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Monotherapy with lefamulin, a novel, pleuromutilin antibiotic with intravenous and oral formulation options, was noninferior to moxifloxacin for efficacy and generally safe and well tolerated for community-acquired bacterial pneumonia (CABP). Lefamulin’s spectrum of activity targets bacteria that cause CABP. Abstract Background Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. Methods In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5–10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). Results There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference −2.9%, 95% confidence interval [CI] g −8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference −2.6%, 95% CI −8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference −2.5%, 95% CI −8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. Conclusions Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. Clinical Trials Registration NCT02559310.

PurposeTo evaluate the pharmacokinetic properties of UGN-101, a mitomycin-containing reverse thermal gel used as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC), in a subset of patients participating in a phase 3 clinical trial.MethodsPharmacokinetic parameters (Cmax, Tmax, AUC(0–6), λz, t½, and AUCinf) were evaluated in six participants (male or female, ≥ 18 years) with biopsy-proven, low-grade UTUC who received the first of 6 once-weekly instillations of UGN-101 to the renal pelvis and calyces via retrograde ureteral catheter. Plasma samples were collected prior to instillation and 30 min, 1, 2, 3, 4, 5, and 6 h post-instillation. Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring.ResultsThe mean age of the six participants was 69 years; most were male (5/6) and Caucasian (5/6). Mean (SD) Cmax was 6.24 (4.11) ng/mL and mean Tmax was 1.79 (1.89) hours after instillation. Mean apparent t½ following instillation was 1.27 (0.63) hours. Mean total systemic exposure to mitomycin up to 6 h post-instillation was 20.30 (19.69) ng h/mL. At 6 h post-instillation, mitomycin plasma concentrations of 5/6 participants were < 2 ng/mL. There were no clinically important adverse events or changes in laboratory values in any participant after a single instillation of UGN-101.ConclusionThe reverse thermal gel formulation of UGN-101 is associated with higher concentration and extended dwell time of mitomycin in contact with the urothelium of the upper urinary tract while limiting systemic absorption of mitomycin.RegistrationNCT02793128; registered June 8, 2016.

Background. Dalbavancin, a novel lipoglycopeptide with a pharmacokinetic profile that allows weekly dosing, is active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The efficacy of dalbavancin for treatment of skin and skin structure infections (SSSIs) was demonstrated in a phase 2 study. Methods. In a phase 3 noninferiority study, patients with complicated SSSIs, including infections known or suspected to involve MRSA, were randomized (ratio, 2 : 1) in a double-blind manner to receive dalbavancin (1000 mg given intravenously on day 1 and 500 mg given intravenously on day 8) or linezolid (600 mg given intravenously or intravenously/orally every 12 h for 14 days). Efficacy was assessed by determining clinical and microbiological responses at the end of therapy and at the test-of-cure visit. Relapses were identified by additional follow-up ∼1 month later. Results. MRSA was identified in 51% of patients from whom a pathogen was isolated at baseline. Dalbavancin and linezolid demonstrated comparable clinical efficacy in the clinically evaluable population at the test-of-cure visit (88.9% and 91.2% success, respectively). The rate of clinical success at the end of therapy was >90% in both arms. Less than 1.0% of patients in either treatment arm experienced relapse after the test-of-cure visit. Both treatments yielded successful microbiological response in excess of 85% among microbiologically evaluable patients at end of therapy and at the test-of-cure visit for all pathogens combined, for all S. aureus strains, and for MRSA. Gastrointestinal symptoms were among the most common adverse events in both arms. A higher proportion of patients in the linezolid arm reported adverse events that were judged by the investigator to be probably/possibly related to treatment (dalbavancin arm, 25.4% of subjects; linezolid arm, 32.2% of subjects). Conclusions. Two doses of dalbavancin (1000 mg given on day 1 followed by 500 mg given on day 8) were as well tolerated and as effective as linezolid given twice daily for 14 days for the treatment of patients with complicated SSSI, including those infected with MRSA.

Background. Catheter-related bloodstream infections (CR-BSIs) are associated with substantial mortality, prolongation of hospital stay, and increased cost of care. Dalbavancin, a new glycopeptide antibiotic with unique pharmacokinetic properties that have allowed clinical development of a weekly dosing regimen, possesses excellent activity against clinically important gram-positive bacteria, suggesting utility in the treatment of patients with CR-BSIs. Methods. A phase 2, open-label, randomized, controlled, multicenter study of 75 adult patients with CR-BSIs compared treatment with intravenous dalbavancin, administered as a single 1000-mg dose followed by a 500-mg dose 1 week later, with intravenous vancomycin, administered twice daily for 14 days. Gram-positive bacteria isolated in this study included coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). Results. Infected patients who received weekly dalbavancin (n = 33) had an overall success rate (87.0%; 95% confidence interval [CI], 73.2%–100.0%) that was significantly higher than that of those who received vancomycin (n = 34) (50.0%; 95% CI, 31.5%–68.5%). Adverse events and laboratory abnormalities were generally mild and were comparable for the 2 drugs. Conclusions. Dalbavancin thus appears to be an effective and well-tolerated treatment option for adult patients with CR-BSIs caused by CoNS and S. aureus, including MRSA.

Dalbavancin, a novel glycopeptide with a long elimination half-life (∼9-12 days), was compared to standard antimicrobial therapy for skin and soft-tissue infections (SSTIs). In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standard-of-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study.

Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5–15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4–6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47–71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1–12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. UroGen Pharma.

The US Food and Drug Administration solicited evidence-based recommendations to improve guidance for studies of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM). ACM at day 28 differed for ventilated HABP (27.8%), VABP (18.0%), and nonventilated HABP (14.5%). A \"mortality-plus\" (ACM+) composite endpoint was constructed by combining ACM with patient-relevant, infection-related adverse events from the Medical Dictionary for Regulatory Activities toxic/septic shock standardized query. The ACM+ rate was 3-10 percentage points above that of ACM across the studies and treatment groups. Predictors of higher ACM/ACM+ rates included older age and elevated acute physiology and chronic health evaluation (APACHE) II score. Only patients in the nonventilated HABP group were able to report pneumonia symptom changes. If disease groups and patient characteristics in future studies produce an ACM rate so low (<10%-15%) that a fixed noninferiority margin of 10% cannot be justified (requiring an odds ratio analysis), an ACM+ endpoint could lower sample size. Enrichment of studies with patients with a higher severity of illness would increase ACM. Data on symptom resolution in nonventilated HABP support development of a patient-reported outcome instrument.

Background New CABP treatments with targeted activity and improved tolerability are needed. LEF, a novel pleuromutilin antibiotic that binds to a conserved region of the bacterial ribosome, is in development for IV or oral CABP treatment. This Phase 3 clinical study evaluated the efficacy of LEF vs. MOX in adults with CABP. Methods In this multicenter, randomized, double-blind study, 551 adult patients with CABP (Patient Outcomes Research Team Risk Class ≥III) were randomized to LEF 150 mg IV Q12 hours (n = 276) or MOX 400 mg IV Q24 hours (n = 275). After 6 IV doses, qualifying patients could be switched to oral therapy. Adjunctive linezolid was given with MOX for suspected methicillin-resistant S. aureus. Primary outcomes were early clinical response (ECR) in the intent-to-treat (ITT) population (FDA endpoint), and investigator assessment of clinical response (IACR) at test of cure in the modified ITT (mITT) and clinically evaluable (CE-TOC) populations (co-primary EMA endpoints). The microITT population included all patients with a baseline CABP pathogen detected by respiratory tract or blood culture, urinary antigen test, serology, and real-time PCR from sputum, oropharyngeal and nasopharyngeal swabs. The microITT2 population included patients with a CABP pathogen detected by methods excluding PCR. Confirmatory identification and susceptibility testing of isolates, serology, and PCR were performed by a central laboratory. Results LEF was noninferior to MOX for ECR and IACR (LEF 87.3% [ITT], 81.7% [mITT], 86.9% [CE-TOC]; MOX 90.2% [ITT], 84.2% [mITT], 89.4% [CE-TOC]). The most common pathogen identified was S. pneumoniae. In the microITT population (n = 159 per arm), LEF and MOX demonstrated similar ECR and IACR rates (figure). LEF was efficacious against S. pneumoniae (including resistant phenotypes), H. influenzae, M. catarrhalis, S. aureus, and atypical pathogens. In the microITT2 population, response rates remained similar across baseline pathogens but showed more variation likely due to smaller sample sizes. Conclusion In this first Phase 3 clinical trial, LEF showed similar efficacy to MOX against the most commonly identified CABP pathogens. LEF demonstrates promise as a targeted monotherapy for the treatment of CABP in adults. Disclosures T. File, BioMerieux: Scientific Advisor, Consulting fee. Curetis: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. MotifBio: Scientific Advisor, Consulting fee. Nabriva: Investigator and Scientific Advisor, Consulting fee and Research grant. Pfizer: Scientific Advisor, Consulting fee. Paratek: Scientific Advisor, Consulting fee. L. Goldberg, Nabriva: Employee, Employee Stock Options and Salary. S. Paukner, Nabriva: Employee and Shareholder, Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Zavante: Consultant, Consulting fee. UTILITY: Consultant, Consulting fee. S. P. Gelone, Nabriva Therapeutics: Employee, Equity, Shareholder and Salary. Achaogen: Shareholder, Equity, Shareholder. J. Saviski, Nabrica Therapeutics, plc: Employee, Salary. C. Sweeney, Nabriva: Employee, employee stock options and Salary. E. Seltzer, Nabriva (previous employee and salary): Employee and Shareholder, Salary. G. H. Talbot, Nabriva Therapeutics: Board Member, Consultant and Shareholder, Consulting fee and stock options, board fees. L. B. Gasink, Nabriva: Employee, Salary.