Exebacase in Addition to Standard-of-Care Antibiotics for Staphylococcus aureus Bloodstream Infections and Right-Sided Infective Endocarditis: A Phase 3, Superiority-Design, Placebo-Controlled, Randomized Clinical Trial (DISRUPT).

BACKGROUND: Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics. METHODS: In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population. RESULTS: A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported. CONCLUSIONS: Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis. Clinical Trials Registration.NCT04160468.

Outcomes by Candida spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.

BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

Stress responses in surgical trainees during simulation-based training courses in laparoscopy.

BACKGROUND: Simulation-based training courses in laparoscopy have become a fundamental part of surgical training programs. Surgical skills in laparoscopy are challenging to master, and training in these skills induces stress responses in trainees. There is limited data on trainees' stress levels, the stress responses related to training on different laparoscopic simulators, and how previous experiences influence trainees' stress response during a course. This study investigates physiologic, endocrine and self-reported stress responses during simulation-based surgical skills training in a course setting. METHODS: We conducted a prospective observational study of trainees attending basic laparoscopic skills training courses at a national training centre. During the three-day course, participants trained on different laparoscopic simulators: Two box-trainers (the D-box and P.O.P. trainer) and a virtual reality simulator (LAPMentor™). Participants' stress responses were examined through heart rate variability (HRV), saliva cortisol, and the State Trait Anxiety Inventory-6 (STAI-6). The correlation between previous laparoscopic experiences and stress response measurements was explored. RESULTS: Twenty-four surgical trainees were included in the study. Compared to resting conditions, stress measures were significantly higher during simulation-training activity (the D-box (SDNN = 58.5 ± 23.4; LF/HF-ratio = 4.58 ± 2.71; STAI-6 = 12.3 ± 3.9, P < 0.05), the P.O.P trainer (SDNN = 55.7 ± 7.4; RMSSD = 32.4 ± 17.1; STAI-6 = 12.1 ± 3.9, P < 0.05), and the LAPMentor™ (SDNN = 59.1 ± 18.5; RMSSD = 34.3 ± 19.7; LF/HF-ratio = 4.71 ± 2.64; STAI-6 = 9.9 ± 3.0, P < 0.05)). A significant difference in endocrine stress response was seen for the simulation-training activity on the D-box (saliva cortisol: 3.48 ± 1.92, P < 0.05), however, no significant differences were observed between the three simulators. A moderate correlation between surgical experience, and physiologic and endocrine stress response was observed (RMSSD: r=-0.31; SDNN: r=-0.42; SD2/SD1 ratio: r = 0.29; Saliva cortisol: r = 0.46; P < 0.05), and a negative moderate correlation to self-reported stress (r=-0.42, P < 0.05). CONCLUSION: Trainees have a significant higher stress response during simulation-training compared to resting conditions, with no difference in stress response between the simulators. Significantly higher cortisol levels were observed on the D-box, indicating that simulation tasks with time pressure stress participants the most. Trainees with more surgical experience are associated with higher physiologic stress measures, but lower self-reported stress scores, demonstrating that surgical experience influences trainees' stress response during simulation-based skills training courses.

Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

Omadacycline for Acute Bacterial Skin and Skin-Structure Infections.

BACKGROUND: Acute bacterial skin and skin-structure infections are associated with substantial morbidity and health care costs. Omadacycline, an aminomethylcycline antibiotic that can be administered once daily either orally or intravenously, is active against pathogens that commonly cause such infections, including antibiotic-resistant strains. METHODS: In this double-blind trial, we randomly assigned adults with acute bacterial skin and skin-structure infections (in a 1:1 ratio) to receive omadacycline (100 mg given intravenously every 12 hours for two doses, then 100 mg given intravenously every 24 hours) or linezolid (600 mg given intravenously every 12 hours). A transition to oral omadacycline (300 mg every 24 hours) or oral linezolid (600 mg every 12 hours) was allowed after 3 days; the total treatment duration was 7 to 14 days. The primary end point was an early clinical response at 48 to 72 hours, defined as survival with a reduction in lesion size of at least 20% without rescue antibacterial therapy. A secondary end point was an investigator-assessed clinical response at the post-treatment evaluation 7 to 14 days after the last dose, with clinical response defined as survival with resolution or improvement in signs or symptoms of infection to the extent that further antibacterial therapy was unnecessary. For both end points, the noninferiority margin was 10 percentage points. RESULTS: In the modified intention-to-treat population, omadacycline (316 patients) was noninferior to linezolid (311 patients) with respect to early clinical response (rate of response, 84.8% and 85.5%, respectively; difference, -0.7 percentage points; 95% confidence interval [CI], -6.3 to 4.9). Omadacycline also was noninferior to linezolid with respect to investigator-assessed clinical response at the post-treatment evaluation in the modified intention-to-treat population (rate of response, 86.1% and 83.6%, respectively; difference, 2.5 percentage points; 95% CI, -3.2 to 8.2) and in the clinical per-protocol population (96.3% and 93.5%, respectively; difference, 2.8 percentage points; 95% CI, -1.0 to 6.9). In both groups, the efficacy of the trial drug was similar for methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections. Adverse events were reported in 48.3% of the patients in the omadacycline group and in 45.7% of those in the linezolid group; the most frequent adverse events in both groups were gastrointestinal (in 18.0% and 15.8% of the patients in the respective groups). CONCLUSIONS: Omadacycline was noninferior to linezolid for the treatment of acute bacterial skin and skin-structure infections and had a similar safety profile. (Funded by Paratek Pharmaceuticals; OASIS-1 ClinicalTrials.gov number, NCT02378480 .).

Omadacycline for Community-Acquired Bacterial Pneumonia.

BACKGROUND: Omadacycline, a new once-daily aminomethylcycline antibiotic agent that can be administered intravenously or orally, reaches high concentrations in pulmonary tissues and is active against common pathogens that cause community-acquired bacterial pneumonia. METHODS: In a double-blind trial, we randomly assigned (in a 1:1 ratio) adults with community-acquired bacterial pneumonia (Pneumonia Severity Index risk class II, III, or IV) to receive omadacycline (100 mg intravenously every 12 hours for two doses, then 100 mg intravenously every 24 hours), or moxifloxacin (400 mg intravenously every 24 hours). A transition to oral omadacycline (300 mg every 24 hours) or moxifloxacin (400 mg every 24 hours), respectively, was allowed after 3 days; the total treatment duration was 7 to 14 days. The primary end point was early clinical response, defined as survival with improvement in at least two of four symptoms (cough, sputum production, pleuritic chest pain, and dyspnea) and no worsening of symptoms at 72 to 120 hours, without receipt of rescue antibacterial therapy. A secondary end point was investigator-assessed clinical response at a post-treatment evaluation 5 to 10 days after the last dose, with clinical response defined as resolution or improvement in signs or symptoms to the extent that further antibacterial therapy was unnecessary. A noninferiority margin of 10 percentage points was used. RESULTS: The intention-to-treat population included 386 patients in the omadacycline group and 388 patients in the moxifloxacin group. Omadacycline was noninferior to moxifloxacin for early clinical response (81.1% and 82.7%, respectively; difference, -1.6 percentage points; 95% confidence interval [CI], -7.1 to 3.8), and the rates of investigator-assessed clinical response at the post-treatment evaluation were 87.6% and 85.1%, respectively (difference, 2.5 percentage points; 95% CI, -2.4 to 7.4). Adverse events that emerged after treatment initiation were reported in 41.1% of the patients in the omadacycline group and 48.5% of the patients in the moxifloxacin group; the most frequent events were gastrointestinal (10.2% and 18.0%, respectively), and the largest difference was for diarrhea (1.0% and 8.0%). Twelve deaths (8 in the omadacycline group and 4 in the moxifloxacin group) occurred during the trial. CONCLUSIONS: Omadacycline was noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia in adults. (Funded by Paratek Pharmaceuticals; OPTIC ClinicalTrials.gov number, NCT02531438 .).

Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial.

BACKGROUND: Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). METHODS: Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. RESULTS: Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. CONCLUSIONS: RZF was safe and efficacious in the treatment of candidemia and/or IC. CLINICAL TRIALS REGISTRATION: NCT02734862.

Shared decision-making in standardized cancer patient pathways in Norway-Narratives of patient experiences.

BACKGROUND: Cancer patient pathways (CPPs) were implemented in Norway in 2015-2017 to advance cancer diagnostics and treatment initiation. The aim of CPPs is to ensure standardized waiting times, but also to strengthen patient participation and shared decision-making. This study investigates how patients enrolled in a CPP experienced shared decision-making. METHODS: This study comprised of 19 individual semistructured interviews with patients who had been enrolled in a CPP at three hospitals in Norway. Twelve patients had breast cancer, four patients had prostate cancer and three patients had malignant melanoma. We analyzed their experiences using a narrative approach. FINDINGS: This study showed how participating in a standardized CPP provided different possibilities for shared decision-making. The patients' narratives of shared decision-making in CPPs included stories from the three cancer diagnoses through the following themes: (1) The predictable safeness of standardizations, (2) the ambivalence of making decisions and (3) opposing standardizations and pushing for action. CONCLUSION: Standardized CPPs provided patients with predictability and safety. Shared decision-making was possible when the cancer diagnoses supported preference-sensitive treatment options. Balancing standardizations with individualized care is necessary to facilitate patient participation in CPPs, and the possibility of shared decision-making needs to be discussed for each specific CPP. PATIENT OR PUBLIC CONTRIBUTION: A service user representative from the Norwegian Cancer Society participated in designing this study.

Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities.

BACKGROUND: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. CONCLUSIONS: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

The generality of the GUGA MRCI approach in COLUMBUS for treating complex quantum chemistry.

The core part of the program system COLUMBUS allows highly efficient calculations using variational multireference (MR) methods in the framework of configuration interaction with single and double excitations (MR-CISD) and averaged quadratic coupled-cluster calculations (MR-AQCC), based on uncontracted sets of configurations and the graphical unitary group approach (GUGA). The availability of analytic MR-CISD and MR-AQCC energy gradients and analytic nonadiabatic couplings for MR-CISD enables exciting applications including, e.g., investigations of π-conjugated biradicaloid compounds, calculations of multitudes of excited states, development of diabatization procedures, and furnishing the electronic structure information for on-the-fly surface nonadiabatic dynamics. With fully variational uncontracted spin-orbit MRCI, COLUMBUS provides a unique possibility of performing high-level calculations on compounds containing heavy atoms up to lanthanides and actinides. Crucial for carrying out all of these calculations effectively is the availability of an efficient parallel code for the CI step. Configuration spaces of several billion in size now can be treated quite routinely on standard parallel computer clusters. Emerging developments in COLUMBUS, including the all configuration mean energy multiconfiguration self-consistent field method and the graphically contracted function method, promise to allow practically unlimited configuration space dimensions. Spin density based on the GUGA approach, analytic spin-orbit energy gradients, possibilities for local electron correlation MR calculations, development of general interfaces for nonadiabatic dynamics, and MRCI linear vibronic coupling models conclude this overview.

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial.

BACKGROUND: Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit. OBJECTIVE: This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation. STUDY DESIGN: This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle. RESULTS: Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40]. CONCLUSION: In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

Areca Nut and Betel Quid Control Interventions: Halting the Epidemic.

Background: Areca nut (AN) and betel quid (BQ) are classified as Group 1 carcinogens. There are approximately 600 million AN/BQ users globally; the majority of users live in the Asia-Pacific region which, correspondingly, has the highest rates of oral cancer. Despite significant disease burden associated with AN/BQ use, there have been no systematic reviews of interventions to reduce product use. Objectives: To analyze interventions that prevent use of AN/BQ, present a basis for a future systematic review on the topic, and provide decision makers with examples of strategies that have demonstrated reduced AN/BQ use. Methods: To identify publications, we searched the literature using terms for AN/BQ and related synonyms in three databases: PubMed, Embase, and Scopus. Interventions that prevent AN/BQ use, that are published in English and that provide original data analysis, were included in this review. Interventions focused primarily on disease outcomes e.g. oral cancers (secondary prevention) were excluded. Results: Our search revealed 21 interventions targeting AN/BQ use between 1990 and 2018. Strategies include product bans, media campaigns, education, cessation, and taxation at individual and population levels, with varying evidence of impact. While these studies yielded some novel and promising findings, particularly regarding the impact of product bans, mass media campaigns, and cessation interventions, research on interventions specific to AN/BQ use remains limited. Conclusions: We have assessed published interventions that reduce AN/BQ use and identified future research priorities. These findings can be used to develop evidence-based interventions and help guide policymakers in implementing evidence-based policy to regulate these products.

Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: 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). METHODS: We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM). RESULTS: 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. CONCLUSIONS: 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.

Omadacycline for Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: Within the last decade, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a frequent cause of purulent skin and soft tissue infections. New therapeutic options are being investigated for these infections. METHODS: We report an integrated analysis of 2 randomized, controlled studies involving omadacycline, a novel aminomethylcycline, and linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Omadacycline in Acute Skin and Skin Structure Infections Study 1 (OASIS-1) initiated patients on intravenous omadacycline or linezolid, with the option to transition to an oral formulation after day 3. OASIS-2 was an oral-only study of omadacycline versus linezolid. RESULTS: In total, 691 patients received omadacycline and 689 patients received linezolid. Infection types included wound infection in 46.8% of patients, cellulitis/erysipelas in 30.5%, and major abscess in 22.7%. Pathogens were identified in 73.2% of patients. S. aureus was detected in 74.7% and MRSA in 32.4% of patients in whom a pathogen was identified. Omadacycline was noninferior to linezolid using the Food and Drug Administration primary endpoint of early clinical response (86.2% vs 83.9%; difference 2.3, 95% confidence interval -1.5 to 6.2) and using the European Medicines Agency primary endpoint of investigator-assessed clinical response at the posttreatment evaluation. Clinical responses were similar across different infection types and infections caused by different pathogens. Treatment-emergent adverse events, mostly described as mild or moderate, were reported by 51.1% of patients receiving omadacycline and 41.2% of those receiving linezolid. CONCLUSIONS: Omadacycline was effective and safe in ABSSSI. CLINICAL TRIALS REGISTRATION: NCT02378480 and NCT02877927.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial.

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.

Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial.

IMPORTANCE: New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. OBJECTIVE: To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. INTERVENTIONS: Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). MAIN OUTCOMES AND MEASURES: The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. RESULTS: Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). CONCLUSIONS AND RELEVANCE: Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.