Update on activity of dalbavancin and comparators against clinical isolates of Gram-positive pathogens from Europe and Russia (2017-2018), and on clonal distribution of MRSA.

BACKGROUND: Gram-positive pathogens remain a major cause of healthcare- and community-associated infections. In particular, the dissemination of methicillin-resistant staphylococci, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), have significantly reduced the therapeutic options, making the management of these infections even more challenging. Dalbavancin is a second-generation lipoglycopeptide approved for the treatment of moderate to severe acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms, showing a bactericidal effect and a low propensity towards the selection of resistance over time. AIM: To evaluate the antimicrobial activity of dalbavancin and other comparators against recent clinical isolates of Gram-positive pathogens obtained from different sources and from several European countries, including countries of Southern and Eastern Europe, and Russia, where resistance rates are typically high. This study also aimed to describe the clonal relationship of MRSA strains circulating in Southern and Eastern Europe and Russia. RESULTS: In total, 1478 isolates were collected. Study results demonstrated the excellent and stable activity of dalbavancin against Gram-positive microorganisms, including MRSA. Interestingly, dalbavancin has retained unaltered minimum inhibitory concentration (MIC50 and MIC90) values over the years, and seems to have a low propensity towards the selection of resistance. CONCLUSIONS: These data support the potential efficacy of dalbavancin against Gram-positive bacteria and uncommon Gram-positive pathogens in patients with ABSSSIs. Of note, few coagulase-negative staphylococci (CoNS) isolates were resistant to dalbavancin and susceptible to vancomycin, highlighting the importance of testing for susceptibility to dalbavancin before its administration for CoNS infections.

Impact of Lurasidone and Other Antipsychotics on Body Weight: Real-World, Retrospective, Comparative Study of 15,323 Adults with Schizophrenia.

PURPOSE: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥7%) weight changes. PATIENTS AND METHODS: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019. RESULTS: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥7% weight loss was significantly greater with lurasidone versus all antipsychotics (p<0.05), except ziprasidone. CONCLUSION: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.

Prulifloxacin Effectiveness in Moderate-to-Severe Acute Exacerbations of Chronic Bronchitis: Α Noninterventional, Multicentre, Prospective Study in Real-Life Clinical Practice-The "AIOLOS" Study.

Real-world evidence regarding the effectiveness of prulifloxacin in the treatment of acute exacerbations of chronic bronchitis (AECB) is limited. Therefore, this study aimed to assess the rates and time to symptom improvement and resolution in patients with moderate-to-severe AECB who were given prulifloxacin in the routine care in Greece. This observational, prospective study, conducted in 15 hospital-based clinics across Greece, enrolled outpatients >40 years old, with moderate-to-severe AECB, for whom the physician had decided to initiate treatment with prulifloxacin. Data were collected at prulifloxacin onset (baseline), 7-10 days after baseline, and at least 28 days after therapy completion. Between 23 November 2015 and 27 January 2018, 305 patients (males: 76.4%; mean (standard deviation) (SD) age: 69.7 (9.8) years; Anthonisen type I/II: 94.8%; chronic bronchitis duration >10 years: 24.9%) were consecutively enrolled. At baseline, >80% had increased sputum volume, cough, dyspnoea, and sputum purulence. Prulifloxacin improved symptoms in 99.7% of the patients after a mean (SD) of 5.47 (3.57) days, while symptoms fully recovered after a mean (SD) of 10.22 (5.00) days in 95.4%. The rate of adverse events related to prulifloxacin was 1.3% (serious: 0.7%). In the routine care in Greece, prulifloxacin was highly effective in moderate-to-severe AECB, while displaying a predictable safety profile.

Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin.

OBJECTIVES: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. MATERIALS AND METHODS: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. RESULTS: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. CONCLUSION: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study.

BACKGROUND: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. OBJECTIVE: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. METHODS: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety. RESULTS: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. CONCLUSIONS: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. CLINICAL TRIAL REGISTRATION: NCT03202979, date of registration: 29/06/2017.

A novel rizatriptan oral gel formulation: Bioavailability and bioequivalence.

OBJECTIVES: To establish the relative bioavailability between a newly developed oral gel and a marketed oral lyophilisate-containing rizatriptan benzoate. MATERIALS AND METHODS: A total of 47 out of 48 healthy subjects, aged 34 ± 10 (SD) years and body mass index 24.7 ± 3.3 (SD) kg/m2 completed this single-center, open-label, randomized, 2-period cross-over trial with single-dose fasted administrations. Intake of both investigational products was separated by a washout period of at least 6 days. For pharmacokinetic evaluation, blood samples were withdrawn until 24 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for the determination of rizatriptan in plasma. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Adverse events (AEs) were descriptively analyzed in the study population. Palatability of the new product was investigated based on a questionnaire. RESULTS: The geometric means of the parameters related with the extent of total exposure, i.e., AUC0-tlast and AUC0-∞, were 60.285 ng × h/mL and 60.865 ng × h/mL for test and 62.729 ng × h/mL and 63.312 ng × h/mL for reference, respectively. The geometric means of the peak exposure, i.e., Cmax, were 21.262 ng/mL for test and 21.447 ng/mL for reference. The point estimates (PEs) of the test/reference (T/R) adjusted geometric mean ratios of AUC0-tlast, Cmax, and AUC0-∞ (secondary parameter) were 96.11%, 99.12%, and 96.15%, respectively, and all of them showed 90% confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 13 subjects experienced 20 AEs during the trial; the most frequently reported AEs were headache (5 cases) and dizziness (3 cases). No AEs of severe intensity were reported. Palatability assessment of the new product provided sufficient data to discuss its acceptability. CONCLUSION: Bioequivalence was demonstrated in terms of rate and extent of absorption after administration of test and reference products. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. Based on ratings by the subjects no relevant problem concerning acceptability of the new formulation in particular regarding taste and smell is to be expected.

Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

New Insights on the Pharmacokinetics of Ulifloxacin After Administration of Prulifloxacin in Patients with Mild, Moderate and Severe Renal Impairment.

BACKGROUND: The antibacterial agent prulifloxacin, a prodrug of ulifloxacin, is indicated in the treatment of acute lower urinary tract infections, acute exacerbation of chronic bronchitis and acute bacterial rhinosinusitis. OBJECTIVE: We aimed to provide new insights on the pharmacokinetics (PK) of ulifloxacin in patients with different degrees of renal impairment. METHODS: A two-site, international, open-label, parallel-group, single- and repeated-dose study was performed. The drug was administered as a single dose of 600 mg to subjects with normal renal function and patients with mild, moderate and severe renal impairment. Subsequently, the same dose was administered daily for 7 days to subjects with normal renal function and patients with mild and moderate renal impairment, while a dose of 300 mg was administered daily for 7 days to patients with severe renal impairment. Plasma and urine ulifloxacin levels were measured. Complete safety evaluation was performed. RESULTS: Exposure to ulifloxacin increased as renal function decreased due to a lower ulifloxacin clearance. Ulifloxacin PK were significantly changed only in patients with severe renal impairment. The amount of ulifloxacin excreted in urine over a 24-h dosing period was similar in subjects with normal renal function and patients with mild impaired renal function, but lower in those with moderate and severe renal impairment. CONCLUSION: Our data show that prulifloxacin is a safe quinolone and is well tolerated in both subjects with normal renal function and patients with impaired renal function, requiring a minimal dosage adjustment only in patients with severe renal impairment.

A randomized, double-blind, placebo-controlled trial of paracetamol and ketoprofren lysine salt for pain control in children with pharyngotonsillitis cared by family pediatricians.

BACKGROUND: To evaluate the analgesic effect and tolerability of paracetamol syrup compared to placebo and ketoprofen lysine salt in children with pharyngotonsillitis cared by family pediatricians. METHODS: A double-blind, randomized, placebo-controlled trial of a 12 mg/kg single dose of paracetamol paralleled by open-label ketoprofren lysine salt sachet 40 mg. Six to 12 years old children with diagnosis of pharyngo-tonsillitis and a Children's Sore Throat Pain (CSTP) Thermometer score > 120 mm were enrolled. Primary endpoint was the Sum of Pain Intensity Differences (SPID) of the CSTP Intensity scale by the child. RESULTS: 97 children were equally randomized to paracetamol, placebo or ketoprofen. Paracetamol was significantly more effective than placebo in the SPID of children and parents (P < 0.05) but not in the SPID reported by investigators, 1 hour after drug administration. Global evaluation of efficacy showed a statistically significant advantage of paracetamol over placebo after 1 hour either for children, parents or investigators. Patients treated in open fashion with ketoprofen lysine salt, showed similar improvement in pain over time. All treatments were well-tolerated. CONCLUSIONS: A single oral dose of paracetamol or ketoprofen lysine salt are safe and effective analgesic treatments for children with sore throat in daily pediatric ambulatory care.