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ABSTRACTA mathematical pharmacodynamic model was developed to describe the bactericidal activity of marbofloxacin against Escherichia colistrains with reduced susceptibility levels (determined using MICs) under optimal and intestinal growth conditions. Model parameters were estimated using nonlinear least-square curve-fitting procedures for each E. colistrain. Parameters related to bactericidal activity were subsequently analyzed using a maximum-effect (Emax) model adapted to account for a direct and a delayed effect. While net growth rates did not vary significantly with strain susceptibility, culture medium had a major effect. The bactericidal activity of marbofloxacin was closely associated with the concentration and the duration of exposure of the bacteria to the antimicrobial agent. The value of the concentration inducing a half-maximum effect (C50) was highly correlated with MIC values (R2= 0.87 and R2= 0.94 under intestinal and optimal conditions, respectively). Our model reproduced the time-kill kinetics with good accuracy (R2of >0.90) and helped explain observed regrowth.

ABSTRACTFood animals are a potential source of CTX-M resistance genes for humans. We evaluated the transfer of the blaCTX-M-9gene from an animal strain of Salmonella entericaserotype Virchow to Enterobacteriaceaeof the human intestinal flora by using human flora-associated (HFA) rats with and without cefixime treatment. In the absence of antibiotic, no transconjugant enterobacteria were found in the feces of HFA rats. However, the transfer rate was high if Escherichia coliJ5 recipient strains were coinoculated orally with Salmonella. S. entericaserotype Virchow persisted in the rat fecal flora both during and after treatment with therapeutic doses of cefixime. The drug did not increase the transfer rate, and E. coliJ5 transconjugants were eliminated from the flora before the end of cefixime treatment. No cefixime was recovered in the rat feces. In the presence of recipient strains, the blaCTX-M-9resistance gene was transferred from a strain of animal origin to the human intestinal flora, although transconjugant colonization was transient. Antibiotic use enhanced the persistence of donor strains, increasing the resistance gene pool and the risk of its spread.

ABSTRACTThe ability of Mycoplasma hyopneumoniaeto persist despite fluoroquinolone treatments was investigated with pigs. Groups of specific-pathogen-free pigs were experimentally infected with M. hyopneumoniaestrain 116 and treated with marbofloxacin at the therapeutic dose (TD) or half of the therapeutic dose (TD/2) for 3 days. Results showed that, despite tissue penetration of marbofloxacin, particularly in the trachea and the tracheal secretions, the treatments did not have any influence on M. hyopneumoniaerecovery from tracheal swabs. Mycoplasmas were also isolated from inner organs and tissues such as liver, spleen, kidneys, and bronchial lymph nodes. Recontamination of pigs via environment could not explain mycoplasma persistence after medication, as decontamination of pigs and allocation to a new disinfected environment did not have any significant effect on the phenomenon. A significant decrease in the susceptibility level to marbofloxacin of 12 mycoplasma clones reisolated after the treatments (TD/2 and TD) was observed. Two point mutations were found in the ParC quinolone resistance-determining region (QRDR) of DNA topoisomerase IV (Ser80→Phe and Asp84→Asn), and one point mutation was observed just behind the QRDR of ParC (Ala116→Glu). This is the first time that mutations in a gene coding for topoisomerase IV have been described for M. hyopneumoniaeafter in vivo marbofloxacin treatments in experimentally infected pigs. However, development of resistance is not sufficient to explain M. hyopneumoniaepersistence in vivo since (i) marbofloxacin concentrations were above the marbofloxacin MIC of the wild-type strain and (ii) mycoplasmas reisolated after a single injection of marbofloxacin did not display an increased marbofloxacin MIC.

An interlaboratory study was organised in 1996 in order to determine laboratory testing performance for measuring oxytetracycline (OTC) and 4-epioxytetracycline (4-epiOTC) residues in pig muscle. The organisation was designed according to the ‘International Harmonised Protocol for Proficiency Testing of (Chemical) Analytical Laboratories’ produced by the Association of Official Analytical Chemists (AOAC International) and the International Union of Pure and Applied Chemistry (IUPAC). Fourteen National Reference Laboratories (NRLs) out of the 15 asked to participate agreed to analyse the samples. These laboratories were from 13 different European Union (EU) Member States and each participant was allowed to use the extraction method of their own choice but had to use liquid chromatography as the analytical technique. Most of the methods used were based on UV detection (simple wavelength or diode-array detection) but some involved fluorimetric detection. The production of incurred samples was prepared on-site. The OTC and 4-epiOTC concentrations present in the samples were determined by taking the mean of the results (excluding outliers) and the deviation of each result from the assigned value was measured. The performance of the laboratories was evaluated by calculating the ‘z-scores’. The results were globally satisfactory and showed that all 14 laboratories were capable of determining OTC and 4-epiOTC in pig muscle with satisfactory accuracy. Only two laboratories obtained a questionable result in terms of repeatability.

Experiments were conducted in the ewe to determine the effects of mating on the activity of the genital tract and on blood levels of oxytocin and cortisol. The activity of the uterus and cervix was recorded by electromyography, oxytocin was measured by radioimmunoassay, and cortisol by high performance liquid chromatography. Mating itself did not increase circulating oxytocin or cortisol; uterine motility remained unchanged during and after copulation but the cervix was significantly stimulated during teasing and after copulation. It is suggested that increased cervical activity resulting from adrenergic mechanisms may facilitate the generation of a cervical reserve of spermatozoa.J. Endocr.(1985) 105, 323–329

Utero-cervical responsiveness to alpha-adrenergic receptor stimulation was electromyographically evaluated in vivo in adult ovariectomized ewes. Spontaneous motility and drug-induced changes were quantified with a microcomputer.Our results suggested that the two activity patterns previously described on the ovine genital tract could be respectively controlled by alpha-2 and alpha-1 adrenergic mechanisms. Alpha-2 receptors could be assigned to a chronotropic function by activating a hypothetical zone triggering the outbreak of discrete episodes of motility (regular activity); this function is apparent at the cervix even in the absence of estrogen priming. On the other hand, alpha-1 receptors could be assigned to an inotropic function, regulating mainly the magnitude of estrogen-dependent utero-cervical motility (irregular activity).