After 30 years of therapeutic use, thiamphenicol glycinate acetylcysteinate (CAS 20192-91-0) is still widely employed in the treatment of upper and lower respiratory tract infections. This is due to its particular characteristic to exert at pulmonary level, either the antibacterial activity of thiamphenicol (CAS 15318-45-3) and the mucolytic activity of N-acetylcysteine (CAS 616-91-1). The aim of this study was to evaluate the present pattern of susceptibility of several clinical isolates to thiamphenicol and the interference of N-acetylcysteine on this parameter. The studies have been performed In vitro. Equimolar concentrations of N-acetylcysteine and even higher concentrations did not interfere with the antibacterial activity of thiamphenicol against Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae. The spectrum of activity of thiamphenicol was similar to that observed in the past and was superior to that of erythromycin and amoxicillin. The activity of thiamphenicol was greater than that of erythromycin against H. influenzae and streptococci and equivalent versus Branhamella catarrhalis. In comparison with amoxicillin the activity of thiamphenicol was higher against H. influenzae and B, catarrhalis and slightly lower against streptococci. The results demonstrate that thiamphenicol maintains its therapeutic Value confirming the importance of thiamphenicol glycinate acetylcysteinate in the treatment of respiratory tract infections.

Escherichia coli (E. coli) is the most commonly isolated microorganism in uncomplicated lower urinary tract infections (UTI). Due to the increased isolation of E. coli strains resistant to quinolones, it is important to have available alternative drugs to this class of antibiotics as therapy for UTIs caused by this pathogen. Among the large number of currently available antimicrobial agents, fosfomycin trometamol is a useful alternative due to its peculiar microbiological and pharmacokinetic properties. Therefore, we tested the in vitro susceptibility of 79 quinolone-resistant clinical urinary isolates of E. coli to fosfomycin trometamol in comparison with amoxicillin, chloramphenicol, cotrimoxazole, netilmicin, nitrofurantoin and tetracycline. Fosfomycin trometamol showed high activity with a MIC90 of 4 mg/l. While no strains were resistant to fosfomycin trometamol, 83.5%, 63.3%, 58.2%, and 48.1% of the isolates were resistant to tetracycline, amoxicillin, chloramphenicol and cotrimoxazole, respectively. Nitrofurantoin and netilmicin resistance was present only in 12.7% and 6.3% of the strains, respectively. In conclusion, fosfomycin trometamol has retained its activity against quinolone-resistant strains of E. coli and cross-resistance with other classes of antimicrobial agents is not presently a problem. The strains tested did present high levels of resistance to other classes of antibiotics.

Thiamphenicol glycinate acetylcysteinate (TGA, CAS 20192-91-0) is a water soluble ester of thiamphenicol (TAP) that allows a rapid utilization by the systemic route but also a direct local action when used as aerosol. To assess the efficacy of aerosolized TGA in the treatment of experimental pneumonia in mice, we compared its in vivo activity with that of thiamphenicol glycinate hydrochloride (TG), erythromycin (ERT) and amoxicillin (AMX), the last two compounds being more active in vitro than TAP. TGA, administered by aerosol route, showed better efficacy than the aerosolized TG, particularly as far as survival rate is concerned, and was significantly more potent than ERT and similar to AMX either administered by oral route. No significantly different therapeutic efficacy was observed when TGA was parenterally administered. The rapid release, at the site of infection, of TAP and N-acetylcysteine and the favourable pharmacokinetic properties of TGA accounted in large part for its high therapeutic efficacy against Streptococcus pyogenes pneumonia.

The pharmacokinetics of fosfomycin trometamol has been assessed in 12 healthy volunteers given oral doses of 2, 3, and 4 g of fosfomycin and 3 g intravenously of fosfomycin as fosfomycin sodium, all in the fasting state. The assay was microbiological (Proteus mirabilis ATCC 21100). There was a gradual rise in both peak serum concentrations and total area under the curve by rising oral doses, from 16.0 mg/l and 106.7 mg x h/l, after 2 g to 30.9 mg/l and 189.7 mg x h/l after 4 g respectively. The serum half-life was 4 h after the oral doses and 2.1 h after the intravenous dose. After the oral doses, the amounts excreted in urine in the active form ranged from 36 to 40% compared to 93% after the intravenous dose. The bioavailability was slightly below 40%. Concentrations in urine covers the usual urinary tract pathogens after oral doses of 2, 3, and 4 g.

In order to assess the resistance profile for fosfomycin trometamol after several years of clinical use in Italy, this study has explored the susceptibility to fosfomycin and eight other antibacterial drugs of 6,021 strains isolated from 23,816 urines during 1990 in three teaching hospitals located in Genoa, Parma and Catania. Gram-negative strains, notablyEscherichia coli (41.6%), were primarily involved. Amoxicillin was the least active compound with resistance in 41.4% of the isolates. Fosfomycin showed the lowest rate of resistance in both gram-negative (2.8%) and gram-positive (2.1%) pathogens. This was followed by norfloxacin with a resistance rate of 11.8% and netilmicin with 12.2%. These results indicate that fosfomycin-trometamol may continue to be used in single-dose treatment of urinary tract infections even in the absence of microbiological data since the prevalence of resistance to the drug is, at present, so low that therapeutic failure is highly improbable.

The synthesis of new 2-(3-bromo-5-isoxazolylideneamino-oxy)acetic acids and their condensation derivatives with suitable beta-lactam nuclei is reported. Their antibacterial properties have been tested in vitro. An interesting activity against Gram-positive bacteria including beta-lactamase-producing microorganisms was found among the cephalosporanic acid derivatives.

The synthesis of 3-bromo-4,5,6,7-tetrahydro-1,2-benzoisoxazole derivatives and their activity against human pathogen fungi are reported. In particular, compound 3,5-dibromo-6,7-dihydro-1,2-benzoisoxazol-4-(5H)-one showed a broad antifungal spectrum and good fungicidal activity against Trichophyton mentagrophytes.

The mono- and bis(sulfooxy) derivatives of ursodeoxy-cholic acid are, contrary to a previous report, easily prepared by a very simple direct sulfation procedure.

AbstractThe nitrile oxides (I) react with the allylamine (II) to form the intermediate aminomethylisoxazolines (III) and the N‐allylbenzamidoximes (IV) which are coupled with the hydroxamic acid chlorides (V), yielding the isoxazolines (VI).

The present study was undertaken to define an interpretative guideline for disk diffusion susceptibility testing with fosfomycin trometamol, a new antimicrobial agent which has been developed for the treatment of urinary tract infections. Two potencies of fosfomycin disk were used: 50 and 200 micrograms, prepared in the presence and absence of glucose-6-phosphate. To verify the reliability of the results obtained in susceptibility testing, we have also evaluated the bactericidal activity of fosfomycin trometamol versus sensitive and resistant strains in an 'in vitro' model simulating the hydrokinetic aspects involved in the treatment of bacterial cystitis. The data obtained evidenced the role of glucose-6-phosphate in antimicrobial susceptibility tests as well as the importance of the urinary antibiotic concentrations to define sensitive and resistant bacteria. On the basis of our results, we recommend that a 200-microgram disk of fosfomycin containing 50 micrograms of glucose-6-phosphate should be used in antimicrobial susceptibility testing with fosfomycin trometamol.

The in vitro transformation, under anaerobic conditions, of 3- and 7-monosulfated and unsulfated bile acids, was studied in incubates of fecal flora from three healthy subjects. Chenodeoxycholic acid 7 alpha-sulfate and ursodeoxycholic acid 7 beta-sulfate were recovered unchanged, in all cultures, at the end of the incubation time. 3-Sulfated bile acids were metabolized in a different way by the three stool specimens. During the transformation of chenodeoxycholic acid 3-sulfate, desulfation, 7-dehydroxylation and 3-epimerization were observed. In contrast, 3-epimerization was not noticed when ursodeoxycholic acid 3-sulfate and lithocholic acid 3-sulfate were metabolized, the latter being principally transformed into delta 3-cholenic acid, probably by a bacterially mediated trans-elimination of sulfate group. The results obtained seem to prove that the presence of a SO3H group in 7-position usually hinders microbial transformations, which are not affected by a sulfate group in 3-position. Moreover, the 3-sulfated bile acids proved to be less sensitive to the microbial action than the corresponding unsulfated acids, with exception of lithocholic 3-sulfate.

The synthesis of new 2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetic acids and their condensation derivatives with a suitable cephalosporanic nucleus, is reported. Their antibacterial properties were tested in vivo and in vitro also against beta-lactamase producer microorganisms; particularly the oral bioavailability of some of these new derivatives was studied.

The inclusive process ..pi../sup -/A-italic..-->..p-italic/sub back/X-italic for the nuclear targets C, Cu, and Pb has been studied at a pion momentum 40 GeV/c-italic in the MIS magnetic spark spectrometer at the Joint Institute for Nuclear Research. Invariant cross sections for emission of protons into the backward hemisphere in the lab have been obtained in the momentum region 0.3--1 GeV/c-italic and the interval of angles 120--175/sup 0/. The dependence of the invariant cross section for this process on the mass number of the target is discussed.

An in vitro study was made of the bactericidal activity against Escherichia coli of fosfomycin trometamol, a new fosfomycin salt characterized by high bioavailability in relation to the pH, inoculum and culture medium, the latter being nutrient broth or human urine. Cotrimoxazole and norfloxacin were used for comparison. The results obtained show that both in nutrient broth and human urine, fosfomycin trometamol had higher bactericidal action than that of the other two antimicrobial agents.

The backward production of protons in the reaction π−A → p↓X is studied at 40 GeV incident energy with the different nuclear targets : C, Cu, Pb. The structure function shows a slope independent of the target atomic weightA and slightly dependent on the proton production angle. The invariant cross-section, normalized to the nucleon, increases withA up to a plateau which varies with the incident energy. Finally the ratiosR = (FA/A)/(FC/AC) andn = ln(FA/FC)/ln(A/AC), whereF = (E/p2)(d2σ/(dp dΩ)), show a flat dependence on the momentum of the proton backward produced. These results are in favour of few-nucleon correlation models.