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1.
Environ Pollut ; 314: 120129, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36113642

RESUMO

Antimicrobial resistance (AMR) is a recognised threat to global health. Obtaining data on the prevalence of AMR in environmental bacteria is key to understanding drivers and routes of transmission. Here, 325 Shiga toxin negative deer faecal samples-gathered from across the Scottish mainland-were screened for the presence of AMR Escherichia coli and investigated for potential risk factors associated with AMR occurrence. E. coli with resistance to antimicrobials of clinical health concern, including carbapenems and 3rd generation cephalosporins, were targeted. Ninety-nine percent of samples yielded E. coli, and the prevalence of resistant E. coli at the level of faecal samples was 21.8% (n = 71) for tetracycline, 6.5% (n = 21) for cefpodoxime, 0.3% for ciprofloxacin (n = 1), with no recorded resistance to meropenem. Potential risk factors for tetracycline and cefpodoxime resistance were investigated. The presence of broadleaved woodlands was significantly associated with both AMR phenotypes, which may relate to land use within or around such woodlands. Associated risk factors varied across resistance phenotype and deer species, with proximity or density of horses an indicator of significantly decreased and increased risk, respectively, or tetracycline and cefpodoxime resistance in E. coli from roe deer, but not from red deer. Distance from wastewater treatment plants was a significant risk factor for tetracycline resistance in E. coli from red deer but not from roe deer. Data indicated that AMR E. coli can occur in wild deer populations that are not directly exposed to the selective pressure exerted by antimicrobial treatment. Overall, resistance to critically important antimicrobials was found to be low in the studied population, suggesting no immediate cause for concern regarding human health. Utilising existing culling frameworks, wild deer in Scotland could function well as a sentinel species for the surveillance of AMR in the Scottish environment.


Assuntos
Anti-Infecciosos , Cervos , Infecções por Escherichia coli , Humanos , Animais , Cavalos , Escherichia coli , Prevalência , Meropeném , Cervos/microbiologia , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/veterinária , Infecções por Escherichia coli/microbiologia , Antibacterianos/farmacologia , Animais Selvagens , Ceftizoxima , Anti-Infecciosos/farmacologia , Ciprofloxacina , Fatores de Risco , Tetraciclinas , Toxinas Shiga , Farmacorresistência Bacteriana
2.
Microb Drug Resist ; 28(4): 419-424, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35451880

RESUMO

Infections due to extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales are an increasingly common problem. For many of these infections, no oral treatment options are available. The activity of amoxicillin-clavulanate combined with ceftibuten or cefpodoxime was evaluated against a group of Escherichia coli and Klebsiella pneumoniae clinical isolates possessing a variety of CTX-M- and SHV-type ESBLs; some possessed blaTEM1 as well. In time-kill studies, the combination of subinhibitory concentrations of amoxicillin-clavulanate with ceftibuten was bactericidal and synergistic for all strains with an amoxicillin-clavulanate MIC ≤32 µg/mL, regardless of the type of ESBL and the cephalosporin minimal inhibitory concentration (MIC). The combination with cefpodoxime was also bactericidal and synergistic against all but one of these strains. These combinations were further tested against two strains of K. pneumoniae and one E. coli in a sepsis model using Galleria mellonella larvae. The combination of amoxicillin-clavulanate with ceftibuten demonstrated a synergistic survival benefit against all three strains. The combination with cefpodoxime also improved survival against the two K. pneumoniae strains, but not the E. coli strain. These findings support combining amoxicillin-clavulanate with ceftibuten, and possibly cefpodoxime, for the treatment of infections due to ESBL producers and suggest that having an amoxicillin-clavulanate MIC of 32 µg/mL or less may predict activity at clinically achievable concentrations. Clinical studies are warranted to further evaluate this therapeutic approach.


Assuntos
Escherichia coli , Klebsiella pneumoniae , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/farmacologia , Ceftibuteno , Ceftizoxima/análogos & derivados , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
3.
Transpl Infect Dis ; 24(3): e13820, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35279926

RESUMO

BACKGROUND: Preservation fluid (PF) contamination, especially by multidrug-resistant (MDR) Gram-negative bacteria (GNB), poses a high risk of donor-derived infection (DDI) and severe clinical outcomes. We sought to determine whether the use of colistin sulfate to decontaminate PF in kidney transplantation can decrease the incidence of probable DDI (p-DDI) caused by MDR GNB. METHODS: In a retrospective study of 916 recipients who received deceased donation, 864 PF samples were collected and cultured, and microbiological contaminants were recorded with the recipients' clinical data and outcomes. From March 2016 to May 2019, 624 samples were decontaminated with ceftizoxime, and from June 2019 to March 2021, 240 samples were decontaminated with colistin sulfate. Between-group comparisons were performed to assess the ability of the two decontamination regimens to decrease the incidence of p-DDI, especially MDR GNB-related infection. RESULTS: The overall PF contamination rate was 54.51% (471/864), and 80 samples were positive for MDR GNB contamination. All p-DDIs occurred in the ceftizoxime group (p < 0.001), and 67.65% of p-DDIs were MDR GNB-related. In the ceftizoxime group, 23 of 61 cases of MDR GNB contamination led to related p-DDIs, while none occurred in the colistin sulfate group (p = 0.002). Among the 23 patients with p-DDIs, 5 died due to severe infection, and 2 experienced graft loss. CONCLUSIONS: The goal of decontamination should be to decrease the risk of MDR GNB-related p-DDI, and colistin sulfate could be an effective and feasible option.


Assuntos
Infecções por Bactérias Gram-Negativas , Transplante de Rim , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftizoxima/farmacologia , Colistina/uso terapêutico , Descontaminação , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/prevenção & controle , Humanos , Incidência , Transplante de Rim/efeitos adversos , Estudos Retrospectivos
4.
J Biol Phys ; 48(2): 177-194, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35094207

RESUMO

The quality and strength of drug and albumin interaction affecting the drug-free concentration and physiological activity are important issues in pharmacokinetic research. In the present study, not only did we evaluate the binding strength of ceftriaxone and ceftizoxime to bovine serum albumin (BSA), but we also investigated the kinetic and thermodynamic parameters including KD, KA, ΔS, and ΔH. We applied in vitro optical fluorescence spectroscopy and surface plasmon resonance (SPR) sensing approaches as well as molecular docking analyses. The kinetic and thermodynamic investigations were done using different concentrations of drugs at three temperatures. Thermodynamic parameters visibly demonstrated that the binding was an exothermic and spontaneous process. The obtained negative values of both enthalpy change (ΔH) and entropy change (ΔS) in fluorescence and SPR and also molecular docking investigations showed that the major binding force involved in the complexation of drugs to BSA was hydrogen bonding. Static quenching was the foremost fluorescence quenching mechanism between them. Furthermore, the results of ΔG and KD values proved that the interaction of ceftriaxone-BSA was stronger than ceftizoxime-BSA. Finally, molecular docking confirmed that the preferable binding sites of ceftizoxime and ceftriaxone were site IIA and site IB of albumin, respectively.


Assuntos
Ceftriaxona , beta-Lactamas , Sítios de Ligação , Ceftizoxima , Ceftriaxona/farmacologia , Interações Medicamentosas , Simulação de Acoplamento Molecular , Ligação Proteica , Soroalbumina Bovina/química , Espectrometria de Fluorescência/métodos , Espectrofotometria Ultravioleta , Termodinâmica
5.
Curr Drug Deliv ; 19(3): 395-406, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34353259

RESUMO

BACKGROUND: Cefpodoxime Proxetil (CPD) is a broad-spectrum cephalosporin indicated in respiratory and urinary tract infections. CPD is a BCS class IV drug with pH-dependent solubility and has poor bioavailability. This study investigated the challenges of developing ternary components based on solid SNEDDS of CPD for in vitro dissolution rate enhancement and self-solidifying behaviour. METHODS: Tween 80, Transcutol and PEG6000 were employed as surfactants, solvents and solidifiers for a base of ternary components to develop self-solidifying solid SNEDDS, respectively. Ternary phase diagrams were used to characterize solidifying behaviour of ternary components in different proportions. S-SNEDDS formulations were drawn on the solidification areas available in the phase diagram and characterized for IR, XRD, DSC and in vitro drug release in various pH media. RESULTS: Ternary components for the preparation of self-solidifying solid SNEDDS were selected based on drug solubility. FTIR and DSC characterization studies ruled out any drug interaction between CPD and components chosen to prepare S-SNEDDS. CPD was transformed from a crystalline into an amorphous state in ternary dispersions as revealed from XRD data. Optimized formulation (S-S 1) demonstrated more than 95% of drug release irrespective of the pH environments of the medium. Calculation of dissolution efficiency and similarity factors indicate that S SNEDDS resulted in a higher drug dissolution rate over binary dispersion (p<0.01). The stability studies showed that the S SNEDDS were stable in performances and CPD assay. CONCLUSION: The present investigation provides an alternative approach for enhancing the CPD dissolution rate using self-solidifying solid SNEDDS exhibited solidification behaviour at ambient temperature conditions and drug loading, which could be exploited over conventional dosage form.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Administração Oral , Disponibilidade Biológica , Ceftizoxima/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Nanopartículas/química , Tamanho da Partícula , Solubilidade , Tensoativos/química
6.
Eur J Med Res ; 26(1): 111, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544476

RESUMO

Eggerthella lenta is a normal human microflora that is anaerobic, non-sporulating, and Gram positive. However, an increasing number of studies have shown that it could also be an important pathogen for humans, even causing life-threatening infection under certain conditions. However, understanding its pathogenic mechanism and treatment options still need to be improved; more clinical data are needed to explore it further. In this article, we report a case of ceftizoxime-cured E. lenta bacteremia and review the recent literature to provide more clinical data for the diagnosis of E. lenta bacteremia. Our report suggests that the frequency of E. lenta bacteremia is increased in patients with hematologic or solid organ cancer, diabetes mellitus and also in those with appendicitis.


Assuntos
Actinobacteria/patogenicidade , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Ceftizoxima/uso terapêutico , Actinobacteria/isolamento & purificação , Adulto , Bacteriemia/microbiologia , Bacteriemia/patologia , Humanos , Masculino , Prognóstico
7.
Medicine (Baltimore) ; 100(44): e27564, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34871221

RESUMO

ABSTRACT: The aim of this study was to compare the clinical efficacy of azithromycin and ceftizoxime (AC) and erythromycin and amoxicillin/sulbactam (EAS) in the treatment of children with Mycoplasma pneumoniae pneumonia (MPP).In this retrospective study, a total of 92 eligible children with MPP were included, and they were divided into a treatment group (n = 46) and a control group (n = 46). All patients were treated with intravenous ambroxol, and nebulized inhalation of budesonide and terbutaline. In addition, patients in the treatment group received AC. Patients in the control group underwent EAS. All patients in both groups were treated for a total of 10 days. Outcomes consist of erythrocyte sedimentation rate, C-reactive protein, serum lactate dehydrogenase, and interleukin 6, fever clearance time, time of cough disappearance, time of rale disappearance, time of signs disappeared by X-ray, and adverse events. All outcomes were measured after 10-day treatment.After treatment, patients who received AC exerted better improvements in erythrocyte sedimentation rate (P < .01), C-reactive protein (P < .01), serum lactate dehydrogenase (P < .01), interleukin 6 (P < .01), fever clearance time (P < .01), time of cough disappearance (P < .01), time of rale disappearance (P < .01), and time of signs disappeared by X-ray (P < .01), than those in patients who received EAS. In addition, there were not significant differences in adverse events between 2 groups.The results of this study showed that AC may benefit more than EAS for the children with MPP.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Ceftizoxima/uso terapêutico , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/tratamento farmacológico , Criança , Eritromicina/uso terapêutico , Feminino , Febre/tratamento farmacológico , Humanos , Lactato Desidrogenases , Masculino , Mycoplasma pneumoniae/efeitos dos fármacos , Estudos Retrospectivos , Sulbactam/uso terapêutico , Resultado do Tratamento
8.
PLoS One ; 16(12): e0261264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34914757

RESUMO

BACKGROUND: The objectives of this study were; (I) to determine the proportion of pathogens isolated from patients with infected chronic wounds in the surgical ward of MRRH that are resistant to the third-generation cephalosporins and (II) to determine the factors associated with resistance to third-generation cephalosporins in the surgical ward of MRRH. METHOD(S): This study was a descriptive analytical survey of bacterial isolates from infected chronic wounds among patients admitted in the surgical ward of MRRH, Uganda. Seventy five (75) study participants were recruited in the study using convenient sampling technique. Bacterial culture and identification was performed using standard microbiology laboratory procedures whereas broth microdilution method was used to establish the susceptibility of the identified pathogens. Data for objective one (1) was summarized as proportions while the categorized variables were analyzed using logistic regression to determine whether they were associated with the resistance patterns. The level of significance was preset at 5% and p-values less than 0.05 were considered statistically significant. RESULTS: Generally, all isolates had complete susceptibility (100%) to Cefoperazone+Sulbactam 2g except 7.1% of proteus spp that were resistant. Of all the bacterial isolates studied, Staphylococcus aureus, Enterobacter agglomerans, providencia spp and pseudomonas earuginosa had complete resistance (100%) to Cefopodoxime 200mg while providencia spp and pseudomomas earuginosa had complete resistance (100%) to Cefixime 400mg and cefotaxime 1g. Finally, higher odds of bacterial resistance to more 2 brands of the third generation cephalosporins were observed among participants who had prior exposure to the third generation cephalosporins (OR, 2.22, 95% CI, 0.80-6.14), comorbidities (OR, 1.76, 95% CI, 0.62-4.96) and those who had more than two hospitalizations in a year (OR, 1.39, 95% CI 0.46-4.25). However, multivariate logistic regression was not performed since no factor was significantly associated with resistance to more than two brands of third generation cephalosporins (p >0.05). CONCLUSION: This study found that cefixime and cefpodoixme had high rates of resistance and should not be used in routine management of infected chronic wounds. In addition, the factors investigated in this study were not significantly associated with bacterial resistance to more than two brands of third generation cephalosporins.


Assuntos
Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana/fisiologia , Infecção dos Ferimentos/tratamento farmacológico , Adulto , Idoso , Antibacterianos/uso terapêutico , Cefixima/farmacologia , Cefoperazona/uso terapêutico , Ceftizoxima/análogos & derivados , Ceftizoxima/farmacologia , Doença Crônica/tratamento farmacológico , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Hospitais , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sulbactam/uso terapêutico , Uganda/epidemiologia , Infecção dos Ferimentos/microbiologia
9.
Solid State Nucl Magn Reson ; 115: 101752, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34340119

RESUMO

The structure and dynamics of cefpodoxime proxetil are elucidated by measuring chemical shift anisotropy (CSA) tensor, spin-lattice relaxation time, and local correlation time at twenty-one crystallographically different 13C nuclei sites. The principal components of CSA tensor of cefpodoxime proxetil are extracted by the two-dimensional phase adjusted sinning sideband (2DPASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment, and the spin-lattice relaxation time is measured by the method outlined by Torchia(T1CP). The local correlation time is calculated by bearing in mind that the spin-lattice relaxation mechanism of 13C nuclei is mainly governed by the CSA interaction and the heteronuclear dipole-dipole interaction. The aminothiazole ring, ß-lactam ring, and dihydrothiazine ring provide stability to the drug molecule and increase the affinity of the drug to penicillin-binding proteins (PBPs) receptors. The principal components of CSA parameters, spin-lattice relaxation time, and local correlation time vary substantially for carbon nuclei residing on these three rings. These signify that not only the electronic environment, but the molecular conformation, and the local dynamics are also altered within the ring. The substitution of the acyl side chain, oxime group, and the aminothiazole ring at the C7 position of the ß-lactam ring enhances the antibacterial activity and the binding affinity of the drug. A huge variation of the spin-lattice relaxation time and local correlation time is observed in those regions. The change in the electron charge distribution and nuclear spin dynamics at different parts of the drug molecule is clear by CSA and spin-lattice relaxation measurements, which will enrich the field "NMR crystallography".


Assuntos
Antibacterianos , Ceftizoxima , Antibacterianos/farmacologia , Ceftizoxima/análogos & derivados , Espectroscopia de Ressonância Magnética , Ressonância Magnética Nuclear Biomolecular/métodos
10.
J Antimicrob Chemother ; 76(11): 2839-2846, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34453533

RESUMO

OBJECTIVES: Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of ß-lactamases and Enterobacterales' genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs. MATERIALS AND METHODS: In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates' ST and their type of ß-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed. RESULTS: All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant ß-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54). CONCLUSIONS: Despite the frequent association of ESBL genes with inhibitor-resistant ß-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children.


Assuntos
Andinocilina , Infecções Urinárias , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefixima/farmacologia , Ceftizoxima/análogos & derivados , Criança , Ácido Clavulânico/farmacologia , Humanos , Infecções Urinárias/tratamento farmacológico
11.
Sci Rep ; 11(1): 15565, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330977

RESUMO

L-Cysteine coated zinc oxide (ZnO) nano hollow spheres were prepared as a potent drug delivery agent to eradicate Salmonella enterica serovar Typhimurium (S. typhimurium). The ZnO nano hollow spheres were synthesized by following the environmentally-friendly trisodium citrate assisted method and L-cysteine (L-Cys) conjugate with its surface. ZnO/L-Cys@CFX nanocarrier drug has been fabricated by incorporating ceftizoxime with L-Cys coated ZnO nano hollow spheres and characterized using different techniques such as scanning electron microscope (SEM), attenuated total reflection Fourier transform infrared (ATR-FTIR), and X-ray diffraction (XRD) etc. Furthermore, the drug-loading and encapsulation efficiency at different pH levels was measured using UV-vis spectrometer and optimized. A control and gradual manner of pH-sensitive release profile was found after investigating the release profile of CFX from the carrier drug. The antibacterial activity of ZnO/L-Cys@CFX and CFX were evaluated through the agar disc diffusion method and the broth dilution method, which indicate the antibacterial properties of antibiotics enhance after conjugating. Surprisingly, the ZnO/L-Cys@CFX exhibits a minimum inhibitory concentration (MIC) of 5 µg/ml against S. typhimurium is lower than CFX (20 µg/ml) itself. These results indicate the nanocarrier can reduce the amount of CFX dosed to eradicate S. typhimurium.


Assuntos
Ceftizoxima/química , Cisteína/química , Salmonella typhimurium/efeitos dos fármacos , Óxido de Zinco/química , Antibacterianos/química , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana
12.
J Antimicrob Chemother ; 76(10): 2593-2599, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34215878

RESUMO

OBJECTIVES: To establish the epidemiological cut-off values (ECOFFs) for cefoselis against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa. METHODS: We collected 2288 non-repetitive clinical isolates from five laboratories throughout four cities in China. The cefoselis MICs and inhibition zone diameters for all isolates were established using the broth microdilution method and the disc diffusion method following EUCAST guidelines. MIC ECOFFs were determined by visual estimation and ECOFFinder software. Zone diameter ECOFFs were set if a high correlation of MICs and inhibition zone diameters was found by Pearson correlation. Zone diameter ECOFFs were finally determined by the visual estimate method. RESULTS: MICs of cefoselis were distributed from 0.008 to >256 mg/L for the four Enterobacterales species and from 0.25 to >256 mg/L for P. aeruginosa. MIC ECOFFs were 0.125 mg/L for E. coli, K. pneumoniae and P. mirabilis, 0.25 mg/L for E. cloacae and 32 mg/L for P. aeruginosa. A high correlation of MICs and zone diameters was observed for all Enterobacterales (|r| > 0.8, P < 0.001) and a relatively high correlation was found for P. aeruginosa (|r| = 0.71, P < 0.001). The zone diameter ECOFF was 24 mm for E. cloacae, E. coli and K. pneumoniae, 26 mm for P. mirabilis and 21 mm for P. aeruginosa. CONCLUSIONS: We determined MIC and zone diameter ECOFFs for cefoselis against four Enterobacterales species and P. aeruginosa. The establishment of ECOFFs for cefoselis provides clinicians with helpful guidance to differentiate WT and non-WT pathogens.


Assuntos
Escherichia coli , Klebsiella pneumoniae , Antibacterianos/farmacologia , Ceftizoxima/análogos & derivados , Enterobacter cloacae , Testes de Sensibilidade Microbiana , Proteus mirabilis , Pseudomonas aeruginosa
13.
Pharm Dev Technol ; 26(4): 476-489, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33616480

RESUMO

The aim of this study was the development of hard-cellulose capsules containing cefpodoxime proxetil (CEF) (BCS Class II) loaded novel Pluronic® F127 (P127)/Polyvinylpyrrolidone K30 (PVP) solid dispersions (SDs) using ultrasonic probe induced solvent-lyophilization method for effective antibacterial treatment by means of improved saturated aqueous solubility, dissolution rate, reduced particle size, and wettability. SDs were evaluated for physical and solid-state analyses. The solubility of pure CEF was calculated as 0.269 ± 0.005 mg/mL, SDs formulated with P127/PVP exhibited increased solubility from 3.5- to 8-fold. Molecular distribution of CEF in SDs and formation of CEF loaded amorphous polymeric network were confirmed with morphological study, thermal analysis, Fourier-transform infrared spectroscopy (FT-IR), and 1H-NMR studies. Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), and Klebsiella pneumoniae (ATCC 700603) were used to investigate the antibacterial effectiveness of the SDs. The minimum inhibitory concentration (MIC) values of the P127/PVP SDs were found 2-8 times lower than the pure CEF. All SDs from hard-cellulose capsules exhibited significantly faster release than unprocessed CEF. The profiles of SDs and reference were detected to be dissimilar according to difference (f1) and similarity factor (f2). Hard-cellulose capsules containing CEF loaded P127/PVP SDs appear to be feasible alternative to commercially available CEF tablets for effective antibacterial therapy at lowest dose.


Assuntos
Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Ceftizoxima/análogos & derivados , Portadores de Fármacos/química , Antibacterianos/química , Antibacterianos/farmacologia , Cápsulas , Ceftizoxima/administração & dosagem , Ceftizoxima/química , Ceftizoxima/farmacologia , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Liofilização , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Poloxâmero/química , Povidona/análogos & derivados , Povidona/química , Solubilidade , Molhabilidade
14.
Curr Drug Metab ; 22(5): 383-390, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33568029

RESUMO

BACKGROUND: Clinical mastitis is an important production disease of dairy animals, causing significant economic losses. OBJECTIVE: Disposition kinetics of ceftriaxone was conducted in healthy lactating and staphylococcal mastitic crossbred cows in field condition following single-dose intravenous administration of only ceftriaxone. METHODS: A single dose of ceftriaxone at 20 mg kg-1 body weight was administered intravenously through jugular vein to six clinically healthy and six mastitic crossbred cows after proper diagnosis and three mastitic cows remained untreated (positive control). Blood and milk samples were collected at 0 (pre-dosing), 5, 15, 30 min, and 1, 24, 48, 72, 96 and 120 h post drug administration and analyzed for ceftriaxone and its active metabolite (ceftizoxime) by high-performance liquid chromatography. RESULTS: Ceftriaxone achieved a peak mean plasma concentration of 131.67±1.83 µg mL-1 at 5 min, which decreased sharply until 1 h (35.56±0.44 µg mL-1) and was below detection limit at 24 h post drug administration in mastitic crossbred cows. On the other hand, ceftizoxime (active metabolite of ceftriaxone) achieved a peak level of 55.42±3.34 µg mL-1 at 72 h and could not be detected at 120 h post drug administration in the milk of those mastitic crossbred cows. The Staphylococcus aureus colony count in mastitic crossbred cows was 49.33±6.55 × 105 c.f.u./mL and the lowest colony count was achieved at 72 h with no colony at 120 h post drug administration. All the staphylococcal mastitis affected crossbred cows were cured on day 5. CONCLUSION: Ceftriaxone may prove to be effective in the treatment of staphylococcal mastitis in crossbred cows following single-dose intravenous administration at 20 mg kg-1 body weight.


Assuntos
Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Mastite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Administração Intravenosa , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bovinos , Ceftizoxima/sangue , Ceftriaxona/sangue , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Feminino , Lactação/metabolismo , Leite/química , Leite/efeitos dos fármacos , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/efeitos dos fármacos
15.
J Pharm Pract ; 34(1): 163-165, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31382812

RESUMO

Cefpodoxime is a common antibiotic with a favorable side effect profile. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome has been described with several cephalosporins but not cefpodoxime. We report the probable first case of cefpodoxime-induced DRESS syndrome in a 52-year-old female patient. In our case, the patient presented with symptoms of DRESS syndrome 16 days after initiation of cefpodoxime. This case highlights the necessity of consideration of an iatrogenic reason for presenting signs and symptoms at all times. Reinforcing the importance of taking a thorough drug history and considering drug reactions even if onset of symptoms are delayed.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Exantema , Preparações Farmacêuticas , Ceftizoxima/análogos & derivados , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Eosinofilia/induzido quimicamente , Eosinofilia/diagnóstico , Exantema/induzido quimicamente , Exantema/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade
16.
J Biomol Struct Dyn ; 39(11): 3975-3985, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32448083

RESUMO

In recent reports, NR2B-NMDA receptor antagonists showed more research value because of its strong targeting ability and less side effects potential. In 2016, EVT-101 was reported to bind in an almost entirely new binding region of this target. Whether strikingly different binding modes can improve targeting and reduce side effects is worth studying. In our preliminary work, we explored the binding patterns of ifenprodil and EVT-101, found the key amino acids and summarized the pharmacophores, hoping to find such antagonists that target the two binding modes simultaneously. In this study, we developed a scalable virtual screening workflow in the FDA-approved drugs library to identify novel NR2B-NMDAR antagonists based on the combination of two pharmacophores. Cefpodoxime proxetil (5) was identified as the hit compound, and it was found for the first time that 5 might have neuroprotective activity as a NR2B-NMDAR antagonist. This result interested us to make further study, the ligand-receptor interactions modeled by molecular docking studies showed that the compound could perfectly merge both the pharmacophore characteristics of ifenprodil and EVT-101 at the binding cavity between the ATDs of GluN1 and GluN2B. The accuracy of molecular docking results and binding stability of ligand-receptor complexes were validated through 100 ns molecular dynamics simulation and binding free energy calculation. Afterwards, MTT assay (49.8%±0.1%, 5 µM) on NMDA injured SH-SY5Y cells and evidence of the effect on attenuating Ca2+ influx induced by NMDA were applied to validate the computational results, further investigation showed that 5 could suppress the NR2B upregulation induced by NMDA. [Formula: see text] Communicated by Ramaswamy H. Sarma.


Assuntos
Fármacos Neuroprotetores , Ceftizoxima/análogos & derivados , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo
17.
ACS Infect Dis ; 7(1): 79-87, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33291867

RESUMO

Mutations in KPC-2 and KPC-3 ß-lactamase can confer resistance to the ß-lactam/ß-lactamase inhibitor antibacterial intravenous drug combination ceftazidime-avibactam, introduced in 2015. Avibactam was the first of the diazabicyclooctane class of non-ß-lactam ß-lactamase inhibitors to be approved for clinical use. The orally bioavailable prodrug ETX0282 of the diazabicyclooctane ß-lactamase inhibitor ETX1317 is in clinical development in combination with the oral ß-lactam prodrug cefpodoxime proxetil for use against complicated urinary tract infections. We investigated the effects of 3 ceftazidime-avibactam resistance mutations in KPC-3 (V240G, D179Y, and D179Y/T243M) on the ability of ETX1317 to overcome KPC-3-induced cefpodoxime resistance. Isogenic Escherichia coli strains, each expressing the wild-type or a mutant KPC-3 at similar levels, retained susceptibility to cefpodoxime-ETX1317 (1:2) with essentially identical minimal inhibitory concentrations of 0.125-0.25 µg/mL cefpodoxime. The KPC-3 mutations had little or no effect on the kinact/Ki values for inhibition by each of 3 diazabicyclooctanes: avibactam, durlobactam (ETX2514), and ETX1317. The KM values for hydrolysis of cefpodoxime were similar for all 4 variants, but the kcat values of the D179Y and D179Y/T243M variants were much lower than those of the wild-type and V240G mutant enzymes. All 4 KPC-3 variants formed stable, reversibly covalent complexes with ETX1317, but dissociation of ETX1317 was much slower from the D179Y and D179Y/T243M mutants than from the wild-type and V240G mutant enzymes. Thus, the KPC-3 variants examined here that cause resistance to ceftazidime-avibactam do not cause resistance to cefpodoxime-ETX1317.


Assuntos
Compostos Azabicíclicos , beta-Lactamases , Compostos Azabicíclicos/farmacologia , Ceftazidima , Ceftizoxima/análogos & derivados , Combinação de Medicamentos , Mutação , beta-Lactamases/genética
18.
Drug Dev Ind Pharm ; 47(8): 1261-1278, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34606394

RESUMO

OBJECTIVE: The aim of the current research was the development hard cellulose capsules containing cefpodoxime proxetil (CEF) (BCS-Class II) encapsulated nanospheres of inclusion complexes with ß-CD, HP-ß-CD and M-ß-CD for efficient antibacterial therapy. SIGNIFICANCE: The reason for this phenomenon is to bring an innovative approach to effective oral antimicrobial therapy with hard cellulose capsules containing spray dried nanospheres of CEF with ß-CD, HP-ß-CD and M-ß-CD by means of increased solubility, dissolution rate and improved antibacterial efficiency with lower oral dose. METHODS: Phase solubility analyses was performed to evaluate the drug/CD interaction, involving the stoichiometry and apparent stability constant. Following the preparation of inclusion complexes by spray-drying method, complexes were characterized for physical, solid-state and microbiological analyses. In vitro dissolution from hard cellulose capsules containing CEF and CEF/ß-CD, CEF/HP-ß-CD and CEF/M-ß-CD complexes were performed. RESULTS: According to AL type phase solubility curves, complexes were formulated as 1:1 molar ratio. The solubility of pure CEF was determined as 0.241 ± 0.002 mg mL-1, the solubility of inclusion complexes increased solubility from 3 to 5 times. The strong host-guest interaction was confirmed for CEF/HP-ß-CD and CEF/M-ß-CD complexes with SEM, DSC, FT-IR and 1H-NMR analyses. Inclusion complexes were more efficient on bacterial cells (2-4 fold) than pure CEF both Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. Hard-cellulose capsules filled with inclusion complexes exhibited significantly faster release than unprocessed CEF. CONCLUSION: Hard-cellulose capsules containing CEF/HP-ß-CD and CEF/M-ß-CD complexes appear to be superior alternative to commercially available CEF tablets for effective antibacterial therapy.


Assuntos
Nanosferas , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Antibacterianos/química , Antibacterianos/farmacologia , Varredura Diferencial de Calorimetria , Cápsulas , Ceftizoxima/análogos & derivados , Celulose , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , beta-Ciclodextrinas/química
19.
Eur Urol Focus ; 7(5): 980-986, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33358884

RESUMO

BACKGROUND: After recommended restriction of the use of fluoroquinolones, the optimal antibiotic prophylaxis for transrectal prostate biopsy is still under debate. OBJECTIVE: To test the effectiveness of cefpodoxime as oral antibiotic prophylaxis for transrectal prostate biopsies and the complication rates relative to fluoroquinolones. DESIGN, SETTING, AND PARTICIPANTS: Antibiotic prophylaxis for transrectal prostate biopsies at the Department of Urology at University Hospital Frankfurt was fluoroquinolones for 342 consecutive patients in January 2018 and December 2019 and cefpodoxime for 100 patients from January 2020 to July 2020. Data were prospectively evaluated and retrospectively analyzed. Patients were followed up according to clinical routine at 6 wk after biopsy at the earliest. Patients without follow-up (n = 98) and those receiving antibiotic prophylaxis other than cefpodoxime or fluoroquinolones (n = 15) were excluded. INTERVENTION: Use of cefpodoxime or fluoroquinolones as antibiotic prophylaxis for transrectal prostate biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression models were used to predict biopsy-related complications according to antibiotic prophylaxis. RESULTS AND LIMITATIONS: Of 442 patients, 100 (22.6%) received cefpodoxime as antibiotic prophylaxis. Patient baseline and biopsy characteristics were comparable between the cefpodoxime and fluoroquinolone groups. Moreover, there were no differences in the number of prior prostate biopsies or the proportions of systematic vs. fusion biopsies (p > 0.05). There were no differences between the groups in infectious complications such as epididymitis and prostatitis after biopsy. Infectious complication rates were very low, at 2.0% in the cefpodoxime and0.9%fluoroquinolone group. Moreover, there were no differences between the groups in patient-reported complications, such as gross hematuria occurring at more than 5 d after biopsy, hematospermia, or rectal bleeding. In multivariable analyses, after adjustment for patient and prostate biopsy characteristics, cefpodoxime was not associated with higher complication rates than fluoroquinolones (p > 0.05). CONCLUSIONS: Complications after transrectal prostate biopsies are rare and cefpodoxime might be a sufficient choice as oral antibiotic prophylaxis and noninferior compared to fluoroquinolones. PATIENT SUMMARY: Cefpodoxime might be a sufficient choice as an easily applicable oral antibiotic prophylaxis for transrectal prostate biopsy. The safety profile of cefpodoxime is comparable to the safety profile of fluoroquinolones.


Assuntos
Antibioticoprofilaxia , Fluoroquinolonas , Antibioticoprofilaxia/métodos , Ceftizoxima/análogos & derivados , Fluoroquinolonas/uso terapêutico , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Próstata/patologia , Estudos Retrospectivos , Ultrassonografia de Intervenção/métodos
20.
BMC Vet Res ; 16(1): 404, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109179

RESUMO

BACKGROUND: Disease prevention and control is a significant part in the ex-situ conservation of the endangered red panda (Ailurus fulgens), being bacterial infection is one of the most important health threats to the captive population. To date, studies about the infection caused by Escherichia coli in the red panda are scarce. This study was conducted to determine the cause of death of a captive red panda through clinical symptoms, complete blood count, biochemical analysis, pathological diagnosis and bacterial whole genome sequencing. CASE PRESENTATION: The following report describes a case of a 1.5 year old captive red panda (Ailurus fulgens) that was found lethargic and anorectic. She was moved to the quarantine area for daily treatment with 50 mg of Cefpodoxime Proxetil. During the three-day treatment, she did not eat or defecate, and then died. Clinical hematology revealed the values of neutrophils, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood urea nitrogen (BUN) were significantly higher. Histological analysis demonstrated major pathological damage in the kidneys, liver and lungs, characterized by hyperemia, parenchymal cell degeneration and necrosis and inflammatory cell infiltration which were predominantly neutrophilic. A bacterial strain confirmed as Escherichia coli was isolated post mortem. Whole genome sequencing of the E. coli showed the complete genome size was 4.99 Mbp. PapA, PapC, OmpA, OmpU and other virulence factors which specific to Uropathogenic Escherichia coli (UPEC) were found in the isolate. Among the virulence factors, P pili, type I pili and related factors of the iron uptake system were associated with nephrotoxicity. CONCLUSION: The red panda died of bacterial infection caused by an uropathogenic strain of Escherichia coli. The pathogenic mechanisms of the strain are closely related to the expression of specific virulence genes.


Assuntos
Ailuridae , Infecções por Escherichia coli/veterinária , Escherichia coli Uropatogênica/isolamento & purificação , Animais , Antibacterianos/uso terapêutico , Ceftizoxima/análogos & derivados , Ceftizoxima/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Feminino , Genoma Bacteriano , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/patogenicidade , Fatores de Virulência/genética , Sequenciamento Completo do Genoma/veterinária
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