30 research outputs found
Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents
ABSTRACT We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.
Maternal Administration of Solithromycin, a New, Potent, Broad-Spectrum Fluoroketolide Antibiotic, Achieves Fetal and Intra-Amniotic Antimicrobial Protection in a Pregnant Sheep Model
Solithromycin (CEM-101) is a new antibiotic that is highly potent against Ureaplasma and Mycoplasma spp. and active against many other antibiotic-resistant organisms. We have explored the maternal-amniotic-fetal pharmacokinetics of CEM-101 in a pregnant sheep model to assess its potential for treating intrauterine and antenatal infection. Chronically catheterized pregnant ewes (n = 6 or 7) received either a single maternal intravenous (i.v.) infusion of CEM-101 (10 mg/kg of body weight), a single intra-amniotic (i.a.) injection (1.4 mg/kg of estimated fetal weight), or a combined i.v. and i.a. dose. Maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) samples were taken via catheter at intervals of 0 to 72 h postadministration, and concentrations of solithromycin and its bioactive polar metabolites (N-acetyl [NAc]–CEM-101 and CEM-214) were determined. Following maternal i.v. infusion, peak CEM-101 concentrations in MP, FP, and AF were 1,073, 353, and 214 ng/ml, respectively, representing a maternal-to-fetal plasma transfer efficiency of 34%. A single maternal dose resulted in effective concentrations (>30 ng/ml) in MP, FP, and AF sustained for >12 h. NAc–CEM-101 and CEM-214 exhibited delayed accumulation and clearance in FP and AF, resulting in an additive antimicrobial effect (>48 h). Intra-amniotic solithromycin injection resulted in elevated (∼50 μg/ml) and sustained CEM-101 concentrations in AF and significant levels in FP, although the efficiency of amniotic-to-fetal transfer was low (∼1.5%). Combined i.v. and i.a. administration resulted in primarily additive concentrations of CEM-101 in all three compartments. Our findings suggest that CEM-101 may provide, for the first time, an effective antimicrobial approach for the prevention and treatment of intrauterine infection and early prevention of preterm birth
Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure
Background
The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of ‘responsible’ antibiotic use.
Objectives
To identify consensually validated quantity metrics for antibiotic use in the outpatient setting.
Methods
First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics.
Results
A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use.
Conclusions
A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use
Conditions in the intestine affecting in vitro growth and enterotoxin production of Vibrio cholerae
Antibiotics in late clinical development
AbstractMost pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections caused by multi-drug resistant bacteria, because the return on investment has been mostly negative for antibiotics that received marketing approved in the last few decades. In contrast, a few small companies have taken on this challenge and are developing new antibiotics. This review describes those antibiotics in late-stage clinical development. Most of them belong to existing antibiotic classes and a few with a narrow spectrum of activity are novel compounds directed against novel targets. The reasons for some of the past failures to find new molecules and a path forward to help attract investments to fund discovery of new antibiotics are described
Molecular Characterization of Off-Target Activities of Telithromycin: a Potential Role for Nicotinic Acetylcholine Receptors
Erratum for Piccinelli et al., "In Vitro Activity of Solithromycin against Erythromycin-Resistant Streptococcus agalactiae"
Activities of Combinations of Antistaphylococcal Antibiotics with Fusidic Acid against Staphylococcal Biofilms in In Vitro Static and Dynamic Models
Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral fusidic acid is currently being redeveloped in the United States for skin, skin structure, and orthopedic infections, in which biofilms play a major role. The aim of this study was to examine the activity of fusidic acid alone or combined with other antistaphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static and dynamic models (microtiter plates and a CDC reactor) exposed to clinically relevant concentrations. In microtiter plates, antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking the free-drug human maximum concentration of drug in serum (Cmax), the combination of fusidic acid with linezolid, daptomycin, or vancomycin resulted in increased activity against 4 to 5 strains, while the combination with doxycycline, rifampin, or moxifloxacin increased activity against 1 to 3 strains only. In the CDC reactor, biofilms were grown under constant flow and antibiotic concentrations decreased over time according to human elimination rates. A bactericidal effect was obtained when fusidic acid was combined with daptomycin or linezolid, but not with vancomycin. The higher tolerance of biofilms to antibiotics in the CDC reactor is probably attributable to the more complex architecture they adopt when growing under constant flow. Because biofilms grown in the CDC reactor are considered more similar to those developing in vivo, the data support further testing of combinations of fusidic acid with daptomycin or linezolid in models pertinent to chronic skin, skin structure, or orthopedic infections