oritavancin and Skin-Diseases--Bacterial

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Skin Diseases, Bacterial

To discuss the currently available evidence about the use oritavancin and dalbavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and for other potential indications.. In this review, we briefly summarize the available data on efficacy (from randomized controlled trials) and on effectiveness and cure rates (from observational studies) pertaining to the use of oritavancin and dalbavancin either for ABSSSI or for other indications.. Oritavancin and dalbavancin are valid options for outpatient therapy and early discharge in patients with ABSSSI, especially when adherence to oral therapy cannot be guaranteed or no oral choices are available. Furthermore, it is worth noting that a non-negligible portion (sometimes the majority) of oritavancin and dalbavancin use in available real-life experiences is for indications other than ABSSSI, especially for Gram-positive osteomyelitis and endocarditis. The number of studies on the use of long-acting lipoglycopeptides for these currently off-label indications is rapidly increasing and will help to further optimize the use of these peculiar antibiotics in the forthcoming future.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Teicoplanin

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.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Osteomyelitis; Retrospective Studies; Skin Diseases, Bacterial; Staphylococcal Infections; Treatment Outcome; Vancomycin

Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Several new MRSA-active antibiotics have been developed, including semisynthetic glycopeptides (telavancin, dalbavancin and oritavancin). Of these, dalbavancin and oritavancin offer extended dosing intervals.. We performed a systematic review, network meta-analysis and cost analysis to compare the newer glycopeptides to standard care and to each other for the treatment of complicated SSTIs (cSSTI). A search for randomized controlled trials (RCTs) was conducted in Medline, Embase and the Cochrane Central Register of Controlled Trials. We also developed a model to evaluate the costs associated with dalbavancin and oritavancin from the third-party payer perspective.. Seven RCTs met the inclusion criteria. Network meta-analyses suggested that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.90-1.33; OR 0.78, 95% CI 0.52-1.18; and OR 1.06, 95% CI 0.85-1.33, respectively). Head-to-head comparisons showed no difference in clinical response between oritavancin and dalbavancin (OR 1.36; 95% CI 0.85-2.18), oritavancin and telavancin (OR 0.98; 95% CI 0.72-1.31) or dalbavancin and telavancin (OR 0.72; 95% CI 0.45-1.13). Telavancin had a higher incidence of overall adverse events compared to standard care (OR 1.33; 95% CI 1.10-1.61). Compared to telavancin, there were fewer overall adverse events with dalbavancin (OR 0.58; 95% CI 0.45-0.76) and oritavancin (OR 0.71; 95% CI 0.55-0.92). Studies were of high quality overall. Our cost analyses demonstrated that dalbavancin and oritavancin were less costly compared to standard care under baseline assumptions and many scenarios evaluated. The use of dalbavancin could save third-party payers $1442 to $4803 per cSSTI, while the use of oritavancin could save $3571 to $6932 per cSSTI.. Dalbavancin and oritavancin demonstrate efficacy and safety comparable to standard care in well-designed RCTs and result in cost savings when standard care is treatment that covers MRSA.

Topics: Anti-Bacterial Agents; Costs and Cost Analysis; Drug Therapy; Glycopeptides; Humans; Lipoglycopeptides; Network Meta-Analysis; Skin Diseases, Bacterial; Soft Tissue Infections; Teicoplanin

To assess critically oritavancin, a second-generation  lipoglycopeptide, for the treatment of Acute Bacterial Skin and Skin Structure Infections caused by susceptible Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus.. An evaluation report of oritavancin in Acute Bacterial Skin and Skin  Structure Infections was carried out according to the methodology of the Group  for drug evaluation, standardization and research in drug selection of the  Spanish Society of Hospital Pharmacy (SEFH)1, with the MADRE 4.0 program. A  search was made in PubMed, in the web www.clinicaltrials. gov, Embase,  PubMed and UptoDate. The European Medication Agency and Food and Drug  Administration evaluation reports were also used.. Single-dose oritavancin demonstrated its non-inferiority efficacy versus  vancomycin in Acute Bacterial Skin and Skin Structure  nfections, with a similar safety profile. Its potential advantage over other  therapeutic alternatives lies in its administration in single dose and in its no need for plasma levels monitoring, which would allow its administration on an outpatient basis. Regarding to the other alternative possibilities of oral  (linezolid, tedizolid) or IM (teicoplanin) treatment, oritavancin would improve the  adherence to the treatment. Although oritavancin could be more  efficient in certain scenarios (outpatient treatment versus inpatient treatment  with alternatives), there are no convincing studies in this regard so far. On the  other hand, alternative drugs above-mentioned, can also allow outpatient  treatment, reducing advantages of oritavancin and further increasing cost  differences. Therefore, given that the efficacy is similar to the alternatives, a  cost minimization analysis could be considered.. Oritavancin is comparable in terms of efficacy and safety to the  existing alternatives in Acute Bacterial Skin and Skin Structure Infections,  without improvements in the cost-effectiveness ratio, because of the proposed  positioning is to consider it for the treatment of  vancomycinresistant enterococcal infection in adult patients when the use of  linezolid or tedizolid is contraindicated.. Objetivo: Evaluar críticamente la oritavancina, lipoglicopéptido de segunda generación, para el tratamiento de la infección bacteriana aguda de la  piel y tejidos blandos causada por bacterias Gram-positivas susceptibles,  incluyendo Staphylococcus aureus resistente a meticilina.Método: Se realizó un informe de evaluación según la metodología del Grupo de Evaluación de Novedades, Estandarización e Investigación en Selección de  Medicamentos de la Sociedad Española de Farmacia Hospitalaria, con el  programa MADRE 4.0. Se llevó a cabo una búsqueda en PubMed, en  www.clinicaltrials.gov, Embase y UptoDate. También se utilizaron informes  publicados de agencias de evaluación.Resultados: La oritavancina en dosis única demostró no ser inferior a la vancomicina en Infección bacteriana aguda de la piel y tejidos blandos, con un perfil de seguridad similar. Sus ventajas potenciales frente a otras alternativas  terapéuticas radicarían en su administración en dosis única y en la no necesidad  de monitorización de los niveles plasmáticos (lo que posibilitaría su  administración ambulatoria), y en la mejora de la adherencia. Aunque podría ser  eficiente en determinados escenarios (tratamiento ambulatorio frente al  hospitalario con las alternativas), no hay estudios convincentes en este sentido.  Por otra parte, los fármacos alternativos por vía oral (linezolid, tedizolid) o IM  (teicoplanina) pueden permitir también el tratamiento ambulatorio, reduciendo  las ventajas de la oritavancina y agrandando las diferencias de coste. Dado que  su eficacia es similar a las alternativas, cabría considerar un análisis de  minimización de costes.Conclusiones: La oritavancina es de una eficacia y seguridad comparables a las alternativas existentes en Infección bacteriana aguda de la piel y tejidos blandos y no mejora la relación coste-efectividad, por lo que el posicionamiento  propuesto sería el tratamiento de la infección por enterococo resistente a  vancomicina en pacientes adultos cuando esté contraindicado el uso de linezolid  o tedizolid.

Topics: Anti-Bacterial Agents; Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Skin Diseases, Infectious; Wounds and Injuries

Acute bacterial skin and skin structure infections (ABSSSIs) are some of the most commonly encountered infections worldwide. Hospitalizations as a result of ABSSSIs are associated with high mortality. This article discusses the role of oritavancin and dalbavancin, the two newest lipoglycopeptides, in the context of the other available I.V. infusion standard therapy options.

Topics: Anti-Bacterial Agents; Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Teicoplanin

To review the pharmacology, pharmacokinetics, drug interactions, microbiologic profile, dosage and administration, safety, clinical efficacy, and potential place in therapy for the new lipoglycopetide, oritavancin.. MEDLINE and PubMed searches of available literature in English were conducted for oritavancin. Principal supplementary sources include the Food and Drug Administration (FDA) package insert, and FDA/European Medicines Agency guidances on acute bacterial skin and skin structure infections (ABSSSI).. Information from all stages of clinical development was evaluated to provide an overview of oritavancin, from in vitro susceptibility, to early human studies, to the latter stages of clinical trials.. Oritavancin is a lipoglycopeptide antibiotic that has a mechanism of action and broad-spectrum gram-positive coverage similar to other glycopeptides. Compared with other glycopeptides, oritavancin minimum inhibitory concentrations tend to be lower. Oritavancin also has coverage against glycopeptide-resistant gram-positive organisms. Oritavancin does not require dose adjustment for mild-to-moderate hepatic or renal impairment, and its prolonged half-life of 245 hours allows for a one-time administration in the treatment of ABSSSI. In phase 2 and 3 clinical trials, oritavancin was shown to be well-tolerated in addition to being noninferior to vancomycin for the treatment of ABSSSI. The most common side effects experienced were gastrointestinal in nature.. Oritavancin was approved by FDA for the treatment of ABSSSI in August 2014 and is marketed under the trade name Orbactiv. Its reduced dosing and monitoring requirements and efficacy against resistant gram-positive pathogens provide a unique profile that distinguishes it from current options in the treatment of ABSSSI.

Topics: Anti-Bacterial Agents; Drug Interactions; Drug Monitoring; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Skin Diseases, Bacterial

In 2013 the US Food and Drug Administration (FDA) issued recommendations and guidance on developing drugs for treatment of skin infection using a new definition of acute bacterial skin and skin-structure infection (ABSSSI). The new classification includes cellulitis, erysipelas, major skin abscesses and wound infection with a considerable extension of skin involvement, clearly referring to a severe subset of skin infections. The main goal of the FDA was to better identify specific infections where the advantages of a new antibiotic could be precisely estimated through quantifiable parameters, such as improvement of the lesion size and of systemic signs of infection. Before the spread and diffusion of methicillin-resistant Staphylococcus aureus (MRSA) in skin infections, antibiotic therapy was relatively straightforward. Using an empiric approach, a β-lactam was the preferred therapy and cultures from patients were rarely obtained. With the emergence of MRSA in the community setting, initial ABSSSI management has been changed and readdressed. Dalbavancin, oritavancin and tedizolid are new drugs, approved or in development for ABSSSI treatment, that also proved to be efficient against MRSA. Dalbavancin and oritavancin have a long half-life and can be dosed less frequently. This in turn makes it possible to treat patients with ABSSSI in an outpatient setting, avoiding hospitalization or potentially allowing earlier discharge, without compromising efficacy. In conclusion, characteristics of long-acting antibiotics could represent an opportunity for the management of ABSSSI and could profoundly modify the management of these infections by reducing or in some cases eliminating both costs and risks of hospitalization.

Topics: Ambulatory Care; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Glycopeptides; Humans; Lipoglycopeptides; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Teicoplanin; United States; United States Food and Drug Administration

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Glycopeptides; Humans; Injections, Intravenous; Lipoglycopeptides; Skin Diseases, Bacterial

Oritavancin, a lipoglycopeptide antibiotic, recently received US FDA approval for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI). Oritavancin, unlike other intravenous antibiotics that are currently available for the treatment of ABSSSI (e.g., vancomycin, daptomycin, telavancin, dalbavancin), offers the option of a single-dose complete regimen. The dosing schedule of oritavancin eliminates the need for an indwelling catheter and introduces the possibility of avoidance of a hospital admission; although, treatment in non-hospital settings has not been adequately evaluated in clinical trials. The availability of oritavancin adds another agent to our antibiotic armamentarium providing dosing flexibility and an alternative treatment option for treatment of ABSSSI caused by susceptible bacteria, including methicillin-resistant Staphylococcus aureus.

Topics: Acute Disease; Anti-Bacterial Agents; Drug Administration Schedule; Drug Approval; Drug Dosage Calculations; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Injections, Intravenous; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Streptococcus

Inpatient treatment of acute bacterial skin and skin structure infections (ABSSSIs) exerts a significant economic burden on the healthcare system. Oritavancin is a concentration-dependent, rapid bactericidal agent approved for the treatment of ABSSSIs. Its prolonged half-life with one-time intravenous (i.v.) dosing offers a potential solution to this burden. In addition, oritavancin represents an alternative therapy for Streptococci and multidrug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Animal models have also shown promising results with oritavancin for other disease states including those that require long courses of i.v.. This review covers oritavancin's basic chemistry, spectrum of activity, pharmacodynamics/pharmacokinetics and efficacy in clinical trials, and provides expert opinion on future directions. To compose this review, a search of PubMed was performed, and articles written in the English language were selected based on full text availability.. If oritavancin is proven to be a cost-effective strategy for outpatient treatment and prevents complications of prolonged i.v. therapy, it will be sought as an alternative antibiotic therapy for ABSSSIs. In addition, further clinical data demonstrating efficacy in Gram-positive infections requiring prolonged therapy such as endocarditis and osteomyelitis could support oritavancin's success in the current market.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Cellulitis; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Glycopeptides; Half-Life; Lipoglycopeptides; Skin Diseases, Bacterial; Wound Infection

Oritavancin is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). This antibiotic has multiple mechanisms of action including inhibiting peptidoglycan cell wall synthesis and disrupting bacterial cell membrane, leading to cell death. Oritavancin is highly active against common gram-positive pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus, and vancomycin-resistant enterococci. The drug is administered as a single intravenous dose of 1200 mg over 3 hours in adult patients, and because of its terminal half-life of 393 hours, repeat dosing is not required in the treatment of ABSSIs. There is a very slow elimination from tissue sites, and no dosing adjustments are required for renal or hepatic insufficiency. Two clinical trials have demonstrated noninferiority compared with vancomycin in the treatment of ABSSSIs. Other than liver enzyme elevation and the occurrence of osteomyelitis, oritavancin has been associated with adverse events similar to those of vancomycin in follow-up for up to 60 days. Patients should be monitored for osteomyelitis and alternate therapy given in the case of confirmed or suspected osteomyelitis. Although oritavancin is an attractive antibiotic to consider in the outpatient area, its efficacy and safety in the treatment of other sites of infection are yet to be established.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Enzymes; Glycopeptides; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Liver; Osteomyelitis; Skin Diseases, Bacterial; Soft Tissue Infections

The objective was to conduct a systematic review and network meta-analysis (NMA) of existing treatments for ABSSSI focusing on the novel lipoglycopeptide oritavancin.. EMBASE, MEDLINE, MEDLINE in Process, CENTRAL (Cochrane), and select conferences were searched for randomized controlled trials investigating antimicrobial agents for the treatment of ABSSSI. NMA was used to estimate the odds ratios of the Test-Of-Cure (TOC) and Early Clinical Response (ECR) outcomes for treatments relative to vancomycin in the ITT populations. Sub-group analyses in MRSA and MSSA populations were conducted for TOC; sensitivity analyses investigated the use of the clinically evaluable (CE) populations and the restriction to trials following the recent FDA guidelines for clinical trials.. The systematic review identified 52 trials. The most commonly investigated treatments were vancomycin and linezolid; most trials reported TOC, but not ECR. The posterior mean and 95% credible intervals for odds ratios of TOC for antimicrobial agents relative to vancomycin were: linezolid (1.55; 0.91-2.57), daptomycin (2.18; 0.90-5.42), and oritavancin 1200 mg (1.06; 0.80-1.43). The odds ratio of ECR for oritavancin 1200 mg was 1.02 (0.23-4.33). In the MRSA sub-group the odds ratios relative to vancomycin for TOC were: linezolid (1.55; 0.96-2.46), daptomycin (0.74; 0.13-3.66), and oritavancin 1200 mg (0.94; 0.44-2.02). In the MSSA sub-group they were linezolid (1.36; 0.15-13.34) and oritavancin 1200 mg (0.82; 0.08-7.83). These results were robust to the sensitivity analyses.. This NMA provides a unified framework for the comparison of all available antimicrobial agents used in the treatment of ABSSSI and is the first to assess the ECR end-point. The results suggest equivalence of clinical efficacy between vancomycin, daptomycin, linezolid, and novel antimicrobial agents including oritavancin for the treatment of ABSSSI at TOC. The wide uncertainty margins indicate the heterogeneity of the available evidence and the need for further research.

Topics: Acute Disease; Anti-Bacterial Agents; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Skin Diseases, Bacterial; Vancomycin

Oritavancin (Orbactiv(®)) is a new generation lipoglycopeptide approved for use in adult patients with acute bacterial skin and skin structure infections (ABSSSI). It is administered as a single 1200 mg intravenous infusion over 3 h. In phase 3 trials in adult patients with ABSSSI, oritavancin was noninferior to vancomycin in terms of a composite outcome (cessation of spreading or reduction in the size of the baseline lesion, absence of fever and no rescue antibacterials required; primary endpoint) assessed at an US FDA-recommended early timepoint of 48-72 h after initiation of treatment. Oritavancin was also noninferior to vancomycin in terms of a ≥20 % reduction in the baseline lesion size at the early timepoint and clinical cure rate 7-14 days after the end of treatment. Oritavancin was generally well tolerated in the phase 3 trials, with most treatment-emergent adverse reactions being mild in severity. The most common adverse events occurring in oritavancin recipients were nausea, headache, vomiting, limb and subcutaneous abscesses, and diarrhoea. Oritavancin offers a number of potential advantages, including a convenient single dose treatment that may shorten or eliminate hospital stays, a reduction in healthcare resource utilization and cost, no need for dosage adjustment in patients with mild to moderate hepatic or renal impairment, no need for therapeutic drug monitoring, and elimination of compliance concerns. Therefore, oritavancin is a useful treatment option for adults with ABSSSI.

Topics: Anti-Bacterial Agents; Glycopeptides; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Skin Diseases, Bacterial

Health care-associated infections, especially those caused by multidrug-resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are a growing public health threat. In 2014, the U.S. Food and Drug Administration approved two new lipoglycopeptides, oritavancin and dalbavancin, for the treatment of acute bacterial skin and skin structure infections. The rationale for the development of these antimicrobials was partly to aid in the battle against vancomycin resistance in both Staphylococcus and Enterococcus. Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d-alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails. This addition allows for these agents to have prolonged half-lives, giving them unique dosing profiles. In addition, by concentrating at the site of action, they have increased potency against MRSA compared with vancomycin, the current mainstay of therapy. In this review, we focus on comparing and contrasting these two new agents with regard to their pharmacology, mechanisms of action, spectrum of activity, safety profiles, dosage and administration, and drug and laboratory interactions, and we review the clinical trials evaluating their use.

Topics: Animals; Anti-Bacterial Agents; Cross Infection; Drug Interactions; Glycopeptides; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Teicoplanin; United States; Vancomycin Resistance

Vancomycin has been the cornerstone of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections. This review describes new MRSA-active antibiotics that have recently been introduced and highlights emerging resistance.. Elevations in the vancomycin minimum inhibitory concentration within the susceptible range are associated with treatment failure and mortality in the treatment of MRSA infections. Ceftaroline and ceftobiprole are anti-MRSA cephalosporins and are noninferior to comparator agents in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and pneumonia. Tedizolid is more potent than linezolid, has improved pharmacokinetics and reduced toxicity and is active against cfr-containing S. aureus. Telavancin now has approval for treatment of hospital-acquired pneumonia, and recent phase 2 trial data showed similar cure rates in S. aureus bacteremia. Dalbavancin and oritavancin are administered once weekly and are noninferior to comparators for acute bacterial skin and skin structure infections. Resistance has emerged against many new anti-MRSA antimicrobials including ceftaroline. Combination therapy of β-lactams with vancomycin or daptomycin is increasing.. Several new MRSA-active agents are now approved for use, although much of the data is derived from treatment of acute bacterial skin and skin structure infections or pneumonia. Further studies are required for more invasive infections, such as bacteremia and endocarditis.

Topics: Acetamides; Anti-Bacterial Agents; Cephalosporins; Cost-Benefit Analysis; Drug Administration Routes; Drug Therapy, Combination; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Severity of Illness Index; Skin Diseases, Bacterial; Staphylococcal Infections; Tetrazoles; Vancomycin

Oritavancin (Orbactiv(®)) is a lipoglycopeptide antibacterial drug with activity against Gram-positive bacteria developed by The Medicines Company as a single-dose treatment for acute bacterial skin and skin structure infections (ABSSSI). The drug received its first global approval for this indication in the US in August 2014, and is under regulatory review in the EU. This article summarises the milestones in the development of oritavancin leading to this first approval for the treatment of ABSSSIs caused by Gram-positive bacteria.

Topics: Anti-Bacterial Agents; Drug Approval; Glycopeptides; Gram-Positive Bacteria; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Skin Diseases, Bacterial

There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Teicoplanin

Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.).

Topics: Administration, Intravenous; Adult; Double-Blind Method; Female; Gram-Positive Bacteria; Humans; Lipoglycopeptides; Male; Middle Aged; Skin Diseases, Bacterial

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Double-Blind Method; Female; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Skin Diseases, Bacterial; Treatment Outcome; Young Adult

Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment.. In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7-10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48-72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7-14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48-72 hours.. A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], -7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, -2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, -3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups.. A single 1200-mg dose of oritavancin was noninferior to 7-10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs. Clinical Trials Registration. NCT01252732.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Double-Blind Method; Female; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Treatment Outcome; Vancomycin; Young Adult

Oritavancin is a lipoglycopeptide with bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and prolonged half-life allow for single-dose treatment.. We 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.. The 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.. A 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.).

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Double-Blind Method; Drug Administration Schedule; Female; Glycopeptides; Humans; Infusions, Intravenous; Intention to Treat Analysis; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Nausea; Skin Diseases, Bacterial; Vancomycin; Young Adult

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥ 18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Drug Administration Schedule; Glycopeptides; Gram-Positive Bacteria; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Young Adult

Topics: Anti-Bacterial Agents; Emergency Service, Hospital; Glycopeptides; Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Soft Tissue Infections; Vancomycin

Oritavancin is a lipoglycopeptide antibiotic with in vitro bactericidal activity against gram-positive pathogens indicated for use in adults with acute bacterial skin and skin structure infections (ABSSSI). Its concentration-dependent activity and prolonged half-life provide a convenient single-dose alternative to multi-dose daily therapies for ABSSSI. This retrospective cohort study was conducted to quantify the clinical and economic advantages of using oritavancin compared to other antibiotic agents that have been historically effective for ABSSSI.. Seventy-nine patients received oritavancin who had failed previous outpatient antibiotic therapy (OPAT) for cellulitis or abscess and were subsequently readmitted to the hospital as an inpatient between 2016 and 2018. These patients were compared to a cohort of 28 patients receiving other antibiotics following OPAT failure and subsequent hospitalization for these two infection types. The primary clinical end point was average length of stay (aLOS) and secondary endpoints included readmission rates for the same indication at 30 and 90 days after discharge and the average hospital cost (aHC).. A total of 107 patients were hospitalized for treatment of cellulitis or abscess. Demographic characteristics of both the oritavancin and comparator groups were similar except for the presence of diabetes. The primary clinical endpoint showed a non-significant decrease in aLOS between the oritavancin group versus comparator (2.12 days versus 2.59 days; p = 0.097). The secondary endpoints revealed lower readmission rates associated with oritavancin treatment at 30 and 90 days; the average hospital cost was 5.9% lower for patients that received oritavancin.. The results of this study demonstrate that oritavancin provides not only a single-dose alternative to multi-day therapies for skin and skin structure infections, but also a clinical and economic advantage compared to other antibiotic agents.

Topics: Abscess; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cellulitis; Female; Humans; Lipoglycopeptides; Male; Middle Aged; Patient Readmission; Retrospective Studies; Skin Diseases, Bacterial; Treatment Outcome; Young Adult

Acute bacterial skin and skin structure infections (ABSSSI) are some of the most commonly encountered infections worldwide. Hospitalizations as a result of ABSSSI are associated with high mortality. This article discusses the role of oritavancin and dalbavancin, two new lipoglycopeptides, in the context of the other I.V. available standard therapy options.

Topics: Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Teicoplanin

Topics: Acute Disease; Anti-Bacterial Agents; Glycopeptides; Humans; Lipoglycopeptides; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Teicoplanin

Nearly 10% of all US hospital admissions are attributed to acute bacterial skin and skin structure infections (ABSSSIs). While most antibacterials used to treat these infections require multi-day and multi-dose regimens, a single-dose treatment is now available. The objective of this analysis is to estimate the annual budget impact of using single-dose oritavancin in patients with moderate to severe ABSSSIs receiving intravenous methicillin-resistant Staphylococcus aureus (MRSA)-active antibacterials from a US hospital perspective.. A decision-analytic model based on current clinical practice was developed to estimate the economic impact of oritavancin. Utilization of antibacterials and rates of hospital admission were derived from the Premier Research Database. Demographic and clinical data were informed by the published literature and 2014 wholesale drug acquisition costs were used. Other costs were based on the published literature and Medicare National Limitation amounts. All costs were inflated to 2014 US dollars. Two base-case scenarios were considered: one for hospitals with ambulatory services and one for hospitals without ambulatory services.. For a US hospital with ambulatory services with 1000 ABSSSI patients receiving intravenous MRSA antibiotics annually, use of oritavancin in 26% of patients is estimated to reduce the total annual budget by 12.9% (US$1.23 million), or approximately US$1234.67 per patient. Total inpatient costs will be reduced by 22.3% (US$1.40 million) and outpatient costs will increase slightly by 1.7% (US$55,310). Pharmaceutical cost increases are offset by savings in the inpatient setting from fewer hospital admissions. Hospitals without ambulatory services are estimated to receive overall cost savings of 9.3% (US$0.63 million).. Use of single-dose oritavancin in select ABSSSI patients with suspected or confirmed MRSA involvement is estimated to save US hospitals approximately 9.3-12.9% per year by reducing hospital admissions and lowering drug administration burden.

Topics: Acute Disease; Administration, Intravenous; Ambulatory Care; Anti-Bacterial Agents; Costs and Cost Analysis; Decision Support Techniques; Drug Costs; Economics, Hospital; Female; Glycopeptides; Hospitalization; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Models, Economic; Skin Diseases, Bacterial; Staphylococcal Infections

Data indicate that acute bacterial skin and skin structure infection (ABSSSI) patients without major comorbidities can be managed effectively in the outpatient setting. Because most patients with ABSSSIs present to the emergency department, it is essential that clinicians identify candidates for outpatient treatment given the substantially higher costs associated with inpatient care. We examined the potential cost avoidance associated with shifting care from inpatient treatment with vancomycin to outpatient treatment with oritavancin for ABSSSI patients without major complications or comorbidities.. A decision analytic, cost-minimization model was developed to compare costs of inpatient vancomycin versus outpatient oritavancin treatment of ABSSSI patients with few or no comorbidities (Charlson Comorbidity Index score ≤1) and no life-threatening conditions presenting to emergency department. Hospital discharge data from the Premier Research Database was used to determine the costs associated with inpatient vancomycin treatment.. Mean costs for inpatient treatment with vancomycin ranged from $5973 to $9885, depending on Charlson Comorbidity Index score and presence of systemic symptoms. Switching an individual patient from inpatient vancomycin treatment to outpatient oritavancin treatment was estimated to save $1752.46 to $6475.87 per patient, depending on Charlson Comorbidity Index score, presence of systemic symptoms, and use of observation status. Assuming some patients may be admitted to the hospital after treatment with oritavancin, it is estimated that up to 38.12% of patients could be admitted while maintaining budget neutrality.. This cost-minimization model indicates that use of oritavancin in the emergency department or observation setting is associated with substantial cost savings compared with inpatient treatment with vancomycin.

Topics: Acute Disease; Ambulatory Care; Anti-Bacterial Agents; Comorbidity; Cost Savings; Decision Trees; Emergency Service, Hospital; Glycopeptides; Hospitalization; Humans; Lipoglycopeptides; Models, Economic; Skin Diseases, Bacterial; Vancomycin

Rates of acute bacterial skin and skin structure infections (ABSSSI) have sharply increased since 2000. Treatment may be administered in the inpatient or outpatient setting; clinical decision-making regarding hospitalization is inconsistent, often leading to hospitalization of some patients with ABSSSI who qualify for outpatient parenteral antimicrobial therapy, which leads to increased overall care costs. New antibiotics such as oritavancin are hypothesized to be a cost-effective option improving accessibility to ambulatory treatment of ABSSSI. The goal of this study was to understand the patient attributes that affect clinical decision-making regarding the setting of care for ABSSSI treatment.. An observational, cross-sectional study was conducted that surveyed clinicians of various specialties from the United States and the United Kingdom. The survey collected quantitative responses and used a series of choice-based experimental designs to evaluate patient attributes influencing clinical treatment decisions.. Infection severity, severe comorbidities, and age ≥ 75 years were observed to have the greatest impact on treatment location decisions (odds ratio [OR], 0.000-0.004 [95% CI, 0.000-0.011], vs mild ABSSSI; OR, 0.246-0.484 [95% CI, 0.154-0.788], vs no active comorbidities; OR, 0.136-0.523 [95% CI, 0.070-0.888], vs ≤ 18 years, respectively). The majority of respondents indicated they would consider oritavancin to avoid postdischarge outpatient parenteral antimicrobial therapy or oral therapy, regardless of the pathogen (63.5%-83.5%).. Key factors influencing ABSSSI treatment setting were severity of infection, severity of comorbidities, and age. Clinicians surveyed identified patient profiles in which single-dose oritavancin might enable wholly outpatient or shortened inpatient management. Additional studies to elucidate the ABSSSI care pathways that include oritavancin and other novel antibiotics are needed.

Topics: Adult; Age Factors; Ambulatory Care; Anti-Bacterial Agents; Clinical Decision-Making; Comorbidity; Cross-Sectional Studies; Female; Glycopeptides; Hospitalization; Humans; Lipoglycopeptides; Male; Middle Aged; Severity of Illness Index; Skin Diseases, Bacterial; United Kingdom; United States

The FDA guidance published in 2013 provided requirements for conducting ABSSSI trials. In 2014, dalbavancin, oritavancin, and tedizolid were introduced into the market after phase III noninferiority clinical trials against vancomycin (for the lipoglycopeptides) and linezolid (for tedizolid), demonstrating clinical efficacy for the treatment of ABSSSI. Great interest exists for these agents because of the postulated financial impact. Due to favorable pharmacokinetics which allow for less frequent medication administration and shorter treatment durations, these agents may prove to reduce hospital admissions and length of stay.

Topics: Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Costs and Cost Analysis; Glycopeptides; Humans; Lipoglycopeptides; Organophosphates; Oxazoles; Practice Guidelines as Topic; Skin Diseases, Bacterial; Teicoplanin; Treatment Outcome

To assess oritavancin activity in vitro against clinically relevant Gram-positive pathogens causing skin and soft-tissue infections (SSTIs) in European and US hospitals.. 13 262 consecutive and unique isolates deemed to be responsible for SSTIs were included. Isolates originated from 36 and 27 institutions in Europe (Israel included) and the USA, respectively, between 2010 and 2013.. Oritavancin (98.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.03, 0.03 and 0.06 mg/L, respectively, for Staphylococcus aureus. CoNS from the USA (MIC50, 0.015 mg/L) demonstrated an MIC50 value of oritavancin slightly lower than those from Europe (MIC50, 0.03 mg/L). Overall, vancomycin-resistant (VanA-phenotype) Enterococcus faecalis had oritavancin MICs (MIC50/90, 0.25/0.5 mg/L) that were 16-fold higher than those obtained for vancomycin-susceptible isolates (MIC50/90, 0.015/0.03 mg/L; 99.2%-99.8% susceptible); nevertheless, oritavancin inhibited all VanA E. faecalis at ≤0.5 mg/L. Equivalent oritavancin MICs (MIC50/90, 0.004/0.008 mg/L) were noted for all VanB and vancomycin-susceptible Enterococcus faecium, while higher MICs (MIC50/90, 0.03/0.12 mg/L) were obtained for VanA strains. Oritavancin had low MICs against the overall populations of Streptococcus pyogenes (MIC50/90, 0.03/0.12 mg/L; 98.4%-98.6% susceptible), Streptococcus agalactiae (MIC50/90, 0.03/0.06 mg/L; 97.9%-98.0% susceptible) and the Streptococcus anginosus group (MIC50/90, 0.008/0.015 mg/L; 100.0% susceptible), with slightly higher MICs for Streptococcus dysgalactiae (MIC50/90, 0.06/0.25 mg/L; ≥98.3% susceptible).. Oritavancin had potent activity in vitro against this contemporary collection of European and US isolates causing SSTIs. These results describe oritavancin activity against Gram-positive pathogens collected shortly prior to its regulatory approval in the USA.

Topics: Anti-Bacterial Agents; Cross Infection; Drug Resistance, Bacterial; Europe; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Public Health Surveillance; Skin Diseases, Bacterial; Soft Tissue Infections; United States

Oritavancin is a lipoglycopeptide that has been approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible organisms. Oritavancin causes cell death by inhibiting cell wall synthesis as well as depolarising and permeabilising the cellular membrane of Gram-positive pathogens. The activities of oritavancin in comparison with vancomycin, daptomycin and linezolid were determined against a collection of over 11000 recent clinical Gram-positive isolates from patient infections (2011-2014), including skin and skin-structure infections. A total of 7253 Staphylococcus aureus, 839 coagulase-negative staphylococci (CoNS), 1464 enterococci and 1637 β-haemolytic streptococci (βHS) were collected from the USA and Europe. Minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, and susceptibility was determined using CLSI and US Food and Drug Administration (FDA) (for oritavancin) breakpoint criteria. Equivalent in vitro activity (MIC50/90, 0.015-0.03/0.06 μg/mL) was observed for oritavancin against meticillin-resistant S. aureus (MRSA), meticillin-susceptible S. aureus (MSSA) and Enterococcus faecalis in both regions. Slightly higher oritavancin MICs were obtained against CoNS, Streptococcus agalactiae, Enterococcus faecium (MIC90, 0.12 μg/mL) and against other βHS (MIC90, 0.25 μg/mL). Oritavancin demonstrated comparatively lower MICs than daptomycin and vancomycin when tested against multidrug-resistant S. aureus, vancomycin-resistant enterococci and erythromycin-resistant βHS. Oritavancin exhibited potent in vitro activity against the most common pathogens associated with ABSSSIs in the USA and Europe.

Topics: Anti-Bacterial Agents; Daptomycin; Drug Resistance, Multiple, Bacterial; Enterococcus; Europe; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; North America; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus; Vancomycin

Topics: Anti-Bacterial Agents; Female; Glycopeptides; Humans; Lipoglycopeptides; Male; Skin Diseases, Bacterial; Teicoplanin; Vancomycin

Antibiotics currently under study by the Food and Drugs Administration include: faropenem (for treatment of sinusitis, bronchitis, and community-acquired pneumonia), dalbavancin (for catheter infections), telavancin (for treatment of nosocomial pneumonia), oritavancin (for bacteremia), ceftobiprole and iclaprim (for pneumonias). Moreover, all of them would be useful for skin and soft tissue infections.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteria; beta-Lactams; Cephalosporins; Drug Approval; Drug Resistance, Bacterial; Glycopeptides; Humans; Lipoglycopeptides; Pyrimidines; Skin Diseases, Bacterial; Skin Diseases, Viral; Teicoplanin; United States; United States Food and Drug Administration

Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC(blister fluid)/AUC(plasma) ratios) were evaluated using a t test (alpha = 0.05). Mean maximum concentration of drug in plasma or blister fluid was approximately 8-fold and 11-fold higher in plasma than in blister fluid following the 200- or 800-mg doses of oritavancin, respectively. Mean AUC(blister fluid)/AUC(plasma) ratios at 24 h were 0.190 (standard deviation [SD], 0.052) and 0.182 (SD, 0.062) for groups A and B, respectively (P = 0.791). To place these results in a clinical context, mean drug concentrations in blister fluid exceed the oritavancin MIC at which 90% of strains are inhibited of Staphylococcus aureus (2 microg/ml) by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h following administration of both dosing regimens. These results support the potential use of oritavancin for the treatment of cSSSI.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Blister; Dose-Response Relationship, Drug; Glycopeptides; Humans; Lipoglycopeptides; Male; Middle Aged; Plasma; Skin; Skin Absorption; Skin Diseases, Bacterial