Divergent genetic landscapes drive lower levels of AmpC induction and stable de-repression in Serratia marcescens compared to Enterobacter cloacae.

The chromosomally encoded AmpC beta-lactamase is widely distributed throughout the Enterobacterales. When expressed at high levels through transient induction or stable de-repression, resistance to ceftriaxone, a commonly used antibiotic, can develop. Recent clinical guidance suggests, based on limited evidence, that resistance may be less likely to develop in Serratia marcescens compared to the better-studied Enterobacter cloacae and recommends that ceftriaxone may be used if the clinical isolate tests susceptible. We sought to generate additional data relevant to this recommendation. AmpC de-repression occurs predominantly because of mutation in the ampD peptidoglycan amidohydrolase. We find that, in contrast to E. cloacae, where deletion of ampD results in high-level ceftriaxone resistance (with ceftriaxone MIC = 96 µg/mL), in S. marcescens deletion of two amidohydrolases (ampD and amiD2) is necessary for AmpC de-repression, and the resulting ceftriaxone MIC is 1 µg/mL. Two mechanisms for this difference were identified. We find both a higher relative increase in ampC transcript level in E. cloacae ΔampD compared to S. marcescens ΔampDΔamiD2, as well as higher in vivo efficiency of ceftriaxone hydrolysis by the E. cloacae AmpC enzyme compared to the S. marcescens AmpC enzyme. We also observed higher relative levels of transient AmpC induction in E. cloacae vs S. marcescens when exposed to ceftriaxone. In time-kill curves, this difference translates into the survival of E. cloacae but not S. marcescens at clinically relevant ceftriaxone concentrations. In summary, our findings can explain the decreased propensity for on-treatment ceftriaxone resistance development in S. marcescens, thereby supporting recently issued clinical guidance.

Chlorogenic acid inhibits macrophage PANoptosis induced by cefotaxime-resistant Escherichia coli.

Antibiotics are commonly used in clinical practice to treat bacterial infections. Due to the abuse of antibiotics, the emergence of drug-resistant strains, such as cefotaxime sodium-resistant Escherichia coli (CSR-EC), has aggravated the treatment of diseases caused by bacterial infections in the clinic. Therefore, discovering new drug candidates with unique mechanisms of action is imperative. Chlorogenic acid (CGA) is an active component of Yinhua Pinggan Granule, which has antioxidant and anti-inflammatory effects. We chose the CGA to explore its effects on PANoptosis in cultured macrophages infected with CSR-EC. In this study, we explored the protective impact of CGA on macrophage cell damage generated by CSR-EC infection and the potential molecular mechanistic consequences of post-infection therapy with CGA on the PANoptosis pathway. Our findings demonstrated that during CSR-EC-induced macrophage infection, CGA dramatically increased cell survival. CGA can inhibit pro-inflammatory cytokine expression of IL-1ß, IL-18, TNF-α, and IL-6. CGA decreased ROS generation and increased Nrf-2 expression at the gene and protein levels to lessen the cell damage and death brought on by CSR-EC infection. Additionally, we discovered that the proteins Caspase-3, Caspase-7, Caspase-8, Caspase-1, GSDMD, NLRP-3, RIPK-3, and MLKL were all inhibited by CGA. In summary, our research suggests that CGA is a contender for reducing lesions brought on by CSR-EC infections and that it can work in concert with antibiotics to treat CSR-EC infections clinically. However, further research on its mechanism of action is still needed.

Alginate/chitosan hydrogels as perspective transport systems for cefotaxime.

This work reports synthesis of pH-responsive alginate/chitosan hydrogel spheres with the average diameter of 2.0 ± 0.05 mm, which contain cefotaxime that is an antibiotic of the cefalosporine group. The spheres provided the cefotaxime encapsulation efficiency of 95 ± 1%. An in vitro release of cefotaxime from the spheres in the media that simulate human biological fluids in peroral delivery conditions was found to be a pH-dependent process. The analysis of cefotaxime release kinetics by the Korsmeyer-Peppas model revealed a non-Fickian mechanism of its diffusion, which may be related to intermolecular interactions occurring between the antibiotic and chitosan. Conductometry, UV spectroscopy, and IR spectroscopy were used to study complexation of chitosan with cefotaxime in aqueous media with varied pH, characterize the composition of the complexes, and calculate their stability constants. The composition of the cefotaxime-chitosan complexes was found to correspond to the 1.0:4.0 and 1.0:2.0 molar ratios of the components at pH 2.0 and 5.6, respectively. Quantum chemical modeling was used to evaluate energy characteristics of chitosan-cefotaxime complexation considering the influence of a solvent.

Cefotaxime-induced drug reaction with eosinophilia and systemic symptom in a child with cross-reactivity to other cephalosporins and cosensitization to teicoplanin.

Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction. Commonly related to anticonvulsant and allopurinol, DRESS can affect both adults and children. Cefotaxime is rarely associated with DRESS, especially with children. We report a cefotaxime-induced DRESS in a child and emphasize the role of allergological work-up to point out the culprit drug in exploring cross-reactivity and identifying a possible cosensitization. A 2-year-old boy was treated with cefotaxime, vancomycin and metronidazole for acute otomastoiditis. Metronidazole was withdrawn and vancomycin was changed by teicoplanin 10 and 15 days later, respectively. Nineteen days after ongoing cefotaxime and 4 days after teicoplanin intake, the patient developed hyperthermia, a widespread exanthema, facial oedema with neither mucosal involvement nor palpable lymphadenopathy. Biological tests revealed eosinophilia, atypical lymphocytes, mild cytolysis and a high lactate dehydrogenase level. Serological tests for viral and bacterial infections were negative. DRESS was suspected and the 2 antibiotics were withdrawn. Intradermal tests (IDT) were carried out 2 months later with cefotaxime and teicoplanin. They revealed a positive result at 48-hour reading. To assess cross-reactivity among ß-lactams, IDT to penicillins (benzylpenicillin, amoxicillin and oxacillin) was performed showing negative results at 48-hour reading. Nevertheless, IDT to cephalosporins (cefazolin, cefuroxime, ceftazidime and ceftriaxone) displayed positive results at 48-hour reading. As a result, IDT are of great interest and should be performed to confirm the role of cefotaxime and detect a potential cross-reactivity with chemically similar drugs and drugs taken before and during the episode of DRESS.

Dose optimization of cefotaxime as pre-emptive treatment in critically ill adult patients: A population pharmacokinetic study.

AIMS: To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus. METHODS: Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NONMEM (v7.4.2). The percentage of patients reaching 100% fT>MICECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus. RESULTS: This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h-1 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h-1 for S. aureus resulted in a minimum of 99% PTA. CONCLUSION: Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h-1 was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h-1 would be preferred if eGFR and albumin concentration exceed 80 mL min-1 and 40 g L-1 respectively.

Antibacterial activity of Lagerstreomia speciosa and its active compound, corosolic acid, enhances cefotaxime inhibitory activity against Staphylococcus aureus.

AIMS: Various epidemiology studies have reported the emergence of Staphylococcus aureus and its methicillin resistance strain causing global health concerns, especially during and post-COVID-19 pandemic. This pathogen presents as a co-infection in patients with COVID-19. In addition, certain virulence factors and resistance to ß-lactam antibiotics, including cefotaxime, have been identified. We aimed to investigate the antibacterial activity of Lagerstreomia speciosa, a medicinal plant with antidiabetic activity, against S. aureus, including the strain resistant to methicillin. Furthermore, we examined whether the extract and one of its bioactive compounds, corosolic acid, can enhance the therapeutic effect of cefotaxime on antibiotic-resistant S. aureus. METHODS AND RESULTS: The minimum inhibitory concentration of each substance was determined using the standard broth microdilution test following the checkerboard dilution. The type of interactions, synergistic, additivity, indifference, or antagonism, were determined using isobolograms analysis and the dose reduction index (DRI). The evaluation of synergy and bactericidal activity of the natural products in combination with cefotaxime was performed using the time-kill kinetic assay. Corosolic acid, L. speciosa leaves extract, and bark extract alone showed antibacterial activity against all tested S. aureus ATCC 33591, S. aureus ATCC 29213, S. aureus ATCC 25923, and clinical isolated S. aureus. Corosolic acid enhanced the antibacterial activity of cefotaxime, showing a synergistic effect and greater DRI of cefotaxime against all tested S. aureus strains. Time-kill kinetic assay showed that corosolic acid has a more profound effect than L. speciosa extracts to potentiate the bactericidal activity of cefotaxime. Whereas L. speciosa leaves and bark extract showed some inhibitory effect on the growth of S. aureus after a single administration. CONCLUSIONS: Lagerstreomia speciosa leaves and bark extract and its active compound, corosolic acid, could be used as a potential anti-Staphylococcus aureus treatment to enhance the therapeutic use of cefotaxime.

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study.

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg.L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. CONCLUSION: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion. WHAT IS KNOWN: • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported. WHAT IS NEW: • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

Green Chemometric Determination of Cefotaxime Sodium in the Presence of Its Degradation Impurities Using Different Multivariate Data Processing Tools; GAPI and AGREE Greenness Evaluation.

Four eco-friendly, cost-effective, and fast stability-indicating UV-VIS spectrophotometric methods were validated for cefotaxime sodium (CFX) determination either in the presence of its acidic or alkaline degradation products. The applied methods used multivariate chemometry, namely, classical least square (CLS), principal component regression (PCR), partial least square (PLS), and genetic algorithm-partial least square (GA-PLS), to resolve the analytes' spectral overlap. The spectral zone for the studied mixtures was within the range from 220 to 320 nm at a 1 nm interval. The selected region showed severe overlap in the UV spectra of cefotaxime sodium and its acidic or alkaline degradation products. Seventeen mixtures were used for the models' construction, and eight were used as an external validation set. For the PLS and GA-PLS models, a number of latent factors were determined as a pre-step before the models' construction and found to be three for the (CFX/acidic degradants) mixture and two for the (CFX/alkaline degradants) mixture. For GA-PLS, spectral points were minimized to around 45% of the PLS models. The root mean square errors of prediction were found to be (0.19, 0.29, 0.47, and 0.20) for the (CFX/acidic degradants) mixture and (0.21, 0.21, 0.21, and 0.22) for the (CFX/alkaline degradants) mixture for CLS, PCR, PLS, and GA-PLS, respectively, indicating the excellent accuracy and precision of the developed models. The linear concentration range was studied within 12-20 µg mL-1 for CFX in both mixtures. The validity of the developed models was also judged using other different calculated tools such as root mean square error of cross validation, percentage recoveries, standard deviations, and correlation coefficients, which indicated excellent results. The developed methods were also applied to the determination of cefotaxime sodium in marketed vials, with satisfactory results. The results were statistically compared to the reported method, revealing no significant differences. Furthermore, the greenness profiles of the proposed methods were assessed using the GAPI and AGREE metrics.

Synergistic activity of Thymus capitatus essential oil and cefotaxime against ESBL-producing Klebsiella pneumoniae.

The objective of the current study was to evaluate the interaction between Tunisian Thymus capitatus essential oil (EO) and cefotaxime against Extended-Spectrum Beta-lactamases (ESBLs) producing Klebsiella pneumoniae hospital strains. GC-MS revealed that the major component of EO was found to be carvacrol (69.28%). The EO exerts an advanced bactericidal effect against all strains. Synergy between EO and cefotaxime was obtained by combined disk diffusion and checkerboard techniques. Combined use of EO and cefotaxime reduced the MIC of imipenem by 8- to 128-fold for all strains (fractional inhibitory concentration index ˂ 0.5, synergy). The time kill curve assay confirmed the advanced activity of combinatory effects of EO and cefotaxime, with total reduce of bacterial number (CFU/mL) after 6 h of culture. Synergistic activity of the combination between EO and cefotaxime constitute an important strategy as therapeutical option to combat infections caused by ESBLs producing Klebsiella pneumoniae.

Food wastes as a potential hotspot of antibiotic resistance: synergistic expression of multidrug resistance and ESBL genes confer antibiotic resistance to microbial communities.

This study investigated antibiotic resistance (ABR) and extended-spectrum ß-lactamases (ESBL) patterns in bacterial isolates collected from the dairy, hotel, meat, and canteen food waste samples. A total of 144 bacterial strains were collected and screened for resistance against 9 standard antibiotics belonging to three generations and ESBL production. The ABR profile of the bacterial isolates was observed against all four major antibiotic groups (aminoglycosides, ß-lactams, quinolone, and others), where resistance against cefotaxime (> 70%) and methicillin (> 50%) was high. Though the ABR pattern of strains from dairy waste (> 50%) was high against first-generation antibiotics, the strains from meat waste (> 50%) showed considerable resistance against second- and third-generation antibiotics. ESBL-producing isolates were screened (> 60%, n = 144) through primary identification tests (combined disk test and double disk synergy tests) and further confirmed through Hexa G-minus 23 and 24 and MIC E-stripe following CLSI guidelines. Genes conferring ESBL resistance blaCTX-M, blaSHV, blaOXA, blaTEM, blaKPC genes and multidrug resistance (MDR) mexF gene were detected in the selected isolates with ABR and ESBL traits. Isolates with multidrug ABR and ESBL phenotype were further genotypically identified through 16 s rRNA gene sequencing. The synergy of ABR was detected through the co-expression of ESBL and MDR in isolates with a high occurrence of ABR and ESBL. The results demonstrate the significance of food waste as a natural reservoir of ABR and ESBL-producing pathogens, highlighting the importance of resistance monitoring and its interventions.

Penicillin- and Cephalosporin-Resistant Pneumococcal Meningitis: Treatment in the Real World and in Guidelines.

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 (P = 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.

Punicalagin, an Inhibitor of Sortase A, Is a Promising Therapeutic Drug to Combat Methicillin-Resistant Staphylococcus aureus Infections.

Antimicrobial resistance (AMR) poses a major threat to human health globally. Staphylococcus aureus is recognized as a cause of disease worldwide, especially methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). The enzyme sortase A (SrtA), present on the cell surface of S. aureus, plays a key role in bacterial virulence without affecting the bacterial viability, and SrtA-deficient S. aureus strains do not affect the growth of bacteria. Here, we found that punicalagin, a natural compound, was able to inhibit SrtA activity with a very low half maximal inhibitory concentration (IC50) value of 4.23 µg/mL, and punicalagin is a reversible inhibitor of SrtA. Moreover, punicalagin has no distinct cytotoxicity toward A549, HEK293T, or HepG2 cells at a much higher concentration than the IC50 detected by MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assays. In addition, punicalagin visibly attenuated the virulence-related phenotype of SrtA in vitro by decreasing adhesion of S. aureus to fibrinogen, reducing the ability of protein A (SpA) displayed on the surface of the bacteria and biofilm formation. Fluorescence quenching elucidated the interaction between punicalagin and SrtA. Molecular docking further implied that the inhibitory activity lay in the bond between punicalagin and SrtA residues LYS190, TYR187, ALA104, and GLU106. In In vivo studies, we surprisingly found that punicalagin had a more effective curative effect combined with cefotaxime when mice were infected with pneumonia caused by MRSA. Essentially, punicalagin, a therapeutic compound targeting SrtA, demonstrates great potential for combating MRSA infections.

PEG-mesoporous material modified by superparamagnetic nanoparticles as a delivery system of cefotaxime.

The fight against infectious bacterial diseases has been taking major steps forward by designing new nanodrugs and nanoscale biological carriers with unique physicochemical properties. Here, polyethylene glycol (PEG)-silica mesoporous material/superparamagnetic CuFe2O4 nanoparticle nanocomposite was synthesized using a facile chemical approach, and proposed as a carrier for the delivery of cefotaxime (CTX) drug. The resulting nanocomposite material and nanocomposite CTX drug carrier were characterized by different techniques. Antibacterial activity of the nanocomposite drug carrier was investigated against E.coli and S. aureus bacteria, and compared with that of commercial CTX drug. It was found that the minimum inhibitory concentrations of the nanocomposite drug carrier (1.25 and 5 µg/mL) were significantly less than those of the commercial drug (10 and 80 µg/mL) against the bacteria. Furthermore, enhanced performance of the nanocomposite CTX carrier for both the Gram-negative and Gram-positive bacteria was evidenced.

High carriage of plasmid-mediated quinolone resistance (PMQR) genes by cefotaxime-resistant Escherichia coli recovered from surface-leaking sanitary sewers.

There is a rapid rise in the incidence of quinolone resistant bacteria in Nigeria. Most studies in Nigeria have focused on isolates from the clinical settings, with few focusing on isolates of environmental origin. This study aimed to investigate the antibiogram and carriage of plasmid-mediated quinolone resistance (PMQR) genes by quinolone-resistant isolates obtained from a pool of cefotaxime-resistant Escherichia coli (E. coli) recovered from sewage leaking out of some surface-leaking sanitary sewers in a University community in Nigeria. Isolation of E. coli from the sewage samples was done on CHROMagar E. coli, after enrichment of the samples was done in Brain Heart Infusion broth amended with 6 µg/mL of cefotaxime. Identification of presumptive E. coli was done using molecular methods (detection of uidA gene), while susceptibility to antibiotics was carried out using the disc diffusion method. Detection of PMQR genes (qnrA, qnrB, qnrS, aac(6')-lb-cr, qepA and oqxAB) was carried out using primer-specific PCR. A total of 32 non-repetitive cefotaxime-resistant E. coli were obtained from the sewage, with 21 being quinolone-resistant. The quinolone-resistant isolates showed varying level of resistance to the tested antibiotics, with imipenem being the only exception with 0% resistance. The PMQR genes: aac(6')-lb-cr, qnrA, qnrB, qnrS and qepA and oqxAB were detected in 90.5%, 61.9%, 47.6%, 38.1%, 4.8% and 0% respectively of the isolates. The findings of this study showed a high level of resistance to antibiotics and carriage of PMQR genes by quinolone-resistant E. coli obtained from the leaking sanitary sewers, suggesting a potential environmental and public health concern.

Population pharmacokinetics of cefotaxime in intensive care patients.

PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Co-administration of drugs with parenteral nutrition in the neonatal intensive care unit-physical compatibility between three components.

There is a lack of compatibility data for intravenous therapy to neonatal intensive care unit (NICU) patients, and the purpose of this study was to contribute with documented physical compatibility data to ensure safe co-administration. We selected Numeta G13E, the 3-in-1 parenteral nutrition (PN) used at our NICU, together with the frequently used drugs morphine, dopamine and cefotaxime in two- but also three-component combinations. Incompatibility may lead to particle formation (precipitation) and oil-droplet growth (emulsion destabilisation), both which are undesirable and pose a safety risk to already unstable patients. We assessed potential particle formation of three mixing ratios for each combination (always including 1 + 1 ratio) using light obscuration, turbidity and pH measurements combined with visual inspection by focused Tyndall beam. Potential droplet-growth and emulsion destabilisation was assessed by estimating PFAT5 from droplet size measurements and counts, mean droplet diameter and polydispersity index from dynamic light scattering, and pH measurements. Mixed samples were always compared to unmixed controls to capture changes as a result of mixing and samples were analysed directly after mixing and after 4 h to simulate long contact time. None of the samples showed any sign of precipitation, neither in the drug-drug nor in the two- or three-component mixture with PN. Neither did we detect any form of emulsion destabilisation. CONCLUSION: Dopamine, morphine and cefotaxime were found to be compatible with NumetaG13E, and it is safe to co-administer these drugs together with this PN in NICU patients. WHAT IS KNOWN: • The need for co-administration of drugs and complex PN admixtures occurs frequently in NICU due to limited venous access. • Available compatibility data are scarce and for combinations of more than two components non-existent. WHAT IS NEW: • Here we report physical compatibility data of two- as well as three-component combinations of frequently used NICU drugs and a 3-in-1 PN admixture. • Co-administration of Numeta G13E with dopamine and morphine, but also with morphine and cefotaxime is safe in NICU.

Genetic heterogeneity and predominance of blaCTX-M -15 in cefotaxime-resistant Enterobacteriaceae isolates colonizing hospitalized children in Tunisia.

Extended-spectrum ß-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.

ROLE OF PRE-CESAREAN SECTION CEFOTAXIME IN AMELIORATED POST-CESAREAN COMPLICATION.

OBJECTIVE: The aim: The purpose of this study was to examine the efficacy of cefotaxime before and after skin incision in avoiding post-operative infection complications in caesarean section women, also evaluation the efficacy of cefotaxime in reducing post-caesarean section complications. PATIENTS AND METHODS: Materials and methods: We conducted 150 women who undergoing caesarean section in the Obstetrics & Gynecological Department, Babylon government from January, 2021 to March, 2021. The caesarean operations were done by using standard protocols. Each patient was examined daily and post-operative infectious. Women were randomly divided into three groups; each group contains 50 women; Group 1: (control) given normal saline 12 hr. before and after skin incision. Group 2 (pre-operation antibiotic): given single dose of cefotaxime 1 g intravenously 12 hr. before skin incision, and Group 3 (post-operation antibiotic): given single dose of cefotaxime 1 g intravenously 12 hr after operation. RESULTS: Results: The outcome measures were post-operative febrile morbidity, healing period and urinary tract infections, in addition to socioeconomic state of each woman. CONCLUSION: Conclusions: cefotaxime pre-cesarean section could ameliorate post-operative problems such as infection of surgical wound, febrile, and urinary tract infections.

Cranberry-Derived Proanthocyanidins Potentiate ß-Lactam Antibiotics against Resistant Bacteria.

The emergence and spread of extended-spectrum ß-lactamases (ESBLs), metallo-ß-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using ß-lactam antibiotics. Although combinations of ß-lactamase inhibitors with ß-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new-generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-ß-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the in vitro effect of cPAC in overcoming ESBL-, MBL-, and PBP2a-mediated ß-lactam resistance. The results show that cPAC exhibit variable potentiation of different ß-lactams against ß-lactam-resistant Enterobacteriaceae clinical isolates as well as ESBL- and MBL-producing E. coli We also discovered that cPAC have broad-spectrum inhibitory properties in vitro on the activity of different classes of ß-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic-potentiating efficacy in vivoIMPORTANCE The emergence of ß-lactam-resistant Enterobacteriaceae and staphylococci compromises the effectiveness of ß-lactam-based therapy. By acquisition of ESBLs, MBLs, or PBPs, it is highly likely that bacteria may become completely resistant to the most effective ß-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance the effectiveness of existing ß-lactam agents.

Pharmacokinetic/pharmacodynamic evaluation of the antimicrobial therapy of pneumococcal invasive disease in adults in post-PCV13 vaccine period in Madrid, Spain.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.