Advertisement

Newer glycopeptide antibiotics for treatment of complicated skin and soft tissue infections: systematic review, network meta-analysis and cost analysis

  • R. Agarwal
    Correspondence
    Corresponding author. R. Agarwal, Division of Hospital Medicine, North Mississippi Medical Center, 830 South Gloster, Tupelo, MS 38801, USA.
    Affiliations
    Division of Hospital Medicine, North Mississippi Medical Center, Tupelo, MS, USA

    Kelley School of Business, Indiana University, Indianapolis, IN, USA
    Search for articles by this author
  • S.M. Bartsch
    Affiliations
    Public Health Computational and Operations Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Global Obesity Prevention Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    Search for articles by this author
  • B.J. Kelly
    Affiliations
    Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for articles by this author
  • M. Prewitt
    Affiliations
    Division of Infectious Diseases, North Mississippi Medical Center, Tupelo, MS, USA
    Search for articles by this author
  • Y. Liu
    Affiliations
    Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for articles by this author
  • Y. Chen
    Affiliations
    Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for articles by this author
  • C.A. Umscheid
    Affiliations
    Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, PA, USA

    Division of General Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for articles by this author
Open ArchivePublished:September 04, 2017DOI:https://doi.org/10.1016/j.cmi.2017.08.028

      Abstract

      Objectives

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

      Introduction

      Skin and soft tissue infections (SSTIs) carry a significant economic burden, mainly driven by the high cost of hospitalization and inpatient treatment with intravenous (iv) antibiotics [
      • Jenkins T.C.
      • Sabel A.L.
      • Sarcone E.E.
      • Price C.S.
      • Mehler P.S.
      • Burman W.J.
      Skin and soft-tissue infections requiring hospitalization at an academic medical center: opportunities for antimicrobial stewardship.
      ,
      • Lee B.Y.
      • Singh A.
      • David M.Z.
      • Bartsch S.M.
      • Slayton R.B.
      • Huang S.S.
      • et al.
      The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).
      ]. SSTIs that require complex management (e.g. surgical procedures) or that occur in the setting of significant comorbidities are broadly referred to as complicated SSTIs (cSSTIs) [
      • Miller L.G.
      • Eisenberg D.F.
      • Liu H.
      • Chang C.L.
      • Wang Y.
      • Luthra R.
      • et al.
      Incidence of skin and soft tissue infections in ambulatory and inpatient settings, 2005–2010.
      ,
      • Russo A.
      • Concia E.
      • Cristini F.
      • De Rosa F.G.
      • Esposito S.
      • Menichetti F.
      • et al.
      Current and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections.
      ,
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ]. In 2013, the US Food and Drug Administration (FDA) introduced a new definition for such skin infections termed acute bacterial skin and skin structure infections (ABSSSI). These infections include cellulitis, erysipelas, major skin abscesses and wound infections with a minimum lesion surface area of 75 cm2 and accompanied by signs of systemic inflammation or significant medical comorbidities (https://www.fda.gov/downloads/Drugs/Guidances/ucm071185.pdf). While uncomplicated SSTIs respond well to oral antibiotic therapy, cSSTIs typically require iv antibiotic therapy [
      • Miller L.G.
      • Daum R.S.
      • Creech C.B.
      • Young D.
      • Downing M.D.
      • Eells S.J.
      • et al.
      Clindamycin versus trimethoprim–sulfamethoxazole for uncomplicated skin infections.
      ].
      Additionally, there has recently been a sharp rise in the incidence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) [
      • Chambers H.F.
      The changing epidemiology of Staphylococcus aureus?.
      ,
      • Daum R.S.
      Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus.
      ]. This has resulted in increased use of vancomycin and the emergence of vancomycin-resistant strains of S. aureus [
      • Daum R.S.
      Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus.
      ,
      • Cosgrove S.E.
      • Carroll K.C.
      • Perl T.M.
      Staphylococcus aureus with reduced susceptibility to vancomycin.
      ]. As a consequence, there has been an emergence of new antibiotics to combat the potential increase in morbidity and mortality from Gram-positive (e.g. Staphylococcus, Streptococcus, Corynebacterium, Clostridium, Listeria) SSTIs [
      • Tsoulas C.
      • Nathwani D.
      Review of meta-analyses of vancomycin compared with new treatments for Gram-positive skin and soft-tissue infections: are we any clearer?.
      ].
      Vancomycin is the most frequently prescribed treatment for MRSA infections overall and is currently the second most common antibiotic used in hospitals [
      • Cardona A.F.
      • Wilson S.E.
      Skin and soft-tissue infections: a critical review and the role of telavancin in their treatment.
      ]. Continued efforts to develop safe and effective alternatives to vancomycin have led to the development of more potent semisynthetic glycopeptides: telavancin, dalbavancin and oritavancin [
      • Klinker K.P.
      • Borgert S.J.
      Beyond vancomycin: the tail of the lipoglycopeptides.
      ]. Of these, dalbavancin and oritavancin have long half-lives and extensive tissue distribution, thus allowing the benefit of extended dosing intervals [
      • Klinker K.P.
      • Borgert S.J.
      Beyond vancomycin: the tail of the lipoglycopeptides.
      ,
      • Lin G.
      • Credito K.
      • Ednie L.M.
      • Appelbaum P.C.
      Antistaphylococcal activity of dalbavancin, an experimental glycopeptide.
      ,
      • Saravolatz L.D.
      • Stein G.E.
      Oritavancin: a long-half-life lipoglycopeptide.
      ,
      • Zhanel G.G.
      • Schweizer F.
      • Karlowsky J.A.
      Oritavancin: mechanism of action.
      ].
      Current national guidelines on treatment of SSTIs do not incorporate evidence on semisynthetic glycopeptides, which may offer the advantage of outpatient treatment given their novel dosing regimens [
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ]. Here we compare the efficacy and safety of the newer glycopeptide antibiotics with standard care and each other for the treatment of cSSTI using the technique of network meta-analysis. For the purposes of this review, we defined standard care as vancomycin or its traditional alternatives (such as linezolid, tedizolid, daptomycin, clindamycin, trimethoprim/sulfamethoxazole, doxycycline, oxacillin, cefazolin, ceftaroline and tigecycline) used for treatment of Gram-positive SSTIs. We then performed a cost analysis to compare the costs of standard care to treatment with dalbavancin and oritavancin and each other, given their novel dosing regimens. Our cost analysis is relevant for cases in which the empirical treatment of choice is a drug that covers MRSA.

      Methods

       Study design

      A systematic review and network meta-analysis of randomized controlled trials (RCTs) was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ]. Network meta-analysis (also known as mixed-treatment comparisons) allows the synthesis of direct and indirect evidence across a network of randomized trials to infer the relative effectiveness of multiple treatments or interventions. In this method, evidence on the relative performance of treatments A and B is obtained from trials that directly compare them (known as direct evidence) and also from trials that compare them through a common comparator (known as indirect evidence). By combining direct and indirect evidence, more precise estimates on relative performance can be obtained. Moreover, relative performance on treatments that have not been directly compared in trials can be estimated [
      • Cipriani A.
      • Higgins J.P.
      • Geddes J.R.
      • Salanti G.
      Conceptual and technical challenges in network meta-analysis.
      ,
      • Salanti G.
      Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.
      ].

       Literature review

      We searched Medline (including articles in process and nonindexed citations) using the search strategy described in Supplementary Table S1, the Cochrane Central Register of Controlled Trials and Embase using the keywords ‘telavancin,’ ‘dalbavancin’ and ‘oritavancin.’ We searched ClinicalTrials.gov for any relevant completed studies pending results. Searches were completed in May 2017. Screening of titles and abstracts was done by one author (RA) which was followed by full-text screening by two independent authors (RA and MP). We included in our review all RCTs that included adults with cSSTIs and that compared one of the newer glycopeptide antibiotics to standard care for Gram-positive SSTIs.
      The primary outcome was the clinical response 1 to 2 weeks after end of therapy, broadly defined as an improvement in the signs and symptoms associated with the cSSTI. Secondary efficacy outcomes included the clinical response among patients infected with S. aureus (both methicillin sensitive and resistant), and the clinical response at 48 to 72 hours among patients with ABSSSI. We also examined the overall and serious adverse events reported in the RCTs.
      We extracted data on patient population, details of the intervention and comparison, size of the study sample and our outcome measures. We evaluated the quality of included RCTs by examining the randomization and blinding procedures and the extent of attrition using the Cochrane risk of bias tool (http://handbook-5-1.cochrane.org/).

       Meta-analysis

      We performed two types of meta-analysis. First, we performed standard pairwise meta-analyses in RevMan 5.3 using the Mantel-Haenszel procedure that assumes a fixed effect size [
      • Collins R.
      • Gray R.
      • Godwin J.
      • Peto R.
      Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews.
      ]. We measured between-study heterogeneity using the I2 statistic [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. We defined substantial heterogeneity as an I2 statistic of ≥50%, which would imply that real differences exist between study results that would not be explained by chance alone. We also evaluated the significance of between-study heterogeneity using the likelihood ratio test statistic comparing fixed-effects and random-effects meta-analysis models. In the presence of substantial heterogeneity, meta-analysis using the random-effects model was considered [
      • DerSimonian R.
      • Kacker R.
      Random-effects model for meta-analysis of clinical trials: an update.
      ]. Second, we performed a fixed-effects network meta-analysis using the netmeta package in R 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org/). The estimates used in our meta-analyses were odds ratios (OR) and 95% confidence intervals (CI). Results from network meta-analyses are reported in the text unless the results from the network and pairwise meta-analyses were inconsistent. In such cases, both estimates are reported.
      A fundamental assumption for network meta-analysis is transitivity. This means that one can learn about treatment A versus B via treatment C (i.e. the common comparator C is transitive). An interpretation of transitivity is that the common comparator C (e.g. the standard care in our analysis) is similar when it appears in A versus C and B versus C trials (e.g. dalbavancin vs. standard care RCTs; and oritavancin vs. standard care RCTs). An equivalent way to assess transitivity is that studies which directly compare A with C and B with C would have similar distributions of effect modifiers [
      • Salanti G.
      Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.
      ]. We assessed our transitivity assumption conceptually and if our network contained a closed loop, we assessed the consistency assumption (i.e. agreement between direct and indirect evidence) statistically by comparing direct and indirect summary effects [
      • Cipriani A.
      • Higgins J.P.
      • Geddes J.R.
      • Salanti G.
      Conceptual and technical challenges in network meta-analysis.
      ].

       Cost analysis

      Using TreeAge Pro 2016 (TreeAge Software, Williamstown, MA, USA), we developed a computer simulation model to compare the costs associated with dalbavancin and oritavancin from the third-party payer perspective (i.e. direct costs). We focused on these two drugs (and not telavancin) on the basis of our hypothesis that despite their high requisition costs, outpatient treatment of cSSTI would help offset the hospitalization costs associated with the use of standard treatment. Adult cSSTI patients enter the model and receive either one of the new drugs or one of the commonly used vancomycin-based regimens (vancomycin only or vancomycin followed by one of linezolid, trimethoprim/sulfamethoxazole, doxycycline or clindamycin). A patient's drug treatment regimen determined the location of treatment, where newer antibiotics for cSSTI are provided in an outpatient setting or freestanding infusion centre, while standard antibiotics for cSSTI require initial hospitalization.
      The dosing and treatment regimen for all drugs followed those described in the literature [
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ,
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      ,
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ]. Patients treated with dalbavancin received 1 g over 30 minutes on the first day and 500 mg over 30 minutes 7 days later (i.e. two doses over the course of 1 week, each requiring an outpatient visit) [
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      ]. Patients treated with oritavancin received 1200 mg once over 3 hours [
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ]. Those treated with only vancomycin received 15 mg/kg every 12 hours for 7 to 10 days. Patients treated with vancomycin followed by another drug received 15 mg/kg of vancomycin every 12 hours for 3 days, followed by linezolid (600 mg), trimethoprim/sulfamethoxazole (two double strength 800–160 mg tablets twice a day), doxycycline (100 mg twice daily) or clindamycin (300 mg four times daily) for the remainder of their 10- to 14-day treatment regimen. Patients receiving dalbavancin or oritavancin incurred the costs of the drug, evaluation and management (i.e. outpatient visit cost), infusion supplies and infusion services for each hour of infusion and the therapy duration, while those treated with any of the standard treatment approaches incurred the costs of the drugs as well as hospitalization.
      Table 1 shows the model input parameters, values and sources. All parameters are age specific where available (age distribution of patients based on SSTI discharges from the Healthcare Cost and Utilization Project; http://hcupnet.ahrq.gov/HCUPnet.jsp). We used mean hospitalization costs per patient for a primary discharge diagnosis of SSTI (International Classification of Diseases, 9th Revision, code 682.9). All drug costs are based on average wholesale unit price for all available products, including generics and repackages (https://truvenhealth.com/products/micromedex/product-suites/clinical-knowledge/red-book). All costs are presented in 2017 US dollars, converted using a 3% discount rate [
      ].
      Table 1Model input parameters, values, and sources
      ParameterMean or medianStandard deviation or rangeSource
      Costs (2017 US$)
       Oritavancin (per 400 mg)1194.8
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Dalbavancin (per 500 mg)1841.64
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Vancomycin (per mg)0.0150.008
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Linezolid (per 600 mg)190.0523.69
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Trimethoprim/sulfamethoxazole (per 800–160 mg)3.160.85
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Doxycycline (per 100 mg)3.311.85
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Clindamycin (per 300 mg)4.450.54
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      Age at hospitalization
      Mean and standard deviation of hospitalization costs for patients with a discharge diagnosis of skin and soft tissue infection (International Classification of Diseases, 9th Revision, code 682.9).
       18–44 years5318.03565.01
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       45–64 years8113.79818.24
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       65–84 years7973.10956.68
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       ≥85 years8657.41970.19
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      First hour of infusion71.91https://www.cms.gov/apps/physician-fee-schedule/overview.aspx
      Additional hours of infusion19.55https://www.cms.gov/apps/physician-fee-schedule/overview.aspx
      Office visit for infusion (evaluation and management)111.37https://www.cms.gov/apps/physician-fee-schedule/overview.aspx
      Infusion supplies45.070.93https://www.cms.gov/medicare/medicare-fee-for-service-payment/DMEPOSFeeSched/DMEPOS-Fee-Schedule.html
      Duration
       Oritavancin (hours)3
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       Dalbavancin (hours)0.5
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Vancomycin only (days)7–10
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       Vancomycin followed by linezolid (days)
      Total treatment duration represented 3 days of intravenous vancomycin followed by oral antibiotic to complete therapy.
      10–14
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
       Vancomycin followed by trimethoprim/sulfamethoxazole, doxycycline or clindamycin (days)
      Total treatment duration represented 3 days of intravenous vancomycin followed by oral antibiotic to complete therapy.
      10–14
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      Age distribution of patients (%) for age range:
       18–44 years21.3
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       45–64 years34.7
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       65–84 years36.6
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
       ≥85 years7.5
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      Average weight (kg) for age range:
       18–44 years82.873.5–91.5https://www.cdc.gov/nchs/data/series/sr_03/sr03_039.pdf
       45–64 years84.576.6–91.5https://www.cdc.gov/nchs/data/series/sr_03/sr03_039.pdf
       65–84 years78.664.4–90.6https://www.cdc.gov/nchs/data/series/sr_03/sr03_039.pdf
       ≥85 years71.8https://www.cdc.gov/nchs/data/series/sr_03/sr03_039.pdf
      a Mean and standard deviation of hospitalization costs for patients with a discharge diagnosis of skin and soft tissue infection (International Classification of Diseases, 9th Revision, code 682.9).
      b Total treatment duration represented 3 days of intravenous vancomycin followed by oral antibiotic to complete therapy.
      Each simulation ran 1000 adult cSSTI patients through the model 1000 times for a total of 1 million trials with unique outcomes. Monte Carlo simulation (i.e. probabilistic sensitivity analysis) varied each parameter throughout the ranges in Table 1. Because the economic value of outpatient therapy may change with the cost of the new drug and/or changes in hospitalization cost, additional sensitivity analyses varied the cost of hospitalization for all ages (using values from $4000 to $8000, as well as the median value of $5466), the cost of dalbavancin per 500 mg (0.5 to 2 times the current cost), and the cost of oritavancin per 400 mg (0.5 to 2 times the current cost). Last, we performed analyses to estimate the additional days of treatment avoided with use of dalbavancin and oritavancin.

      Results

       Study selection

      Our searches yielded a total of 573 citations, of which 15 were retrieved for full-text review after title and abstract screening. Seven studies met inclusion criteria [
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      ,
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ,
      • Stryjewski M.E.
      • O’Riordan W.D.
      • Lau W.K.
      • Pien F.D.
      • Dunbar L.M.
      • Vallee M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to Gram-positive bacteria.
      ,
      • Stryjewski M.E.
      • Chu V.H.
      • O’Riordan W.D.
      • Warren B.L.
      • Dunbar L.M.
      • Young D.M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by Gram-positive bacteria: FAST 2 study.
      ,
      • Stryjewski M.E.
      • Graham D.R.
      • Wilson S.E.
      • O’Riordan W.
      • Young D.
      • Lentnek A.
      • et al.
      Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms.
      ,
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • Goldberg L.
      • Krievins D.
      • Frederick M.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      ,
      • Corey G.R.
      • Kabler H.
      • Mehra P.
      • Gupta S.
      • Overcash J.S.
      • Porwal A.
      • et al.
      Single-dose oritavancin in the treatment of acute bacterial skin infections.
      ] (Fig. 1). Among the excluded studies was an early RCT comparing dalbavancin to standard care that did not have a defined treatment regimen in the comparison group (it was determined by the clinician before randomization) [
      • Seltzer E.
      • Dorr M.B.
      • Goldstein B.P.
      • Perry M.
      • Dowell J.A.
      • Henkel T.
      • et al.
      Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections.
      ].
      Fig. 1
      Fig. 1Selection process for included studies.

       Study characteristics

      Combined, the seven studies included 6398 patients. Study characteristics are detailed in Supplementary Table S2. All study participants had cSSTI caused by a suspected or confirmed Gram-positive organism and defined by the presence of a major abscess, infected burn, extensive cellulitis, wound infection or ulcer, along with systemic and local signs of infection. Of note, the definitions of cSSTI used by the included studies varied, but all incorporated the principles of the 2013 FDA definition (e.g. accompanying signs of systemic inflammation or significant medical comorbidities). Mean age in all studies was less than 50 years, and patients were predominantly white and male. Cellulitis, abscess and wound infection were the most common infection types. The interventions used were iv telavancin in three studies [
      • Stryjewski M.E.
      • O’Riordan W.D.
      • Lau W.K.
      • Pien F.D.
      • Dunbar L.M.
      • Vallee M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to Gram-positive bacteria.
      ,
      • Stryjewski M.E.
      • Chu V.H.
      • O’Riordan W.D.
      • Warren B.L.
      • Dunbar L.M.
      • Young D.M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by Gram-positive bacteria: FAST 2 study.
      ,
      • Stryjewski M.E.
      • Graham D.R.
      • Wilson S.E.
      • O’Riordan W.
      • Young D.
      • Lentnek A.
      • et al.
      Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms.
      ], iv dalbavancin (administered as 1 g on day 1, followed by 500 mg on day 8) in two studies [
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      ,
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • Goldberg L.
      • Krievins D.
      • Frederick M.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      ] and iv oritavancin (provided as a single 1200 mg dose) in two studies [
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ,
      • Corey G.R.
      • Kabler H.
      • Mehra P.
      • Gupta S.
      • Overcash J.S.
      • Porwal A.
      • et al.
      Single-dose oritavancin in the treatment of acute bacterial skin infections.
      ]. In all studies, standard therapy was administered and dosing adjustments were made according to standard practice by unblinded personnel. Other drugs (e.g. aztreonam and metronidazole) were permitted for polymicrobial infections. All studies were funded by the pharmaceutical company that manufactured the respective study drugs. One or more authors reported a conflict of interest in all studies.

       Study quality

      Appropriate performance of randomization and allocation concealment was reported in all studies. All studies were described as double blind, although details about participant blinding were not reported in one study [
      • Stryjewski M.E.
      • Graham D.R.
      • Wilson S.E.
      • O’Riordan W.
      • Young D.
      • Lentnek A.
      • et al.
      Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms.
      ]. Outcome assessment was reported as blinded in all studies. Attrition was greater than acceptable limits in one study [
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • Goldberg L.
      • Krievins D.
      • Frederick M.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      ]. Intention-to-treat analysis was performed in all studies. Study quality is depicted in Fig. 2.

       Outcomes

      The network of eligible comparisons for our outcome ‘clinical response—all patients’ is depicted in Fig. 3. The studies form a star-shape network, where node size represents the treatment option and line thickness is proportional to the number of direct comparisons. Similar networks were noted for all other outcomes examined. As depicted in Fig. 3, the network does not contain a closed loop (i.e. triangular loop). In such cases, the assumption of consistency cannot be evaluated statistically. However, the transitivity assumption can be assessed conceptually. Although not identical, the populations, comparators, outcomes and key effect modifiers were clinically similar across our included studies, which supports the transitivity assumption. Results of the direct comparisons and network estimates for the clinical response and safety outcomes are shown in Table 2. For our primary analysis, we used data from intention-to-treat analyses reported in the studies when available. We also performed additional sensitivity analyses using only per-protocol data reported in the studies. Forest plots of the pairwise meta-analyses are included in Supplementary Figs S1 to S5.
      Fig. 3
      Fig. 3Network of treatment comparisons for primary outcome.
      Table 2Results from pairwise and network meta-analysis
      Treatment comparisonNo. of studiesOR (95% CI) for:
      Pairwise meta-analysisNetwork meta-analysis
      Clinical response—all patients
       Oritavancin vs. standard care21.06 (0.85–1.33)1.06 (0.85–1.33)
       Dalbavancin vs. standard care20.79 (0.53–1.20)0.78 (0.52–1.18)
       Telavancin vs. standard care31.09 (0.90–1.33)1.09 (0.90–1.33)
       Oritavancin vs. dalbavancinNANA1.36 (0.85–2.18)
       Oritavancin vs. telavancinNANA0.98 (0.72–1.31)
       Dalbavancin vs. telavancinNANA0.72 (0.45–1.13)
      Clinical response—patients infected with methicillin-resistant Staphylococcus aureus
       Oritavancin vs. standard care20.95 (0.56–1.61)0.95 (0.56–1.61)
       Dalbavancin vs. standard care10.73 (0.06–8.33)0.73 (0.06–8.33)
       Telavancin vs. standard care31.62 (1.01–2.61)1.62 (1.00–2.61)
       Oritavancin vs. dalbavancinNANA1.29 (0.11–15.48)
       Oritavancin vs. telavancinNANA0.59 (0.29–1.19)
       Dalbavancin vs. telavancinNANA0.45 (0.04–5.39)
      Early clinical response at 48–72 hours among patients with acute bacterial skin and skin structure infection (ABSSSI)
       Oritavancin vs. dalbavancinNANA1.02 (0.72–1.46)
       Oritavancin vs. standard care21.02 (0.80–1.27)1.02 (0.80–1.27)
       Dalbavancin vs. standard care10.99 (0.76–1.30)0.99 (0.76–1.30)
      Overall adverse events
       Oritavancin vs. standard care20.94 (0.79–1.13)0.94 (0.79–1.13)
       Dalbavancin vs. standard care20.77 (0.64–0.93)0.77 (0.64–0.93)
       Telavancin vs. standard care31.33 (1.10–1.60)1.33 (1.10–1.61)
       Oritavancin vs. dalbavancinNANA1.23 (0.94–1.58)
       Oritavancin vs. telavancinNANA0.71 (0.55–0.92)
       Dalbavancin vs. telavancinNANA0.58 (0.45–0.76)
      Serious adverse events
       Oritavancin vs. standard care20.99 (0.68–1.45)0.99 (0.68–1.45)
       Dalbavancin vs. standard care20.77 (0.52–1.14)0.77 (0.52–1.15)
       Telavancin vs. standard care31.52 (1.07–2.17)1.54 (1.07–2.21)
       Oritavancin vs. dalbavancinNANA1.28 (0.74–2.22)
       Oritavancin vs. telavancinNANA0.64 (0.38–1.09)
       Dalbavancin vs. telavancinNANA0.50 (0.29–0.86)
      ABSSSI, acute bacterial skin and skin structure infections; CI, confidence interval; NA, not available; OR, odds ratio.

       Clinical response

      All included studies reported data on clinical response. Further, all studies except one [
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • Goldberg L.
      • Krievins D.
      • Frederick M.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      ] reported clinical response among patients infected with S. aureus and MRSA. Pairwise meta-analyses of the included RCTs showed that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care. These results were consistent with those of the network meta-analyses. Telavancin, dalbavancin and oritavancin had similar clinical response in head-to-head comparisons in the network meta-analysis. Among patients with MRSA, telavancin was found to have a superior clinical response compared to standard care (OR 1.62, 95% CI 1.00–2.61) in pairwise and network meta-analysis. Dalbavancin and oritavancin were similar to standard care. Network meta-analysis suggested that oritavancin and dalbavancin were similar to telavancin, and oritavancin was similar to dalbavancin in head-to-head comparisons. Three studies evaluated early clinical response at 48 to 72 hours among patients with ABSSSI [
      • Boucher H.W.
      • Wilcox M.
      • Talbot G.H.
      • Puttagunta S.
      • Das A.F.
      • Dunne M.W.
      Once-weekly dalbavancin versus daily conventional therapy for skin infection.
      ,
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ,
      • Corey G.R.
      • Kabler H.
      • Mehra P.
      • Gupta S.
      • Overcash J.S.
      • Porwal A.
      • et al.
      Single-dose oritavancin in the treatment of acute bacterial skin infections.
      ]. Network meta-analysis of these studies showed no differences between oritavancin and dalbavancin, oritavancin and standard care or dalbavancin and standard care. Studies reported intention-to-treat and per-protocol data separately for the outcome of ‘clinical response—all patients.’ Pairwise and network meta-analyses using per-protocol data showed that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (Supplementary Table S3 and Supplementary Fig. S3). Network meta-analysis showed that telavancin, dalbavancin and oritavancin had similar clinical response in head-to-head comparisons using per-protocol data.

       Adverse events

      All included studies reported data on overall and serious adverse events. Supplementary Table S4 describes the serious adverse events that were deemed to be treatment related. Dalbavancin was found to have fewer overall adverse events compared to standard care (OR 0.77, 95% CI 0.64–0.93) in pairwise and network meta-analyses, but similar odds of serious adverse events. Telavancin had higher overall adverse events (OR 1.33, 95% CI 1.10–1.61) and serious adverse events (OR 1.54, 95% CI 1.07–2.21) compared to standard care in pairwise and network meta-analyses. Oritavancin had fewer overall adverse events compared to telavancin (OR 0.71, 95% CI 0.55–0.92), but the odds of serious adverse events were similar. Dalbavancin had fewer overall adverse events (OR 0.58, 95% CI 0.45–0.76) and serious adverse events (OR 0.50, 95% CI 0.29–0.86) compared to telavancin. There were no differences in the overall and serious adverse events between oritavancin and dalbavancin. Intention-to-treat and per-protocol adverse event data were not separately reported in the included studies [
      • DerSimonian R.
      • Kacker R.
      Random-effects model for meta-analysis of clinical trials: an update.
      ]. Transient elevations in liver enzymes were noted with dalbavancin and oritavancin [
      • Corey G.R.
      • Good S.
      • Jiang H.
      • Moeck G.
      • Wikler M.
      • Green S.
      • et al.
      Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
      ,
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • Goldberg L.
      • Krievins D.
      • Frederick M.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      ,
      • Corey G.R.
      • Kabler H.
      • Mehra P.
      • Gupta S.
      • Overcash J.S.
      • Porwal A.
      • et al.
      Single-dose oritavancin in the treatment of acute bacterial skin infections.
      ], but these differences were not reported as significant when compared to the comparison group.

       Cost analysis

      Table 3 shows the average cost of treatment for cSSTI patients for the evaluated treatment regimens. With baseline assumptions (age-specific hospitalization costs and current drug costs), the use of each of the new drugs was less costly compared to vancomycin-based regimens. The use of dalbavancin could save third-party payers $1442 to $4803 per cSSTI patient treated, while the use of oritavancin could save $3571 to $6932 per cSSTI patient treated. Compared to standard of care, dalbavancin could save between 6.5 and 10.0 days of treatment and oritavancin could save between 7.5 and 11.0 days of treatment.
      Table 3Average total cost (US$) (95% uncertainty interval) of treatment regimens
      Treatment regimenTotal cost for treatment in outpatient settingsTotal cost for treatment requiring hospitalization
      Age-specific SSTI hospitalization costMedian ($5466) SSTI hospitalization cost$4000 SSTI hospitalization cost$8000 SSTI hospitalization cost
      Dalbavancin ($1842 per 500 mg)
      Current cost.
      5 982 (5 982–5 982)
      Dalbavancin ($921 per 500 mg)
      Half current cost.
      3 219 (3 219–3 219)
      Dalbavancin ($3684 per 500 mg)
      Two times current cost.
      11 507 (11 507–11 507)
      Oritavancin ($1195 per 400 mg)
      Current cost.
      3 852 (3 852–3 852)
      Oritavancin ($598 per 400 mg)
      Half current cost.
      2 060 (2 060–2 060)
      Oritavancin ($2390 per 400 mg)
      Two times current cost.
      7 436 (7 436–7 436)
      Vancomycin7 569 (4 425–8 958)5 782 (5 744–5 806)4 318 (4 283–4 339)8 316 (8 279–8 339)
      Vancomycin followed by linezolid10 784 (7 626–12 200)8 998 (8 955–9 041)7 534 (7 491–7 577)11 532 (11 490–11 580)
      Vancomycin followed by trimethoprim-sulfamethoxazole7 478 (4 329–8 890)5 692 (5 678–5 700)4 226 (4 213–4 234)8 225 (8 212–8 234)
      Vancomycin followed by clindamycin7 524 (4 376–8 935)5 738 (5 724–5 747)4 272 (4 260–4 281)8 272 (8 259–8 280)
      Vancomycin followed by doxycycline7 423 (4 274–8 834)5 637 (5 624–5 646)4 172 (4 159–4 180)8 171 (8 158–8 179)
      SSTI, skin and soft tissue infection.
      a Current cost.
      b Half current cost.
      c Two times current cost.
      When all parameters were held at baseline, dalbavancin was the least costly treatment option up to a cost of $1132, at which point oritavancin became the least costly treatment option. Because dalbavancin costs ≥$2600, all other treatment strategies cost less except for the strategy of iv vancomycin followed by oral linezolid for completion of the antibiotic course. When all parameters were held at baseline, oritavancin was the least costly treatment option up to a cost of $1905, at which point dalbavancin became the least costly option. Oritavancin remained less costly than vancomycin-based treatments at twice its current cost ($2390 per 400 mg).
      When hospitalization costs were decreased to $4000 per patient, treatment with dalbavancin was less costly than treatment with vancomycin followed by linezolid, but was more expensive than the other vancomycin-based regimens. In probabilistic sensitivity analysis, 100% of iterations favoured treatment with oritavancin (i.e. it was the least costly option) for all scenarios explored except when hospitalization cost $4000 and oritavancin cost $2390 per 400 mg (twice the current cost), at which point 100% of iterations favoured treatment with vancomycin followed by doxycycline.

      Discussion

      Our systematic review and meta-analysis suggests that newer glycopeptide antibiotics are similar to standard therapy for treatment of cSSTIs caused by a suspected or confirmed Gram-positive organism. This finding was also true for cSSTIs caused specifically by MRSA, with the exception of telavancin, which demonstrated increased odds of clinical response compared to standard care. Head-to-head comparisons suggested no differences in clinical response between the new agents. There was increased odds of adverse events with telavancin. Compared to standard treatment, dalbavancin and oritavancin were less costly compared to standard of care under baseline assumptions and many of the scenarios evaluated. Even reducing the total cost of hospitalization for cSSTI patients to $4000 was not enough to overcome the potential savings of outpatient infusion therapy at oritavancin's current price point. Importantly, our cost analysis is relevant for cases in which the empirical treatment of choice is a drug that covers MRSA.
      In the studies that evaluated telavancin, it was administered iv for 4 to 14 days in two studies [
      • Stryjewski M.E.
      • O’Riordan W.D.
      • Lau W.K.
      • Pien F.D.
      • Dunbar L.M.
      • Vallee M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to Gram-positive bacteria.
      ,
      • Stryjewski M.E.
      • Chu V.H.
      • O’Riordan W.D.
      • Warren B.L.
      • Dunbar L.M.
      • Young D.M.
      • et al.
      Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by Gram-positive bacteria: FAST 2 study.
      ] and 7 to 14 days in one study [
      • Stryjewski M.E.
      • Graham D.R.
      • Wilson S.E.
      • O’Riordan W.
      • Young D.
      • Lentnek A.
      • et al.
      Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms.
      ]. We found that the clinical response to telavancin was superior compared to standard care for patients infected with MRSA. However, the duration of treatment with telavancin is similar to conventional agents. Further, we found increased odds of adverse events with telavancin, which was supported by a past meta-analysis that compared telavancin with vancomycin among patients with cSSTI and hospital-acquired pneumonia, and demonstrated an increased risk of serious adverse events and acute renal failure among telavancin recipients [
      • Polyzos K.A.
      • Mavros M.N.
      • Vardakas K.Z.
      • Makris M.C.
      • Rafailidis P.I.
      • Falagas M.E.
      Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis.
      ]. In light of this, telavancin may have little net advantage over vancomycin for the treatment of cSSTIs, especially in the presence of other vancomycin alternatives, such as linezolid. A recent large meta-analysis demonstrated that linezolid was associated with a significantly higher clinical and microbiologic cure rate as well as a reduction in the length of hospital stay and cost of hospital charges compared to vancomycin among patients with SSTI [
      • Yue J.
      • Dong B.R.
      • Yang M.
      • Chen X.
      • Wu T.
      • Liu G.J.
      Linezolid versus vancomycin for skin and soft tissue infections.
      ].
      The RCTs that evaluated oritavancin and dalbavancin demonstrated that patients with complicated SSTIs can be treated successfully with one or two doses of these agents without an increase in adverse events. Further, a recent RCT demonstrated that a single 1500 mg iv dose of dalbavancin was noninferior to the two-dose regimen [
      • Dunne M.W.
      • Puttagunta S.
      • Giordano P.
      • Krievins D.
      • Zelasky M.
      • Baldassarre J.
      A randomized clinical trial of single-dose versus weekly dalbavancin for treatment of acute bacterial skin and skin structure infection.
      ], and this dosing has now been approved by the FDA. These agents represent an advance in the treatment of these infections by eliminating the need for inpatient or prolonged outpatient parenteral therapy, thus potentially decreasing resource utilization, improving compliance and preventing potential complications from peripherally inserted central catheters. Further, no monitoring for blood concentrations is required, in contrast to vancomycin [
      • Klinker K.P.
      • Borgert S.J.
      Beyond vancomycin: the tail of the lipoglycopeptides.
      ,
      • Saravolatz L.D.
      • Stein G.E.
      Oritavancin: a long-half-life lipoglycopeptide.
      ,
      • Nathwani D.
      • Eckmann C.
      • Lawson W.
      • Stephens J.M.
      • Macahilig C.
      • Solem C.T.
      • et al.
      Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.
      ]. However, use of these agents may be limited by their high acquisition costs [
      Drugs for MRSA skin and soft-tissue infections.
      ], as well as unexpected adverse events. For example, the SOLO II trial reported that osteomyelitis occurred in five patients receiving oritavancin therapy and none in the vancomycin arm. This finding, along with data from earlier studies, led to a warning issued by the FDA (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf).
      Our review is strengthened by the fact that all included studies were described as double blind and had low risk of bias in our quality evaluation using established criteria. A key limitation of the review is that most of the studies were published before the FDA guidance on designing RCTs to evaluate drugs for cSSTIs (https://www.fda.gov/downloads/Drugs/Guidances/ucm071185.pdf), with the result that the definition of cSSTI varied among studies. The comparator regimens were also different, as no formal guidance currently exists on empiric therapy and duration of treatment for cSSTIs.
      Although our cost analysis focuses on the cost of cSSTI treatments in the United States, the direction of our results is likely generalizable to other countries, particularly those with similar standards of care. In addition, we examined nonmonetary outcomes to compare the ‘value’ of each approach, such as number of treatment days avoided, which may be less sensitive to differences in direct drug costs among countries.
      Another potential limitation of the evidence base is that all RCTs were sponsored by the pharmaceutical companies that produced the antibiotics. In addition, our findings are limited to cases of cSSTI where a Gram-positive organism is suspected or confirmed. Future research should test the comparative effectiveness of these newer drugs in patients with cSSTI that meets the criteria defined by the FDA.

      Conclusions

      Dalbavancin and oritavancin demonstrate efficacy and safety comparable to vancomycin alone or followed by linezolid when used to treat cSSTI where a Gram-positive organism is suspected or confirmed. Oritavancin yielded greater cost savings compared to dalbavancin. Treatment with these new antibiotics consists of one or two doses and offers cost savings over standard therapies for cSSTI when standard care is treatment that covers MRSA. These drugs are potential options for the outpatient management of complicated SSTIs, defined as SSTIs with systemic signs of infection or significant medical comorbidities.

      Transparency declaration

      All authors report no conflicts of interest relevant to this article.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

      References

        • Jenkins T.C.
        • Sabel A.L.
        • Sarcone E.E.
        • Price C.S.
        • Mehler P.S.
        • Burman W.J.
        Skin and soft-tissue infections requiring hospitalization at an academic medical center: opportunities for antimicrobial stewardship.
        Clin Infect Dis. 2010; 51: 895-903
        • Lee B.Y.
        • Singh A.
        • David M.Z.
        • Bartsch S.M.
        • Slayton R.B.
        • Huang S.S.
        • et al.
        The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).
        Clin Microbiol Infect. 2013; 19: 528-536
        • Miller L.G.
        • Eisenberg D.F.
        • Liu H.
        • Chang C.L.
        • Wang Y.
        • Luthra R.
        • et al.
        Incidence of skin and soft tissue infections in ambulatory and inpatient settings, 2005–2010.
        BMC Infect Dis. 2015; 15: 362
        • Russo A.
        • Concia E.
        • Cristini F.
        • De Rosa F.G.
        • Esposito S.
        • Menichetti F.
        • et al.
        Current and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections.
        Clin Microbiol Infect. 2016; 22: S27-S36
        • Stevens D.L.
        • Bisno A.L.
        • Chambers H.F.
        • Dellinger E.P.
        • Goldstein E.J.
        • Gorbach S.L.
        • et al.
        Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
        Clin Infect Dis. 2014; 59: e10-52
        • Miller L.G.
        • Daum R.S.
        • Creech C.B.
        • Young D.
        • Downing M.D.
        • Eells S.J.
        • et al.
        Clindamycin versus trimethoprim–sulfamethoxazole for uncomplicated skin infections.
        N Engl J Med. 2015; 372: 1093-1103
        • Chambers H.F.
        The changing epidemiology of Staphylococcus aureus?.
        Emerg Infect Dis. 2001; 7: 178-182
        • Daum R.S.
        Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus.
        N Engl J Med. 2007; 357: 380-390
        • Cosgrove S.E.
        • Carroll K.C.
        • Perl T.M.
        Staphylococcus aureus with reduced susceptibility to vancomycin.
        Clin Infect Dis. 2004; 39: 539-545
        • Tsoulas C.
        • Nathwani D.
        Review of meta-analyses of vancomycin compared with new treatments for Gram-positive skin and soft-tissue infections: are we any clearer?.
        Int J Antimicrob Agents. 2015; 46: 1-7
        • Cardona A.F.
        • Wilson S.E.
        Skin and soft-tissue infections: a critical review and the role of telavancin in their treatment.
        Clin Infect Dis. 2015; 61: S69-S78
        • Klinker K.P.
        • Borgert S.J.
        Beyond vancomycin: the tail of the lipoglycopeptides.
        Clin Ther. 2015; 37: 2619-2636
        • Lin G.
        • Credito K.
        • Ednie L.M.
        • Appelbaum P.C.
        Antistaphylococcal activity of dalbavancin, an experimental glycopeptide.
        Antimicrob Agents Chemother. 2005; 49: 770-772
        • Saravolatz L.D.
        • Stein G.E.
        Oritavancin: a long-half-life lipoglycopeptide.
        Clin Infect Dis. 2015; 61: 627-632
        • Zhanel G.G.
        • Schweizer F.
        • Karlowsky J.A.
        Oritavancin: mechanism of action.
        Clin Infect Dis. 2012; 54: S214-S219
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gotzsche P.C.
        • Ioannidis J.P.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339b2700
        • Cipriani A.
        • Higgins J.P.
        • Geddes J.R.
        • Salanti G.
        Conceptual and technical challenges in network meta-analysis.
        Ann Intern Med. 2013; 159: 130-137
        • Salanti G.
        Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.
        Res Synth Methods. 2012; 3: 80-97
        • Collins R.
        • Gray R.
        • Godwin J.
        • Peto R.
        Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews.
        Stat Med. 1987; 6: 245-254
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • DerSimonian R.
        • Kacker R.
        Random-effects model for meta-analysis of clinical trials: an update.
        Contemp Clin Trial. 2007; 28: 105-114
        • Boucher H.W.
        • Wilcox M.
        • Talbot G.H.
        • Puttagunta S.
        • Das A.F.
        • Dunne M.W.
        Once-weekly dalbavancin versus daily conventional therapy for skin infection.
        N Engl J Med. 2014; 370: 2169-2179
        • Corey G.R.
        • Good S.
        • Jiang H.
        • Moeck G.
        • Wikler M.
        • Green S.
        • et al.
        Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
        Clin Infect Dis. 2015; 60: 254-262
      1. Gold M.R. Siegel J.E. Russell L.B. Weinstein M.C. Cost-effectiveness in health and medicine. Oxford University Press, New York1996
        • Stryjewski M.E.
        • O’Riordan W.D.
        • Lau W.K.
        • Pien F.D.
        • Dunbar L.M.
        • Vallee M.
        • et al.
        Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to Gram-positive bacteria.
        Clin Infect Dis. 2005; 40: 1601-1607
        • Stryjewski M.E.
        • Chu V.H.
        • O’Riordan W.D.
        • Warren B.L.
        • Dunbar L.M.
        • Young D.M.
        • et al.
        Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by Gram-positive bacteria: FAST 2 study.
        Antimicrob Agents Chemother. 2006; 50: 862-867
        • Stryjewski M.E.
        • Graham D.R.
        • Wilson S.E.
        • O’Riordan W.
        • Young D.
        • Lentnek A.
        • et al.
        Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms.
        Clin Infect Dis. 2008; 46: 1683-1693
        • Jauregui L.E.
        • Babazadeh S.
        • Seltzer E.
        • Goldberg L.
        • Krievins D.
        • Frederick M.
        • et al.
        Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
        Clin Infect Dis. 2005; 41: 1407-1415
        • Corey G.R.
        • Kabler H.
        • Mehra P.
        • Gupta S.
        • Overcash J.S.
        • Porwal A.
        • et al.
        Single-dose oritavancin in the treatment of acute bacterial skin infections.
        N Engl J Med. 2014; 370: 2180-2190
        • Seltzer E.
        • Dorr M.B.
        • Goldstein B.P.
        • Perry M.
        • Dowell J.A.
        • Henkel T.
        • et al.
        Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections.
        Clin Infect Dis. 2003; 37: 1298-1303
        • Polyzos K.A.
        • Mavros M.N.
        • Vardakas K.Z.
        • Makris M.C.
        • Rafailidis P.I.
        • Falagas M.E.
        Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis.
        PLoS One. 2012; 7e41870
        • Yue J.
        • Dong B.R.
        • Yang M.
        • Chen X.
        • Wu T.
        • Liu G.J.
        Linezolid versus vancomycin for skin and soft tissue infections.
        Cochrane Database Syst Rev. 2016; CD008056
        • Dunne M.W.
        • Puttagunta S.
        • Giordano P.
        • Krievins D.
        • Zelasky M.
        • Baldassarre J.
        A randomized clinical trial of single-dose versus weekly dalbavancin for treatment of acute bacterial skin and skin structure infection.
        Clin Infect Dis. 2016; 62: 545-551
        • Nathwani D.
        • Eckmann C.
        • Lawson W.
        • Stephens J.M.
        • Macahilig C.
        • Solem C.T.
        • et al.
        Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.
        Clin Microbiol Infect. 2014; 20: 993-1000
      2. Drugs for MRSA skin and soft-tissue infections.
        JAMA. 2014; 312: 1583-1584