Clinical Trial to Reconfirm the Efficacy and Safety of Cefetamet Pivoxil Treatment in Sinusitis Patients: A Double-Blind, Randomized, Parallel Designed, Multicenter, Active Comparator Study (CASIS Study).

OBJECTIVE: To evaluate the clinical efficacy and safety of cefetamet pivoxil for the treatment of acute bacterial rhinosinusitis in Korean patients compared to treatment with cefdinir. METHODS: A prospective, multicenter, randomized double-blind, comparative study was conducted by the Departments of Otorhinolaryngology-Head and Neck Surgery at 17 hospitals or universities in the Republic of Korea from March 2017 to April 2019. A total of 309 patients were screened and 249 patients participated in the study. RESULTS: Treatment with cefetamet pivoxil for 2 weeks showed 82.4% clinical cure and improvement rates in patients with acute bacterial rhinosinusitis compared to 84.68% in those taking cefdinir for 2 weeks, showing that cefetamet pivoxil administered twice a day for 2 weeks was as effective as cefdinir 3 times a day for 2 weeks for the treatment of acute bacterial rhinosinusitis. The overall adverse reaction rates of both drugs were 10.56% in the cefetamet pivoxil group and 15.49% in the cefdinir group, without serious adverse events or drug reactions. CONCLUSIONS: Cefetamet pivoxil twice a day was as efficacious and safe as cefdinir 3 times a day for the treatment of acute bacterial rhinosinusitis, which suggested that cefetamet pivoxil may be a suitable alternative to cefdinir.

Antimicrobial resistant Escherichia coli in Scottish wild deer: Prevalence and risk factors.

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.

In Vitro and In Vivo Activity of Amoxicillin-Clavulanate Combined with Ceftibuten or Cefpodoxime Against Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae.

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.

Colistin sulfate for decontamination of preservation fluid in kidney transplantation to decrease the incidence of donor-derived infections caused by multidrug-resistant Gram-negative bacteria.

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.

Study of ß-lactam-based drug interaction with albumin protein using optical, sensing, and docking methods.

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.

Physical Characterization and In Vitro Evaluation of Dissolution Rate from Cefpodoxime Proxetil Loaded Self Solidifying Solid SNEDDS.

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.

A retrospective study of azithromycin and ceftizoxime for the management of children with Mycoplasma pneumoniae pneumonia.

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.

Resistance pattern of infected chronic wound isolates and factors associated with bacterial resistance to third generation cephalosporins at Mbarara Regional Referral Hospital, Uganda.

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.

Spray dried nanospheres for inclusion complexes of cefpodoxime proxetil with ß-cyclodextrin, 2-hydroxypropyl-ß-cyclodextrin and methyl-ß-cyclodextrin: improved dissolution and enhanced antibacterial activity.

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.

Eggerthella lenta bacteremia successfully treated with ceftizoxime: case report and review of the literature.

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.

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections.

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.

Study of the structure and dynamics at various parts of the antibacterial drug molecule cefpodoxime proxetil.

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".

Establishment of epidemiological cut-off values for cefoselis, a new fourth-generation cephalosporin, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa.

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.

Ceftizoxime loaded ZnO/L-cysteine based an advanced nanocarrier drug for growth inhibition of Salmonella typhimurium.

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.

Development and characterization of lyophilized cefpodoxime proxetil-Pluronic® F127/polyvinylpyrrolidone K30 solid dispersions with improved dissolution and enhanced antibacterial activity.

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.

Pharmacokinetics and Efficacy of Ceftriaxone in Staphylococcal Mastitis in Crossbred Cows Following Single Intravenous Administration.

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.

Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) Syndrome Probably Related to Cefpodoxime: A Case Report.

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.

Repurposing of cefpodoxime proxetil as potent neuroprotective agent through computational prediction and in vitro validation.

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.

Ceftazidime-Avibactam Resistance Mutations V240G, D179Y, and D179Y/T243M in KPC-3 ß-Lactamase Do Not Alter Cefpodoxime-ETX1317 Susceptibility.

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.