Open Forum Infectious Diseases MAJOR ARTICLE A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP) Juan P. Horcajada,1 Robert A. Salata,2 Rodolfo Álvarez-Sala,3 Floarea Mimi Nitu,4 Laura Lawrence,5 Megan Quintas,5 Chun-Yen Cheng,6 and Sue Cammarata5, ; for the DEFINE-CABP Study Group* 1 Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain, 2Case Western Reserve University, Cleveland, Ohio, USA, 3University Hospital la Paz, Madrid, Spain, 4Victor Babes Clinical Hospital of Infectious Diseases and Pneumophtisiology, Craiova, Romania, 5Melinta Therapeutics, Lincolnshire, Illinois, USA, and 6Firma Clinical Research, Hunt Valley, Maryland, USA Background. The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is an- ticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic ap- proved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin’s shape and charge profile uniquely impact its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin with moxifloxacin for the treatment of CABP. Methods. A randomized, double-blind, comparator-controlled, multicenter, global phase 3 study compared the efficacy and safety of delafloxacin 300 mg twice daily or moxifloxacin 400 mg once daily in adults with CABP. The primary end point was early clinical response (ECR), defined as improvement at 96 (±24) hours after the first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. Results. In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events that were considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Conclusions. Intravenous/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for Gram-positive, Gram-negative, and atypical pathogens. ClinicalTrials.gov Identifier. NCT03534622. Keywords. CABP; delafloxacin; fluoroquinolone; moxifloxacin; pneumonia. The most common cause for hospital admission in adults, outcomes [6]. At the same time, antimicrobial resistance con- community-acquired bacterial pneumonia (CABP), carries tinues to evolve as a serious problem in the United States and with it a significant clinical and economic burden. As the pop- Europe, with only a few new antibiotics developed in recent ulation ages and pathogens become more resistant, this burden years [7–11]. is anticipated to increase [1–5]. Delafloxacin, approved by the US Food and Drug The microbiological diagnosis of CABP decreases steadily Administration in 2017 for the treatment of acute bacterial skin with age, making empiric treatment necessary, as early appro- and skin structure infection (ABSSSI), is an anionic fluoroquin- priate antibiotic therapy is associated with improved clinical olone with intravenous (IV) and oral formulations that differs from other quinolones in shape and charge profile, resulting in Received 16 September 2019; editorial decision 25 November 2019; accepted 4 December a beneficial spectrum of activity and side effect profile [12]. 2019. Unlike most other fluoroquinolones, delafloxacin inhibits *Members are listed in the Acknowledgements section. DNA gyrase and topoisomerase IV in both Gram-positive Correspondence: S. Cammarata, MD, Melinta Therapeutics, 300 Tri-State International, Suite 272, Lincolnshire, IL 60069 (scammarata@melinta.com). and Gram-negative bacteria to a similar extent. With a broad Open Forum Infectious Diseases® spectrum of activity targeting Gram-positives, including © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases methicillin-resistant Staphylococcus aureus (MRSA), Gram- 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/ negative organisms, and atypical and anaerobic organisms, this by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any dual targeting also decreases the likelihood of resistance, par- 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 journals.permissions@oup.com ticularly in Gram-positive organisms, by requiring the accumu- DOI: 10.1093/ofid/ofz514 lation of multiple mutations affecting both enzymes [13, 14]. Delafloxacin for the treatment of CABP • ofid • 1 Delafloxacin has the fluoroquinolone class safety warnings, discontinued moxifloxacin placebo once daily, and started but the unique attributes of delafloxacin may also offer a dif- linezolid placebo every 12 hours. ferentiated adverse event (AE) profile compared with other fluoroquinolones, primarily lack of corrected QT interval (QTc) Study Population prolongation, phototoxicity, and major central nervous system Subjects ≥18 years of age with clinical and radiographic ev- (CNS) events [15, 16]. idence consistent with CABP and PORT risk class of II, III, Delafloxacin’s susceptibility profile against respiratory patho- IV, or V comprised the ITT population. Enrollment included gens, bioequivalent IV and oral formulations, and favorable no more than 25% of subjects who were PORT Risk Class II. safety profile support its use for the treatment of CABP [15]. This No more than 25% of subjects received 1 dose of a single, phase 3 study compared the efficacy and safety of delafloxacin potentially effective, short-acting antimicrobial or drug reg- with moxifloxacin for the treatment of CABP. imen for treatment of CABP within 24 hours of enrollment. The complete inclusion/exclusion criteria are detailed in METHODS Supplementary Table 1. Study Design and Conduct Study Visits ML-3341-306 (Compare Delafloxacin to Moxifloxacin for Key visits included early clinical response (ECR), 96 (±24) the Treatment of Adults with Community-Acquired Bacterial hours after the start of the first dose of study drug; end of treat- Pneumonia [DEFINE-CABP]) was a phase 3, randomized, ment (EOT), last dose + 1 calendar day; and test of cure (TOC), double-blind, comparator-controlled, multicenter, global study 5 to 10 days after last dose. A follow-up (FU) visit or phone con- comparing the efficacy and safety of IV/oral delafloxacin with tact was conducted at day 28 (±2 days). that of IV/oral moxifloxacin in adults with CABP. Eighty-eight study centers in 18 countries screened subjects, Efficacy Assessments and End Points and 86 centers enrolled subjects into the study. Efficacy was evaluated through assessment of clinical signs and All study sites were granted approval by their independent symptoms of pneumonia, pathogen identification, and suscep- ethics committee (IEC) or institutional review board (IRB). tibility testing of bacterial isolates. Key efficacy end points in- The study was conducted according to the principles of the cluded the following: International Conference on Harmonisation (ICH) E6(R2), The FDA primary end point of ECR was defined as improve- World Medical Association Declaration of Helsinki, Good ment in at least 2 of the following symptoms: chest pain, fre- Clinical Practice Guidelines, and local laws and regulations. quency or severity of cough, amount and quality of productive Documentation of all IEC and IRB approvals and compliance sputum, dyspnea, and no worsening of the other symptoms with (ICH) E6(R2) was maintained by each study site and avail- in the ITT population. Subjects evaluated for ECR were clas- able for review by the sponsor. All subjects provided written in- sified as responders or nonresponders. Early clinical response formed consent. with the addition of improvement in vital signs required as a response was a predefined FDA secondary efficacy end point Randomization and Treatment of the study. In addition to meeting the criteria for the primary Subjects were randomly assigned in a 1:1 ratio to receive end point of ECR, subjects were required at ECR to show im- delafloxacin 300 mg as a 1-hour infusion every 12 (±2) hours provement and no worsening in all vital sign assessments. In or moxifloxacin 400 mg as a 1-hour infusion every 24 (±2) addition, subgroups were predefined for analysis of efficacy hours with blinding placebo to maintain a 12-hour schedule. outcomes. Subjects who met clinical criteria could switch to oral treat- The investigator defined the clinical outcome based on as- ment after a minimum of 6 IV doses. The total duration of sessment of the subject’s signs and symptoms of infection at treatment (IV and oral) was from 5 to 10 days, as clinically TOC. Assessment of the clinical response was categorized as indicated. success, failure, or indeterminate/missing. To enable sensitivity analysis of the primary Food and Drug All-cause mortality was assessed at FU and compared be- Administration (FDA) end points, randomization was stratified tween the treatment groups. by Pneumonia Patient Outcomes Research Team (PORT) risk class, medical history of chronic obstructive pulmonary disease Microbiological Response (COPD) or asthma, and prior single-dose/regimen systemic Causative pathogens were identified by isolation from a base- antimicrobial use. line culture specimen (respiratory specimen and/or blood), If MRSA was confirmed, the investigator could elect to by urinary antigen, serology, and/or quantitative polymerase switch subjects from moxifloxacin to linezolid (600 mg IV chain reaction analysis. In vitro susceptibility of pathogens to every 12 hours) in a blinded fashion. Subjects randomized to delafloxacin and other comparator antibiotics was determined delafloxacin continued to receive delafloxacin every 12 hours, at the central microbiology laboratory according to Clinical 2 • ofid • Horcajada et al and Laboratory Standards Institute and European Committee (or higher). Medical Dictionary for Regulatory Activities on Antimicrobial Susceptibility Testing guidelines for broth (MedDRA), version 19.1, was used for coding AEs and med- microdilution and disk diffusion [17–19]. Multidrug resist- ical history. The prior and concomitant medications were coded ance (MDR) was defined as resistance to 3 or more antibiotic using the World Health Organization (WHO) Drug Dictionary classes [20]. (WHODrug), version March 2016 [21]. By-subject microbiological responses at TOC were deter- mined by results of baseline and FU cultures (if available), RESULTS and the investigator’s clinical response if not, defined as erad- This study enrolled 859 subjects; 431 subjects were randomized ication, presumed eradication, documented persistence, pre- to the delafloxacin group, and 428 subjects were randomized to sumed persistence, or indeterminate/missing. By-pathogen the moxifloxacin group. For the ITT population, 783 subjects microbiological responses were based on follow-up cultures (91.2%) completed the study with participation through TOC performed at TOC. Clinical outcome at TOC by baseline (394 [91.4%] in the delafloxacin group and 389 [90.9%] in the pathogen was assessed and compared between the 2 treat- moxifloxacin group). Of the 76 subjects (8.8%) who did not ment groups. complete the study through TOC, the most common reasons for premature withdrawal were lack of efficacy (3.1%), AE Safety Assessments/Safety End Points and Evaluation (2.2%), and withdrawal of consent (1.3%) (Figure 1). The me- Safety assessments included physical examination, AEs, vital dian duration of total IV and oral treatment was 9 days in each signs, clinical laboratory tests, and 12-lead electrocardiograms group (median, 6 days IV and 2 days oral). (ECGs) at screening and if clinically indicated after screening by the investigator. Subject Baseline Characteristics/Demographics Treatment-emergent AEs (TEAE) were defined as events Demographic and baseline characteristics were similar be- newly occurring or worsening from the time of the first dose of tween the 2 treatment groups. Subjects in the ITT population study drug through FU. Related TEAE was defined as a TEAE were predominantly men (58.7%), white (91.5%), and European that was at least possibly related to the study drug, per the inves- (85.7%); 6.4% were Hispanic or Latino. A higher percentage of tigator. Subgroup analysis of safety outcomes was predefined. subjects in the delafloxacin group were aged ≥65 years (47.1%) Adverse events of special interest (AESIs) were selected based compared with the moxifloxacin group (41.8%), whereas on medical issues of interest for the fluoroquinolone class of about one-fifth of subjects in both treatment groups were aged antibiotics. This assessment focused on AESIs of potential my- ≥75 years. Of subjects in the ITT population, 60.5% had a base- opathy, Clostridium difficile diarrhea, convulsions, potential line pathogen identified (Table 1). peripheral neuropathy, tendon disorder, potential QT prolon- Of the 26% of subjects who received systemic antibiotic gation, phototoxicity, allergic reactions, dysglycemias (hyper- therapy in the 7 days before enrollment, 21.5% received a single glycemia, hypoglycemia), and hepatic-related events. dose of a short-acting antimicrobial within 24 hours of enroll- ment, and 4.5% had a prior documented treatment failure. Statistical Analysis/Methods Assuming a rate of ECR for moxifloxacin therapy and Clinical Outcomes delafloxacin of 77% and 74%, respectively, it was determined In the ITT population, similar percentages of subjects in each that 860 subjects in the ITT population would provide a 90% arm were responders at ECR. Response rates were 88.9% in the power to assess an FDA-directed noninferiority margin of 12.5% delafloxacin group and 89.0% in the moxifloxacin group (–0.2%; of delafloxacin vs moxifloxacin. The differences in proportions 95% CI, –4.4% to 4.1%). As the lower bound of the 95% CI was for the responders from the 2 treatment groups (delafloxacin greater than –12.5%, using the Miettinen-Nurminen method minus moxifloxacin) were tested for noninferiority using con- without stratification, noninferiority of delafloxacin compared fidence intervals (CIs) generated by the Miettinen-Nurminen with moxifloxacin was demonstrated. Regardless of the analysis method without stratification. Continuous secondary effi- population, responder rates were comparable between treatment cacy measures were analyzed using an analysis of covariance groups. (Figure 2). In the ITT population, at ECR, responder rates, (ANCOVA) model with treatment as the main effect, adjusted when combined with improvement in vital signs, significantly fa- for PORT risk class, medical history of COPD or asthma, and vored delafloxacin (52.7%) over moxifloxacin (43.0%), with a dif- prior antimicrobial therapy, and the baseline measure was the ference of 9.7% (95% CI, 3.0% to 16.3%). covariate. All statistical analyses, unless otherwise specified, Responder rates were similar between the delafloxacin and were based upon 2-sided 95% CIs around the difference in moxifloxacin groups for all subgroups analyzed, except for treatment outcomes. subjects with COPD or asthma, where delafloxacin was signif- All analyses and summaries were produced using SAS icantly better than moxifloxacin (93.4% vs 76.8%; difference, software (SAS Institute, Inc, Cary, NC, USA), version 9.4 16.7%; 95% CI, 4.1% to 30.2%) (Figure 2). Delafloxacin for the treatment of CABP • ofid • 3 860 Randomizeda 431 Delafloxacin (ITT) 428 Moxifloxacin (ITT) 429 (99.5) SAF 427 (99.8) SAF 418 (97.0) CE-ECR 414 (96.7) CE-ECR 397 (92.1) CE-TOC 394 (92.1) CE-TOC 257 (59.6) MITT 263 (61.4) MITT 240 (55.7) ME-TOC 248 (57.9) ME-TOC 37 (8.6) 394 (91.4) 39 (9.1) 389 (90.9) Discontinued Completedb Discontinued Completedb Primary Reason for Withdrawal From Study Primary Reason for Withdrawal From Study 13 (3.0) AE 15 (3.5) Lack of efficacy 12 (2.8) Lack of efficacy 9 (2.1) Withdrawal by subject 6 (1.4) Other 6 (1.4) AE 2 (0.5) Withdrawal by subject 3 (0.7) Lost to follow-up 2 (0.5) Death 2 (0.5) Other 2 (0.5) Physician decision (randomized but never dosed) 3 (0.7) Physician decision (other) 1 (0.2) Physician decision (randomized but never dosed) ITT (intent to treat) All randomized subjects with a signed Informed Consent Form. SAF (safety) All randomized subjects who received at least 1 dose of the study drug. MITT (microbiological ITT population who had baseline pathogen identified. Detected by any methods (i.e., including culture, serology, PCR, intent-to-treat) and urinary antigen). CE (clinically evaluable) ITT population who received study drug based upon random assignment; had evidence of acute-onset CABP; received at least 80% of expected doses of study drug in treatment period; had assessments of the CABP being treated within the appropriate window (ECR or TOC), or was clinical failure and received a minimum of 4 doses of study drug by end of day 3; did not receive potentially effective concomitant systemic antibacterial therapy before assessment, except for lack of efficacy; had no protocol deviations through the time point. ME (microbiologically All subjects in MITT populations who also met criteria for corresponding CE population. evaluable) Abbreviations: AE, adverse event; ECR, Early Clinical Response; EOT, End of Treatment; PK, pharmacokinetics; TOC, Test of Cure. a One subject mistakenly was randomized into the interactive voice and web response system but did not provide informed consent; therefore, this subject was not included in the ITT population. b Completed the study through TOC. Figure 1. Subject disposition and analysis populations. aOne subject was mistakenly randomized into the interactive voice and web response system but did not provide informed consent; therefore, this subject was not included in the intent-to-treat population. bCompleted the study through TOC. Abbreviations: AE, adverse event; ECR, early clinical response; EOT, end of treatment; PK, pharmacokinetics; TOC, test of cure. At TOC in the ITT population, the success rates were clinical outcome of success at TOC, whereas the moxifloxacin 90.5% in the delafloxacin treatment group and 89.7% in subject was a failure at EOT. the moxifloxacin group, with a difference of 0.8% (95% Similar percentages of subjects in the delafloxacin (1.9%) and CI, −3.3% to 4.8%). Clinical outcomes were compa- moxifloxacin groups (1.4%) died during the study (up to day rable between treatment groups in the other analysis sets 28). All events were considered unrelated to the study drug. (Figure 3). Among subjects with bacteremia at baseline, 1 delafloxacin- Microbiological Outcomes treated subject with Klebsiella pneumoniae and 1 moxifloxacin- Five hundred twenty subjects (60.5%) had at least 1 pathogen de- treated subject with Streptococcus pneumoniae were tected at baseline by any method (Table 2). Overall, S. pneumoniae nonresponders at the early time point. The delafloxacin subject was the most commonly identified pathogen, in 43.5% of subjects went on to have presumed eradication of the pathogen and a in the MITT population, followed by Haemophilus parainfluenzae 4 • ofid • Horcajada et al Table 1. Subject Demographics and Baseline Characteristics (ITT Population) Characteristic Delafloxacin (n = 431) Moxifloxacin (n = 428) Total (n = 859) Age, y Mean (SD) 60.7 (16.06) 59.3 (16.58) 60.0 (16.33) Median 63.0 61.0 62.0 Min, max 18, 89 18, 93 18, 93 Age category, No. (%) <65 y 228 (52.9) 249 (58.2) 477 (55.5) ≥65 y 203 (47.1) 179 (41.8) 382 (44.5) ≥75 y 85 (19.7) 97 (22.7) 182 (21.2) Sex, No. (%) Male 251 (58.2) 253 (59.1) 504 (58.7) Female 180 (41.8) 175 (40.9) 355 (41.3) Race, No. (%) White 398 (92.3) 388 (90.7) 786 (91.5) Black or African American 22 (5.1) 33 (7.7) 55 (6.4) Asian 5 (1.2) 5 (1.2) 10 (1.2) American Indian or Alaska Native 4 (0.9) 0 4 (0.5) Other 2 (0.5) 2 (0.5) 4 (0.5) Region, No. (%)a Europe 371 (86.1) 365 (85.3) 736 (85.7) South Africa 30 (7.0) 41 (9.6) 71 (8.3) Latin America 29 (6.7) 17 (4.0) 46 (5.4) North America 1 (0.2) 5 (1.2) 6 (0.7) Weight, kg Mean (SD) 76.40 (17.389) 77.23 (16.765) 76.82 (17.076) Median 75.00 75.65 75.00 Min, max 39.2, 160.0 33.5, 136.0 33.5, 160.0 BMI category, No. (%) <30 kg/m2 328 (76.1) 316 (73.8) 644 (75.0) ≥30 kg/m2 103 (23.9) 112 (26.2) 215 (25.0) Diabetes, No. (%) Yes 70 (16.2) 61 (14.3) 131 (15.3) COPD/asthma, No. (%) Yes 61 (14.2) 56 (13.1) 117 (13.6) Multilobar pneumonia, No. (%) Yes 125 (29.0) 120 (28.0) 245 (28.5) CrCl group, No. (%)b Severe (<30 mL/min) 5 (1.2) 7 (1.6) 12 (1.4) Moderate (30–<60 mL/min) 80 (18.6) 79 (18.5) 159 (18.5) Mild (60–<90 mL/min) 142 (32.9) 134 (31.3) 276 (32.1) Normal (≥90 mL/min) 194 (45.0) 199 (46.5) 393 (45.8) Missing 10 (2.3) 9 (2.1) 19 (2.2) PORT risk class, No. (%) II 54 (12.5) 57 (13.3) 111 (12.9) III 258 (59.9) 260 (60.7) 518 (60.3) IV 115 (26.7) 103 (24.1) 218 (25.4) V 4 (0.9) 8 (1.9) 12 (1.4) PORT risk score Mean (SD) 84.5 (15.75) 84.7 (17.43) 84.6 (16.60) Median 83.0 81.0 82.0 Min, max 50, 146 48, 161 48, 161 Bacteremia, No. (%) Yes 5 (1.2) 8 (1.9) 13 (1.5) Pathogen identified at baseline 257 (59.6) 263 (61.4) 520 (60.5) Abbreviations: BMI, body mass index; BSA, body surface area; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; CRF, case report form; CURB-65, confusion, urea, respiratory rate, blood pressure, age 65 or older; ITT, intent-to-treat; Max, maximum; Min, minimum; NIH, National Institutes of Health; PMN, polymorphonuclear neutrophil; PORT, Patient Outcomes Research Team; SEC, squamous epithelial cell. a Europe comprises Bulgaria, Georgia, Germany, Hungary, Latvia, Poland, Romania, Russia, Serbia, Spain, Slovenia, and Ukraine. North America comprises the United States. Latin America comprises Argentina, Columbia, Peru, and Dominican Republic. b CrCl was based on the Cockcroft-Gault formula without correction for BSA. Delafloxacin for the treatment of CABP • ofid • 5 n/N Analysis Diff Set Dela- Moxi- [95% CI] floxacin floxacin ITT 383/431 381/428 –0.2 (–4.4, 4.1) MITT 236/257 233/263 3.2 (–1.9, 8.5) CE-ECR 381/418 380/414 –0.6 (–4.5, 3.2) ME-ECR 235/253 233/256 1.9 (–3.0, 6.8) –15 –10 –5 0 5 10 15 Difference in Response Rate (%) Favors Moxifloxacin Favors Delafloxacin n/N1 Category Subgroup Diff Dela- Moxi- [95% CI] floxacin floxacin <65 Years 206/228 220/249 2.0 (–3.7, 7.6) Age ≥65 Years 177/203 161/179 –2.8 (–9.2, 3.8) ≥75 Years 73/85 84/97 –0.7 (–11.3, 9.5) Male 221/251 223/253 –0.1 (–5.9, 5.7) Sex Female 162/180 158/175 –0.3 (–6.7, 6.1) <30 kg/m2 289/328 281/316 –0.8 (–5.8, 4.2) BMI ≥30 kg/m2 94/103 100/112 2.0 (–6.4, 10.3) II 50/54 54/57 –2.1 (–13.1, 8.1) III 231/258 229/260 1.5 (–4.1, 7.0) PORT Risk IV 100/115 91/103 –1.4 (–10.3, 7.8) V 2/4 7/8 –37.5 (–78.5, 15.6) CrCl <90 mL/min 199/227 192/220 0.4 (–5.8, 6.7) Renal Disease CrCl ≥90 mL/min 176/194 180/199 0.3 (–5.7, 6.2) History of Yes 57/61 43/56 16.7 (4.1, 30.2) COPD/Asthma Multilobar Subjects with at Baseline 112/125 104/120 2.9 (–5.3, 11.4) pneumonia Diabetes Yes 63/70 54/61 1.5 (–9.6, 13.2) Bacteremia Yes 4/5 7/8 –7.5 (–55.2, 35.2) –25 –20 –15 –10 –5 0 5 10 15 20 25 Difference in Response Rate (%) Favors Moxifloxacin Favors Delafloxacin Figure 2. Early clinical response by analysis set and subgroup (ITT population). Difference was the difference in ECR response rates (delafloxacin treatment group minus moxifloxacin treatment group). The CIs were calculated using the Miettinen-Nurminen method without stratification. Abbreviations: CE, clinically evaluable; CI, confidence interval; ECR, early clinical response; ITT, intent-to-treat; LCL, 95% lower confidence limit; ME, microbiologically evaluable; MITT, microbiological intent-to-treat; UCL, 95% upper confidence limit. (14.6%), Mycoplasma pneumoniae (12.5%), Legionella S. pneumoniae isolates identified, 13.4% were penicillin-resistant pneumophilia (11.9%), Haemophilus influenzae (11.9%), S. aureus (PRSP), 24.6% macrolide-resistant (MRSP), and 8.5% multiple (11.0%), and Chlamydia pneumoniae (7.9%). Of the 142 baseline drug-resistant (MDRSP). S. aureus was encountered frequently, 6 • ofid • Horcajada et al n/N Analysis Diff Set Dela- Moxi- [95% CI] floxacin floxacin ITT 390/431 384/428 0.8 (–3.3, 4.8) MITT 234/257 238/263 0.6 (–4.5, 5.7) CE-TOC 376/397 373/394 0.0 (–3.2, 3.3) ME-TOC 225/240 235/248 –1.0 (–5.4, 3.3) –15 –10 –5 0 5 10 15 Difference in Response Rate (%) Favors Moxifloxacin Favors Delafloxacin n/N1 Category Subgroup Diff Dela- Moxi- [95% CI] floxacin floxacin <65 Years 209/228 221/249 2.90 (–2.5, 8.4) Age ≥65 Years 181/203 163/179 –1.9 (–8.0, 4.3) ≥75 Years 77/85 87/97 0.9 (–8.5, 9.9) Male 223/251 225/253 –0.1 (–5.7, 5.5) Sex Female 167/180 159/175 1.9 (–3.9, 8.0) <30 kg/m2 293/328 284/316 –0.5 (–5.3, 4.3) BMI ≥30 kg/m2 97/103 100/112 4.9 (–2.8, 12.8) II 48/54 54/57 –5.8 (–17.8, 5.0) III 238/258 233/260 2.6 (–2.4, 7.7) PORT Risk IV 102/115 93/103 –1.6 (–10.0, 7.0) V 2/4 4/8 0.0 (–51.9, 51.9) CrCl <90 mL/min 205/227 197/220 0.8 (–4.9, 6.5) Renal Disease CrCl ≥90 mL/min 178/194 179/199 1.8 (–4.1, 7.7) History of Yes 54/61 45/56 8.2 (–5.2, 22.1) COPD/Asthma Multilobar Subjects with at Baseline 113/125 101/120 6.2 (–2.2, 15.0) pneumonia Diabetes Yes 61/70 53/61 0.3 (–11.6, 12.7) Bacteremia Yes 5/5 7/8 12.5 (–35.8, 48.5) –25 –20 –15 –10 –5 0 5 10 15 20 25 Difference in Response Rate (%) Favors Moxifloxacin Favors Delafloxacin Figure 3. Clinical outcome at test of cure by analysis set and subgroup (ITT population). Difference was the difference in ECR response rates (delafloxacin treatment group minus moxifloxacin treatment group). The CIs were calculated using the Miettinen-Nurminen method without stratification. Abbreviations: CE, clinically evaluable; CI, con- fidence interval; ECR, early clinical response; ITT, intent-to-treat; LCL, 95% lower confidence limit; ME, microbiologically evaluable; MITT, microbiological intent-to-treat; UCL, 95% upper confidence limit. with only 2 MRSA isolates identified, both in the delafloxacin K. pneumoniae, Escherichia coli, and Pseudomonas aeruginosa treatment group and both deemed a clinical/microbiolog- (6.3%, 5.2%, and 4.6%, respectively). Based on MIC90 (Minimum ical success at TOC. Gram-negative pathogens ≥4% included Inhibitory Concentration [MIC]) values at baseline, delafloxacin Delafloxacin for the treatment of CABP • ofid • 7 Table 2. Pathogens Identified at Baseline in >1% of Subjects (MITT TEAEs assessed as severe. Two (0.5%) in the delafloxacin Population) group (hypersensitivity and C. difficile colitis) and none in the moxifloxacin group had SAEs that were considered po- No. (%) of Subjects tentially related to the study drug. Fifteen subjects (3.5%) Baseline Pathogens Total (n = 520) in the delafloxacin group and 7 (1.6%) in the moxifloxacin Streptococcus pneumoniae 226 (43.5) group discontinued the study drug because of TEAEs PSSP 102 (19.6) (Tables 4 and 5). Nine subjects (2.1%) in the delafloxacin PISP 25 (4.8) PRSP 19 (3.7) group and 7 (1.6%) in the moxifloxacin group had TEAEs MDRSP 12 (2.3) leading to death. Of these, 2 deaths, 1 in each treatment MRSP 35 (6.7) group, occurred after day 28. All events were considered Haemophilus parainfluenzae 76 (14.6) unrelated to the study drug. Mycoplasma pneumoniae 65 (12.5) There were no TEAEs reported in ≥5% of subjects in either Legionella pneumophila 62 (11.9) treatment group. Diarrhea, increased transaminases, and head- Haemophilus influenzae 62 (11.9) Staphylococcus aureus 57 (11.0) ache were the only TEAEs reported in ≥2% of subjects. A sub- MRSA 2 (0.4) group analysis of adverse events based upon medical history MSSA 55 (10.6) and demographic subgroups was completed. With small num- Chlamydia pneumoniae 41 (7.9) bers of subjects among subgroups, there were no differences ob- Klebsiella pneumoniae 33 (6.3) served in related events. Escherichia coli 27 (5.2) In the safety analysis set, TEAEs of special interest (AESI) Pseudomonas aeruginosa 24 (4.6) Klebsiella oxytoca 10 (1.9) were chosen based upon medical issues of interest for the Moraxella catarrhalis 12 (2.3) fluoroquinolone class. Because of recent fluoroquinolone Pathogens were identified by culture and/or nonculture methods. Organisms isolated by class labeling updates, a search for events related to potential culture were reviewed on a case-by-case basis by the sponsor to determine eligibility as a aortic dissection/rupture was included (Table 6). No subject causative CABP pathogen. Pathogens identified by nonculture methods were determined programmatically. For each subject, if a pathogen was identified by more than 1 method, in either group experienced a potential peripheral neurop- the subject was counted only once. Subjects with both MRSA and MSSA, or any combina- tion of PSSP, PISP, or PRSP, were counted once in the overall category for that organism. athy, tendon disorder, phototoxicity, or potential aortic rup- Abbreviations: CABP, community-acquired bacterial pneumonia; MDRSP, multiple drug- ture/dissection. No subjects in the delafloxacin group had a resistant Streptococcus pneumoniae; MITT, microbiological intent-to-treat; MRSA, methicillin-resistant Staphylococcus aureus; MRSP, macrolide-resistant Streptococcus potential myopathy or QT prolongation, whereas 5 subjects pneumoniae; MSSA, methicillin-susceptible Staphylococcus aureus; PISP, penicillin- (1.2%) and 2 subjects (0.5%) in the moxifloxacin group ex- intermediate Streptococcus pneumoniae; PRSP, penicillin-resistant Streptococcus pneumoniae; PSSP, penicillin-susceptible Streptococcus pneumoniae. perienced a potential myopathy or QT prolongation, respec- tively. Two subjects (0.5%) in the delafloxacin group and 1 subject (0.2%) in the moxifloxacin group had a TEAE of exhibited at least 16-fold greater activity than moxifloxacin for C. difficile colitis. One subject in each treatment group dis- all Gram-positive and fastidious Gram-negative pathogens in the continued treatment because of the AE. In all 3 subjects, the MITT population. TEAE resolved within 10 to 17 days. In the ME-TOC population, the clinical success rates A higher percentage of subjects in the delafloxacin group by pathogen were similar between the delafloxacin group (5.1%) compared with the moxifloxacin group (2.8%) had and the moxifloxacin group (Table 3). Three subjects in the hepatic TEAEs, with transaminase increase reported most delafloxacin group and 4 in the moxifloxacin group had docu- frequently. The hepatic TEAEs were all mild or moderate mented persistence of a baseline pathogen. All 3 subjects in the in severity except for 1 subject in the moxifloxacin group. delafloxacin arm had a clinical outcome of success at TOC. In There were 2 and 1 treatment discontinuations, respec- the moxifloxacin arm, 1 of 3 subjects had a clinical outcome of tively, for delafloxacin and moxifloxacin due to liver enzyme failure at EOT and TOC; the others had an outcome of success elevations. Alanine aminotransferase (ALT) or aspartate at TOC. aminotransferase (AST) values >5× the upper limit of normal (ULN) at any time during the trial were observed in a similar Safety and Tolerability percentage of subjects in the delafloxacin (1.4% and 0.9%) Overall, 131 subjects (30.5%) in the delafloxacin group and moxifloxacin groups (1.6% and 0.5%) (Supplementary and 112 (26.2%) in the moxifloxacin group experienced Table 2). No subject in either treatment group met Hy’s Law TEAEs. Of these, 65 (15.2%) in the delafloxacin group and criteria. 54 (12.6%) in the moxifloxacin group were considered at Mean values and changes from baseline in hematology and least possibly related to the study drug. Most were mild serum chemistry levels were similar across treatment groups in severity. Nineteen subjects (4.4%) in the delafloxacin at all time points. There were no unexpected changes in either group and 14 (3.3%) in the moxifloxacin group experienced treatment group. 8 • ofid • Horcajada et al Table 3. Clinical Outcome at Test of Cure by Baseline Pathogen (ME-TOC Population) Clinical Success, n/N (%)a All Pathogens Delafloxacin (n = 240) Moxifloxacin (n = 248) Streptococcus pneumoniaeb 103/110 (93.6) 94/99 (94.9) PSSP 47/49 (95.5) 44/47 (93.6) PISP 16/17 (94.1) 6/7 (85.7) PRSP 7/8 (87.5) 11/11 (100) MDRSP 4/4 (100) 8/8 (100) MRSP 16/17 (94.1) 17/18 (94.4) Haemophilus parainfluenzae 32/35 (91.4) 34/37 (91.9) Mycoplasma pneumoniae 29/30 (96.7) 29/29 (100) Legionella pneumophila 27/29 (93.1) 32/32 (100) Staphylococcus aureusb 25/27 (92.6) 28/30 (93.3) MSSA 23/25 (92.0) 28/30 (93.3) MRSA 2/2 (100) 0/0 (NA) Chlamydia pneumoniae 24/24 (100) 15/15 (100) Haemophilus influenzae 23/24 (95.8) 31/35 (88.6) Klebsiella pneumoniae 14/17 (82.4) 16/16 (100) Escherichia coli 13/13 (100) 9/9 (100) Pseudomonas aeruginosa 11/12 (91.7) 11/11 (100) Klebsiella oxytoca 6/6 (100) 3/4 (75.0) Moraxella catarrhalis 6/6 (100) 6/6 (100) Enterobacter cloacae complex 3/4 (75.0) 8/8 (100) Abbreviations: MDRSP, multiple drug-resistant Streptococcus pneumoniae; ME, microbiologically evaluable; MRSA, macrolide-resistant Staphylococcus aureus; MRSP, macrolide-resistant Streptococcus pneumoniae; MSSA, methicillin-susceptible Staphylococcus aureus; PISP, penicillin-intermediate Streptococcus pneumoniae; PSSP, penicillin-susceptible Streptococcus pneumoniae; PRSP, penicillin-resistant Streptococcus pneumoniae: TOC, test of cure. a Microbiological success was defined as documented or presumed eradication. b Subjects with both MRSA and MSSA, or any combination of PSSP, PISP, or PRSP, were counted once in the overall category for that organism. DISCUSSION For clinical outcome (success) at TOC, delafloxacin was com- In this study, IV/oral delafloxacin was noninferior to IV/oral parable to moxifloxacin, regardless of subgroup. moxifloxacin at the FDA primary efficacy end point of ECR. Delafloxacin has a broad spectrum of activity and exhibits ECR responder rates with improvement in vital signs favored 2–4-fold lower MICs compared with other fluoroquinolones for delafloxacin over moxifloxacin. Clinical outcome success rates common CABP pathogens [23]. In this study, based on base- at TOC were comparable regardless of population, stratifica- line MIC90 values, delafloxacin exhibited 16-fold greater activity tion, or subgroup, documenting a sustained clinical response. than moxifloxacin for all Gram-positive and Gram-negative At TOC, microbiological eradication rates were comparable in pathogens and was used to successfully treat subjects with the both treatment groups. range of pathogens typically seen in CABP, including MRSP The mean age of subjects was 60 years, with 44.5% of subjects and atypical CABP pathogens plus MRSA. With macrolide re- aged ≥65 years and 21.2% aged ≥75 years. This study only en- sistance rates in S. pneumoniae near 40% and an increased trend rolled 12.5% of PORT 2 subjects in the delafloxacin arm. The of atypical pathogens seen over the last several years with a low rest were PORT 3 and above, representing the serious nature of testing frequency, coverage for these organisms is important this infection type. [24–26]. A predefined exploration of efficacy across subgroups that Postinfluenza bacterial pneumonia continues to play a sig- addressed underlying comorbidities seen in patients with CABP nificant role in the morbidity and mortality associated with demonstrated that delafloxacin was comparable to moxifloxacin influenza and where MRSA is a significant pathogen inducing in all subgroups except subjects with a history of COPD or postinfluenza CABP [27]. That this population was not cap- asthma, who at ECR, favored delafloxacin over moxifloxacin. tured and that a low number of MRSA isolates was seen are lim- However, the clinical outcome at TOC was not statistically itations of this study. better for delafloxacin. Because adults with COPD have a 6–8- Delafloxacin appeared to be safe and well tolerated in this times greater risk of developing CABP than healthy individuals study, with a discontinuation rate of 2.1% due to related TEAEs. and the risk of morbidity, mortality, and economic burden in These results were qualitatively consistent with, though nu- these individuals is greater, further study is warranted [22]. merically different from, an analysis of integrated safety data Delafloxacin for the treatment of CABP • ofid • 9 Table 4. Overall Summary of Treatment-Emergent Adverse Events (Safety Population) TEAE Category Delafloxacin (n = 429) Moxifloxacin (n = 427) Total No. of TEAEs 215 204 No. (%) of subjects with anya TEAE 131 (30.5) 112 (26.2) TEAE at least possibly related to study treatmentb 65 (15.2) 54 (12.6) TEAE by maximum severitya   Mild 67 (15.6) 56 (13.1)   Moderate 45 (10.5) 42 (9.8)   Severe 19 (4.4) 14 (3.3) Serious TEAE 23 (5.4) 20 (4.7) TEAE leading to study drug discontinuation 15 (3.5) 7 (1.6) TEAE leading to death 9 (2.1) 7 (1.6) TEAE of special interest 34 (7.9) 32 (7.5) TEAEs were coded using MedDRA, version 19.1. Abbreviation: TEAE, treatment-emergent adverse event. a At each level of subject summarization, a subject with 1 or more reported TEAEs was counted only once, and the most severe reported TEAE was used for the maximum severity. b Related includes possibly, probably, and definitely related. Table 5. TEAEs in >1% of Subjects in the Safety Population MedDRA System Organ Class and Adverse Event (Preferred Term) No. (%) of Subjects With TEAE Delafloxacin (n = 429) Moxifloxacin (n = 427) Total Relateda Total Relateda Gastrointestinal disorders Diarrhea 20 (4.7) 16 (3.7) 14 (3.3) 13 (3.0) Nausea 5 (1.2) 3 (0.7) 5 (1.2) 4 (0.9) Investigations Transaminases increased 13 (3.0) 11 (2.6) 6 (1.4) 4 (0.9) Nervous system disorders Headache 8 (1.9) 2 (0.5) 11 (2.6) 10 (2.3) Metabolism and nutrition disorders Hypokalemia 8 (1.9) 1 (0.2) 2 (0.5) 0 Hyperglycemia 2 (0.5) 0 6 (1.4) 2 (0.5) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism 1 (0.2) 0 6 (1.4) 1 (0.2) TEAEs were coded using MedDRA, version 19.1. Abbreviation: MedDRA, Medical Dictionary for Regulatory Activities. a Related includes possibly, probably, and definitely related. across the 4 active-controlled phase 2 and phase 3 ABSSSI clin- no target criteria for investigators to report laboratory changes as ical studies [28]. The mean age in this study was 60 years, and AEs. More objective examination of laboratory results showed no subjects had a higher incidence of comorbidities compared with difference in the overall worst postbaseline assessment between those in the ABSSSI studies, with a mean age of 48 years. the groups at >5× ULN (Supplementary Table 2). A range of well-known risks associated with fluoroquinolones has Animal studies with delafloxacin showed no microscopic been recognized, and regulatory agencies have expanded class safety findings of liver injury; in a pooled analysis of phase 1 studies labeling changes. The historical knowledge of the class safety profile (n = 814), hepatic events were seen in 0.9% of subjects and did informed a prospective assessment of AESIs in the development of not increase with increased dose. In a pooled analysis of the delafloxacin. Preclinical and clinical studies have differentiated the phase 3 ABSSSI studies with nonfluoroquinolone comparators safety profile of delafloxacin from other fluoroquinolones [15, 26]. vancomycin (VAN) and aztreonam (AZ), the rates of treatment- A higher percentage of subjects in the delafloxacin group related hepatic events were 2.2% (n = 741) and 2.7% (n = 751) (5.1%) than in the moxifloxacin group (2.8%) reported he- for delafloxacin and VAN/AZ, respectively [13]. patic TEAEs, primarily transaminase increases, with all in the A limitation of this study is that subjects with a history delafloxacin group characterized as mild to moderate. There were of QT prolongation or arrhythmias were excluded due to 10 • ofid • Horcajada et al Table 6. Treatment-Emergent Adverse Events of Special Interest by Type and Preferred Term (Safety Population) No. (%) of Subjects Delafloxacin (n = 429) Moxifloxacin (n = 427) a MedDRA System Organ Class and Adverse Event (Preferred Term) Total Related Total Relateda Total No. of AESIsb 35 25 34 16 Subjects with any AESI, No. (%)b 34 (7.9) 24 (5.6) 32 (7.5) 16 (3.7) Hepatic-related events 22 (5.1) 16 (3.7) 12 (2.8) 8 (1.9) Transaminases increased 13 (3.0) 11 (2.6) 6 (1.4) 4 (0.9) ALT increased 4 (0.9) 2 (0.5) 2 (0.5) 1 (0.2) Hepatic enzyme increased 3 (0.7) 3 (0.7) 3 (0.7) 3 (0.7) Hepatic steatosis 2 (0.5) 0 0 0 GGT increased 1 (0.2) 1 (0.2) 0 0 Hepatic lesion 0 0 1 (0.2) 0 Potential allergic reactions 8 (1.9) 6 (1.4) 4 (0.9) 3 (0.7) Rash 2 (0.5) 2 (0.5) 0 0 Urticaria 2 (0.5) 2 (0.5) 0 0 Bronchospasm 1 (0.2) 0 1 (0.2) 0 Dermatitis allergic 1 (0.2) 1 (0.2) 2 (0.5) 2 (0.5) Gingival swelling 1 (0.2) 0 0 0 Hypersensitivity 1 (0.2) 1 (0.2) 0 0 Rash pruritic 0 0 1 (0.2) 1 (0.2) Clostridium difficile diarrhea 2 (0.5) 2 (0.5) 1 (0.2) 0 C. difficile colitis 2 (0.5) 2 (0.5) 1 (0.2) 0 Hyperglycemia 2 (0.5) 0 7 (1.6) 2 (0.5) Hyperglycemia 2 (0.5) 0 6 (1.4) 2 (0.5) Blood glucose increased 0 0 1 (0.2) 0 Hypoglycemia 0 0 3 (0.7) 1 (0.2) Hypoglycemia 0 0 3 (0.7) 1 (0.2) Potential myopathy 0 0 5 (1.2) 2 (0.5) Acute kidney injury 0 0 1 (0.2) 0 Blood creatinine phosphokinase increased 0 0 2 (0.5) 1 (0.2) Blood creatinine increased 0 0 1 (0.2) 1 (0.2) Myalgia 0 0 1 (0.2) 0 Potential QT prolongation 0 0 2 (0.5) 0 ECG QT prolonged 0 0 1 (0.2) 0 Sudden death 0 0 1 (0.2) 0 AESIs were coded using MedDRA, version 19.1. If an AESI did not occur, it was not presented in the table. There were no events of phototoxicity, tendon disorder, neuropathy, or convulsions. Abbreviations: AESI, adverse event of special interest; ALT, alanine aminotransferase; ECG, electrocardiogram; GGT, γ-glutamyl transferase; MedDRA, Medical Dictionary for Regulatory Activities; SOC, MedDRA System Organ Class. a Assessments of possibly or probably related. b The total number of AESIs counts all AESIs for subjects. Within an SOC, a subject was counted once if they reported >1 type of AESI. moxifloxacin being the comparator. However, although there Precautions sections of the delafloxacin labeling [16]. However, were no events of QT prolongation reported for delafloxacin monitoring use in the clinic for potential adverse events observed in this trial, 2 subjects in the moxifloxacin group experienced with other fluoroquinolones is clinically prudent. this TEAE. Because preclinical and animal studies document Additional study limitations include a low number of subjects that delafloxacin does not cause QTc prolongation, there was enrolled from the United States. Similar to other recent CABP no requirement to directly measure QTc intervals in the phase 3 clinical trials, this enrollment imbalance was due to a combina- trials. There were no QT prolongation–related events reported tion of exclusion criteria and the requirement that no more that with delafloxacin in the phase 3 ABSSSI trials, and there is no 25% of subjects could receive 1 dose of an antibiotic for treat- warning for QTc prolongation on the current delafloxacin label. ment of the CABP within 24 hours of the study drug. Although the FDA Class Boxed warning regarding tendon rup- ture, peripheral neuropathy, CNS effects, myasthenia gravis, and CONCLUSIONS aortic aneurysm and dissection is included on the delafloxacin label, QT/torsades, photosensitivity, hepatotoxicity/hepatitis, and With properties unique from other fluoroquinolones, multiple classes of drug interactions are not found in the Warnings/ delafloxacin monotherapy is effective and well tolerated in the Delafloxacin for the treatment of CABP • ofid • 11 treatment of adult patients with CABP, providing coverage for Ramon Hernadez – Miami, Florida, USA; Richard Griffey – Saint Louis, Missouri, USA; Archana Misra (El Sohl, Ali) – Buffalo, New York, USA; James Gram-positive (including MRSA), Gram-negative, and atyp- Dargin – Burlington, Massachusetts, USA. ical pathogens commonly associated with CABP. The results Financial support. This study was funded by Melinta Therapeutics. of this study were consistent across a wide array of comorbid Editorial assistance was provided by Dothen Healthcare Press, Hillsborough, conditions and ages. With both an IV and oral formulation, New Jersey, USA, funded by Melinta Therapeutics. Potential conflicts of interest. J.H., R.A., R.S., F.N., or their institu- delafloxacin provides expanded treatment options for patients tion received investigational grants from Melinta for the enrolled patients. with CABP that offer continuity and simplicity of treatment as J.H. received personal fees from Pfizer, Zabon, and Angelini and personal patients transition out of the hospital. and grant fees from MSD outside the submitted work; S.C., L.L., and M.Q. are employees of Melinta Therapeutics. C.C. is an employee of Firma Supplementary Data Clinical Research, funded by Melinta Therapeutics. All authors have sub- mitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that Supplementary materials are available at Open Forum Infectious Diseases the editors consider relevant to the content of the manuscript have been online. Consisting of data provided by the authors to benefit the reader, disclosed. the posted materials are not copyedited and are the sole responsibility of Prior presentation. An abstract of the data was presented at IDWeek the authors, so questions or comments should be addressed to the corre- 2019, Washington, DC, USA (abstract #679253). sponding author. Author contributions. All authors participated in the execution and completion of the study and drafting and review of this manuscript. Acknowledgments L. Lawrence, M. Quintas, and S. Cammarata were responsible for the de- We thank Sandra McCurdy, Kara Keedy, Amanda Sheets, and Ashley velopment, execution, and analysis of the protocol. J. Horcajada was a Nenninger for microbiology support. Coordinating Investigator and reviewed the Clinical Study Report. 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