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Current Medical Research and Opinion ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20 Comparative efficacy of antibiotics for the treatment of acute bacterial skin and skin structure infections (ABSSSI): a systematic review and network meta-analysis H. Thom, J. C. Thompson, D. A. Scott, N. Halfpenny, K. Sulham & G. R. Corey To cite this article: H. Thom, J. C. Thompson, D. A. Scott, N. Halfpenny, K. Sulham & G. R. Corey (2015) Comparative efficacy of antibiotics for the treatment of acute bacterial skin and skin structure infections (ABSSSI): a systematic review and network meta-analysis, Current Medical Research and Opinion, 31:8, 1539-1551, DOI: 10.1185/03007995.2015.1058248 To link to this article: https://doi.org/10.1185/03007995.2015.1058248 View supplementary material Accepted author version posted online: 03 Jun 2015. Published online: 29 Jun 2015. Submit your article to this journal Article views: 3241 View Crossmark data Citing articles: 10 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalinformation?journalcode=icmo20

Current Medical Research & Opinion Vol. 31, No. 8, 2015, 1539 1551 0300-7995 Article FT-0165/1058248 doi:10.1185/03007995.2015.1058248 All rights reserved: reproduction in whole or part not permitted Original article Comparative efficacy of antibiotics for the treatment of acute bacterial skin and skin structure infections (ABSSSI): a systematic review and network meta-analysis H. Thom School of Social and Community Medicine, University of Bristol, Bristol, UK J. C. Thompson D. A. Scott N. Halfpenny ICON Health Economics and Epidemiology, ICON plc, Oxford, UK K. Sulham The Medicines Company, Waltham, MA, USA G. R. Corey Department of Medicine, Duke University, Durham, NC, USA Address for correspondence: Katherine Sulham, The Medicines Company, 400 Fifth Avenue, Waltham, MA 02451, USA. kate.sulham@themedco.com Keywords: ABSSSI Oritavancin Systematic review Network meta-analysis Test-of-cure Early clinical response Accepted: 26 May 2015; published online: 29 June 2015 Citation: Curr Med Res Opin 2015; 31:1539 51 Abstract Objective: The objective was to conduct a systematic review and network meta-analysis (NMA) of existing treatments for ABSSSI focusing on the novel lipoglycopeptide oritavancin. Methods: 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. Results: 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. Conclusions: 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. Introduction Acute bacterial skin and skin structure infections (ABSSSI) incidence is rising globally 1, with recent annual incidence estimates requiring healthcare intervention in the US of 4.96% 2, which represents an increased healthcare and economic burden 3,4. The 2010 FDA guidelines define ABSSSI as bacterial! 2015 Informa UK Ltd www.cmrojournal.com Systematic review and NMA of oritavancin in ABSSSI Thom et al. 1539

infections of the skin with a lesion size of at least 75 cm 2 (measured by the area of redness, edema, or induration) and include cellulitis, wound infection, and abscesses with surrounding cellulitis 5. ABSSSI are caused by many different bacteria, most commonly gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) 6,7 and with increasing antibiotic resistance treatment is becoming more difficult 8 10. A surveillance study found 44.6% of ABSSSI in North America were caused by S. aureus and 80% of these exhibited methicillin resistance 11. Current treatment can include administration of broad-spectrum antibiotics; however, in the case of known or suspected MRSA targeted antibiotics are administered over 7 14 days 12 14. Vancomycin, linezolid, and daptomycin are among the most common antibiotics used in the treatment of ABSSSI, but there is limited evidence on their comparative effectiveness 15,16. Recently approved antibiotics for the treatment of ABSSSI, such as oritavancin 17, dalbavancin 18, and tedizolid 19, further highlight the need for comparative effectiveness research. The majority of published randomized controlled trials (RCTs) have been compared to vancomycin and have not achieved statistically significant differences 15, although, arguably, the strongest results have been found in favor of linezolid over vancomycin 20 23. Thirteen meta-analyses have been conducted comparing the efficacy of vancomycin, linezolid, and other anti-microbial agents, the majority comparing linezolid with vancomycin and finding clinical superiority of linezolid 7,12,24 34. However, most of these considered only direct comparisons of two treatments and neglected the impact of indirect evidence. Bayesian network meta-analysis (NMA) is a statistical method used to combine the results from multiple studies and indirectly compare multiple treatments, thus incorporating all available direct and indirect evidence 35 37. Two Bayesian NMAs have been conducted in ABSSSI caused by MRSA. The first compared telavancin, daptomycin, vancomycin, linezolid, tigecycline, and dalbavancin and found higher success rates for linezolid, dalbavancin, and telavancin, but the analysis only included studies published by 2010, and omitted recently approved antimicrobial agents such as oritavancin 7. The second was conducted in 2012 and compared vancomycin, linezolid, and ceftaroline 26. Since the publication of these analyses, the FDA has issued guidance on the conduct of clinical trials in ABSSSI, and studies following these guidelines are expected to be more homogeneous and appropriate for NMA 5. These limitations of the current evidence on the comparative efficacy of antimicrobial agents, particularly with regards oritavancin and other novel therapies for the treatment of ABSSSI, motivates the conduct of a systematic literature review and Bayesian NMA. Methods A systematic literature review and Bayesian NMA was conducted to compare the efficacy and safety of common antimicrobial agents used in the treatment of ABSSSI. Systematic literature review RCTs meeting inclusion criteria were identified by searching the EMBASE, MEDLINE, and MEDLINE in Process and the Cochrane Central Register of Controlled Trials databases. Searches were conducted from database inception to January 2, 2014 (available on request). In addition, conference proceedings from the 2012 and 2013 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Infectious Diseases Week (ID Week), and European Society for Clinical Microbiology and Infectious Diseases (ECCMID) conferences were searched for relevant abstracts describing RCTs meeting inclusion criteria. Publications were included if they recruited adult patients with ABSSSI and if the investigated interventions included oritavancin, vancomycin, linezolid, tigecycline, dalbavancin, daptomycin, ceftaroline, teicoplanin, clindamycin, or telavancin; additional treatments were included if they were investigated in a study that included one of the listed interventions. The following outcomes were considered: clinical response, clinical cure, Early Clinical Response (ECR), lesion size reduction, relapse/recurrence, sustained clinical response, overall incidence of adverse events (AEs), treatment emergent AEs, serious AEs, and the most commonly reported AEs across studies (nausea, vomiting, diarrhea, pain, fever, headache, and pruritus). Studies were restricted to English language RCTs. The risk of bias of the included full publications was assessed using the Cochrane risk of bias tool 38. Important aspects of risk of bias are not normally reported in conference abstracts, so a critical appraisal of trials reported in abstracts only was not conducted. Definitions and outcomes The FDA guidance for ABSSSI recommends four study populations for analyses. The primary population that should be considered is the intention to treat (ITT) population, which includes all randomized patients; other populations are the clinically evaluable (CE) population, which includes patients from the ITT population who follow important components of the trial such as attendance at follow-up examinations and demonstrate compliance to treatment (definitions vary by study), the microbiologically evaluable (ME) population which 1540 Systematic review and NMA of oritavancin in ABSSSI Thom et al. www.cmrojournal.com! 2015 Informa UK Ltd

includes ITT patients with a confirmed baseline bacterial pathogen, and the safety population which includes all patients who received at least one dose of study drug. Base case analyses were conducted using trials reporting efficacy of antimicrobial agents in the treatment of ABSSSI due to a mixture of microbial causes. Two key outcomes were chosen for these analyses. The first is treatment success at the Test-Of-Cure (TOC) visit, commonly 7 14 days after the end of treatment, in the intention to treat (ITT) population (as recommended by the FDA guidance). Treatment success in ABSSSI can be determined either clinically or microbiologically. Clinical success is generally characterized as resolution of the symptoms associated with the infection present at admission or improvement to the extent that no further therapy was necessary; in the absence of a culture it is presumed that microbiological eradication has occurred. When a culture is taken, microbiological success is defined as eradication or presumed eradication of the baseline pathogen in a culture taken at a follow-up visit. These measures of success were judged equivalent for the purposes of this analysis. The second outcome was ECR. As of October 2013, this is the primary end-point for the clinical assessment of treatment success in ABSSSI of the FDA in the US and is defined as cessation of spread of skin lesion erythema and absence of fever at 48 72 h after treatment initiation 5. Sub-group analyses were performed for the microbiologically confirmed MRSA and MSSA populations for the TOC and ECR outcomes. By definition, these were conducted in the microbiologically evaluable (ME) populations. Sensitivity analyses assessing robustness of patient population definitions were conducted. To clinicians, the response of patients who are compliant to treatment (i.e. CE population) can be seen as more informative than response in the ITT population. Therefore, analyses of the TOC and ECR end-points were conducted using the CE population in preference to the ITT population. In addition, the TOC end-point in the ITT and CE populations using the sub-set of trials that followed recent FDA guidance on patient inclusion in clinical trials were analyzed 5. This guidance recommends including patients with the previously noted FDA definition of ABSSSI and a mixture of both male and female patients and ABSSSI types, such as wound infection or major cutaneous abscess. A number of patient types to exclude are also recommended, such as those who have received more than 24 h of successful treatment for the current episode of ABSSSI or those with other medical conditions, for example neutropenia, that may interfere with the interpretation of the primary end-point. This reduces the heterogeneity of ABSSSI patients across trials. Statistical analysis The Bayesian NMA was conducted using recommendations from the NICE Decision Support Unit for count data modeling, and adopted a generalized linear model with a binomial outcome and logistic link function 39. Vague priors were used for baseline and treatment effects. Treatment effects were estimated as mean odds ratios compared to vancomycin, alongside Bayesian credible intervals (CrI). The model code is provided in the Supplementary Appendix. Random treatment effects (RE) models were used to account for heterogeneity across trials 40. The Deviance Information Criterion (DIC) 41 was used to compare the model fit. A random effects model was used for each analysis unless its DIC was five units higher than that of the fixed effects model 42. The exception is if less than three studies were included in the analysis or if the posterior estimates were unstable, in which case the fixed effects model was preferred. Inconsistency between direct and indirect treatment effect estimates may also be present in an evidence network 43,44. The consistency between direct and indirect evidence was assessed for the best fitting model for each end-point using the node-splitting approach 45. Analyses were conducted using OpenBUGS (Version 3.2.2 rev 1063 2012-07-15, Medical Research Council and Imperial College, London, UK) 42,46. Samples from 50,000 iterations of the posterior distribution of two chains, with a 50,000 iteration burn-in to ensure convergence, were used for parameter estimates. Caterpillar and Brooks- Gelman-Rubin (BGR) plots of the estimated parameters were examined to ensure that the models converged satisfactorily 42. Results Results of systematic literature review The systematic review identified 52 trials in 50 published articles (46 trials) and eight conference abstracts (six trials) (Figure 1). Two of the six trials identified in conference abstracts were found to have been published by June 5, 2014 and the clinical study reports for SOLO I 3 and SOLO II 17 were provided by The Medicines Company. Vancomycin and linezolid were the most frequently reported treatments, being included in 26 and 18 out of the 52 trials, respectively. The trials were generally judged to be at low risk of bias (results presented in the Supplementary Appendix). An exception was in studies where TOC was assessed clinically but the assessors were inadequately blinded. Treatment doses and administration across trials were considered clinically homogenous. Two studies were excluded! 2015 Informa UK Ltd www.cmrojournal.com Systematic review and NMA of oritavancin in ABSSSI Thom et al. 1541

INCLUDED ELIGIBILITY SCREENING INDENTIFICATION Records identified through database searching (n = 1259) MEDLINE & MEDLINE in-process (n = 517) EMBASE (n = 562) CENTRAL (n = 180) Records after duplicates removed (n = 689) Records screened for eligibility (n = 689) Full-text article assessed for eligibility (n = 64) Full-text articles included in analysis (n = 48 articles reporting 44 trials) TOTAL n = 52 trials Records excluded (n = 625) Full-text articles excluded, with reasons (n = 16): Not a trial (n = 3) Comparators (n = 3) Patient Population (n = 6) Language (n = 1) Abstract/review (n = 3) Additional records identified through other sources (n = 10 conference abstracts reporting 8 trials) Corey, 2014 NEJM* publication of SOLO I Boucher, 2014 NEJM* publication of DISCOVER 1 and DISCOVER 2 Data on file provided by MDCO Figure 1. PRISMA flowchart illustrating systematic literature review strategy and article selection process. from the analysis for administering doses not used in clinical practice; the daptomycin arm of Katz et al. 47 and the dalbavancin arm of Seltzer et al. 48. Oritavancin doses were considered separately. Six trials with comparator arms where patients continued current therapy or received an option of treatments after randomization were considered too heterogeneous and were excluded from the analysis 48 53. Five trials were excluded as TOC or ECR were not reported in the ITT population 21,54 57. A further five trials, all published in 1990 or earlier, investigated treatments that could not be connected to the evidence network and, thus, were not included in the analysis 58 62. The Teras et al. 63 study was excluded as it was a sub-group analysis of the Breedt et al. 64 trial. Summaries of the 33 trials included in the NMA are provided in Table 1. The definition of ECR varied widely across studies; definitions included characterization solely by absence of fever or absence of fever as well as absence of need for rescue antibiotics. The evidence network for ECR included only 10 studies, while TOC included 26 studies. Results of base case mixed treatment comparisons In total, there were 19 treatments in 26 studies that reported TOC and were connected to the evidence network (Figure 2). Clindamycin (and combinations) and telavancin did not connect to the evidence network, so relative treatment effects could not be calculated. Treatment effects are presented as odds ratios vs vancomycin, with ratios greater than one indicating a superior TOC outcome for the comparator (Table 2). The posterior mean and 95% credible intervals (CrI) for odds ratios of TOC for antimicrobial agents relative to vancomycin were linezolid (OR ¼ 1.55; 95% CrI ¼ 0.91 2.57), dalbavancin 1542 Systematic review and NMA of oritavancin in ABSSSI Thom et al. www.cmrojournal.com! 2015 Informa UK Ltd

Table 1. Summary of studies include in network meta-analysis with results for TOC ITT outcomes. Ref Authors, year Treatment TOC r ITT n ECR or sub-groups reported Key pathogens Mean age Male (%) Mean weight (kg) 68 18 64 69 17 3 70 71 72 73 74 75 16 76 23 77 78 79 65 66 80 81 82 19 83 22 84 49 50 85 Aikawa et al., 2013 Daptomycin NR 55 MRSA MRSA 53.4 Vancomycin NR 19 68.2 Boucher et al., 2013 Dalbavancin NR 288 ECR NR 48.8 59 Vancomycin NR 285 48.9 60.7 Breedt et al., 2005 Tigecycline 220 261 MRSA, MSSA Mixed 48.8 60.9 82.5 Vancomycin 225 259 50.1 60.6 81.5 Corey et al., 2010 Ceftaroline 304 351 MRSA, MSSA Mixed 47.2 62.7 Vancomycin 297 347 49.2 62.8 Corey et al., 2013 Oritavancin 416 503 ECR, MRSA Mixed 45 67.2 76.2 Vancomycin 404 502 44.4 68.3 78 Corey et al., 2014 Oritavancin 378 475 ECR, MRSA, MSSA Mixed 46.2 63.4 81.9 Vancomycin 383 479 44.3 62.8 82.7 Covington et al., 2011 JNJ-Q2 55 83 ECR, MRSA, MSSA Mixed 36.9 64.6 Linezolid 48 78 36.9 64.6 Craft et al., 2011 CEM-102 67 78 ECR, MRSA S. aureus 41.5 72 Linezolid 73 77 40.6 65 Fang et al., 2012 Linezolid 288 335 ECR Mixed 43.3 Tedizolid 284 332 43.3 Dunbar et al., 2011 Oritavancin 200 mg 63 87 MRSA, MSSA Mixed Oritavancin 800 mg 68 87 (with option of additional 400 mg) Oritavancin 1200 mg 72 88 Fang, 2013 Linezolid 293 334 Mixed 45.6 64.1 Tedizolid 292 332 Mixed 45.6 67.8 Florescu et al., 2008 Tigecycline NR 70 MRSA MRSA 65 80.1 Vancomycin NR 23 59 75.5 Itani et al., 2010 Linezolid NR MRSA MRSA 49.7 57 85.4 Vancomycin NR 49.4 61 85.9 Jauregui et al., 2005 Dalbavancin 505 571 Mixed 47 62 Linezolid 246 283 46 61 Kohno et al., 2007 Linezolid NR 17 MRSA MRSA 68.4 70 50.7 Vancomycin NR 10 67.5 70.6 53 Krievins et al., 2009 Iclaprim 0.8 28 30 MRSA Mixed 49.7 70 85 Iclaprim 1.6 29 32 45.6 78.1 84.6 Vancomycin 28 30 43.5 73.3 82.7 Noel et al., 2008 Ceftobiprole 448 547 MRSA, MSSA Mixed 52.9 63 Vancomycin 227 281 48 55 81 Noel et al., 2008 Ceftobiprole 309 397 MRSA, MSSA Mixed 46.7 61 82.7 Vancomycin 300 387 51.9 64 Noel et al., 2012 Omadacycline 98 111 MRSA Mixed 53 Linezolid 82 108 36.2 70.8 Noel et al., 2012 Linezolid 64 72 Mixed 59 Omadacycline 58 68 41.7 61.8 Pertel et al., 2009 Daptomycin 36 50 S. aureus 34 Vancomycin 28 51 49 Postier et al., 2004 Tigecycline NR 4 MRSA, MSSA Mixed 49.3 67 85.8 Tigecycline NR 4 48.7 80 86.3 Prince et al., 2013 BC-3781 100 NR 66 ECR Mixed 41.7 68.6 91.3 BC-3781 150 NR 332 42.2 66.2 96.7 Vancomycin NR 335 40.4 59.1 89 Prokocimer et al., 2013 Tedizolid 284 332 ECR, MRSA, MSSA Mixed 43.1 59.1 Linezolid 288 335 43.6 61.4 Sacchidanand et al., 2005 Tigecycline 209 277 MRSA, MSSA Mixed 49.4 61.6 81.5 Vancomycin 200 260 48.4 66.9 82 Sharpe et al., 2005 Linezolid NR 30 MRSA MRSA 66 33 Vancomycin NR 30 76 50 Stevens et al., 2000 Linezolid 279 400 MRSA Mixed 46.8 63 79.1 Oxacillin-dicloxacillin 272 419 49.2 60.9 79 Stryjewski et al., 2005 Telavancin 66 84 MRSA Mixed 44.3 55 Standard therapy 66 83 44.6 64 Stryjewski et al., 2006 Telavancin 82 100 MRSA Mixed 42.3 65 Standard therapy 81 95 44.7 55 Stryjewski, 2012 TD-1792 79 98 ECR, MRSA, MSSA Mixed 40 62 Vancomycin 82 99 40 60 (continued )! 2015 Informa UK Ltd www.cmrojournal.com Systematic review and NMA of oritavancin in ABSSSI Thom et al. 1543

Table 1. Continued. Ref Authors, year Treatment TOC r ITT n ECR or sub-groups reported Key pathogens Mean age Male (%) Mean weight (kg) 86 20 87 88 89 Talbot et al., 2007 Ceftaroline 59 67 Mixed 44 59.4 Vancomycin 26 32 41.6 55.2 Weigelt et al., 2005 Linezolid 439 476 MRSA, MSSA Mixed 51.7 63.3 Vancomycin 402 454 51.8 61.7 Wilcox et al., 2004 Linezolid 99 106 S. aureus 53 54 75 Teicoplanin 89 102 55 54 73 Wilcox et al., 2010 Ceftaroline 291 342 MRSA, MSSA Mixed 47.8 65.5 Vancomycin 289 338 47.5 59.5 Wilcox, 2013 Dalbavancin NR 371 ECR NR 49.1 60.1 Vancomycin NR 368 51.4 54.6 Oritavancin 800 mg Iclaprim 1.6 Vancomycin Oritavancin 1200 mg Dalhavancin Daptomycin Linezolid Iclaprim 0.8 CEM-102 Omadacycline JNJ-Q2 Tedizolid Ceftaroline Ceftobiprole Tigecycline Teicoplanin Oxacillin-dicloxacillin TD-1792 Oritavancin 200 mg Figure 2. Evidence network for TOC end-point ITT analysis. The thickness of the lines represents the number of studies available for each comparison and the size of the nodes represents the number of studies available for each treatment. (OR ¼ 1.76; 95% CrI ¼ 0.84 3.61), daptomycin (OR ¼ 2.18; 95% CrI ¼ 0.90 5.42), and oritavancin 1200 mg (OR ¼ 1.06; 95% CrI ¼ 0.80 1.43), showing no evidence of a difference in efficacy. Omadacycline showed a statistically significant improvement in TOC over vancomycin (OR ¼ 2.48; 95% CrI ¼ 1.10 5.43). All other 95% credible intervals crossed one and, therefore, none of the other treatments showed a statistically significant difference in TOC compared to vancomycin. The network for ECR included six treatments in 10 studies so was much more limited than the TOC endpoint, allowing fewer indirect comparisons, in particular omitting linezolid (Figure 3). The 95% credible intervals around the mean odds ratio relative to vancomycin of ECR for dalbavancin (OR ¼ 1.01; 95% CrI ¼ 0.24 4.41), oritavancin 1200 mg (OR ¼ 1.02; 95% CrI ¼ 0.23 4.33), and all other treatments crossed unity. There was, therefore, no statistically significant evidence of improvement in ECR compared to vancomycin (Table 2). Fixed effects results for both these analyses were similar and are presented in the Supplementary Appendix. Results of subgroup analyses MRSA and MSSA populations The evidence networks of the sub-groups for the TOC endpoint in the ME population analysis are shown in the Supplementary Appendix. The MRSA network included 15 treatments in 25 studies, while the MSSA network was 1544 Systematic review and NMA of oritavancin in ABSSSI Thom et al. www.cmrojournal.com! 2015 Informa UK Ltd

Table 2. Mean odds ratios (95% credible intervals) of treatments vs vancomycin for base case and sub-group analyses. Treatment TOC ITT ECR ITT TOC MRSA TOC MSSA TOC CE ECR CE TOC ITT FDA TOC CE FDA Random effects (DIC ¼ 476.4)* Random effects (DIC ¼ 137.6) Random effects (DIC ¼ 436.3) Random effects (DIC ¼ 243.2) Random effects (DIC ¼ 346.1) Fixed effects (DIC ¼ 44.65) Fixed effects (DIC ¼ 83.40) Fixed effects (DIC ¼ 146.90) BC-3781 100 1.95 (0.16, 25.51) 1.60 (0.12, 4.07) 0.94 (0.17, 2.85) BC-3781 150 1.4 (0.13, 15.44) 2.74 (0.11, 3.8) 0.83 (0.16, 2.53) Ceftaroline 1.07 (0.77, 1.51) 0.82 (0.26, 2.61) 0.76 (0.14, 4.18) 2.29 (0.21, 2.48) Ceftobiprole 1.04 (0.76, 1.42) 1.31 (0.47, 3.65) 0.98 (0.17, 5.30) 1.63 (0.31, 3.41) CEM-102 0.48 (0.11, 1.82) 0.36 (50.01, 27.44) 0.65 (0.01, 2.3) Dalbavancin 1.76 (0.84, 3.61) 1.01 (0.24, 4.41) 1.16 (0.47, 2.35) 1.04 (0.55, 1.77) Daptomycin 2.18 (0.90, 5.42) 0.74 (0.13, 3.66) Iclaprim 0.8 1.06 (0.11, 12.85) Iclaprim 1.6 0.68 (0.08, 4.88) JNJ-Q2 1.90 (0.79, 4.48) 1.41 (0.35, 5.54) 1.55 (0.05, 45.92) Linezolid 1.55 (0.91, 2.57) 1.55 (0.96, 2.46) 1.36 (0.15, 13.34) 1.65 (0.68, 3.53) Omadacycline 2.48 (1.10, 5.43) 6 (0.32, 172.43) Oritavancin 1.06 (0.80, 1.43) 1.02 (0.23, 4.33) 0.94 (0.44, 2.02) 0.82 (0.08, 7.83) 1.24 (0.41, 2.26) 0.89 (0.65, 1.16) 1.07 (0.85, 1.33) 1.03 (0.71, 1.45) Oritavancin 200 mg 0.62 (0.26, 1.43) 1.32 (0.24, 7.25) 0.08 (50.01, 2.70) 2.96 (0.12, 2.68) 0.66 (0.29, 1.30) 0.65 (0.26, 1.38) Oritavancin 800 mg 0.84 (0.34, 1.99) 2.58 (0.42, 18.52) 0.15 (50.01, 5.13) 9.44 (0.16, 3.60) 0.91 (0.38, 1.83) 0.87 (0.33, 1.89) Oxacillin-dicloxacillin 1.24 (0.64, 2.39) 3.21 (0.28, 5.09) TD-1792 0.87 (0.40, 1.87) 0.99 (0.12, 8.20) 1.71 (0.20, 16.68) 0.65 (0.01, 53.25) 1.79 (0.25, 5.25) 0.92 (0.41, 1.79) 1.33 (0.38, 3.45) Tedizolid 1.51 (0.82, 2.73) 1.23 (0.44, 3.30) 0.57 (0.02, 15.39) Teicoplanin 0.72 (0.22, 2.21) Tigecycline 0.87 (0.61, 1.26) 0.9 (0.24, 3.28) 0.63 (0.11, 3.60) 0.90 (0.31, 1.79) *DIC is Deviance Information Criterion, used for comparing fixed and random effects models.! 2015 Informa UK Ltd www.cmrojournal.com Systematic review and NMA of oritavancin in ABSSSI Thom et al. 1545

more limited, with 11 treatments in 13 studies. The ECR outcome was reported in only five studies with MRSA subgroups and four with MSSA sub-groups, and this evidence was too limited to conduct a meaningful network metaanalysis (Table 1). BC-3781 100 Vancomycin TD-1792 For the MRSA sub-group (Figure 4), the odds ratios relative to vancomycin for TOC were linezolid (OR ¼ 1.55; 95% CrI ¼ 0.96 2.46), daptomycin (OR ¼ 0.74; 95% CrI ¼ 0.13 3.66), and oritavancin 1200 mg (OR ¼ 0.94; 95% CrI ¼ 0.44 2.02). In the MSSA subgroup (Figure 5) they were linezolid (OR ¼ 1.36; 95% CrI ¼ 0.15 13.34) and oritavancin 1200 mg (OR ¼ 0.82; 95% CrI ¼ 0.08 7.83). The large uncertainties around some of the results were due to the sparse data available for these treatments. All of the 95% credible intervals for MRSA and MSSA populations crossed unity so none of the treatments led to a statistically significant difference in TOC response compared to vancomycin. The MRSA results for iclaprim 0.8 mg are not presented in the table as they were based on only four MRSA patients in a single study. Fixed effects results are presented in the Supplementary Appendix. Dalbavancin Oritavancin 1200 mg BC-3781 150 Figure 3. Evidence network for ECR end-point ITT analysis. The thickness of the lines represents the number of studies available for each comparison and the size of the nodes represents the number of studies available for each treatment. Results of the four sensitivity analyses The TOC mixed CE population analysis included 14 treatments in 20 studies. All 95% credible intervals included unity, indicating no strong evidence of a difference in efficacy between vancomycin and any of the comparators (Table 2). Only the SOLO I and SOLO II trials were included in the ECR mixed CE populations analysis 3,17, so only Vancomycin Oritavancin 800 mg Oritavancin 1200 mg Iclaprim 0.8 Tigecycline Omadacycline Linezolid Tedizolid CEM-102 Ceftobiprole JNJ-Q2 TD-1792 Daptomycin Ceftaroline Oritavancin 200 mg Figure 4. Evidence network for TOC end-point ME population analysis in MRSA sub-group. The thickness of the lines represents the number of studies available for each comparison and the size of the nodes represents the number of studies available for each treatment. 1546 Systematic review and NMA of oritavancin in ABSSSI Thom et al. www.cmrojournal.com! 2015 Informa UK Ltd

Vancomycin Oritavancin 800 mg Oritavancin 1200 mg Linezolid Tedizolid Ceftobiprole JNJ-Q2 TD-1792 Ceftaroline Oritavancin 200 mg Tigecycline Figure 5. Evidence network for TOC end-point ME population analysis in MSSA sub-group. The thickness of the lines represents the number of studies available for each comparison and the size of the nodes represents the number of studies available for each treatment. oritavancin 1200 mg and vancomycin were comparable on this end-point and population. Fixed effects results are presented in Table 2, as there were fewer than three studies in the analysis. The posterior mean and 95% credible intervals odds ratio of oritavancin 1200 mg relative to vancomycin was OR ¼ 0.89; 95% CrI ¼ 0.65 1.16, and gave no evidence of difference in efficacy. The TOC mixed ITT FDA analysis was limited to five treatments in four studies. The limited evidence caused the random effects analysis to be unstable. Fixed effects results are, therefore, presented in Table 2. There was again no evidence of a difference in efficacy for TOC between each of the comparators and vancomycin. The TOC mixed CE FDA populations analysis was limited to eight treatments in seven studies, so the random effects results were again unstable. Table 2, therefore, presents the fixed effects analysis. There was no evidence of superiority of any treatment over vancomycin. For all sensitivity analyses, results from the alternative, random, or fixed effects, models are presented in the Supplementary Appendix. Consistency checking The evidence networks were inspected to identify loops, not due solely to three arm trials; only one case where inconsistency could be present was identified in the TOC mixed (CE) network. This loop consisted of vancomycin, linezolid, and dalbavancin. The node-splitting method found no substantial differences in the direct and indirect treatment effect estimates and, therefore, no evidence of inconsistency in this network. Discussion The objective of this study was to conduct a systematic review and formal comparison to demonstrate similar efficacy of oritavancin to other available antimicrobial agents for the treatment of ABSSSI, due to a mixture of microbial causes, on the basis of clinical and microbiological success at TOC and on the basis of ECR. The systematic review identified 52 trials. The Bayesian NMA provided a framework for the formal comparison of treatments included in the identified trials. This NMA found evidence that oritavancin 1200 mg was equivalent to vancomycin (OR ¼ 1.06; 95% CrI ¼ 0.80 1.43) at TOC. The indirect evidence also suggests that oritavancin 1200 mg demonstrates equivalence to linezolid (OR ¼ 1.55; 95% CrI ¼ 0.91 2.57) and daptomycin (OR ¼ 2.18; 95% CrI ¼ 0.90 5.42) at TOC. The only significant finding was that omadacycline was superior to vancomycin for TOC in the mixed population (OR ¼ 2.48; 95% CrI ¼ 1.10 5.43). However, only two trials (a total of 359 patients) compared omadacycline to linezolid and! 2015 Informa UK Ltd www.cmrojournal.com Systematic review and NMA of oritavancin in ABSSSI Thom et al. 1547

these studies had contradictory findings 65,66. There were no other statistically significant findings of differences in efficacy between the anti-microbial agents in the mixed populations for TOC or ECR or for TOC in the MRSA or MSSA sub-groups. Sensitivity analyses found the results of the base case to be robust to choice of ITT over CE population and the choice to include studies that did not conform to recent FDA guidance on clinical trials. This is the first systematic review and NMA to include oritavancin and an assessment of ECR in ABSSSI patients. The results for all outcomes and populations were largely consistent with the head-to-head findings of the included clinical trials. Three previous systematic reviews and metaanalyses found linezolid to be more efficacious for the treatment of ABSSSI than vancomycin, with mean and 95% confidence intervals (CI) for the odds ratios of OR ¼ 1.57; 95% CI ¼ 1.18 2.10 28, OR¼ 1.40; 95% CI ¼ 1.01 1.95 31, and OR ¼ 1.67; 95% CI ¼ 1.31 2.12 33. However, the present study is based on a larger and more recent set of trials and includes indirect evidence via the NMA methodology. A recent large meta-analysis 24 of 53 studies in the treatment of ABSSSI comparing vancomycin with linezolid and other anti-microbial agents found only significant differences in efficacy for linezolid (OR ¼ 1.61; 95% CI ¼ 1.07 2.43). This study also neglected indirect evidence and was restricted to comparisons with vancomycin. These results from earlier analyses are consistent with the mean and 95% credible interval for the odds ratio relative to vancomycin for linezolid (OR ¼ 1.55; 95% CrI ¼ 0.96 2.46) found in the present NMA. One previous NMA assessed the comparative efficacy of vancomycin, dalbavancin, linezolid, telavancin, daptomycin, and tigecycline for MRSA complicated skin and soft tissue infections 7. The search was conducted in 2008 and was, thus, limited to only 14 studies in MRSA, while the present study identified 25 studies in MRSA. Their odds ratios for linezolid (1.83), daptomycin (1.21) and tigecycline (0.81) were comparable to the estimates in the MRSA sub-group of the present study. Two further meta-analyses have compared daptomycin with non-daptomycin treatments in skin and soft-tissue infections, one due only to MRSA 29 and another due to both MRSA and MSSA 12. The study in only MRSA caused infections found a mean and 95% confidence interval for the odds ratio of daptomycin relative to other treatments of OR ¼ 0.89; 95% CI ¼ 0.63 1.25 29, consistent with the odds ratio for daptomycin relative to vancomycin in the MRSA sub-group of the present study (OR ¼ 0.74; 95% CrI ¼ 0.13 3.66). The study in ABSSSI due to a mixture of MRSA and MSSA found a mean and 95% confidence interval for the odds ratio of daptomycin relative to vancomycin of OR ¼ 1.05; 95% CI ¼ 0.84 1.31) for clinical success 12, consistent with the odds ratio for TOC of daptomycin relative vancomycin in ABSSSI in the present study (OR ¼ 2.18; 95% CrI ¼ 0.90 5.42). Limitations Across all outcomes and populations, wide credible intervals were seen, pointing to the heterogeneity of available evidence. For the ECR end-point, it was only possible to indirectly compare five treatments to the common comparator, vancomycin. The systematic review was limited to English language publications; it is possible non-english language trials have been missed. As recommended by FDA guidance, the base case analyses for the TOC and ECR end-points were conducted in the ITT populations. Using the ITT population, when a high numbers of dropouts across the studies are observed, could be considered a potential limitation. The impact of this was assessed in sensitivity analyses including patients in the CE populations, i.e. excluding patients who dropped out of the studies or were otherwise not evaluable; results were similar to the base case. Differences in the definition of ABSSSI and other patient characteristics across trials were a further limitation. Sensitivity analyses restricted to studies conducted in accordance with recent FDA guidelines 5, thus ensuring greater similarity in populations, gave results similar to the base case. The NMA methodology suffers from several limitations due to the assumptions necessary to conduct the indirect comparisons 39,67. Fixed effects models must assume that the relative treatment effect across studies is the same and this may not be the case due to heterogeneity 38,40. Random effects models weaken this to an assumption of exchangeability of treatment, but these models can be difficult to fit or lead to highly uncertain estimates. NMA makes a further assumption of consistency of treatment effects across studies 43, although no evidence of inconsistency in the networks was identified 45. Further research As discussed, wide credible intervals were seen across the results of these analyses and several important comparisons in TOC, ECR, and in the sub-groups of MRSA and MSSA infections were not possible due to limitations in the evidence base. A large and high quality trial directly comparing several antimicrobial agents could be of high value to clinical practice and healthcare decision-making. Conclusion This systematic review and NMA has provided an up-to-date and unified framework for the comparison of available antimicrobial agents used in the treatment of ABSSSI; this is the first such analyses to include novel agents such as oritavancin and to look at the ECR end-point. The results suggest equivalence between oritavancin 1200 mg, and other novel antimicrobial agents 1548 Systematic review and NMA of oritavancin in ABSSSI Thom et al. www.cmrojournal.com! 2015 Informa UK Ltd

including daptomycin and linezolid, compared with vancomycin for both TOC and ECR. Transparency Declaration of funding The Medicines Company funded ICON plc to complete this research. Declaration of financial/other relationships HT was a paid consultant of ICON Plc for the duration of this project. DAS, JCT and NH are employees of ICON Plc which was funded by The Medicines Company to complete this research. KS is an employee of The Medicines Company. GRC is an advisor/consultant to The Medicines Company, Pfizer, Merck, GSK, Cubist and others. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose. References 1. Hersch AL, Chambers HF, Maselli JH, et al. National trends in ambulatory visits and antibiotic prescribing for skin and soft-tissue infections. Arch Intern Med 2008;168:1585-91 2. Ray GT, Suaya JA, Baxter R. 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