Analysis of Pooled Phase III Efficacy Data for Delafloxacin in Acute Bacterial Skin and Skin Structure Infections

Clinical Infectious Diseases SUPPLEMENT ARTICLE Analysis of Pooled Phase III Efficacy Data for Delafloxacin in Acute Bacterial Skin and Skin Structure Infections Philip A. Giordano,1 Jason M. Pogue,2 and Sue Cammarata3 1 Department of Emergency Medicine, Orlando Health, Florida; 2Division of Infectious Diseases, Detroit Medical Center, Wayne State University, Michigan; and 3Melinta Therapeutics, Lincolnshire, Illinois Acute bacterial skin and skin structure infections (ABSSSI) are among the most common bacterial infections and are also common reasons for hospitalization [1–6]. Accounting for 6.3 million physician visits per year, the cost of treating these serious infections is substantial, particularly in patients who are hospitalized [7–10]. The clinical manifestations of skin infections vary considerably and range from uncomplicated, superficial infections to limb- or life-threatening infections. ABSSSIs include infected ulcers or burns, major abscesses, wounds, surgical site infections, and extensive cellulitis [11]. These infections may be further complicated by the presence of diabetes mellitus, chronic Correspondence: P. Giordano, Department of Emergency Medicine, Orlando Regional Medical Center, Corporate Research Operations Orlando Health, 1401 Lucerne Terrace, MP 131, Orlando, FL 32806 (). Clinical Infectious Diseases®  2019;68(S3):S223–32 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact DOI: 10.1093/cid/ciz006 kidney disease, or peripheral arterial disease [11, 12]. While overall mortality rates are relatively low, at 10%, ABSSSIs are the third most frequent cause of severe sepsis or septic shock, after pneumonia (55–60%) and intra-abdominal infections (25%), and impact both clinical and economic outcomes [1, 13]. The etiologies of ABSSSI are diverse and depend on a number of factors, including the epidemiological setting (community, hospital, long-term care setting, etc.), the site of infection, and patient risk factors [14, 15]. While the most frequent causative pathogens are the gram-positive bacteria, gram-negative bacteria can also play an important role. Among patients hospitalized with serious skin infections, monomicrobial gram-negative infections have been reported at a rate of 12.8% and mixed infections (both gram-positive and gram-negative) have been observed in 10.6% to 20.5% [7, 16]. The risk of inappropriate antimicrobial therapy has been shown to increase in skin infections when gram-negative and mixed cultures are present [7, 16]. Further compounding the challenge clinicians face is the fact that risk stratification for the purpose of identifying a likely pathogen and targeting antibiotic therapy to that pathogen is unreliable, as few organism-specific risk factors have been identified [17]. Therefore, most antibiotics Analysis of Pooled Phase III Efficacy Data for Delafloxacin in ABSSSI • cid 2019:68 (Suppl 3) • S223 Background. Delafloxacin is an oral or intravenous (IV) antibiotic indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI), including both gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]) and gram-negative organisms. Chemically distinct from other quinolones, delafloxacin exhibits enhanced potency, particularly against gram-positive pathogens. The integration of efficacy data across the Phase III ABSSSI studies is presented here and allows for additional examination of results across subgroups. Methods. Results of 2 multicenter, randomized, double-blind trials of 1510 adults with ABSSSI were pooled for this analysis. Subjects in the vancomycin arm received 15 mg/kg, plus 1–2 g of aztreonam every 12 hours. Delafloxacin was dosed at 300 mg IV every 12 hours in Study 302; dosing in Study 303 was 300 mg IV every 12 hours for 3 days, with a mandatory, blinded switch to delafloxacin at 450 mg orally every 12 hours. The primary endpoint was objective response (OR), defined as a ≥20% reduction of lesion spread of erythema area at the primary infection site at 48 to 72 hours (±2 hours), in the absence of clinical failure. Investigatorassessed response, based on the resolution of signs and symptoms at follow-up (FU; Day 14 ± 1) and late follow-up (LFU; Day 21– 28), were secondary endpoints. Results. In the intent-to-treat analysis set, the OR was 81.3% in the delafloxacin arm and 80.7% in the comparator arm (mean treatment difference 0.8%, 95% confidence interval -3.2% to 4.7). Results for OR in the defined subgroups showed delafloxacin to be comparable to vancomycin/aztreonam. Investigator-assessed success was similar at FU (84.7% versus 84.1%) and LFU (82.0% versus 81.7%). Delafloxacin was comparable to vancomycin/aztreonam in the eradication of MRSA, at 98.1% versus 98.0%, respectively, at FU. The frequencies of treatment-emergent adverse events between the groups were similar. Conclusions. Overall, IV/oral delafloxacin fixed-dose monotherapy was non-inferior to IV vancomycin/aztreonam combination therapy and was well tolerated in each Phase III study, as well as in the pooled analysis, regardless of endpoint or analysis population. Keywords. delafloxacin; ABSSSI; skin; vancomycin; fluoroquinolone. must be given empirically and, in fact, initial empiric treatment without documented microbiology is given in up to 88.8% of patients [18]. The failure to provide appropriate initial antibiotic therapy in cSSTI has been shown to increase not only the cost of treatment, but also the risk of mortality [19–21]. Delafloxacin Table 1. Delafloxacin In Vitro Activity Against Staphylococcus aureus in Isolates From Phase III Trials Stratified by Levofloxacin Susceptibility Organism N MIC Range (μg/ml) MIC90 S. aureus 685 0.002–4 0.25 Levofloxacin–non-susceptible S. aureus 232 0.004–4 0.25 MRSA 294 0.002–4 0.25 Levofloxacin–non-susceptible MRSA 195 0.004–4 0.25 MSSA 395 0.002–0.5 0.03 Levofloxacin–non-susceptible MSSA 39 0.004–0.5 0.25 Pooled data for the delafloxacin and comparator treatment arms for the microbiological intent to treat population. N = number of available MIC values from isolates cultured at baseline from primary infection site or blood. If the same pathogen is identified from both the blood and the culture of the acute bacterial skin and skin structure infections, it is counted only once in the summary. Patients with both MRSA and MSSA at baseline are included once in the overall Staphylococcus aureus category. Abbreviations: MRSA, methicillin-resistant Staphylococcus au (...truncated)