Cefepime is an antibiotic with a broad spectrum of antimicrobial activity. However, this antibiotic has several side effects and a high degradation rate. For this reason, the preparation and ...characterization of new liposomes that are able to encapsulate this antibiotic seem to be an important research line in the pharmaceutical industry. Anionic and cationic liposomes were prepared and characterized. All cationic structures contained the same cationic surfactant,
,
,
-triethyl-
-(12-naphthoxydodecyl)ammonium. Results showed a better encapsulation-efficiency percentage (EE%) of cefepime in liposomes with phosphatidylcholine and cholesterol than with 1,2-dioleoyl-
-glycero-3-phosphoethanolamine (DOPE). The presence of cholesterol and the quantity of egg-yolk phospholipid in the liposome increased the encapsulation percentage. The bactericidal activity against
of cefepime loaded into liposomes with phosphatidylcholine was measured. The inhibitory zone in an agar plate for free cefepime was similar to that obtained for loaded cefepime. The growth-rate constant of
culture was also measured in working conditions. The liposome without any antibiotic exerted no influence in such a rate constant. All obtained results suggest that PC:CH:12NBr liposomes are biocompatible nanocarriers of cefepime that can be used in bacterial infections against
with high inhibitory activity.
Temocillin is an old antimicrobial that is resistant to hydrolysis by ESBLs but has variable activity against carbapenemase-producing Enterobacteriaceae. The current EUCAST susceptibility breakpoints ...for Enterobacterales are set at ≤16 mg/L (susceptible with increased exposure) based on a dose of 2 g q8h, but there is limited information on the efficacy of this dose against temocillin-susceptible carbapenemase-producing Klebsiella pneumoniae isolates.
To evaluate the efficacy of this dose using a hollow-fibre infection model (HFIM) against six KPC-2-producing clinical isolates of K. pneumoniae.
The isolates were characterized by WGS and temocillin susceptibility was determined using standard and high inoculum temocillin. Mutant frequencies were estimated and temocillin activity was tested in time-kill assays and in the HFIM. At standard conditions, three of the isolates were classified as susceptible (MIC ≤ 16 mg/L) and three as resistant (MIC > 16 mg/L). The HFIM was performed over 3 days to mimic human-like pharmacokinetics of 2 g q8h. Bacterial counts were performed by plating on Mueller-Hinton agar (MHA) and MHA containing 64 mg/L temocillin to detect resistant subpopulations.
All isolates showed a reduction in bacterial population of at least 3 log cfu/mL within the first 8 h of simulated treatment in the hollow-fibre assay. Regrowth was observed for the three resistant isolates and one of the susceptible ones. The MIC value for these isolates was higher by at least two dilutions compared with their initial values.
These data suggest that an optimized pharmacokinetic regimen may be of clinical interest for the treatment of KPC-2-producing K. pneumoniae susceptible to temocillin. These data showed activity of temocillin against KPC-2-producing K. pneumoniae susceptible to temocillin; however, a dose of 2g q8h administered over 30 min may be inadequate to prevent the emergence of resistant variants.
Background
Therapeutic drug monitoring of infliximab levels in patients with inflammatory bowel disease (IBD) optimizes patients’ treatment. The reference technique is based on enzyme-linked ...immunosorbent assay (ELISA) although point of care (POC) assays are being developed.
Aims
To assess the performance of a new rapid immunochromatographic POC assay (Promonitor Quick IFX) compared with ELISA technique to measure infliximab levels in patients with IBD.
Methods
A prospective, observational, unicentric study was performed on capillary blood samples from patients with IBD before infliximab infusion (trough levels). Infliximab levels and anti-infliximab antibodies were measured using the ELISA technique (Promonitor IFX) and the POC assay. Correlation between both techniques was assessed by Pearson’s coefficient. Quantitative differences were evaluated by Bland–Altman analysis. Samples were stratified according to infliximab therapeutic ranges (< 3 μg/mL, 3–8 μg/mL, and > 8 μg/mL).
Results
A total of 135 experimental samples were assessed. Infliximab levels showed a high correlation between POC and ELISA tests (
r
= 0.84,
P
< 0.001). The mean difference between tests was 1.46 μg/mL (
P
< 0.001), being minimal for concentrations < 8 μg/mL. POC and ELISA assays showed an overall concordance of 87.4%. Most samples were in the same therapeutic range, which lead to equivalent therapeutic decisions. POC and ELISA assays detected the presence of anti-infliximab antibodies in 2.2% and 3.7% of the samples, respectively.
Conclusions
POC assay results in blood samples from patients with IBD were comparable to those obtained with the reference ELISA technique. The POC assay could be considered for routine testing based on its ease of use and rapidity.
Background:
Several studies have reported positive efficacy outcomes for patients with inflammatory bowel disease treated with CT-P13, an infliximab biosimilar. Data from follow-up periods longer ...than 1 year are still scarce. Here, we assessed the long-term efficacy data, loss of response and safety after switching from infliximab to CT-P13 in patients with inflammatory bowel disease.
Methods:
This was a prospective single-center observational study involving patients with moderate-to-severe Crohn’s disease and ulcerative colitis switched from infliximab to CT-P13 treatment and reviewed up to 24 months. Efficacy and loss of response were measured using the Harvey–Bradshaw (HB) index and partial Mayo score for patients with Crohn’s disease and ulcerative colitis respectively. C-reactive protein, infliximab drug levels, adverse events and antidrug antibodies were also monitored throughout the study.
Results:
A total of 64 patients with Crohn’s disease and 36 patients with ulcerative colitis were included. Most of them (72%) remained on CT-P13. Overall, 28% of patients discontinued the therapy due to loss of response, adverse events or long-lasting clinical remission. Remission at 18 and 24 months occurred in 69.9% and 68.5% of patients, respectively. Dose increase was performed in 22% of patients, with remission being reached in 60% of them. HB index, partial Mayo score, C-reactive protein and infliximab drug levels did not show significant changes. Serious adverse events were reported in 14% of patients. Overall, two patients developed low levels of antidrug antibodies.
Conclusions:
Most of the patients switching from original infliximab were maintained on CT-P13 at 2 years of follow up with a good profile of efficacy and safety.
The objective of this study was to evaluate the in vitro activity of fosfomycin under different physiological concentrations of inorganic phosphate (Pi).
The wild-type BW25113 strain, four isogenic ...mutants (ΔglpT, ΔuhpT, ΔglpT-uhpT, and ΔphoB) and six clinical isolates of Escherichia coli with different fosfomycin susceptibilities were used. EUCAST breakpoints were used. Susceptibility was evaluated by agar dilution using standard Mueller–Hinton agar (Pi concentration of 1 mM similar to human plasma concentration) and supplemented with Pi (13 and 42 mM, minimum and maximum urinary Pi concentrations) and/or glucose-6-phosphate (25 mg/L). Fosfomycin transporter promoter activity was assayed using PglpT::gfpmut2 or PuhpT::gfpmut2 promoter fusions in standard Mueller–Hinton Broth (MHB), supplemented with Pi (13 or 42 mM) ± glucose-6-phosphate. Fosfomycin activity was quantified, estimating fosfomycin EC50 under different Pi concentrations (1, 13 and 42 mM + glucose-6-phosphate) and in time–kill assays using fosfomycin concentrations of 307 (maximum plasma concentration (Cmax)), 1053 and 4415 mg/L (urine Cmax range), using MHB with 28 mM Pi (mean urine Pi concentration) + 25 mg/L glucose-6-phosphate.
All the strains showed decreased susceptibility to fosfomycin linked to increased Pi concentrations: 1–4 log2 dilution differences from 1 to 13 mM, and 1–8 log2 dilution differences at 42 mM Pi. Changes in phosphate concentration did not affect the expression of fosfomycin transporters. By increasing Pi concentrations higher fosfomycin EC50 bacterial viability was observed, except against ΔglpT-uhpT. The increase in Pi reduced the bactericidal effect of fosfomycin.
Pi variations in physiological fluids may reduce fosfomycin activity against E. coli. Elevated Pi concentrations in urine may explain oral fosfomycin failure in non-wild-type but fosfomycin-susceptible E. coli strains.
•Drug-resistant epilepsy (DRE) is considered a severe condition.•DRE is associated with important burden for patients and the healthcare system.•Cenobamate provides greater value than alternatives in ...DRE.•Multi-Criteria Decision Analysis helps to assess value contribution of cenobamate.
Epilepsy is one of the most common neurological conditions worldwide. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, despite the availability of many anti-seizure medications, including the latest options, called third-generation anti-seizure medications (ASMs), approximately 40% of people with epilepsy present drug-resistant epilepsy (DRE). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. In a chronic disease with a portfolio of available ASMs, the decision to introduce a new therapeutic alternative must follow a holistic evaluation of value provided. Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine the value contribution of a treatment in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders.
The aim of this study was to determine the relative value contribution of cenobamate in the treatment of FOS in patients with DRE compared with third-generation ASMs using reflective MCDA-based methodology.
A systematic literature review (combining biomedical databases and grey literature sources) was performed to populate the Evidence and Value: Impact on DEcisionMaking (EVIDEM) MCDA framework adapted to determine what represents value in the management of FOS in patients with DRE in Spain. The study was conducted in two phases. The first took place in 2021 with a multi-stakeholder group of eight participants. The second phase was conducted in 2022 with a multi-stakeholder group of 32 participants. Participants were trained in MCDA methodology and scored four evidence matrices (cenobamate vs. brivaracetam, vs. perampanel, vs. lacosamide and vs. eslicarbazepine acetate). Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology.
DRE is considered a very severe condition associated with many important unmet needs, mainly with regard to the lack of more effective treatments to achieve the ultimate goal of treatment. Compared to third-generation ASMs, cenobamate is perceived to have a better efficacy profile based on improvements in responder rate and seizure freedom. Regarding safety, it is considered to have a similar profile to alternatives and a positive quality-of-life profile. Cenobamate results in lower direct medical costs (excluding pharmacological) and indirect costs. Overall, cenobamate is regarded as providing a high therapeutic impact and supported by high-quality evidence.
Based on reflective MCDA methodology and stakeholders’ experience in clinical management of epilepsy in Spain, cenobamate is perceived as a value-added option for the treatment of patients with DRE when compared with third-generation ASMs.
The study aimed to reach a consensus on the most relevant patient-reported outcomes (PROs), the corresponding measures (PROMs), and measurement frequency during severe asthma patient follow-up.
Two ...Delphi rounds were conducted. The questionnaire was developed based on a systematic literature review, a focus group with patients, and a nominal group with experts. It assessed PROs' relevance and the appropriateness (A) and feasibility (F) of PROMs using a Likert scale (1=totally agree; 9=totally disagree). The consensus was established when ≥75% of participants agreed (1-3) or disagreed (7-9).
Sixty-three professionals (25 hospital pharmacists, 14 allergists, 13 pulmonologists, and 11 nurses) and 5 patients answered the Delphi questionnaire. A consensus was reached on all PROs regarding their relevance. Experts agreed on the use of ACT (A:95.24%; F:95.24%), mini AQLQ (A:93.65; F:79.37%), mMRC dyspnea scale (A:85.71%; F:85.71%), TAI (A:92.06%; F:85.71%), MMAS (A:75.40%; F:82%), and the dispensing register (A:96.83%; F:92.06%). Also considered suitable were: SNOT-22 (A:90.48%; F:73.80%), PSQI (A:82.54; F:63.90%), HADS (A:82.54; F:64%), WPAI (A:77.78%; F:49.20%), TSQM-9 (A:79.37; F:70.50%) and knowledge of asthma questionnaire (A:77%; F:68.80%); however, their use in clinical practice was considered unfeasible. Panelists also agreed on the appropriateness of EQ-5D, which was finally included despite being considered unfeasible (A: 84.13%; F:67.20%) in clinical practice. Agreement was reached on using ACT, TAI, mMRC, and a dispensing register every three months; mini-AQLQ and MMAS every six months; and EQ-5D every twelve months.
This consensus paves the way toward patient-centered care, promoting the development of strategies supporting routine assessment of PROs in severe asthma management.
A new subcutaneous formulation of the infliximab biosimilar CT-P13 has recently been developed for the treatment of inflammatory bowel disease (IBD), providing response rates similar to intravenous ...treatment. The use of this new formulation was requested, in an effort to limit patient attendance at intravenous infusion centers and to maintain biological treatment during the COVID-19 pandemic. The objective of this observational, retrospective and descriptive study was to assess CT-P13 efficacy and safety after switching from intravenous to a subcutaneous formulation in patients with IBD receiving maintenance therapy. This article shows preliminary results after six months of follow-up.
The objective of this review is to gather the available evidence on the different drugs used in immune-mediated inflammatory diseases in pregnancy, lactation, their influence on female and male ...fertility, advice on discontinuation before conception and to help in routine clinical practice for better patient advice on family planning.
A bibliographic search was carried out, where published articles (review studies, observational studies and case series) in English or Spanish until April 2020 that analyzed the management of pregnancy, lactation and/or fertility in patients on treatment in immune-mediated diseases were selected.
A total of 95 references were selected and the information on each drug was synthesized in tables. Drugs contraindicated in pregnancy are topical retinoids, pimecrolimus, cyclooxygenase 2 inhibitors, methotrexate, mycophenolate mofetil, leflunomide, acitretin, and thiopurines. The lack of data advises against the use of apremilast, tofacitinib, baricitinib, anakinra, abatacept, tocilizumab and the new biologicals. Topical salicylates, paracetamol, ultraviolet therapy and hydroxychloroquine treatment are safe, and anti-TNF biological therapy are considered low risk, with certolizumab being the drug of choice throughout pregnancy and lactation. Most are compatible with paternal exposure except for sulfasalazine, mycophenolate and leflunomide, for which suspension of treatment prior to conception is recommended, and cyclosporine with dose requirements of less than 2mg/kg/day.
In this context of chronic treatments with teratogenic potential, it is necessary to highlight the importance of pregnancy planning to select the safest drug. Given the quality of the available data, it is still necessary to continuously update the information, as well as to promote observational studies of cohorts of pregnant patients and men of childbearing age, including prospective studies, in order to generate more scientific evidence.
To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 and 10 mg/mL eye drops for use in ocular pathologies ...such as Sjögren's syndrome and dry eye syndrome.
The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5±3 °C), at room temperature (25±2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones.
The eye drops stored at 5 °C were the most stable; in the 1 mg/mL eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/mL eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/mL, presented a white precipitate from day 14 and 28, respectively. Non-refrigerated 1 mg/mL eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers.
1 mg/mL MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/mL eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.
Estudiar la estabilidad fisicoquímica y microbiológica de dos colirios de metilprednisolona succinato sódico (MTPSS) a 1 mg/mL y 10 mg/mL sin conservantes durante 90 días para su uso en patologías oculares como el síndrome de Sjögren y el síndrome del ojo seco.
los dos colirios se elaboraron partiendo de MTPSS inyectable (Solu-moderin® y Urbason®), agua para inyectables y suero salino fisiológico. Posteriormente se almacenaron, según normas ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) por triplicado en condiciones de refrigeración (5 ± 3 °C), temperatura ambiente (25 ± 2 °C) y a 40 °C (±2 °C). De acuerdo con la USP (United States Pharmacopeia), se realizaron controles fisicoquímicos de contenido en principio activo por HPLC-UV (High Performance Liquid Chromatography-Ultraviolet detector), control de pH, control de osmolalidad y controles visuales. Además, se realizó un estudio de esterilidad microbiológica en las condiciones de refrigeración, tanto en envases abiertos (hasta 30 días), como en envases cerrados (hasta 90 días).
Los colirios almacenados a 5 °C fueron los más estables y el principio activo se degradó por debajo del 90% a partir del día 21 en el colirio a 1 mg/mL.y a partir del día 42 en el colirio a 10 mg/mL. La variación del pH no fue ≥1 unidad en las formulaciones almacenadas a 5 °C, al contrario que en el resto. La osmolalidad no presentó cambios superiores al 5% a día 90 en ninguna de las condiciones de almacenamiento. Las muestras de los colirios a 10 mg/mL no refrigerados presentaron un precipitado blanco a partir del día 14 y 28 respectivamente. Los colirios a 1 mg/mL no refrigerados presentaron partículas en suspensión el día 90. No hubo cambios de color. El análisis microbiológico demostró esterilidad durante los 90 días en los envases cerrados, pero en los abiertos se detectó contaminación microbiana a partir del día 21.
Los colirios de MTPSS a 1 mg/mL presentan una estabilidad fisicoquímica y microbiológica de 21 días en refrigeración, frente a los 42 días que admiten los colirios a 10 mg/mL almacenados bajo las mismas condiciones. No obstante, al no incluir conservantes en su composición, no se deben utilizar durante más de 7 días desde su apertura.
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![[Translated article] Physic...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1130-6343/small "[Translated article] Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops")