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DLX is a novel investigational anionic fluoroquinolone antibiotic with broad-spectrum activity, including Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. DLX can be administered by either an intravenous (IV) infusion route or orally as a tablet for the treatment ABSSSI. Two global Phase 3 studies of DLX vs VAN/AZ in ABSSSI have been completed (RX-3341-302 and RX-3341-303). DLX is more active than levofloxacin against most Gram-positive pathogens. Notably, the MIC50 is at least 32‐fold lower for DLX compared to levofloxacin and ciprofloxacin for methicillin-resistant Staphylococcus aureus (MRSA).1 The increased potency of DLX relative to other fluoroquinolones against Gram-positive bacteria and the enhanced activity of DLX at acidic pH are largely due to its structure-activity relationships profile. The collaboration between a large N1 substitution and a weakly‐polar group at C8 results in increased potency against quinolone-resistant Gram‐positive bacteria, a phenotype common among MRSA. The basicity at C7 leads to increased potency at acidic pH.2 DLX is equally effective at stabilizing cleavable complexes by binding either gyrase or topoisomerase IV in both S. aureus and E. coli and, as such, is considered dual-targeting fluoroquinolone. Due to enhanced potency of DLX against MRSA, it was of interest to further investigate the in vitro activity of DLX and the percent microbiological response in Phase 3 clinical trial subjects infected with fluoroquinolone non-susceptible S. aureus isolates. Further, microbiological responses were examined for clinical trial S. aureus isolates characterized for mutations in the quinolone resistance determining region (QRDR). INTRODUCTION •  High rates of microbiological eradication were observed in global Phase 3 studies for ABSSSI with DLX treatment. These high eradication rates extended to include both levofloxacin non-susceptible S. aureus and MRSA isolates as well as S. aureus isolates with mutations in the QRDR. •  100% microbiological response rates were observed for subjects with S. aureus isolates with mutations in Ser84Leu in gyrA/Ser80-Phe in parC, the most commonly observed mutation in global Phase 3 studies. •  The data suggest that DLX may be considered as a treatment option for S. aureus ABSSSI isolates where high rates of ciprofloxacin and levofloxacin non-susceptibility are observed, including MRSA. CONCLUSION IDWEEK New Orleans, Louisiana, USA October 26-30th POSTER #2039 S. McCurdy1, L. Lawrence1, L. Woosley2, R. Flamm2, C. Tseng3, S. Cammarata1 1.  Van Bambeke F. Delafloxacin, a non-zwitterionic fluoroquinolone in Phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy. Future Microbiol. 2015;10(7):1111-23. 2.  2014 JMI Surveillance Paper (in preparation). 3.  Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: Approved standard. 10th ed. CLSI document M07-A10. Wayne, PA. Clinical and Laboratory Standards Institute; 2015. 4.  Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; Twenty-sixth informational supplement. CLSI document M100-S26. Wayne, PA. Clinical and Laboratory Standards Institute; 2016. REFERENCES Background: Delafloxacin (DLX) is an investigational anionic fluoroquinolone antibiotic with broad-spectrum activity, including Gram-positive organisms, Gramnegative organisms, atypical organisms, and anaerobes. The in vitro activity of DLX and percent microbiological response in subjects infected with fluoroquinolone nonsusceptible S. aureus isolates was determined from 2 global Phase 3 studies of DLX vs vancomycin plus aztreonam (VAN/AZ) in ABSSSI. Methods: Patients were enrolled in 23 countries predominately in the US but also Eastern Europe, South America, and Asia. The microbiological intent-to-treat population (MITT) included 1042 patients from which 1716 isolates were submitted for identification and susceptibility testing per CLSI guidelines at a central laboratory (JMI Laboratories, N. Liberty, IA). Comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Non-susceptibility to these antibiotics was determined using CLSI breakpoints. Results: S. aureus isolates were 33.8% levofloxacin non-susceptible (FQ-NS). DLX activity and percent microbiological response are presented in the following table. Conclusion: DLX demonstrated high rates of microbiological response against FQNS isolates. The data suggest that DLX could be a good treatment option for S. aureus ABSSSI isolates where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed, including MRSA. MATERIALS AND METHODS RESULTS RX-3341-302 and RX-3341-303 Study Design: Pooled data from the 2 pivotal, global, Phase 3 ABSSSI studies (RX-3341-302 and RX-3341-303) are presented. •  Stratified, randomized, double-blind, phase 3, multicenter studies of DLX vs VAN/ AZ for the treatment of ABSSSIs •  Patients had wounds, burns, major abscesses, or cellulitis with lesions of ≥75 cm2 in size; ≥2 systemic signs of infections; and met study entry criteria •  Patients randomly assigned in 1:1 ratio to either DLX 300 mg IV/450 mg oral q12h, or VAN 15 mg/kg IV (actual body weight) with AZ. Total treatment duration was 5-14 days at investigators’ discretion •  Patients evaluated at screening, daily on therapy, at Follow-up (FU, Day 14 ± 1) and Late Follow-up (LFU, Day 21-28) •  Efficacy evaluated through assessments of signs and symptoms of infection; measurement of lesion size by digital planimetry; and culture and susceptibility testing of bacterial isolates Microbiological Analysis Populations •  Microbiological ITT (MITT) Analysis Set –  All patients in the ITT analysis set who had a baseline bacterial pathogen identified by the sponsor that was known to cause ABSSSI. –  The MITT population for the 2 global phase 3 studies consisted of 1042 subjects (N=518 DLX arm; 524 VAN/AZ arm). •  Microbiologically Evaluable (ME) Analysis Sets –  All patients in the MITT analysis set who also met the criteria for the corresponding clinically evaluable analysis sets. –  The ME at follow-up population for the two global phase 3 studies consisted of 806 subjects (N=410 DLX arm; 396 VAN/AZ arm) 1Patients with MRSA and MSSA were counted only once in S. aureus. Baseline Organisms (MITT; both treatment arms) Number of Isolates FQ-S/FQNS DLX FQ-S MIC50/90 (μg/mL) DLX FQ-S Range (μg/mL) DLX FQ-NS MIC50/90 (μg/mL) DLX FQNS Range (μg/mL) Number of Subjects with FQS/FQ-NS isolates (ME Inv-Assessed Endpoint at Follow-Up) Percent Micro Response for Subjects with FQ-NS isolates S. aureus1 455/232 0.008/0.008 0.002-0.12 0.25/0.25 0.004-4 168/81 80/81 (98.8%) MRSA 101/195 0.008/0.008 0.002-0.12 0.25/0.25 0.004-4 37/71 70/71 (98.6%) MSSA 358/39 0.008/0.008 0.002-0.12 0.12/0.25 0.004-0.5 132/10 10/10 (100%) 1Melinta Therapeutics, Inc., New Haven, CT, 2JMI Labs, North Liberty, IA, 3H20 Clinical, Hunt Valley, MD Microbiology Outcomes Microbiological response for patients in the ME and MITT analysis sets were based on results of baseline and post-baseline cultures (FU and LFU) and susceptibility testing, together with the clinical response assigned by investigators. The definitions of documented eradicated, presumed eradicated and documented persisted were: •  Documented eradicated The baseline pathogen was absent in cultures of the original site of infection at the post-baseline visit. Investigator-assessed response was not considered a determining factor for this microbiologic response definition. •  Presumed eradicated There was no material available for culture or no culture was done and the patient had an investigator-assessed response of success. •  Documented persisted The baseline pathogen was present in cultures of the original site of infection at the visit. Investigator-assessed response was not considered a determining factor for this microbiologic response definition. •  Presumed persisted There was no material available for culture or no culture was done and the patient had an investigator-assessed response of failure. Microbiology Methods •  Isolates (1716 S. aureus isolates) were submitted for identification and susceptibility testing per CLSI guidelines at a central laboratory (JMI Laboratories, N. Liberty, IA).3 •  Comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Non-susceptibility to these antibiotics was determined using CLSI breakpoints.4 •  For analysis tables using subject outcome and isolates microbiological data, fluoroquinolone susceptibility/non-susceptibility was based upon levofloxacin data. •  For QRDR analysis, testing was performed on fluoroquinolone (ciprofloxacin or levofloxacin) resistant isolates. Molecular characterization of the QRDR was performed by PCR amplification of the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC/grlA and parE/grlB) genes, followed by sequencing of the amplicons. Protein amino acid sequences of selected isolates were compared to wild type sequences of S. aureus NCTC 8325 strain. •  Similar eradication rates were observed for subjects with levofloxacin non-susceptible S. aureus isolates (80/81; 98.8%) (Table 2) and MRSA isolates (70/71; 98.6%) (Data not shown). •  Subjects with isolates with DLX MIC values as high as 4 μg/mL were eradicated/presumed eradicated (Table 2). •  The predominant mutation observed was Ser84-Leu in gyrA/Ser80-Phe in parC. The DLX MIC90 for baseline S. aureus isolates with this mutation was 0.25 μg/mL (n=80) whereas the MIC90 for levofloxacin and ciprofloxacin was 8 μg/mL and > 8 μg/mL, respectively (Table 3). Microbiological response rates for subjects with S. aureus isolates with this mutation were 100% (80/80). •  These data also demonstrated that DLX MIC values do not increase beyond 0.5 μg/mL until at least double mutations in

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In Vitro Activity of Delafloxacin and Microbiological Response Against Fluoroquinolone Susceptible and Non-Susceptible S. aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections (ABSSSIs)