The positive and negative consequences of stress and its relationship with coping in medical students: A qualitative study.

Rates of mental health problems among medical students have prompted efforts to reduce stress during medical training. However, stress can be motivating and is a feature of clinical work. This qualitative study explores what makes an experience stressful, and how medical students respond to such experiences. In-depth interviews were conducted with a purposive sample of 15 medical students. Experiences were distressing when they threatened students' self-perception, goals or coping mechanisms, or when they reminded the student of distressing past events. Moderate stress was motivating and could build resilience. Students selected coping mechanisms based on their availability, acceptability, likely outcome and their previous experience of using these mechanisms. Social support, extra-curricular activities and exercise were helpful. High levels of distress, poor self-esteem and course factors, including remote placements, impaired engagement with coping strategies. Perception of stressors as being insurmountable or beyond one's control, led to increasing distress and the adoption of avoidant coping strategies. University strategies need to consider the beneficial effects of stress and seek to bolster coping resources as well as minimising unnecessary sources of stress.

Synthetic cannabinoid receptor agonists are monoamine oxidase-A selective inhibitors.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of 'monoaminergic toxicity' for users of MAOIs and some SCRA use. We have studied the potential for SCRA-mediated inhibition of MAO-A and MAO-B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO-A-specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA 'head' group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA-specific.

Clinical Efficacy of Patients With Secondary Bacteremia Treated With Omadacycline: Results From Phase 3 Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia Studies.

In this post hoc analysis of the 63 patients with secondary bacteremia enrolled in the 3 omadacycline phase 3 studies of acute bacterial skin/skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), we determined that omadacycline is a viable therapeutic option for appropriate patients with secondary bacteremia.

Efficacy of Omadacycline Versus Moxifloxacin in the Treatment of Community-Acquired Bacterial Pneumonia by Disease Severity: Results From the OPTIC Study.

BACKGROUND: Severity/mortality risk scores and disease characteristics may assist in deciding whether patients with community-acquired bacterial pneumonia (CABP) require outpatient treatment or hospitalization. The phase 3 OPTIC (Omadacycline for Pneumonia Treatment In the Community) study enrolled patients with Pneumonia Outcomes Research Team (PORT) risk class II-IV. Omadacycline demonstrated noninferiority to moxifloxacin in adults with CABP, at early clinical response (ECR) and posttreatment evaluation (PTE). We assessed efficacy of omadacycline versus moxifloxacin in these patients based on disease severity. METHODS: Patients were randomized 1:1 to receive intravenous (IV) omadacycline (100 mg every 12 hours for 2 doses followed by 100 mg daily [q24h], with optional transition to omadacycline 300 mg orally q24h after 3 days of IV treatment) or moxifloxacin IV 400 mg q24h (with optional transition to 400 mg orally q24h after 3 days of IV treatment). Total treatment duration was 7-14 days. We compared rates of early clinical success (72-120 hours after first dose) and investigator-assessed clinical success at PTE (5-10 days after last dose) in subgroups based (1) on severity/mortality risk scores (PORT, CURB-65, systemic inflammatory response syndrome, quick Sequential [Sepsis-related] Organ Failure Assessment, modified ATS, SMART-COP) and (2) on presence of baseline radiographic characteristics, chronic obstructive pulmonary disease (COPD)/asthma, or bacteremia. RESULTS: Altogether, 774 patients (omadacycline, n = 386; moxifloxacin, n = 388) were randomized. Clinical success rates (ECR/PTE) were similar between treatment groups (across all subgroups). Efficacy across treatment groups was similar in patients with baseline radiographic characteristics or COPD/asthma, but moxifloxacin had higher clinical success rates in patients with bacteremia. CONCLUSIONS: Efficacy of omadacycline was similar to that of moxifloxacin, regardless of disease severity/mortality risk and disease characteristics.

Omadacycline vs moxifloxacin in adults with community-acquired bacterial pneumonia.

OBJECTIVE: Community-acquired bacterial pneumonia (CABP) is a major clinical burden worldwide. In the phase III OPTIC study (NCT02531438) in CABP, omadacycline was found to be non-inferior to moxifloxacin for investigator-assessed clinical response (IACR) at post-treatment evaluation (PTE, 5-10 days after last dose). This article reports the efficacy findings, as specified in the European Medicines Agency (EMA) guidance. METHODS: Patients were randomized 1:1 to omadacycline 100 mg intravenously (every 12 h for two doses, then every 24 h) with optional transition to 300 mg orally after 3 days, or moxifloxacin 400 mg intravenously (every 24 h) with optional transition to 400 mg orally after 3 days. The total treatment duration was 7-14 days. The primary endpoint for EMA efficacy analysis was IACR at PTE in patients with Pneumonia Patient Outcomes Research Team (PORT) risk class III and IV. RESULTS: In total, 660 patients were randomized as PORT risk class III and IV. Omadacycline was non-inferior to moxifloxacin at PTE. The clinical success rates were 88.4% and 85.2%, respectively [intent-to-treat population; difference 3.3; 97.5% confidence interval (CI) -2.7 to 9.3], and 92.5% and 90.5%, respectively (clinically evaluable population; difference 2.0; 97.5% CI 3.2-7.4). Clinical success rates with omadacycline and moxifloxacin were similar against identified pathogens and across key subgroups. CONCLUSIONS: Omadacycline was non-inferior to moxifloxacin for IACR at PTE, with high clinical success across pathogen types and patient subgroups.

The Effect of Verapamil, a P-gp Inhibitor, on the Pharmacokinetics, Safety, and Tolerability of Omadacycline in Healthy Adults: A Phase I, Open-Label, Single-Sequence Study.

BACKGROUND: Omadacycline is a semisynthetic aminomethylcycline antibacterial derived from the tetracycline class. It is approved in the USA to treat adults with acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia. OBJECTIVES: This phase I, open-label study evaluated the effect of a potential drug-drug interaction of verapamil-a known P-glycoprotein (P-gp) inhibitor-with omadacycline on the pharmacokinetic profile of omadacycline in healthy adults. The safety and tolerability of omadacycline taken alone and in combination with verapamil were also evaluated. METHODS: A single oral dose of 240 mg verapamil extended release (ER) was given 2 h prior to a single oral dose of 300 mg omadacycline. RESULTS: Ten (83.3%) of the 12 participants enrolled in the study completed the study, and all enrolled participants were included in the safety and pharmacokinetic populations. An increase of 14-25% in systemic exposure to omadacycline was seen when administered following a single oral dose of 240 mg verapamil ER compared with omadacycline alone, as measured by the area under the concentration-time curve (AUC) from time 0 to 24 h after dosing (AUC0-24), from time 0 to the last quantifiable concentration (AUC0-t), from time 0 extrapolated to infinity (AUC0-inf), and by maximum (peak) observed plasma concentration (Cmax). Treatment-emergent adverse events were reported by one participant (nausea and headache). CONCLUSIONS: These findings suggest that, if given with a known P-gp inhibitor, dose adjustment of oral omadacycline is not warranted based on small increases in absorption and systemic exposure. No safety signals were identified.

Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial.

BACKGROUND: Pathogen resistance and safety concerns limit oral antibiotic options for the treatment of acute bacterial skin and skin structure infections (ABSSSI). We aimed to compare the efficacy and safety of once-daily oral omadacycline, an aminomethylcycline antibiotic, versus twice-daily oral linezolid for treatment of ABSSSI. METHODS: In this phase 3, double-blind, randomised, non-inferiority study, eligible adults with ABSSSI at 33 sites in the USA were randomly assigned (1:1) to receive omadacycline (450 mg orally every 24 h over the first 48 h then 300 mg orally every 24 h) or linezolid (600 mg orally every 12 h) for 7-14 days. Randomisation was done via an interactive response system using a computer-generated schedule, and stratified by type of infection (wound infection, cellulitis or erysipelas, or major abscess) and receipt (yes or no) of allowed previous antibacterial treatment. Investigators, funders, and patients were masked to treatment assignments. Primary endpoints were early clinical response, 48-72 h after first dose, in the modified intention-to-treat (mITT) population (randomised patients without solely Gram-negative ABSSSI pathogens at baseline), and investigator-assessed clinical response at post-treatment evaluation, 7-14 days after the last dose, in the mITT population and clinically evaluable population (ie, mITT patients who had a qualifying infection as per study-entry criteria, received study drug, did not receive a confounding antibiotic, and had an assessment of outcome during the protocol-defined window). The safety population included randomised patients who received any amount of study drug. We set a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, NCT02877927, and is complete. FINDINGS: Between Aug 11, 2016, and June 6, 2017, 861 participants were assessed for eligibility. 735 participants were randomly assigned, of whom 368 received omadacycline and 367 received linezolid. Omadacycline (315 [88%] of 360) was non-inferior to linezolid (297 [83%] of 360) for early clinical response (percentage-point difference 5·0, 95% CI -0·2 to 10·3) in the mITT population. For investigator-assessed clinical response at post-treatment evaluation, omadacycline was non-inferior to linezolid in the mITT (303 [84%] of 360 vs 291 [81%] of 360; percentage-point difference 3·3, 95% CI -2·2 to 9·0) and clinically evaluable (278 [98%] of 284 vs 279 [96%] of 292; 2·3, -0·5 to 5·8) populations. Mild to moderate nausea and vomiting were the most frequent treatment-emergent adverse events in omadacycline (111 [30%] of 368 and 62 [17%] of 368, respectively) and linezolid (28 [8%] of 367 and 11 [3%] of 367, respectively) groups. INTERPRETATION: Once-daily oral omadacycline was non-inferior to twice-daily oral linezolid in adults with ABSSSI, and was safe and well tolerated. Oral-only omadacycline represents a new treatment option for ABSSSI, with potential for reduction in hospital admissions and cost savings. FUNDING: Paratek Pharmaceuticals.

Early Clinical Response in Community-acquired Bacterial Pneumonia: From Clinical Endpoint to Clinical Practice.

BACKGROUND: Early clinical response (ECR) is a new endpoint to determine whether a drug should be approved for community-acquired bacterial pneumonia in the United States. The Omadacycline for Pneumonia Treatment In the Community (OPTIC) phase III study demonstrated noninferiority of omadacycline to moxifloxacin using this endpoint. This study describes the performance of the ECR endpoint and clinical stability relative to a posttreatment evaluation (PTE) of clinical success. METHODS: ECR was defined as symptom improvement 72-120 hours after the first dose of study drug (ECR window), no use of rescue antibiotics, and patient survival. Clinical success at PTE was an investigator assessment of success. Clinical stability was defined based on vital sign stabilization, described in the American Thoracic Society and Infectious Diseases Society of America community-acquired pneumonia treatment guidelines. RESULTS: During the ECR window, ECR was achieved in 81.1% and 82.7% of omadacycline and moxifloxacin patients, respectively. Similar numbers of patients achieved clinical stability in each treatment group (omadacycline 74.6%, moxifloxacin 77.6%). The proportion of patients with improved symptoms who were considered clinically stable increased across the ECR window (69.2-77.6% for omadacycline; 68.0-79.7% for moxifloxacin). There was high concordance (>70%) and high positive predictive value (>90%) of ECR and clinical stability with overall clinical success at PTE. CONCLUSIONS: Omadacycline was noninferior to moxifloxacin, based on a new ECR endpoint. Clinical stability was similarly high when measured in the same time frame as ECR. Both ECR and clinical stability showed high concordance and high positive predictive value with clinical success at PTE. CLINICAL TRIALS REGISTRATION: NCT02531438.

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.

Pharmacokinetics, Safety, and Clinical Outcomes of Omadacycline in Women with Cystitis: Results from a Phase 1b Study.

Omadacycline, an aminomethylcycline antibiotic, is approved as once-daily intravenous (i.v.) and oral (p.o.) monotherapy for acute bacterial skin and skin structure infections and for community-acquired bacterial pneumonia, and it is under development for treatment of urinary tract infection (UTI). This is a phase 1b, randomized, open-label study of omadacycline in women with cystitis (defined as UTI symptoms and a positive urine leukocyte esterase test). Patients received omadacycline for 5 days (group 1: 200 mg intravenously on day 1, then 300 mg orally every 24 h [q24h]; group 2: 300 mg orally every 12 h [q12h] on day 1, then 300 mg orally q24h; group 3: 450 mg orally q12h on day 1, then 450 mg orally q24h). Blood and urine samples were collected over 5 days. Investigator-assessed clinical response was determined at end of treatment (EOT; day 6) and posttreatment evaluation (PTE; 5 to 9 days after last dosing). A total of 31 women were treated. At steady state (day 5), the range of mean omadacycline urine concentrations over 24 h across the groups was 17.94 to 48.12 µg/ml. The most common treatment-emergent adverse events were gastrointestinal (including nausea [60% to 73%] and vomiting [20% to 40%]) and were generally mild and transient. Investigator-determined clinical success was observed in 94% and 84% of patients at EOT and PTE, respectively, with similar results across groups. A favorable microbiological response at PTE was observed in 78% of patients who had a baseline pathogen. Omadacycline is partially excreted in urine and appears to be safe and well tolerated. These preliminary results indicate that omadacycline warrants further evaluation in larger controlled UTI studies.

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 .).

Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple-Dose Regimens.

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ∼50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

Pharmacokinetics and Safety of Omadacycline in Subjects with Impaired Renal Function.

Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 µg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 µg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 µg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 µg/ml when it was administered after dialysis and 2.33 µg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 µg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects.

The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0-24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0-24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0-12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0-12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

Effect of Food on the Bioavailability of Omadacycline in Healthy Participants.

Omadacycline is a first-in-class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, open-label, 4-period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ≥6-hour fast, (B) high-fat, nondairy meal 4 hours before dosing, (C) high-fat, nondairy meal 2 hours before dosing, and (D) high-fat meal containing dairy 2 hours before dosing. Participants received a single 300-mg oral dose of omadacycline during each treatment period; periods were separated by ≥5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least-squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty-one participants were included in the PK analysis. Fasted AUC0-∞ , AUC0-t , and AUC0-24 were 10.2, 7.2, and 7.2 µg·h/mL, respectively, and Cmax was 0.6 µg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300-mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.

Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis.

OBJECTIVE: Methylnaltrexone, a selective peripherally acting mu-opioid receptor antagonist, effectively treats opioid-induced constipation (OIC) in patients with advanced illness and shows efficacy in patients with chronic nonmalignant pain. The objective was to identify patients who achieved maximal treatment effect based on response to initial four methylnaltrexone doses. DESIGN: A post hoc analysis of a randomized, double-blind, placebo-controlled study evaluating patients with OIC and chronic nonmalignant pain who received 12 mg subcutaneous methylnaltrexone daily for 4 weeks was performed to determine if response to the first four methylnaltrexone doses predicted overall response during the study. Patients receiving ≥8 doses were included. OUTCOME MEASURES: Patients having ≥3 rescue-free bowel movements (RFBMs)/week; change from baseline in RFBMs/week; percentage of doses with RFBMs within 4 hours after dosing. RESULTS: Of 137 patients, 58 patients (42.3%) had RFBMs after ≥2 of four doses. Among those with response to ≥2 of four doses, 81% had ≥3 RFBMs/week vs. 43% for those with response to <2 of four (P < 0.0001). Those with RFBMs after ≥2 of first four doses averaged 4.8 RFBMs/week vs. 2.0 RFBMs/week for those with <2 of four (P < 0.0001). Percentage of subsequent injections resulting in RFBMs within 4 hours was 45.9 ± 27.6 for those with response to ≥2 of four doses vs. 17.1 ± 19.1 for those with response to <2 of four (P < 0.0001). Abdominal pain was the most frequently reported adverse event. CONCLUSION: Early response to ≥2 of first four doses of methylnaltrexone identified patients who demonstrated a particularly robust effect of treatment over the duration of use.

Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.

UNLABELLED: Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups. PERSPECTIVE: We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.

Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms.

BACKGROUND: Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia. OBJECTIVES: To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores. METHODS: A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate. RESULTS: A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant. CONCLUSION: The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores.

Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder.

OBJECTIVE: To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD). RESEARCH DESIGN AND METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. The primary efficacy measure was the HAM-D(17). Changes from baseline in HAM-D(17) scores were analyzed using analysis of covariance. The final on-therapy evaluation was the primary endpoint for efficacy analyses, using last-observation-carried-forward data. MAIN OUTCOMES MEASURES AND RESULTS: The intent-to-treat population included 447 patients. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018); the 100-mg dose group (-11.0) did not achieve statistical significance (p=0.065). The 100-mg dose group experienced significant improvements compared with placebo on several secondary efficacy measures, including the 6-item Hamilton Depression Rating Scale (p=0.038) and the Visual Analog Scale-Pain Intensity total score (p=0.041). Both desvenlafaxine doses were generally well-tolerated. The most common adverse events (incidence > or =10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness. CONCLUSIONS: These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. The significant findings on secondary measures support the efficacy of desvenlafaxine 100 mg, as seen in other trials. Conclusions may be limited by the exclusion of MDD patients with comorbid conditions and the short-term desvenlafaxine treatment duration.