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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 Ca 2+ 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.

Infective endocarditis (IE) is uncommon in children, affecting predominantly subjects with congenital heart disease (CHD) and patients with indwelling central lines. The principles of antibiotic treatment in paediatric population are similar to those in adults. Prolonged intravenous administration of bactericidal rather than bacteriostatic agents is preferred. Outpatient intravenous therapy after initial treatment in the hospital may be considered only in selected patients. Partial oral treatment has been described in cases of left-sided, uncomplicated IE caused by common pathogens in adult patients. There are no guidelines or trials in paediatric population regarding switching therapy from intravenous to oral route. We present two cases of IE in children caused by uncommon pathogenic bacteria ( Abiotrophia defectiva and Haemophilus parainfluenzae ) successfully treated with oral third-generation cephalosporin - cefpodoxime proxetil after initial intravenous therapy. This paper provides observations on different therapeutic approach for IE in children as well as another potential use of cefpodoxime proxetil.

The objective of the study was to use Monte Carlo simulation to determine the optimal treatment dosing regimen of the cefetamet sodium for injection by analysing the pharmacokinetics (PK) parameters in healthy Chinese volunteers, and antibacterial activity in vitro was also examined. A three-cross Latin square single-dose PK study was designed. Twelve healthy volunteers were randomized to receive 500, 1000, and 2000 mg of cefetamet sodium for IV infusion over 30 minutes in three periods sequentially; and the washout time in between periods was 3 days. The drug concentrations in plasma were analysed by high-performance liquid chromatography, and the PK parameters were calculated using DAS2.0 PK software. The peak concentrations (Cmax) at 0.5 hours were 37.78±7.29, 76.18±12.81, and 149.32±29.94 mg/l, the areas under concentration-time curve (AUC0-t) were 69.75±14.44, 139.06±22.62, and 278.54±53.12 mg h/l, and the elimination half-life (t1/2) were 1.69±0.19, 1.69±0.27, and 1.81±0.23 hours for 500, 1000, and 2000 mg of cefetamet sodium for injection, respectively. The disposition of cefetamet was appear to fit a two-compartment model with linear kinetics. Antibacterial activity in vitro showed that most Gram-negative bacteria, including non-extended-spectrum beta-lactamases (ESBL)-producing Enterobacter, Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, were sensitive to cefetamet. The result of Monte Carlo simulation showed that the probability of target attainment for bactericidal response (%fT>MIC≧50%) for susceptible bacteria was reached at all three dosing regimens of 500 mg, q6h, 1000 and 2000 mg, q8h and q6h. Considering the efficacy, safety, and pharmacoeconomy comprehensively, we recommended the dosing regimen of 500 mg, q6h for further clinical treatment based on the principle of minimum daily dosage.

The present study deals with the development of mucoadhesive controlled release tablets of Cefpodoxime Proxetil to increase the gastric residence time and thus prolong drug release, reduce dosing frequency and improve oral bioavailability. Tablets were prepared using sodium alginate and karaya gum, a natural polymer, with a synthetic polymer hydroxypropylmethylcellulose (K100LV) and Karaya gum with HPMC K100LV in various ratios to optimize the drug release profile using D-Optimal technique. Pre- and post-compression parameters of tablets prepared with various formulations (S1-S9, C1-C9) were evaluated. The FTIR and DSC studies revealed that no physiochemical interaction between excipients and drug. The formulation S7 showed prolonged drug release, and the mechanism of drug release from the optimized formulation was confirmed using the Korsmeyer-Peppas model to be non-Fickian release transport and n value was found 0.605 indicating both diffusion and erosion mechanism from these natural gums. The optimized formulation showed mucoadhesive strength >35 g. An in vivo study was performed on rabbits using an X-ray imaging technique. The radiological evidence suggests that the tablets adheres (more than 10 hours) to a rabbit's stomach. No significant changes were found in the physical appearance, drug content, mucoadhesive study and in vitro dissolution pattern after storage at 40 °C/75% relative humidity for 3 months.

This case-control study of full-term newborns with presumed or proven bacterial infection compared the efficacy, safety and tolerability of switch antibiotic therapy and traditional completely intravenous antibiotic administration. there were 36 newborns treated with switch therapy (i.v. ampicillin + sulbactam combined with i.v. amikacin for 3 days followed by oral cefpodoxime proxetil for 5 days); there were 72 full-term newborns with the same characteristics as controls who received i.v. ampicillin + sulbactam combined with i.v. amikacin for 3 days followed by i.v. ampicillin + sulbactam alone for a further 5 days. the results showed that full-term newborns with presumed or proven bacterial infection initially treated with intravenous antibiotics can be switched to oral antibiotics after 3 days' therapy if physical and laboratory data indicate the disappearance of infection, thus significantly reducing the length of stay in the neonatal intensive care unit and significantly increasing breastfeeding, without having any negative clinical impact.

Pharmacodynamic parameters and bactericidal activity against Streptococcus pneumoniae were investigated by simulating total and free serum concentrations of cefpodoxime versus cefditoren. Total drug T>MIC against the penicillin-intermediate (PISP) and resistant (PRSP) strains were 70.6% and 42.9% for cefpodoxime, and 89.6% and 62.5% for cefditoren, respectively. Comparing activity of free versus total cefpodoxime, there were reductions of 8.5% and 19.1% in T>MIC, related to bactericidal activity reductions from approximately 4.5 to 3 log(10), and from 3 to 2.5 log(10 )against PISP and PRSP, respectively, at 10-12h. For cefditoren, reductions of 45.4% and 100% in T>MIC, were related to bactericidal activity reductions from approximately 5.5 to 2-2.5 log(10 )and from approximately 2.5 to 1.5 log(10 )against PISP and PRSP, respectively, at 10-12h. Higher differences in activity were found against the less resistant strains when comparing total versus free-drug profile.

Killing curves and a sepsis model were performed with Streptococcus pneumoniae strains (MICs of penicillin = 0.01, 1, 2 and 4 mg/L) to assess the in vivo effect of in vitro early bactericidal activity. Optimal bactericidal concentration (OBC) was defined as the minimal concentration needed to obtain the maximal bactericidal activity during the sampling time for colony counting in killing curves. Animals were treated with amoxycillin, cefuroxime or cefpodoxime every 8 h for 48 h, with doses ranging from 2.5 to 50 mg/kg. ED100 (minimal antibiotic dose obtaining a 100% survival) was used as efficacy endpoint. Cmax/MIC, AUC/MIC and deltaT >MIC did not accurately predict efficacy against the most resistant strains, deltaT >OBC being the most predictive efficacy parameter indicating the in vivo effect of early bactericidal activity. Lower deltaT >OBC values for amoxycilin vs oral cehalosporins were needed for efficacy. The higher early bactericidal activity of amoxycillin may explain its higher in vivo efficacy.

Purpose: This paper reports experimental data on the ESR identification of four irradiated cephalosporins (cefpodoxime, cefsulodin, cefixime and ceftizoxime)., Materials and Methods: Equations to describe the ESR curves versus the dose and storage time were developed using mathematical procedures., Results: Limits of detection (LOD) and limits of quantification (LOQ), estimated on the basis of the S/N ratios are 1.0+/-0.5 kGy and 2.5+/-0.5 kGy respectively. The yield of free radicals are in the range 4.6 10(19) - 2.2 10(20) radicals mol(-1) (G values from 0.1 to 0.4). Besides a very unstable situation (cefsulodin), the time limit of detection of free radicals after storage ranges from about 1 year to over 2 years. These time intervals are comparable with the shelf-life of the antibiotics and to the time limits found for 10 other cephalosporins described previously. Apart from qualitative detection, ESR spectrometry can be used for dose estimation. Exponential loss of ESR signal (first-order reaction) correlates well with the data., Conclusion: Given the sensitivity of ESR spectrometry, this experimental technique is promising for identification of irradiated cephalosporins.

Spontaneous bacterial peritonitis is a potentially fatal complication of ascites, most often caused by the Enterobacteriaceae or streptococci. We have evaluated the in vitro activity of FK-037, a new cephalosporin, cefotaxime, cefpirome, ceftazidime, levofloxacin, and ofloxacin against a collection of 124 isolates from patients with spontaneous bacterial peritonitis. Levofloxacin (< or = 2 mg/L) was active against all isolates and ofloxacin (< or = 2 mg/L) against 98.4% of isolates. The cephalosporins (< or = 8 mg/L) were less active against cefpirome = 95.4%, FK-037 = 94.4%, and cefotaxime and ceftazidime = 91.1%. Given the high mortality associated with spontaneous bacterial peritonitis, clinical studies of the quinolones (specifically of levofloxacin) and the alternative cephalosporins presented for treatment of spontaneous bacterial peritonitis appears warranted.

Betalactams, mainly when orally administered, may lead to intestinal flora modifications related to their spectrum of activity, rate of absorption and degradation. therefore it is important to investigate the possible influence of recently developed oral cephem derivatives on normal human microflora. We have investigated the impact on normal human intestinal flora in a 10-day course with cefetamet-pivoxil (CET, 500 mg BID) in comparison to cefixime (CFX, 400 mg qD) or cefuroxime axetil (CA, 250 mg BID) in 24 patients suffering from acute exacerbation of chronic bronchitis. Stool specimens were taken before (day 0), at the end (day 10) and 14 days after treatment (day 24) and quali-quantitative microflora composition was determined with a detection limit of 10 CFU/g dry weight. Treatment with CET caused slight and non-significant modifications of normal intestinal flora. On the contrary CFX and CA significantly affect Enterobacteriaceae and clostridia with a concomitant increase in enterococci for CFX. With both CFX and CA there was a new appearance of Salmonella spp. as well as Clostridium difficile in 4 and 2 cases, respectively. Therefore CET seems to affect normal bowel flora minimally in comparison to other oral cephalosporins. This aspect might contribute to the low incidence of GI related side effects in patients treated with CEt for longer than 1 week.

In order to provide additional data on the in vitro antibacterial activity of cefetamet-pivoxil against respiratory pathogens, we determined the bactericidal kinetics of this antibiotic in comparison to cefixime and ceftibuten against H. influenzae, M. catarrhalis, K. pneumoniae, E. coli, S. pneumoniae and S. pyogenes. time-kill studies were performed by using concentrations equal to a x MIC, and 4 x MIC of the antibiotics tested and different inocula (10(5), 10(7) and 10(9) CFU/ml). The strains were incubated in a shaking incubator at 37 degrees C and 1 ml samples were removed at regular intervals for viable count determination. The antibiotics were eliminated by serial ten-fold dilutions in physiological saline before plating. At 4 x MIC of cefetamet and at 10(5) CFU/ml inoculum the results were 99.9% killing or more of H. influenzae and M. catarrhalis at 4 h, and of E. coli and K. pneumoniae within 4 to 6 h, and of E. coli and K. pneumoniae within 4 to 6 h. At the same concentration of MIC and with the same inoculum a 99.9% reduction was achieved against S. pneumoniae within 4 h and against S. pyogenes within 2 h with no regrowth at 24 h in both cases. Similar results were obtained using 10(7) and 10(9) CFU/ml inocula. Cefetamet had efficient killing activity even at lower concentrations. Bactericidal kinetics of cefetamet favorably compare with those of cefixime and ceftibuten. The efficient bactericidal activity of cefetamet-pivoxil indicates a clinical role for this new oral cephalosporin in the treatment of respiratory tract infections.

In this open comparative and prospective study 180 adults of either sex were randomised to treatment with either amoxicillin/clavulanic acid (AMC) 500/125mg tid or cefetamet pivoxil (CAT) 500mg bid for 7 days. Demographic data and assessable findings were similar in both groups. Clinical outcomes of 169 assessable patients showed high efficacy of both drugs: 92% with AMC and 96% with CAT. Bacteriological response rates were equivalent in 141 evaluable cases: 84% vs. 89%, respectively. Baseline susceptibility testing (DIN) revealed a notable number of Haemophilus species either intermediately susceptible or resistant to AMC. Gastrointestinal disorders predominated among the adverse events with diarrhea occurring nearly twice as often in the AMC group. CAT is an effective and safe alternative option in the treatment of AECB in adults. The advantage of CAT is its enhanced activity against gram-negative bacteria. It is well tolerated.

Penicillin therapy has considerably reduced the occurrence of serious late complications of streptococcal pharyngotonsillitis. However, treatment failure with this antibiotic is currently reported in up to 30% of the cases. Beta-lactamase production by the commensal flora of the tonsils, and poor compliance of patients have been implicated as the main causes of treatment failure. Cefetamet pivoxil is a new oral cephalosporin with a twice daily dosage and striking stability against beta-lactamases. We are conducting a prospective, randomized study in 120 children, comparing the efficacy of cefetamet pivoxil 10 mg/kg bid for 5 and 10 days and phenoxymethyl penicillin 25,000 U/kg tid for 10 days in the treatment of group A beta-hemolytic streptococcus (GABHS) pharyngotonsillitis. Children are enrolled after the positive culture of a throat swab and randomly assigned to one of the three groups. A follow-up check-up is performed at the end of the therapy (clinical check-up) and 3 to 5 days later (bacteriological check-up). The preliminary analysis of 55 cases shows that in 88.9%, 100% and 87.5% of children GABHS was eradicated by 5 days or 10 days of cefetamet pivoxil, or 10 days of penicillin respectively (p = NS). Side effect were mild and transient in cefetamet pivoxil-treated patients, but required cessation of treatment in 2 children treated with penicillin. These results suggest that cefetamet pivoxil therapy for 5 days eradicates GABHS from the throat in streptococcal pharyngotonsillitis as efficiently as cefetamet pivoxil or phenoxymethyl penicillin for 10 days.

In our study we considered the possible interference of cefetamet-pivoxil with the intestinal microflora. We used 60 germ-free mice in which an intestinal microflora similar to the human one had been implanted. They were treated with 14.3 mg/Kg/die (standard dose) and a 28.6 mg/kg/die (daily dose) of cefetamet-pivoxil by oral route. The results obtained in vivo proved that cefetamet-pivoxil at therapeutic doses does not influence the normal intestinal microflora.

The in-vitro post-antibiotic effect (PAE) was determined for two newer beta-lactams, FK-037 (a cephalosporin) and biapenem (a carbapenem). Our PAE results for these drugs were consistent with what has been reported previously for similar beta-lactams, e.g. Gram-positive organisms had measurable effects (0.4-2.2 hours), while Gram-negatives had variable results (0.0 to 1.4 hours). Even though the PAE test conditions generally coincided with achievable clinical levels for most organisms tested (< or = 4 mg/L for biapenem and < or = 8 mg/L for FK-037), the marginal or species dependent, short PAE values support the selection of multiple daily doses (two-to-four) based on conventional pharmacokinetic parameters such as the Cmax, AUC, and serum elimination half-life.

We report tensile, shearing, and bending tests on bone cement to which cefuzonam sodium (Cosmosin), a third generation cephalosporin, had been mixed. Mixing 3 g of cefuzonam sodium to 40 g of polymethyl methacrylate (PMMA) polymer did not diminish the strength of the bone cement in any of the tests. We speculated that this lack of influence was because the cefuzonam sodium powder used was in the form of relatively uniform-sized spheres and therefore did not become the origin of stress concentration within the cement.

RU 51746-2 (which is the water soluble Na-salt of RU 51763) proved stable toward the most common beta-lactamases tested, with the sole exception of CEP-1, a plasmid-determined enzyme which is homologous to chromosomal beta-lactamases of some enterobacterial species. We studied the interaction of RU 51746-2 with CEP-1 in an E. coli C600 derivative containing pNU104, a multicopy plasmid in which an up-promoter mutation has increased the level of beta-lactamase expression. We found that RU 51746-2 was indeed hydrolyzed with slow, but significant, rates, which might account for the high minimum inhibitory concentration (MIC) values (> 128 microg/ml) we found for this laboratory strain. However, when the same test was performed with an 100-fold dilution of the sonic extract, in order to obtain enzyme levels comparable to those usually found in clinical isolates, no appreciable hydrolysis could be measured. This suggests that the slow hydrolysis of RU 51746-2 has no clinical meaning, since the activity of this drug is virtually unaffected by the amount of beta-lactamases usually found in wild strains.

997 strains isolated from clinical specimens arrived at the "Pio Albergo Trivulzio" microbiology laboratory were tested using disks of cefpodoxime, amoxicillin + clavulanic acid, cefaclor, cefuroxime, ofloxacin, cotrimoxazole, ceftriaxone and cefalexin. Gram-positive strains were tested also with erythromycin, while gram-negative bacteria were tested against aztreonam. Cefpodoxime overall activity was well above the effectiveness of the other oral cephalosporins and on the same order as ceftriaxone and ofloxacin. Cefpodoxime proved to be also more active than the combination amoxicillin-clavulanic acid.

The activity of RU 51,746-2 was determined against strains of Escherichia coli producing different types of beta-lactamases or showing alterations of permeability. The production of TEM 1, OXA 2, CARB 3 and PSE 1 beta-lactamases had no influence on susceptibility to the antibiotic, whereas the synthesis of TEM 2, SHV 1 and OXA 1 beta-lactamases increased minimum inhibitory concentrations (MIC) by 2-4 times. Highly resistant to the antibiotic was a strain producing CEP 1 beta-lactamase. E. coli mutans deficient in Omp F but not in Omp C had a decreased susceptibility to RU 51,746-2. RU 51,746-2 showed a good affinity for high molecular weight penicillin binding proteins (PBPs) of E. coli. PBP 3 was found to be the target for growth inhibition, whereas the additional saturation of PBP 1 and 2 was required for obtaining the best bactericidal activity.