Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET)

Abstract

Background: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens.

Methods: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection.

Results: In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles.

Conclusions: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit.

Clinical trials registration: NCT03137173.

Keywords: ABSSSI; bacterial skin infections; ceftobiprole.

Figure 1.

Patient disposition. One patient in the vancomycin/aztreonam group died post-randomization but prior to receiving a first dose of drug. Abbreviations: ITT, intent-to treat; ME, microbiologically evaluable; mITT, microbiological intent-to-treat population.

Figure 2.

Primary endpoint analyses. ^aProportion differences (95% CI) (ceftobiprole minus vancomycin/aztreonam) were computed using the Cochran-Mantel-Haenszel weights method adjusted for geographical region and actual type of ABSSSI. ^bSecondary endpoint. The objective for the FDA-defined primary endpoint was based on a noninferiority assessment of the ITT population only. The EMA-defined primary endpoint was based on a noninferiority assessment in both the ITT and CE populations. Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; CE, clinically evaluable; CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; ITT, intent-to treat.

Figure 3.

Early clinical response (A) and investigator-assessed clinical success at the TOC visit (B) in select subgroups defined by region (ITT), infection type (ITT), comorbidities (ITT), and causative pathogen (mITT). ^aProportion differences (95% CI) (ceftobiprole minus vancomycin/aztreonam) were computed using the Cochran-Mantel-Haenszel weights method adjusted for geographical region and actual type of ABSSSI. Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; ITT, intent-to-treat; mITT, microbiological intent-to-treat; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NE, not evaluable; n/N, number of patients achieving the endpoint/total number of patients evaluated; TOC, test-of-cure; WBC, white blood cell.

Figure 3.

Early clinical response (A) and investigator-assessed clinical success at the TOC visit (B) in select subgroups defined by region (ITT), infection type (ITT), comorbidities (ITT), and causative pathogen (mITT). ^aProportion differences (95% CI) (ceftobiprole minus vancomycin/aztreonam) were computed using the Cochran-Mantel-Haenszel weights method adjusted for geographical region and actual type of ABSSSI. Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; ITT, intent-to-treat; mITT, microbiological intent-to-treat; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NE, not evaluable; n/N, number of patients achieving the endpoint/total number of patients evaluated; TOC, test-of-cure; WBC, white blood cell.

Figure 4.

Microbiological response by study visit (mITT and ME populations). Proportion differences (95% CI) (ceftobiprole minus vancomycin/aztreonam) were computed using the Cochran-Mantel-Haenszel weights method adjusted for geographical region and actual type of ABSSSI. P values were computed using the Cochran-Mantel-Haenszel test for general association between treatment group and response. Microbiological response was defined as eradication or presumed eradication (eradication defined as no growth of the baseline pathogen[s] based on post-treatment cultures obtained from the primary infection site at the respective time points; presumed eradication was defined as no post-treatment culture due to lack of culturable material accompanied by investigator-assessed clinical success). Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; CI, confidence interval; EOT, end-of-treatment; LFU, last follow-up; ME, microbiologically evaluable; mITT, microbiological intent-to-treat; TOC, test-of-cure.