Due to the expanded bacterial genetic tolerance to antibiotics through different mechanisms, infectious diseases of MDR bacteria are difficult for treatment. Consequently, we synthesized drug ...conjugated nanoparticles to dissolve this problem. Moreover, the present study aims to display the cell death status treated with cefotaxime-CS-AgNPs and also, apoptosis pathways of human RPE-1 normal cells and human MCF-7 breast cancer cells.
Here, we demonstrate the possibility to synthesize AgNPs and conjugate them with cefotaxime to survey the probability of cefotaxime-CS-AgNPs as an antimicrobial agent against cefotaxime-resistant strains
and MRSA.
TEM showed the size of AgNPs, CS-AgNPs and cefotaxime-CS-AgNPs ranged from 7.42 to 18.3 nm, 8.05-23.89 nm and 8.48-25.3 nm, respectively, with a spherical shape. The cefotaxime-CS-AgNPs enhanced the high antimicrobial properties compared to AgNPs or pure antibiotic. The MIC of Cefotaxime-CS-AgNPs ranged from 3 µg/mL to 8 µg/mL against tested
and MRSA bacteria. Consequently, the highest reduction in the MIC of cefotaxime-CS-AgNPs was noted against tested strains ranging from 22% to 96%. Comparing cefotaime-CS-AgNPs to AgNPs we showed that cefotaime-CS-AgNPs have no cytotoxic effect on normal cells at even 12 µg/mL for 24 hrs. The IC50 for the AgNPs and cefotaxime-CS-AgNPs was 12 µg/mL for human RPE-1 normal cells and human MCF-7 breast cancer cell lines. The pro-apoptotic genes p53, p21, and Bax of cancer cell lines significantly upregulated followed by downregulated by anti-apoptotic gene Bcl-2 after 48 hrs at 24 µg/mL, and this concentration represents the most effective dose.
Results enhanced the conjugating utility in old unresponsive cefotaxime to AgNPs to restore its efficiency against previous strains and demonstrated potential therapeutic applications of cefotaxime-CS-AgNPs. Moreover, this research gives remarkable insights for designing nanoscale delivery and curative systems that have a pronounced cytotoxic activity on cancer cells and are safe to normal cells.
The objective of this study was to describe the pharmacokinetics of cefotaxime (CTX) in critically ill patients with acute kidney injury (AKI) when treated with continuous renal replacement therapy ...(CRRT) in the intensive care unit (ICU). This single-center prospective observational pilot study was performed among ICU-patients with AKI receiving ≥48 h concomitant CRRT and CTX. CTX was administered intravenously 1,000 mg (bolus) every 6 h for 4 days. CRRT was performed as continuous venovenous hemofiltration (CVVH). Plasma concentrations of CTX and its active metabolite desacetylcefotaxime (DAC) were measured during CVVH treatment. CTX plasma levels and patient data were used to construct concentration-time curves. By using this data, the duration of plasma levels above 4 mg/liter (four times the MIC) was calculated and analyzed. Twenty-seven patients were included. The median CTX peak level was 55 mg/liter (range, 19 to 98 mg/liter), the median CTX trough level was 12 mg/liter (range, 0.8 to 37 mg/liter), and the median DAC plasma level was 15 mg/liter (range, 1.5 to 48 mg/liter). Five patients (19%) had CTX plasma levels below 4 mg/liter at certain time points during treatment. In at least 83% of the time any patient was treated with CTX, the CTX plasma level stayed above 4 mg/liter. A dosing regimen of 1,000 mg of CTX given four times daily is likely to achieve adequate plasma levels in patients with AKI treated with CVVH. Dose reduction might be a risk for suboptimal treatment.
Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary ...considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age GA range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.
Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in ...the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R
= 9.5%, adjusted p-value = 0.001 and R
= 7.5%, adjusted p-value = 0.001, respectively) and normalize over 12 months (R
= 1.1%, adjusted p-value = 0.03 and R
= 0.6%, adjusted p-value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects.
Multidrug-resistant Escherichia coli infections are a global health challenge, notably in North America, Europe, Asia, and Africa. This systematic review and meta-analysis evaluates the effectiveness ...and safety of cefotaxime combined with avibactam, aiming to mitigate these infections' impact and lessen their burden on healthcare systems worldwide.
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and PICO frameworks, we conducted a comprehensive literature search across 4 primary databases on May 6, 2023. Studies evaluating the efficacy and safety of cefotaxime and avibactam were included. Key outcomes included treatment success, adverse effects, and microbiological eradication. Quality assessment utilized the Cochrane Collaboration Risk of Bias instrument. Heterogeneity was analyzed using chi-square statistics and the I2 index. Both fixed- and random-effects models were applied as appropriate. Publication bias was rigorously evaluated using Egger linear regression test and funnel plot analysis, ensuring the study's integrity and reliability.
The clinical cure rate derived from 8 studies showed no significant difference between the treatment groups (odds ratio OR = 1.97, 95% CI: 0.69 to 1.36, P = .86). Analysis of the bacterial clearance rate from the 5 studies also indicated no significant difference (OR = 0.97, 95% CI: 0.42 to 2.25, P = .36). Notably, a reduced mortality rate favoring the experimental group was observed in 6 studies (OR = 0.64, 95% CI: 0.44 to 0.92, P = .012). Comprehensive sensitivity analyses and the assessment of publication bias strengthened the reliability of the results.
Ceftazidime combined with avibactam significantly reduced mortality among patients with multidrug-resistant Escherichia coli infections, indicating its potential as a therapeutic option, especially for carbapenem-resistant Enterobacteriaceae. However, extensive large-scale clinical trials are required to validate these findings.
To report on the therapy used for penicillin- and cephalosporin-resistant pneumococcal meningitis, we conducted an observational cohort study of patients admitted to our hospital with pneumococcal ...meningitis between 1977 and 2018. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations, we defined pneumococci as susceptible and resistant to penicillin with MIC values of ≤0.06 mg/L and > 0.06 mg/L, respectively; the corresponding values for cefotaxime (CTX) were ≤0.5 mg/L and >0.5 mg/L. We treated 363 episodes of pneumococcal meningitis during the study period. Of these, 24 had no viable strain, leaving 339 episodes with a known MIC for inclusion. Penicillin-susceptible strains accounted for 246 episodes (73%), penicillin-resistant strains for 93 (27%), CTX susceptible for 58, and CTX resistant for 35. Nine patients failed or relapsed and 69 died (20%), of whom 22% were among susceptible cases and 17% were among resistant cases. During the dexamethasone period, mortality was equal (12%) in both susceptible and resistant cases. High-dose CTX (300 mg/Kg/day) helped to treat failed or relapsed cases and protected against failure when used as empirical therapy (
= 0.02), even in CTX-resistant cases. High-dose CTX is a good empirical therapy option for pneumococcal meningitis in the presence of a high prevalence of penicillin and cephalosporin resistance, effectively treating pneumococcal strains with MICs up to 2 mg/L for either penicillin or CTX.
•We have found that cefotaxime interacts to minor groove of DNA.•The values of banding constants show a direct interaction between cefotaxime and DNA.•This complexation reaction was found to be ...spontaneous, thermodynamically favourable and enthalpy driven.•The binding of cefotaxime provides stability to DNA that might contribute in its DNA protection.
Cefotaxime is third generation antibiotic with known therapeutic efficacy against bacterial infections including cerebral abscesses and bacterial meningitis. The β-lactam group of drugs are considered safest antibiotics. Many antibiotics directly interact with DNA and alter their expression profile. Thus, it is necessary to understand the binding mode and its relevance to drug activity and toxicity. There is considerably a remarkable focus on deciphering the binding mechanism of these therapeutic agents as DNA is one of the major target for wide range of drugs. Cefotaxime has been extensively studied for its pharmacological properties while its binding mode to DNA has not been explicated so far. In this study, we have unveiled the binding mechanism of cefotaxime to DNA by using various biophysical, thermodynamic and in silico techniques. UV–vis spectroscopy confirmed the formation cefotaxime-DNA complex along with a brief idea about the extent of interaction. Fluorescence spectroscopy yielded the values of various binding constants and explained mode of fluorescence quenching to be static. CD spectroscopy, thermal denaturation, KI quenching and viscosity measurement explained that cefotaxime is groove binder. Measuring the effect of ions on cefotaxime-DNA complex ensured that it does not bind to DNA electrostatically. Dye displacement experiments finally confirmed that cefotaxime binds to the minor groove of DNA. ITC gave the thermodynamic profile of this binding in which negative value of Gibb’s free energy change revealed that the process is spontaneous. Molecular modelling finally strengthened our experimental results that cefotaxime was located in curved contour of minor groove of DNA. The findings support on safety of drug and may have a little interference on normal biological functions.
Clonal complex 4821 (CC4821) Neisseria meningitidis, usually resistant to quinolones but susceptible to penicillin and third-generation cephalosporins, is increasing worldwide. To characterize the ...penicillin-nonsusceptible (Pen
) meningococci, we analyzed 491 meningococci and 724 commensal Neisseria isolates in Shanghai, China, during 1965-2020. The Pen
proportion increased from 0.3% in 1965-1985 to 7.0% in 2005-2014 and to 33.3% in 2015-2020. Of the 26 Pen
meningococci, 11 (42.3%) belonged to the CC4821 cluster; all possessed mutations in penicillin-binding protein 2, mostly from commensal Neisseria. Genetic analyses and transformation identified potential donors of 6 penA alleles. Three Pen
meningococci were resistant to cefotaxime, 2 within the CC4821 cluster. With 96% of the Pen
meningococci beyond the coverage of scheduled vaccination and the cefotaxime-resistant isolates all from toddlers, quinolone-resistant CC4821 has acquired penicillin and cefotaxime resistance closely related to the internationally disseminated ceftriaxone-resistant gonococcal FC428 clone, posing a greater threat especially to young children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacteriaceae have emerged as important nosocomial pathogens. Community infections by these organisms have been also reported and were associated ...with previous intestinal colonization. We aimed to characterize cefotaxime‐resistant Enterobacteriaceae (CTX‐R‐En) isolated from hospitalized children in a Tunisian paediatric ward. Seventy CTX‐R‐En isolates were collected from 227 rectal swabs from hospitalized children in a paediatric ward. Antimicrobial susceptibility testing was determined according to the EUCAST guidelines. Isolates were characterized by polymerase chain reaction (PCR, genes encoding: ESBLs, pAmpC, carbapenemases, plasmid‐mediated quinolone resistance, virulence factors in Escherichia coli and Klebsiella pneumoniae isolates, occurrence of classes 1 and 2 integrons, phylogenetic groups of E. coli isolates, ERIC‐PCR and PCR‐based replicon typing) and conjugal transfer experiments. In total, 65 out of 227 (28·6%) hospitalized children were colonized with CTX‐M‐R‐En, and 70 isolates were identified. Isolates were 59 ESBL‐, 7 plasmidic‐AmpC (pAmpC)‐, 3 ESBL+pAmpC‐, and one ESBL+carbapenemase producers. The following bla genes were identified: blaCTX‐M‐15 (n = 54), blaCTX‐M‐1 (n = 5), blaCTX‐M‐9 (n = 2), blaCTX‐M‐13 (n = 1) and blaCTX‐M‐14 (n = 1), blaCMY‐2 (n = 5), blaCMY‐4 (n = 4), blaACC‐1 (n = 1) and blaOXA‐48 (n = 1). Our results showed that hospitalized children were colonized with various CTX‐R‐En‐producing several beta‐lactamase enzymes.
Significance and Impact of the Study: Our study showed that extended‐spectrum β‐lactamase‐, plasmidic‐AmpC‐ and carbapenemases‐producing Enterobacteriaceae colonized hospitalized children at a rather high incidence and some of them belonged to high‐risk clonal lineages. Therefore, it is important to implement and reinforce preventative measures to restrict the selection and spread of such strains.
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