The prognostic value of the antibiogram.
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Amniotic Fluid↗
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Meningitis due to Micrococcus luteus.
We are presenting a new case of meningitis due to the Micrococcus luteus species. This germ was isolated twice in eight days from the CSF of a 57-year old woman. The patient had a ventriculoperitoneal shunt implanted for hydrocephalus following a meningeal haemorrhage. Antibiotic therapy was efficient but the patient died of a recurrent haemorrhage.
Amoxicillin↗
Studies on drug monitoring in thrice and once daily treatment with aminoglycosides.
OBJECTIVES: To investigate at what time the peak level should be determined under conventional thrice daily (t.i.d.) administration of the aminoglycoside netilmicin and to study its serum concentrations under once daily (od) treatment to define the required daily dose and to gain information about convenient drug monitoring. DESIGN: The design of the study was a consecutive sample trial. SETTING: The study took place in a university hospital. PATIENTS: 41 intubated patients of a surgical ICU who received netilmicin as a short-term infusion over 30 min for life-threatening infections were included in the study. INTERVENTIONS: In 21 patients netilmicin was administered t.i.d. The virtual peak levels which had been determined by pharmacokinetic dosage calculation were compared with the serum concentrations obtained directly after the administration as well as after 15, 30, 60 and 180 min. In 20 patients the netilmicin serum concentrations during od treatment were determined directly before and immediately after the application as well as 0.5, 1, 3, 7 and 12 h later. To achieve a virtual peak level of 25 mg/l and a trough level of 0.5 mg/l individual adjustment of the dosage based on pharmacokinetic calculations was performed. MEASUREMENTS AND RESULTS: In t.i.d. treatment the serum concentration measured after 30 min was closest to the virtual peak level; therefore, this is the best time to determine the peak level. In od treatment the required daily dose was 7.86 mg/kg body weight (median) in patients with normal renal function. During od dosing the trough level was extremely important in drug monitoring, whereas determination of the high peak level was of doubtful value. CONCLUSIONS: The peak level should be determined during t.i.d. administration at 30 min. In od treatment the initial daily dose should be 7 mg/kg body weight; in drug monitoring the trough level is very important.
Adolescent↗
Pharmacokinetics and metabolism of fosmidomycin, a new phosphonic acid, in rats and dogs.
The absorption, distribution, metabolism, and excretion of 3-(N-formylhydroxylamino) propylphosphonic acid monosodium salt (fosmidomycin), a new antibiotic, were investigated in rats and dogs after i.v. and oral dosing. After i.v. administration of 10 mg/kg of body weight, [14C]-fosmidomycin was excreted mainly in the urine (about 90% of dose within 72 h); and only a little was excreted in the expired air (14CO2) and bile of rats (less than 1% of dose), which suggested the absence of enterohepatic circulation. After oral administration of 10 mg/kg of body weight to rats, 34% and 61% of dose were excreted in the urine and faeces, respectively, suggesting about 30% gastro-intestinal absorption. No metabolites were found by autoradiography of the urine after thin layer chromatography. Radioactivity levels in the serum essentially agreed with the unchanged fosmidomycin levels determined by reverse isotope dilution method. [14C]-fosmidomycin was rapidly distributed in the tissues of rats, and was maintained in high concentration in the liver, kidneys, and bone. The serum level data after i.v. administration closely fitted a 3-compartment open model with first order kinetics after nonlinear least squares regression by NONLIN. The half-lives of the serum level curves for the early, midway, and terminal phases were: 0.13, 0.51, and 17.3 h, respectively in rats; and 0.44, 0.75, and 2.0 h, respectively in dogs.
Animals↗
Antisense and chemical suppression of the nonmevalonate pathway affects ent-kaurene biosynthesis in Arabidopsis.
Transgenic plants of Arabidopsis thaliana (L.) Heynh. (ecotype Columbia) expressing the antisense AtMECT gene, encoding 2- C-methyl- D-erythritol 4-phosphate cytidylyltransferase, were generated to elucidate the physiological role of the nonmevalonate pathway for production of ent-kaurene, the latter being the plastidic precursor of gibberellins. In transformed plants pigmentation and accumulation of ent-kaurene were reduced compared to wild-type plants. Fosmidomycin, an inhibitor of 1-deoxy- D-xylulose 5-phosphate reductoisomerase (DXR), caused a similar depletion of these compounds in transgenic plants. These observations suggest that both AtMECT and DXR are important in the synthesis of isopentenyl diphosphate and dimethylallyl diphosphate and that ent-kaurene is mainly produced through the nonmevalonate pathway in the plastid.
Aldose-Ketose Isomerases↗
On-line analysis of the (13)CO(2) labeling of leaf isoprene suggests multiple subcellular origins of isoprene precursors.
Isoprene (2-methyl-1,3-butadiene) is the most abundant biogenic hydrocarbon released from vegetation, and there is continuing interest in understanding its biosynthesis from photosynthetic precursors in leaf chloroplasts. We used on-line proton-transfer-reaction mass spectrometry (PTR-MS) to observe the kinetics of (13)C-labeling of isoprene following exposure to (13)CO(2) and then the loss of (13)C after a return to normal (12)CO(2) in oak ( Quercus agrifolia Nee) and cottonwood (Populus deltoides Barr.) leaves. Assignments of labeled isoprene species were verified by gas chromatography-mass spectrometry. For the first time, it was possible to observe the half-lives of individually (13)C-labeled isoprene species during these transitions, and to trace some of the label to a C3 fragment that contained the two isoprene carbons derived from pyruvate via the deoxyxylulose-5-phosphate (DOXP) pathway. At steady state (under (13)CO(2)), approximately 80% of isoprene carbon was labeled, with fully labeled isoprene as the major species (approx. 60%). The source of the unlabeled C is suggested to be extrachloroplastic, but not from photorespiratory carbon. After a transfer to (12)CO(2), (13)C-labeling persisted in one isoprene carbon for several hours; this persistence was much more pronounced in (i) leaves inhibited by fosmidomycin, a specific inhibitor of the DOXP pathway, and (ii) in sun leaves which have higher ratios of soluble sugars to starch. From the mass 41-44 fragment data, and labeling predicted from the DOXP pathway in chloroplasts, precursors may arise from cytosolic pyruvate/phospho enolpyruvate equivalents transported into the chloroplast; this idea was supported by an indirect measure of pyruvate labeling. Other sources of cytosolic isoprene precursors (i.e. dimethylallyl diphosphate or pentose phosphate) could not be excluded. The data obtained shed light on the half-lives of photosynthetic metabolites, exchanges of carbon between cellular pools, and suggest multiple origins of isoprene precursors in leaves.
Algorithms↗
Fosmidomycin for the treatment of malaria.
In malaria parasites, isoprenoids are synthesised by the mevalonate independent 1-deoxy- D-xylulose 5-phosphate (DOXP) pathway. Fosmidomycin, a natural antibiotic originally developed for the treatment of bacterial infections, represents an inhibitor of DOXP reductoisomerase, an essential enzyme of this pathway. In recent clinical studies it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.
Animals↗
Therapy of uncomplicated urinary tract infections.
This article deals with many options in utilizing drugs commonly used in the therapy of uncomplicated urinary tract infections (UTIs), their doses and recommended durations of treatment. In addition, it discusses general and specific accompanying measures related to the decrease in prevalence, relapses and recurrences of UTIs, including some of the factors involved in patient adherence or discontinuation of drug regimens.
4-Quinolones↗
Mutagenicity of antibiotics in microbial assays. Problems of evaluation.
5 antibiotics, 4 of which inhibit protein synthesis in different ways, and 1 of which inhibits bacterial cell-wall synthesis, were tested in a battery of microbial assays for possible genetic effects. All the antibiotics, chloramphenicol, tetracycline, gentamicin, oleandomycin and phosphonomycin induced forward mutation to L-azetidine-2-carboxylic acid resistance in Escherichia coli WP2. This response was closely correlated with the toxic effects and was inferred to be deletion mutation. In addition, chloramphenicol was weakly active in reversion of the frame-shift mutation in Salmonella typhimurium TA98, gentamicin caused petite induction in S. cerevisiae at pH 4.4--4.7 and tetracycline gave a significant reponse with gene conversion and petite induction also in S. cerevisiae but at pH 7.2. The results, particularly those with E. coli, cast doubts on the validity of testing specifically designed antibacterial agents in bacteria, and raise serious problems in the evaluation of such data in terms to human populations.
Animals↗
[Study of the formation of N-glycolylmuramic acid from Nocardia asteroides (author's transl)].
Nocardia asteroides was grown in Sauton medium containing sodium [carboxy-14C]acetate. The biosynthesis of the peptidoglycan was inhibited by adding penicillin or phosphonomycin to the growth medium. These antibiotics give an accumulation of radioactive nucleotidic precursors of the peptidoglycan. In the presence of penicillin, there was an accumulation of uridine diphosphate-N-glycolylmuramyl peptide (UDP-MurNGlyc peptide) and of a mixture of uridine diphosphate-N-acetyl and N-glycolylmuramic acid (UDP-MurNAc) and UDP-MurNGlyc). In the presence of phosphonomycin, the biosynthesis of muramic acid was blocked and there was an accumulation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) and uridine diphosphate-N-glycolyglucosamine (UDP-GlcNGlyc). Thus the formation of a N-glycolyl group can be performed upon the neucleotidic derivatives of glucosamine and muramic acid. However in the peptidoglycan synthesized in vivo in the absence of antibiotic, only muramic acid was glycolyated. So, glycolylation seems to take place essentially on UDP-MurNAc. When the binding of peptide chain to muramic acid is achieved, all the muramic acid is glycolylated, then the polymerisation of glycan and peptidoglycan units by the mean of particulate enzymes is carried out on the N-glycolylated derivative of muramic acid. A cell-free preparation from Nocardia asteroides was obtained which can hydroxylate the acetyl group of UDP-MurNAc. The activity was localised in the soluble fraction. This system acts as a hydroxylase and requires the presence of NADPH.
Acetates↗
Cloning of a gene from Escherichia coli that confers resistance to fosmidomycin as a consequence of amplification.
A gene conferring resistance to fosmidomycin (Fs) was cloned from the gene pool of a wild-type strain of Escherichia coli. The cloned DNA fragment was sequenced and shown to encode a putative polypeptide of 406 amino acids (aa) with a molecular weight of 43303. The gene mapped at 10.9 min on the E. coli chromosome and was designated fsr (fosmidomycin resistance). Maxicell analysis revealed that the Fsr protein migrated in sodium dodecyl sulfate-polyacrylamide-gel electrophoresis as a broad band of 35 kDa. A comparison between the aa sequence of Fsr and sequences in a protein database revealed 18% homology to the bacterial drug-export proteins that mediate resistance to tetracycline and chloramphenicol. Hydropathy analysis of the Fsr protein revealed twelve putative transmembrane segments. The degree of FsR of transformants depended on the number of copies of the plasmid that contained fsr. The levels of ubiquinone-8 and undecaprenyl phosphate in cells that harbored a high-copy-number plasmid that included fsr were almost the same as those in the cells without the plasmid. These results suggest that Fsr does not have any direct effect on the biosynthesis of isoprenoid in E. coli, and that the mechanism for FsR involves the efflux of the drug by a process that is facilitated by Fsr.
Amino Acid Sequence↗
Determination of inorganic phosphate in drug formulations and biological fluids using a plant tissue electrode.
A suitable biosensor for the analysis of inorganic phosphate was developed by coupling the enzyme glucose oxidase to a slice of potato (Solanum tuberosum) containing the acid phosphatase, and using an amperometric Clark electrode as an indicating sensor. Phosphate concentration can be determined from its inhibition on the acid phosphatase activity. Measurements were carried out at steady-state conditions and the available concentration range of phosphate, repeatability and accuracy, on phosphate standard solutions, were experimentally determined. Finally the sensor was used in pharmaceutical and biological matrices. The results were compared with those ones obtained by Bartlett's spectrometric method.
Acid Phosphatase↗
[Treatment of Streptococcus pneumoniae meningitis in infants].
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Cefotaxime↗
Preparation and biological characteristics of 99mTc-diol a renal agent.
The present work concerns the production of 1,2-dihydroxypropyl-1-phosphonic acid (diol) by acid hydrolysis of (-cis) 1,2-epoxypropylphosphonic acid (phosphomycin), and its formulation as a kit easily labeled with [99mTc]pertechnetate. Biodistribution studies and whole-body autoradiographies in mice show that 99mTc-diol has a specific affinity for the kidneys: it is rapidly cleared from the blood and excreted in urine (12.09 +/- 6.40% ID are excreted in urine at 5 min and 70.81 +/- 2.41% ID at 30 min post-injection). Part of the injected activity remains in the kidney cortex sufficiently long to permit kidney imaging (5.66 +/- 0.91% ID is still in kidneys 1 h post-injection). In comparison with other agents which also localize in the kidney cortex, such as 99mTc-DMSA and 99mTc-glucoheptonate (99mTc-GHA), the main differences are the following: the peak of renal activity is reached early in the 5 min post-injection period for 99mTc-diol, only at about 10 min post-injection for 99mTc-GHA and after 3 h post-injection for 99mTc-DMSA. The uptake of 99mTc-diol by other organs, especially by bones, is much smaller than in the case of 99mTc-DMSA (1.25 +/- 0.11% ID of 99mTc-diol compared to 11.31 +/- 1.17% ID of 99mTc-DMSA, 1 h post-injection). Unlike 99mTc-DMSA, the biodistribution of 99mTc-diol is not significantly influenced by acid-base imbalance, in addition, its renal uptake decreases in the presence of probenecid whereas its urinary excretion increases.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid-Base Imbalance↗
Complexes of technetium-99m with phosphomycin, obtained by pH shifting: biological characteristics, whole-body autoradiography, gamma-camera study.
Phosphomycin (phos), a large spectrum antibiotic with preferential localization into the kidneys, can be labeled with technetium-99m at various pHs. However, the final pH in the labeling of phos by [99mTc]pertechnetate in the presence of SnCl2 seems to play a significant role in determining the biological properties of the final labeled product. Radiopharmacological characteristics of various forms of 99mTc-phos obtained at pHs 6.8, 4.5 and 2.5 were studied in mice, rats and rabbits. Significant differences in these products were shown by biodistribution studies in Balb/C mice and Wistar rats and confirmed by whole-body autoradiographies in mice and gamma-camera studies in rats and rabbits. 99mTc-phos, pH 6.8, has a high uptake in kidneys from 2 min after injection (10.25 +/- 1.11 %ID) to 3 h after injection (8.26 +/- 0.42 %ID) and a rapid urinary excretion (19.9 +/- 7.35 %ID at 2 min after injection and 75.11 +/- 3.48 %ID at 3 h). Intrarenal pharmacokinetics studied by autoradiography showed a high concentration in the inner medulla and pelvis at 1 min after injection followed by an increased localization in kidney cortex, like 99mTc-DMSA. Preferential uptake in bones was shown by 99mTc-phos, pH 2.5, from 5 min to 3 h after injection (15.05 +/- 2.67 %ID at 3 h compared to 1.79 +/- 0.19 %ID of 99mTc-phos, pH 6.8, at the same time). A high urinary excretion of 99mTc-phos, pH 2.5, is shown as in the case of other bone agents (76.5 +/- 3.46 %ID at 3 h post-injection) but without any kidney retention (1.80 +/- 0.26 %ID in kidneys 3 h post-injection).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Clinical aspects and outcome of meningococcal disease due to Neisseria meningitidis of serogroup W135 in 5 children].
Meningococcal disease due to Neisseria meningitidis of serogroup W135 (N. meningitidis W135) is increasing in France. Clinical and outcome data concerning these infections in children are scarce. We report five cases of children hospitalized between June 2000 and December 2002 for N. meningitidis W135 infection. Extra-meningeal septic and/or non-septic complications were frequent and a prolonged post meningococcal inflammatory syndrome was reported. In N. meningitidis W135 infections a careful clinical evaluation of potential extra-meningeal complications and a long term follow up of children are needed.
Anti-Bacterial Agents↗
[Paravertebral streptococcal myositis complicated by an epidural abscess in a 5-year-old girl].
CASE REPORT: A 5-year-old girl was hospitalised for fever, abdominal and lumbar pain, associated with general impairment state and a whitlow. One of the blood cultures and CSF grew A beta haemolytic Streptococcus, muscular echography and MRI showed paravertebral myositis, which was complicated by an epidural abscess. The outcome was good with medical treatment alone. DISCUSSION: Streptococcal myositis is a rare and severe skeletal muscle infection caused by A beta haemolytic Streptococcus. It is characterized by a muscle necrosis, without abscess formation. It has to be distinguished from pyomyositis, usually caused by Staphylococcus aureus, where a muscle abscess occurs, which must be treated by surgical drainage and antibiotics. Prognosis of this infection is poorer than other muscle infections such as pyomyositis, with a high mortality rate. The diagnosis is difficult and often delayed. Practitioners should keep in mind this diagnosis, even if symptoms are non specific, in front of an undetermined infectious syndrome associated with pain, and make an echography or nuclear magnetic resonance imaging to confirm the diagnosis.
Administration, Oral↗
1-Deoxy-D-xylulose 5-phosphate reductoisomerase: an overview.
The methylerythritol phosphate pathway to isoprenoids, an alternate biosynthetic route present in many bacteria, algae, plants, and the malarial parasite Plasmodium falciparum, has become an attractive target for the development of new antimalarial and antibacterial compounds. The second enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; EC 1.1.1.267), has been shown to be the molecular target for fosmidomycin, a promising antimalarial drug. This enzyme converts 1-deoxy-D-xylulose 5-phosphate (DXP) into the branched compound 2-C-methyl-D-erythritol 4-phosphate (MEP). The transformation of DXP into MEP requires an isomerization, followed by a NADPH-dependent reduction. The discovery of DXR, its subsequent characterization, and the identification of inhibitors will be presented.
Aldose-Ketose Isomerases↗