamics of a Simulated Single 1,200-Milligram Dose of Oritavancin in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Methicillin-Resistant Staphylococcus aureus Infection

The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

Oritavancin does not induce Clostridium difficile germination and toxin production in hamsters or a human gut model

To evaluate the relative propensities of oritavancin and vancomycin to induce Clostridium difficile infection (CDI) in hamster and in vitro human gut models. Hamsters received clindamycin (100 mg/kg orally or subcutaneously), oritavancin (50 mg/kg orally) or vancomycin (50 mg/kg orally). C. difficile spores were administered orally the next day. Control hamsters received vehicle only (polyethylene glycol 400) plus spores or clindamycin but no spores. Hamsters were monitored for clinical signs for 20 days. Caecal contents were analysed for C. difficile cells, spores and the presence of (cyto)toxin. Oritavancin and vancomycin were instilled over 7 days into separate in vitro gut models primed with pooled human faeces and inoculated with C. difficile ribotype 027 spores. Gut flora, C. difficile total viable and spore counts, toxin titres and antimicrobial concentrations were determined. All hamsters treated with oritavancin survived up to 20 days, with no evidence of C. difficile spores, vegetative cells or toxin in their caeca. No hamsters treated with clindamycin or vancomycin survived >6 days after spore administration. Death was associated with high C. difficile counts and toxin in caecal contents. In the gut model, oritavancin dosing elicited a rapid, marked decrease in total viable C. difficile and spore counts to below the limit of detection. Vancomycin did not elicit germination or toxin production in the gut model, but C. difficile remained present as spores throughout. Oritavancin exposure, unlike exposure to vancomycin or clindamycin, did not lead to CDI in hamsters. In both models, oritavancin reduced C. difficile total counts and spores to below detectable limits. The data indicate the potential of oritavancin for CDI treatment, since exposure did not induce C. difficile germination and toxin production, which are known to exacerbate the disease state.