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Objectives: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling., Methods: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L., Results: Thirty-six patients (0.2-12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function., Conclusions: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Critical illness has been shown to affect the pharmacokinetics of antibiotics, which can lead to ineffective antibiotic exposure and the potential emergence of resistant bacteria. The lack of studies describing antibiotic pharmacokinetics in critically ill children has led to significant off-label dosing. This is, in part, due to the ethical and physiological challenges of removing frequent, large-volume samples from children. Capillary microsampling facilitates the collection of small volumes of blood samples to conduct clinical pharmacokinetic studies. A sensitive, rapid, and accurate ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) bioanalytical method to measure cefotaxime and desacetylcefotaxime in 2.8 μL of plasma was developed and validated. Plasma samples were treated with acetonitrile and analytes were separated using a Kinetex C8 (100 × 2.1 mm) column. The chromatographic separation was established using a gradient method, with the mobile phases consisting of acetonitrile and ammonium acetate. An electrospray ionization source interface operated in a positive mode for the multiple reaction monitoring MS/MS analysis of cefotaxime, desacetylcefotaxime, and deuterated cefotaxime (internal standard). The bioanalytical method using microsample volumes met requirements for method validation for both analytes. Cefotaxime had precision within ± 7.3% and accuracy within ± 5% (concentration range of 0.5 to 500 mg/L). Desacetylcefotaxime had precision within ± 9.5% and accuracy within ± 3.5% (concentration range of 0.2 to 10 mg/L). The bioanalytical method was applied for the quantification of cefotaxime and its metabolite to 20 capillary microsamples collected at five time points in one dosing interval from five critically ill children.

Background: Biochemical markers of bone turnover (BTMs), such as the bone alkaline phosphatase (bALP), procollagen type I N propeptide (PINP), serum cross-linked C-telopeptides of type I collagen (bCTx), and urinary cross-linked N-telopeptides of type I collagen (NTx), are used to manage therapy monitoring in osteoporotic patients. This systematic review analyzed the potential of these BMTs in predicting the clinical outcomes in terms of BMD, t-score, rate of fractures, and adverse events during the therapy setting in postmenopausal osteoporosis., Methods: All randomized clinical trials (RCTs) reporting data on biomarkers for postmenopausal osteoporosis were accessed. Only articles reporting quantitative data on the level of biomarkers at baseline and on the outcomes of interest at the last follow-up were eligible., Results: A total of 36,706 patients were retrieved. Greater values of bALP were associated with a greater rate of vertebral (P = 0.001) and non-vertebral fractures (P = 0.0001). Greater values of NTx at baseline were associated with a greater rate of adverse events at the last follow-up (P = 0.02). Greater values of CTx at baseline were associated with a greater rate of adverse events leading to discontinuation (P = 0.04), gastrointestinal adverse events (P = 0.0001), musculoskeletal adverse events (P = 0.04), and mortality (P = 0.04). Greater values of PINP at baseline were associated with greater rates of gastrointestinal adverse events (P = 0.02) at the last follow-up., Conclusion: The present analysis supports the adoption of BMTs during pharmacological therapy setting of patients suffering from osteoporosis., Level of Evidence: I, systematic review of RCTs.

This paper aims to detect the expression levels of blood platelet (PLT) and C-reactive protein (CRP) in severely pneumonic patients and analyze their correlation. For this purpose, eighty-one severely pneumonic patients were retrospectively selected as an observation group and 106 healthy people as a control group. Pretreatment and post-treatment expression levels of PLT and CRP, their predictive values for efficacy, and correlation of PLT, CRP, and PSI scores in observation group after treatment were analyzed. Before treatment, the expression level of PLT in the observation group was higher than the control group (P< 0.05). In the observation group, the expression level of PLT after treatment was significantly lower than that before treatment (P< 0.05). Before treatment, the expression level of CRP in the observation group was higher than the control group (P< 0.05). In the observation group 1) the pretreatment PLT expression level was higher than that in the control group; 2) the post-treatment PLT expression level was significantly lower than that in the pretreatment one; 3) the pretreatment CRP expression level was higher than that in the control group; and 4) the post-treatment CRP expression level was significantly lower than the pretreatment one (All P-values< 0.05). Based upon the efficacy, the observation group was divided into an effective group and an invalid group. The post-treatment expression levels of PLT and CRP in the effective group were lower than those in the invalid group (P< 0.05). Based upon the ROC curve, the area under curves (AUC) of PLT, CRP, and joint detection were 0.843, 0.864, and 0.886, respectively. When the cut-off point was > 0.579, the best specificity and sensitivity were 98.44 and 70.59%, respectively. According to the Pearson test, positive correlations existed between PLT and CRP, between PLT and PSI scores, and between CRP and PSI scores. In conclusion, the expression levels of PLT and CRP in severely pneumonic patients might be used to evaluate the efficacy and conducive to detection of the disease, which have high application values in clinic.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The sensitivity of gas chromatography (GC) combined with the full evaporation technique (FET) for the analysis of aqueous samples is limited due to the maximum tolerable sample volume in a headspace vial. Using an acetone acetal as water scavenger prior to FET-GC analysis proved to be a useful and versatile tool for the analysis of high boiling analytes in aqueous samples. 2,2-Dimethoxypropane (DMP) was used in this case resulting in methanol and acetone as reaction products with water. These solvents are relatively volatile and were easily removed by evaporation enabling sample enrichment leading to 10-fold improvement in sensitivity compared to the standard 10μL FET sample volumes for a selection of typical high boiling polar residual solvents in water. This could be improved even further if more sample is used. The method was applied for the determination of residual NMP in an aqueous solution of a cefotaxime analogue and proved to be considerably better than conventional static headspace (sHS) and the standard FET approach. The methodology was also applied to determine trace amounts of ethylene glycol (EG) in aqueous samples like contact lens fluids, where scavenging of the water would avoid laborious extraction prior to derivatization. During this experiment it was revealed that DMP reacts quantitatively with EG to form 2,2-dimethyl-1,3-dioxolane (2,2-DD) under the proposed reaction conditions. The relatively high volatility (bp 93°C) of 2,2-DD makes it possible to perform analysis of EG using the sHS methodology making additional derivatization reactions superfluous., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To explore the influence of cefodizime on CD4/CD8 and T helper 1(Th1)/Th2 cell ratios in peripheral blood of the senile patients with bacterial pneumonia., Methods: Sixty-three senile patients with bacterial pneumonia were enrolled and divided into two groups randomly. Patients in the control group (n=31) were given intravenous infusion of ceftriaxone sodium, and patients in the observation group (n=32) were given intravenous infusion of cefodizime. The fasting venous blood was taken before and after treatment to detect CD4/CD8 and Th1/Th2 cell ratios with flow cytometry. At the same time, the serum interleukin-2 (IL-2), interferon γ (IFN-γ), IL-4 and IL-10 contents were also detected with ELISA., Results: Before treatment, there was no significant difference in the above indexes between the two groups. After treatment, CD4⁺ cells and Th1 cells of the observation group increased while Th2 cells decreased; as a result, the CD4/CD8 and Th1/Th2 cell ratios of the observation group were significantly higher than those of the control group. At the same time, serum IL-2 and IFN-γ contents of the observation group were significantly higher than those of the control group, while serum IL-4 and IL-10 contents were significantly lower than those of the control group., Conclusion: Cefodizime can improve the cellular immune function and rectify CD4/CD8 and Th1/Th2 imbalance in peripheral blood of the senile patients with bacterial pneumonia.

To know the interaction of cefodizime (CEF) with human serum albumin (HSA), techniques of different spectroscopies and molecular modeling were used. The inner filter effects were eliminated to get accurate binding parameters. Steady state fluorescence suggested a static type for CEF-HSA interaction, and the complex formation had a high affinity of 10(5) L mol(-1). On the basis of the thermodynamic results and site marker competitive experiments, it was considered that CEF was bound to site I (subdomain IIA) of HSA mainly by hydrogen bonds and van der Waals force. The calculated binding distance (r) indicated that the non-radioactive energy transfer came into being in the interaction between CEF and HSA. Furthermore, molecular modeling was applied to further define that CEF interacted with the Trp214, Lys199, Phe211, Leu238 residues of HSA. In addition, three-dimensional fluorescence and circular dichroism (CD) results showed that the binding of CEF can cause conformational and some microenvironmental changes of HSA. This paper provides reasonable models helping us further understand the transportation and distribution of CEF when it spreads into human blood serum which is of great importance in pharmacology and pharmacodynamics., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter-species scaling. While developing a tool to aid imaging agent and drug development, we aimed at accelerating the acceptance and broad use of PBPK modeling by providing a free mechanistic PBPK software that is user friendly, easy to adapt to a wide range of problems even by non-programmers, provided with ready-to-use parameterized models and benchmarking data collected from the peer-reviewed literature.

Background: Chronic hepatic inflammation is characterized by the accumulation of lymphocytes as a consequence of increased recruitment from the blood and retention within the tissue at sites of infection. CXC chemokine ligand 16 (CXCL16) mRNA has been detected in both inflamed and normal liver tissues and is strongly upregulated in the injured liver tissues in a murine model. The aim of this study was to investigate the effect of cefodizime on CXCL16 mRNA of liver tissues in mice with immunological hepatic injury., Methods: The murine model of immunological hepatic injury was induced by Bacillus Calmette Guerin and Lipoposaccharide. The mice with immunological hepatic injury were randomly assigned to the model group, the cefodizime group and the ceftriaxone group. The three groups were continuously given agents for seven days and CXCL16 mRNA of liver tissue was determined and contrasted with the control group treated by normal saline. Reverse transcription-polymerase chain reaction was used to assay CXCL16 mRNA levels in liver tissues., Results: The expressions of CXCL16 mRNA were significantly higher in the model group and the ceftriaxone group than in the control group and the cefodizime group (P < 0.05), indicating the mice in the model group and the ceftriaxone group were immunodeficient. There was no statistical difference in the expressions of CXCL16 mRNA between the control group and the cefodizime group. Similarly, no statistical difference in the expressions of CXCL16 mRNA between the model group and the ceftriaxone group was detected (P > 0.05)., Conclusion: Cefodizime effectively reduces the infiltration of lymphocytes into liver tissues and alleviates the liver damage by decreasing CXCL16 mRNA in liver tissues in mice with immunological hepatic injury.

Extracorporeal membrane oxygenation (ECMO) is used to temporarily sustain cardiac and respiratory function in critically ill infants but can cause pharmacokinetic changes necessitating dose modifications. Cefotaxime (CTX) is used to prevent and treat infections during ECMO, but the current dose regimen is based on pharmacokinetic data obtained for non-ECMO patients. The objective of this study was to validate the standard dose regimen of 50 mg/kg of body weight twice a day (postnatal age [PNA], <1 week), 50 mg/kg three times a day (PNA, 1 to 4 weeks), or 37.5 mg/kg four times a day (PNA, >4 weeks). We included 37 neonates on ECMO, with a median (range) PNA of 3.3 (0.67 to 199) days and a median (range) body weight of 3.5 (2.0 to 6.2) kg at the onset of ECMO. Median (range) ECMO duration was 108 (16 to 374) h. Plasma samples were taken during routine care, and pharmacokinetic analysis of CTX and its active metabolite, desacetylcefotaxime (DACT), was done using nonlinear mixed-effects modeling (NONMEM). A one-compartment pharmacokinetic model for CTX and DACT adequately described the data. During ECMO, CTX clearance (CL(CTX)) was 0.36 liter/h (range, 0.19 to 0.75 liter/h), the volume of distribution of CTX (V(CTX)) was 1.82 liters (0.73 to 3.02 liters), CL(DACT) was 1.46 liters/h (0.48 to 5.93 liters/h), and V(DACT) was 11.0 liters (2.32 to 28.0 liters). Elimination half-lives for CTX and DACT were 3.5 h (1.6 to 6.8 h) and 5.4 h (0.8 to 14 h). Peak CTX concentration was 98.0 mg/liter (33.2 to 286 mg/liter). DACT concentration varied between 0 and 38.2 mg/liter, with a median of 10 mg/liter in the first 12 h postdose. Overall, CTX concentrations were above the MIC of 8 mg/liter over the entire dose interval. Only 1 of the 37 patients had a sub-MIC concentration for over 50% of the dose interval. In conclusion, the standard cefotaxime dose regimen provides sufficiently long periods of supra-MIC concentrations to provide adequate treatment of infants on ECMO.

Microemulsions (MEs) and mixed micelles (MMs) have been used as new drug formulations for high hydrophilic drugs such as cefpirom and cefodizim for oral administration. Cefpirom and cefodizim are neither actively nor passively transported across cell membranes. Up to date, they can be only administrated intravenously (i.v.) or intramuscularly (i.m.). The rabbit (Chinchilla) in vivo model was used in the present work to investigate ways of overcoming the poor oral absorption of these cephalosporins. The cephalosporins at 100mg/kg were formulated in MEs and MMs and administered intraduodenally (i.d.). Very low bioavailability (2.5-3.0%) was observed, if cefpirom or cefodizim i.d. were applied without colloidal vehicle. However, the addition of the cephalosporins to ME or MM is shown to be highly effective in increasing the bioavailability values (up to 64% absolute bioavailability) of the model drugs. In conclusion, MEs and MMs improve essentially the oral bioavailability of the high hydrophilic drugs., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

To ascertain recommendations for the treatment of gonorrhoea in the WHO Western Pacific Region (WPR) following the emergence of "cephalosporin-resistant" Neisseria gonorrhoeae and to relate these to clinical and laboratory measures directed towards disease and antibiotic resistance control. WHO WPR Gonococcal Antimicrobial Resistance Programme members provided data on the type, dose and source of third-generation cephalosporins recommended for the treatment of gonorrhoea. Ceftriaxone was recommended more widely (11/15 respondents) than cefixime (five centres). No cephalosporins were recommended in three jurisdictions. One other oral (ceftibuten) and injectable (cefodizime) agent was recommended. Uniform (400 mg) doses of cefixime were recommended but ceftriaxone regimens ranged between 125 mg and 1 g, with nine of 11 respondents using a 250 mg dose. Both generic and proprietary preparations were widely used. Third-generation cephalosporins are widely recommended for the treatment of gonorrhoea in the WPR, with injectable ceftriaxone more extensively so than oral cefixime and in an expanded dose range. Few other cephalosporins were recommended. Current knowledge suggests that the trend towards ceftriaxone treatment in higher doses may decrease the impact of the circulation of "cephalosporin-resistant" gonococci in the WPR. These recommendations represent public sector practice only and of themselves are unlikely to contain the further spread of "cephalosporin-resistant" gonococci because of the general clinical use of cephalosporins. Optimisation of strategies for laboratory detection of third-generation cephalosporin resistance can be simplified in the WPR because of the restricted spectrum of cephalosporins recommended. Additional efforts are urgently required for both disease and antibiotic resistance control in gonorrhoea.

Preterm premature rupture of the membranes is associated with a high risk of neonatal sepsis. An increase in the incidence of early-onset neonatal sepsis due to ampicillin-resistant Escherichia coli in premature infants has been observed in the past few years. Intrapartum prophylaxis with ampicillin has proven to be efficient for the prevention of early neonatal sepsis due to group B streptococci. To date, there is no strategy for the prevention of early neonatal sepsis due to ampicillin-resistant E. coli. Our aim was to investigate whether a standardized dosage regimen of intrapartum cefotaxime could provide concentrations in the cord blood greater than the cefotaxime MIC(90) for E. coli. Seven pregnant women hospitalized with preterm premature rupture of the membranes and colonized with ampicillin-resistant isolates of the family Enterobacteriaceae were included. Cefotaxime was given intravenously during delivery, as follows: 2 g at the onset of labor and then 1 g every 4 h until delivery. Blood specimens were collected from the mother 30 min after the first injection and just before the second injection, and at birth, blood specimens were simultaneously collected from the mother and the umbilical cord. The concentrations of cefotaxime in the cord blood ranged from 0.5 to 8.5 mg/liter. The MIC(90) of cefotaxime for E. coli strains (0.125 mg/liter) was achieved in all cases. This preliminary study supports the use of cefotaxime for intrapartum prophylaxis in women colonized with ampicillin-resistant isolates of Enterobacteriaceae. The effectiveness of this regimen for the prevention of neonatal sepsis needs to be evaluated with a larger population.

Objectives: Cefodizime is a broad spectrum cephalosporin belonging to the third generation agents. In this study, attention has been paid to the preparation, physicochemical characterization and biological evaluation of new Cu2+, Zn2+, Fe3+, Co2+ and Al3+ complexes of cefodizime., Methods: The stoichiometrics and the mode of bonding of the complexes were deduced from their elemental and metal analysis, electrical conductivity measurements, UV-vis, infrared and Raman spectroscopic investigations. Study of the stoichiometry of these complexes referred to the formation of 1 : 1 ratios of metal to ligand. Antimicrobial activity of the complexes was determined using two strains of Gram-positive (Bacillus subtilis and Proteus vulgaris) and two strains of Gram-negative (Escherichia coli W3110 and Pseudomonas putida) bacteria. The minimal inhibitory concentration was determined as the lowest concentration inhibiting bacterial growth on solid Luria Bertani medium., Key Findings: The spectra gave evidence as to the position of binding. In addition, the aqueous solubility of cefodizime was strongly reduced by complexation., Conclusions: The antibacterial activity of cefodizime was not affected by complexation with Al3+ but it was reduced by complexation with the other tested metal ions against the bacteria under study.

Objectives: The aim of this study was to determine the steady-state plasma and peritoneal concentrations of cefotaxime and its metabolite desacetyl-cefotaxime administered by continuous infusion to critically ill patients with secondary peritonitis., Patients and Methods: In 11 patients, a continuous infusion of 4 g/24 h of cefotaxime following a bolus of 2 g was evaluated. Plasma and peritoneal levels of cefotaxime and desacetyl-cefotaxime were measured at steady state on days 2 and 3 (plasma) and on day 3 (peritoneal) by HPLC. Results are expressed as means +/- SD., Results: Total and unbound plasma levels of cefotaxime were 24.0 +/- 21.5 and 20.3 +/- 19.8 mg/L on day 2 and 22.1 +/- 20.7 and 18.9 +/- 19.2 mg/L on day 3, respectively. Total and unbound levels of cefotaxime in the peritoneal fluids were 16.2 +/- 11.5 and 14.3 +/- 10.4 mg/L, respectively. The unbound fraction of plasma cefotaxime was 81.8 +/- 5.9% on day 2 and 82.6 +/- 7.7% on day 3, and the unbound fraction at the peritoneal site was 87.0 +/- 5.5% on day 3. Total and unbound plasma levels of desacetyl-cefotaxime were 9.0 +/- 8.1 and 8.4 +/- 8.1 mg/L on day 2 and 7.6 +/- 7.6 and 7.2 +/- 7.6 mg/L on day 3, respectively. Total and unbound levels of desacetyl-cefotaxime in the peritoneal fluids were 11.9 +/- 11.5 and 10.9 +/- 10.8 mg/L, respectively. The MICs for the enterobacteria recovered ranged from 0.016 to 0.25 mg/L., Conclusions: Continuous infusion of 4 g/24 h of cefotaxime provided a peritoneal concentration >5x MIC for the recovered Enterobacteriaceae and the susceptibility breakpoint of cefotaxime for facultative Gram-negative bacilli.

Tyrosinase (EC 1.14.18.1) catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones that form brown or black pigments. In the present paper, the effects of Cefazolin and Cefodizime on the activity of mushroom tyrosniase have been studied. The results showed that the Cephalosporin antibacterial drugs (Cefazolin and Cefodizime) could inhibit both monophenolase activity and diphenolase activity of the enzyme. For the monophenolase activity, Both Cefazolin and Cefodizime could lengthen the lag time and decrease the steady-state activities, and the IC(50) values were estimated as 7.0 mM and 0.13 mM for monophenolase activity, respectively. For the diphenolase activity, the inhibitory capacity of Cefodizime was obviously stronger than that of Cefazolin, and the IC(50) values were estimated as 0.02 mM and 0.21 mM, respectively. Kinetic analyses showed that inhibition by both compounds was reversible and their mechanisms were competitive and mixed-type, respectively. Their inhibition constants were also determined and compared. The research may offer a lead for designing and synthesizing novel and effective tyrosinase inhibitors and also under the application field of Cephalosporins.

The objective of this study was to evaluate whether pharmacokinetic parameters (clearance and volume of distribution of the central compartment) from a sparse sampling population pharmacokinetic study can be obtained with a very small sample size. For this study, three drugs were selected from the literature. The pharmacokinetics of all three drugs were studied in healthy adult subjects and plasma concentrations versus time data for individual subjects from extensive blood sampling were available. For population PK analysis, only five subjects were chosen and each subject gave either one or two blood samples. The estimated PK parameters from population PK analysis were compared with the PK parameters obtained from extensive sampling. The results of the study indicated that a reasonable estimate of PK parameters can be obtained with two blood samples from each subject with a sample size of five. The population PK study with sparse sampling scheme may be useful for PK studies in neonates and very young children and in subjects with rare diseases where sample size is small.

Rational dosing of antibiotics in neonates should be based on pharmacokinetic (PK) parameters assessed in specific populations. PK studies of neonates are hampered by the limited total plasma volume, which restricts the sample volume and sampling frequency. Available drug assay methods require large sample volumes and are labor-intensive or time-consuming. The objective of this study was to develop a rapid ultra-performance liquid chromatographic method with tandem mass spectrometry detection for simultaneous quantification of amoxicillin, meropenem, cefazolin, cefotaxime, deacetylcefotaxime, ceftriaxone, and vancomycin in 50 microl of plasma. Cleanup consisted of protein precipitation with cold acetonitrile (1:4) and solvent evaporation before reversed-phase chromatographic separation and detection using electrospray ionization tandem mass spectrometry. Standard curves were prepared over a large dynamic range with adequate limits of quantitation. Intra- and interrun accuracy and precision were within 100% +/- 15% and 15%, respectively, with acceptable matrix effects. Coefficients of variation for matrix effects and recovery were <10% over six batches of plasma. Stability in plasma and aqueous stocks was generally sufficient, but stability of meropenem and ceftriaxone in extracts could limit autosampler capacity. The instrument run time was approximately 3.50 min per sample. Method applicability was demonstrated with plasma samples from an extracorporeal membrane oxygenation-treated neonate. Different beta-lactam antibiotics can be added to this method with additional ion transitions. Using ultra-performance liquid chromatography mass spectrometry, this method allows simple and reliable quantification of multiple antibiotics in 50 microl of plasma for PK studies of neonates.

Two rapid, accurate and sensitive methods are developed and validated for the quantitative simultaneous determination of cefotaxime (CFX) and its active metabolite desacetylcefotaxime (DCFX) in urine. Based on the previous results which showed the four electron reduction of CFX at approximately -0.5 V, and the new findings that DCFX reduction occurred at more positive potential (-0.23 V), the new adsorptive stripping differential pulse voltammetric (AdSDPV) method was developed for determination of CFX in the presence of DCFX. Linear responses were observed over a wide concentration range (0.07-0.52 microg/ml for CFX and 0.22-1.3 microg/ml for DCFX) in urine. The second assay involves subsequent separation on a reversed-phase HPLC column, with ultraviolet detection at 262 nm. Retention times were 4.057 and 1.960 min for CFX and DCFX, respectively. Linear responses were observed over a wide range, 0.55-6.60 microg/ml for CFX and 1.10-11.00 microg/ml for DCFX, in urine. The statistical evaluation for both methods was examined by means of within-day repeatability (n=5) and day-to-day precision (n=3) and was found to be satisfactory with high accuracy and precision.

A single dose of cefodizime (CDZM), ceftriaxone (CTRX), or spectinomycin (SPCM) is recommended for the treatment of gonococcal urethritis or uterine cervicitis in the era of multidrug-resistant Neisseria gonorrhoeae; namely, cefozopran-resistant N. gonorrhoeae (CZRNG). N. gonorrhoeae pharyngeal infection is not so rare in Japan; however, the proper treatment regimen for this infection is not clear. We previously found that a single dose of CDZM completely eradicated multidrug-resistant N. gonorrhoeae in patients with urethritis and uterine cervicitis, so we tried a single 1.0-g dose of CDZM for the treatment of N. gonorrhoeae pharyngeal infection, including infections with CZRNG. The eradication rate of N. gonorrhoeae from the pharynx was 63.0% with a single 1.0-g dose of CDZM, while the rate for CZRNG with the same dose of CDZM was 38.5%. N. gonorrhoeae was completely eradicated from the pharynx when patients received one or two additional doses of CDZM. Therefore, we concluded that two to three doses of CDZM were necessary for the treatment of N. gonorrhoeae pharyngeal infection including infection with CZRNG.

The effects of ciprofloxacin, cefodizime, rifampicine, doxycycline and cefodizime + rifampicine combination on polymorphonuclear leukocyte (PMN) functions (phagocytosis and intracellular killing activity) were investigated in vitro in elderly patients and compared with those of healthy young volunteers before and after zinc supplementation. PMNs of 13 elderly hypertensive patients and 10 healthy young volunteers were isolated by Ficoll-Hypaque gradient centrifugation method from venous blood with EDTA. The subjects were given 22 mg/daily/oral zinc supplementation for 1 month. Serum zinc levels before and after supplementation were measured by flame atomic absorbtion spectrophotometer and the effects of each drug on PMN functions at therapeutic concentrations were investigated. Ciprofloxacin significantly increased the PMN's phagocytic activity of elderly patients (p = 0.002) before zinc supplementation and significantly increased both PMN functions of elderly patients (p = 0.002) after zinc supplementation. The same antibiotic significantly increased both PMN functions of healthy young volunteers (p = 0.005 and p<0.05, respectively) before and after zinc supplementation when compared with the control (drug-free). Cefodizime significantly increased the PMN's phagocytic activity of elderly patients (p = 0.003, p = 0.002) before and after zinc supplementation when compared with the control (drug-free). It also significantly increased both PMN functions of healthy young volunteers (p = 0.005 and p<0.05, respectively) before and after zinc supplementation when compared with the control (drug-free). Doxycycline significantly increased PMN's intracellular killing activity of healthy young volunteers before zinc supplementation (p<0.05) when compared with the control (drug-free) values. Rifampicine significantly decreased PMN's phagocytic activity of elderly patients (p<0.05) after zinc supplementation. Cefodizime+rifampicine combination significantly increased PMN's phagocytic activity at therapeutic concentrations of healthy young volunteers (p = 0.005) before zinc supplementation and PMN's phagocytic activity of elderly patients (p<0.05) after zinc supplementation when compared with the control (drug-free). Consequently, in the present study from the antibiotics ciprofloxacin, cefodizime and cefodizime + rifampicine combination, which are accepted as biological response modifiers have demonstrated stimulatory effects by significantly increasing polymorphonuclear leucocyte functions (phagocytosis and/or intracellular killing activity) of elderly patients and healthy young volunteers in vitro before and after zinc supplementation. Additionally zinc supplementation has more immunostimulatory effects on PMN functions of healthy young volunteers than elderly patients.

Cefodizime (CDZM) has strong antimicrobial activity to Neisseria gonorrhoeae in vitro. However, multidrug-resistant N. gonorrhoea emerged and has been increasing in Japan. To know the effectiveness of CDZM on gonococcal urethritis and uterine cervicitis even in the era of multidrug-resistant N. gonorrhoeae, a clinical trial of single-dose therapy of CDZM for gonococcal urethritis and uterine cervicitis was conducted. N. gonorrhoeae was eradicated from 100% of patients with gonococcal urethritis and uterine cervicitis by a single dose of CDZM. In conclusion, CDZM is one of most suitable drugs for the treatment of gonococcal genital infection in the era of multidrug-resistant N. gonorrhoeae.

Cefodizime is an extended-spectrum third-generation cephalosporin antibiotic that is widely used in the treatment of severe infections of the respiratory and urinary tracts. Pharmacokinetic characteristics of cefodizime were assessed in 13 critically ill elderly patients (median age 73+/-6 years). The mean cefodizime peak serum concentration following a single 2g cefodizime infusion was 219+/-58 mg/L and the mean trough level 12 h after infusion was 29+/-17 mg/L. The elimination half-life was 6.19+/-2.45 h. Total body clearance, area under the plasma concentration-time curve and volume of distribution were 35.8+/-13.2 mL/min, 1089.4+/-505.3 mg h/L and 17.4+/-6.3 L, respectively. Pharmacokinetics of cefodizime in critically ill elderly patients were comparable with those reported previously in healthy volunteers.

A method for the simultaneous determination of cefotaxime (CTX) and desacetylcefotaxime (DES) in plasma was developed, using acetonitrile protein precipitation and high-performance liquid chromatography (HPLC) with UV-detection at 285 nm. Desacetylcefotaxime was also analysed after conversion in highly acidic medium to its lactone form (DES-lactone). The chromatographic separation was performed on a C18 Aqua column. The lower limit of quantitation was 1 microg/ml for CTX and 0.5 microg/ml for DES and DES-lactone, using 25 microl of plasma samples. The linearity of the calibration curves was satisfactory as indicated by correlation coefficients of > or =0.990. The within-day and between-day precisions were <12% (n = 18) for the two products and the accuracy was between 88 and 101%. The developed HPLC method was applied for CTX and DES determination in plasma samples of critically ill patients after continuous intravenous infusion of CTX.

In the development of novel antibiotics, more and more compounds have been found that cannot be absorbed orally and, therefore, must be administered intravenously or intramuscularly. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability has received much attention in pharmaceutical research. Cefodizime, a novel third-generation cephalosporin with significant advantages in the parenteral treatment of common infections, was used as a model drug. Cefodizime behaves as a highly hydrophilic compound, as shown from its extremely low partition coefficient. The effect of cationic absorption enhancers (hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide) on the lipophilicity of cefodizime was investigated by means of the n-octanol/water system. Results showed that the counter-ions had a positive influence on the solubility of cefodizime. These results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in-vitro transport model with artificial and biological membranes (Caco-2-cells). Furthermore, the physiological compatibility of the absorption enhancers was investigated using the active D-glucose transport. The pharmacokinetic profile of cefodizime was evaluated in rabbits after intraduodenal administration with and without an absorption enhancer.

Objective: To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients., Methods: Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach., Results: Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data., Conclusion: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

To explore the immunoregulating effects of cefodizime on neutrophils and its mechanisms, we detected the expression of some cytokines secreted by neutrophils after heat-killed Klebsiella pneumoniae induced inflammation. We analyzed the changes of signal transduction in this process by detecting the mRNA expression of toll like receptor 4 (TLR4) and the inhibitor factor of kappaBalpha (I-kappaBalpha) expressed by neutrophils. The activity of nuclear factor kappaB (NF-kappaB) in neutrophils was also assayed by electrophoretic mobility shift assay (EMSA). We found cefodizime increased neutrophil production of TNF-alpha, IL-1beta in the early stage of inflammation, which was in agreement with the enhanced mRNA expression of TLR4 and DNA-binding activity of NF-kappaB. Taken together, the immunomodulating effects of cefodizime on cytokine production of K. pneumoniae stimulated neutrophils is possibly due to its regulation of TLR4 mRNA expression and DNA binding activities of NF-kappaB through the LPS-TLR4-NF-kappaB pathway.

Clostridium difficile is recognized as an important nosocomial pathogen. C. difficile infection (CDI) is thought to arise as a result of depletion of the normal gut flora by antimicrobial agents. Cefotaxime (CTX) is well-known for its propensity to cause CDI, but the reasons behind its particular predisposition to the disease remain unclear. Previous investigations have so far relied upon the hamster model of CDI or human volunteers. We have used a triple-stage chemostat model of the human gut to investigate the behaviour of C. difficile and components of the normal gut flora, in response to exposure to CTX alone, and in combination with its active metabolite desacetylcefotaxime (dCTX). C. difficile remained in a steady state during non-antibiotic exposed periods, with no detectable cytotoxin. During both antibiotic exposure regimens, proliferation of C. difficile and elevated cytotoxin levels were observed. Cessation of antibiotic instillation produced a reduction in cytotoxin levels and viable counts. Decreases in bacterial counts were observed in response to both antibiotic exposure regimens, notably for bifidobacteria and bacteroides. Numbers of bacteroides were profoundly affected by exposure to the CTX/dCTX combination, and this may indicate a possible role for bacteroides in colonization resistance. We believe that the gut model is a promising method for studying C. difficile pathogenesis in conditions analogous to the in vivo situation.

Objective: To describe an outbreak of acute renal failure (ARF) occurring in a group of patients undergoing open-heart surgery, simultaneously to a change in perioperative antibiotic prophylaxis., Design: Case series., Setting: A nine-bed heart surgery intensive care unit, serving a 1,300-bed University teaching hospital., Patients: Thirty-two patients undergoing open-heart surgery during an 11-day period, when the preoperative surgical prophylaxis protocol had been changed from the usual antibiotic association of ceftriaxone + vancomycin to cefodizime + vancomycin., Results: ARF occurred in 16 of the 32 (50%) patients exposed to the new antibiotic prophylaxis regimen; seven patients had oliguric ARF, and nine patients had an increase in serum creatinine (SCr) levels >50% over 24-48 h. In the seven patients with oliguric ARF, SCr increased from a median preoperative level of 88 micromol/l (80-115 micromol/l) to a peak value of 725 micromol/l (521-857 micromol/l) in 5 days (4-6). Eight patients out of the sixteen with ARF (50%) were diabetics, as opposed to none of the 16 patients not experiencing ARF. Renal biopsy (three patients) showed tubular dilation and necrosis, interstitial edema, and lymphomononuclear infiltrate of moderate degree. Only one patient required hemodialysis, and all recovered renal function. No other cases of unexplained ARF occurred in the unit after the original prophylaxis protocol was resumed., Conclusion: The simultaneous infusion of cefodizime and vancomycin may involve a high risk of substantial renal function derangement, especially in diabetics.

The in vitro effect of amikacin (8 microg/ml), imipenem (30 microg/ml), cefodizime (10 microg/ml), interferon alpha-2a (IFNalpha-2a) (10 IU/ml) and antibiotic combinations with IFNalpha-2a on polymorphonuclear leukocyte (PMN) functions (phagocytosis and intracellular killing of Candida albicans blastospores) was investigated in chronic hepatitis B patients. Phagocytosis and candidacidal activity was not affected after pretreatment of PMNs with amikacin and imipenem (p > 0.05). Phagocytic activity was enhanced after pretreatment of PMNs with cefodizime and IFNalpha-2a compared with that of control PMNs (p < 0.05), but candidacidal activity was not affected by the same drugs (p > 0.05). Phagocytic and intracellular activity of PMNs were not affected by combinations of IFNalpha-2a and antibiotics (p > 0.05).

The stability of the lyophilized substance of cefodizime disodium was investigated. The test for the stability in solid state with and without presence of humidity was arried out by the HPLC method. Kinetic and thermodynamic parameters of the decomposition reaction were calculated.

Cefodizime has modulating effects on the release of diverse cytokines. We determined the modulator activity of this antibiotic on the production of TNF in human monocytic U-937 cells. The measurement of TNF was carried out by ELISA test and by a L-929 cells-based citotoxic bioassay. The results showed that cefodizime alone induced the production of TNF on U-937 cells, however, the addition of LPS led to a decrease in the release of this cytokine (p < 0.05). On the other hand, the combination of cefodizime-PMA had a synergic effect (p < 0.05), while addition of LPS to this combination caused a decrease of TNF production (p < 0.05). With these results we conclude that cefodizime modulates the production of TNF in U-937 cells, which is down regulated by the addition of LPS.

A simple and sensitive HPLC method for the simultaneous determination of cefotaxime (I) and desacetylcefotaxime (II) in human plasma and cerebrospinal fluid (CSF) is described. The assay involves deproteinisation and subsequent separation on a reversed-phase HPLC column, with ultraviolet detection at 262 nm. Retention times were 6.8 and 2.2 min for cefotaxime and desacetylcefotaxime, respectively. Average recoveries for the analytes were 78% (I) and 88% (II) from both matrices. Linear responses were observed over a wide range (0.58-940 microg/ml for (I) in plasma, 0.80-55.8 microg/ml for (I) in CSF, 0.54-148 microg/ml for (II) in plasma and 0.50-36.0 microg/ml for (II) in CSF).

The duration of time that serum levels are above the minimum inhibitory concentration (MIC; T >MIC) seems to be an important pharmacodynamic parameter for beta-lactams. The aim of this study was to evaluate the bactericidal activity of cefodizime and ceftriaxone in a pharmacokinetic model mimicking the concentrations in bronchial mucus and in serum (total and free) obtained at 2, 4, 8, 12 and 24 h, after 1 g i.m. administration once daily. The species investigated were respiratory pathogens (1 strain of Staphylococcus aureus, 2 strains of Streptococcus pneumoniae, 1 strain b-lactamase negative and 1 strain beta-lactamase positive of Haemophilus influenzae, 1 strain of Escherichia coli and 1 strain of Klebsiella pneumoniae); MIC50s of the chosen strains were reported. In this in vitro model the concentrations (serum and bronchial mucus) for both antibiotics are generally at or above the MIC values of the tested strains until 24 hours. The killing curve showed rapid killing for both antibiotics: 99.9% killing (a 3-log reduction in growth) within 6 to 8 h, depending upon the microorganism tested. There was no significant difference in the log kill between cefodizime and ceftriaxone. These data confirm that T >MIC for beta-lactams is the pharmacodynamic parameter which best correlates with bactericidal efficacy. On the basis of the killing curve determined for cefodizime versus ceftriaxone at concentrations that these antibiotics can reach during therapy with 1 g i.m. once daily we expect reasonable clinical efficacy with monoadministration of cefodizime as well as for ceftriaxone in respiratory tract infections.

Cefodizime is a third generation cephalosporin for parenteral use. The pharmacokinetics of this cephem antibiotic were determined in serum and skin suction blister fluid (SBF) after intravenous (i.v.) or intramuscular (i.m.) administration of a single 1 g dose in 8 adult patients with normal renal and hepatic function who volunteered for the study. The concentration versus time curve showed a slower elimination rate from the extravascular compartment: the half-lives were 4.4+/-0.5 and 5.4+/-0.4 hours after i.v. and i.m. route respectively. The relatively long elimination half-life in SBF with a mean residence time of about 8 hours allows the use of cefodizime once-a-day for the treatment of infections due to sensitive pathogens.

The influence of Cefodizime (CDZ) on in vitro activity of polymorphonuclear leukocytes (PMNL) from healthy subjects was assessed. Preincubation with CDZ enhanced phagocytosis and intracellular killing of Staphylococcus aureus by PMNL. Contrary to numerous clinical reports, no significant effect of CDZ preincubation on PMNL response to n-formyl-methionyl-leucyl-phenylalanine was found with respect to intracellular calcium changes, degranulation, hydrogen peroxide production, and chemiluminescence. These results suggest that augmented microbicidal activity of PMNL is not related to the enhanced production of reactive oxygen species in healthy subjects.

The molecular array of the outermost surface of bacteria and their physico-chemical characteristics modulate various functions which, when expressed in terms of the human environment, are generally known as factors of bacterial virulence. The present study investigated the ability of sub-MIC concentrations of cefodizime to interfere with the virulence factors of Escherichia coli. Bacterial adhesiveness to human epithelial cells was inhibited down to 1/32 x MIC of cefodizime, an antibiotic that is also capable of inducing the widespread production of filamentous forms at levels ranging from 1/2 to 1/8 x MIC. Given that this interfered with the correct evaluation of other virulence parameters, the study was extended to consider the effects of 1/16 to 1/128 x MIC. Sub-MIC concentrations of cefodizime inhibit haemagglutination, hydrophobicity and electrophoretic mobility, which are correlated with each other and provide clues relating to the physico-chemical characteristics of the outer surface. Cefodizime also reduces swarming. Phagocytosis was not affected but killing increased significantly. Oxidative bursts investigated by a chemiluminescence procedure were not modified. The interpolation of these pharmacodynamic findings with pharmacokinetic curves indicates that the effect of sub-MIC concentrations of cefodizime can prolong antimicrobial effects on virulence determinants up to 12 h after the antibiotic concentration has fallen below the MIC value.

The MIC and MSC (minimum spirocheticidal concentration) and killing rate for Borrelia burgdorferi, the etiological agent of Lyme disease, were assessed for cefodizime in comparison with ceftriaxone, minocycline, azithromycin, roxithromycin, and ciprofloxacin. The range of cefodizime MICs was greater than those of azithromycin and roxithromycin but comparable to those of ceftriaxone and minocycline. The MSCs were 1 to 2 dilutions higher than the MICs of all of the tested compounds. The killing curves of cefodizime and ceftriaxone showed parallel courses. In conclusion, cefodizime exerted an activity comparable to that of ceftriaxone against B. burgdorferi.

In this manuscript, our recent studies on the transporters on the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the excretion of ligands from the central nervous system (CNS) to the blood are summarized. By comparing the brain entry of quinidine in normal and mdr 1a knock out mice, the predominant role of P-glycoprotein in the brain distribution of this compound was demonstrated. In addition to P-glycoprotein, the presence of transporters responsible for the efflux of organic anions from the brain has been suggested by a pharmacokinetic analysis of the CNS distribution of cefodizime, a third generation cephalosporin antibiotic. This suggestion was confirmed by demonstrating the presence of a specific mechanism for the elimination of p-aminohippuric acid from the brain after microinjection into the cerebral hemisphere. In vitro, the energy-dependent luminal preferential efflux of glutathione-bimane was demonstrated in a monolayer of MBEC4 cells which were derived from mouse brain endothelial cells. Studies with isolated membrane vesicles from MBEC4 cells suggested the presence of a primary active transporter(s) for organic anions, and Western blot analysis indicated the presence of multidrug resistance associated protein (MRP1) and/or its related transporters on MBEC4 cells and freshly isolated rat cerebral endothelial cells. The transcellular transport of 17beta estradiol 17beta-D-glucuronide (E(2)17betaG) across the choroid plexus was also demonstrated by examining the efflux of this compound from CSF after intracerebroventricular administration. The functional significance of organic anion transporting polypeptide (oatp-1) on the brush border membrane of the choroid plexus was demonstrated by comparing the uptake of E(2)17betaG into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in addition, reverse transcription-polymerase chain reaction and Western blot analysis indicated the presence of MRP in the choroid plexus. Together with the direction of transcellular transport, the basolateral localization of MRP on the choroid plexus was suggested. By regulating the activity of these efflux transporters, it is possible to improve the brain entry of certain substrates.

We have prospectively studied 13 episodes of spontaneous bacterial peritonitis (SBP) in 12 patients treated with cefotaxime (CTX) 2 g intravenously every 8 h (mean duration, 5.3 days). Ascitic fluid was inoculated at the bedside. The cultures were done before, during (day 3 after CTX initiation), and 48-72 h (mean, 56 h) after the end of therapy. All SBP episodes were monomicrobial. During treatment, the concentrations of CTX and desacetyl-cefotaxime (d-CTX) in ascitic fluid were high in all 13 SBP episodes, and d-CTX was still present in 6 patients who had residual ascitic bactericidal titer (ABT) activity after the last dose of CTX. ABTs were >/=1:128 during CTX therapy in 12 episodes and were measurable in 7 patients after the last dose. All patients were cured. The present study provides scientific rationale to the clinical studies that suggest treating SBP episodes with lower doses of antibiotics and shorter treatment duration.

Immunoglobulin A (IgA) nephropathy, the most common cause of glomerulonephritis worldwide, is usually idiopathic in origin and renal limited. Secondary IgA nephropathy has been associated with systemic disease, including such gastrointestinal tract disturbances as celiac sprue and inflammatory bowel disease. We describe gross hematuria and reversible acute renal failure from IgA nephropathy in a patient with cephalosporin-induced Clostridium difficile colitis. In addition to mesangial IgA and C3 deposition, renal histological examination showed glomerular bleeding, intratubular red blood cell casts, and acute tubular necrosis. To the best of our knowledge, this is the first report of an association between IgA nephropathy and C difficile colitis.

Encapsulated Klebsiella pneumoniae strains frequently induce fatal nosocomial pneumonia. Cefodizime (CEF) as an antibiotic is suspected to enhance host resistance against various microbial invasions through interactions with bacteria and host cells. To investigate the influence of CEF on the pulmonary response to Klebsiella that does not merely result from direct bacterial clearance by the drug, we inoculated mice with heat-killed fluorescein isothiocyanate-labeled K. pneumoniae. CEF upregulated (P < 0.01) the early Klebsiella-induced secretion of tumor necrosis factor alpha, as well as the number (P < 0.01) and phagocytic efficacy (P < 0.001) of alveolar macrophages. By contrast, the late polymorphonuclear neutrophil recruitment (P < 0.05) and levels of interleukin-1 alpha (IL-1alpha) (P < 0.05) and IL-6 (P < 0.05) were reduced. The stimulation of an early immune response by CEF followed by late reduction in inflammation may be beneficial against bacterial pneumonia.

Objective: The objective of this study was to perform a prospective, randomized, controlled study to evaluate the role of azithromycin and cefixime in the treatment of uncomplicated non-typhoid Salmonella enteritis in children., Methodology: Patients with Salmonella enteritis were randomized to receive oral azithromycin (10 mg/kg/day once daily), cefixime (10 mg/kg/day divided twice daily) or no antibiotics for 5 days. The patients were followed up for the duration of their symptoms. Stool samples were sent for culture weekly following the therapy until two consecutive negative results were obtained. Susceptibility of the isolates to antibiotics was tested by the disk diffusion method., Results: Forty-two patients with acute, uncomplicated, culture-confirmed Salmonella enteritis were studied. Duration of diarrhoea and time to defervescence after the therapy were not significantly different for patients treated with azithromycin, cefixime, or no antibiotics; there also were no significant differences with respect to the rate of clearance of Salmonella from stools among the three groups. Salmonella typhimurium was the most common serotype isolated. All 42 isolates were sensitive to cefixime, while two strains (5%) were resistant to azithromycin., Conclusion: Azithromycin or cefixime provides no benefit to paediatric patient with uncomplicated Salmonella enteritis.