Isolates of Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, and coagulase-positive and -negative staphylococci were investigated for their abilities, in vitro, to develop resistance to LY146032. Exposure of the organisms to incremental concentrations of LY146032 resulted in MICs 8-to 32-fold higher than those for the original isolates. After three passages on antibiotic-free medium, the high MICs were maintained for the coagulase-negative staphylococci and pneumococci, with a twofold decrease observed for the enterococci and a fourfold decrease observed for Staphylococcus aureus. The frequency of spontaneous emergence of resistance was highest with S. pneumoniae (1.2 x 10-6 at 16 times the original MIC) and lowest with S. aureus (7.0 x 10-10 at 8 times the original MIC). For bacteria surviving time-kill studies MICs were also higher than were those for the original isolates. Exposure to LY146032 in vitro selected for strains with decreased susceptibilities to the antimicrobial agent. However, the emergence of resistance in vivo is unpredictable and can be evaluated only after prolonged clinical use of the drug.LY146032, a new cyclic lipopeptide antibiotic, has a spectrum of activity similar to that of vancomycin (3,5,6,(8)(9)(10)(11). Recently, Staphylococcus haemolyticus strains demonstrating resistance in vitro to teicoplanin were described (2). Furthermore, on repeated isolation from a patient on adequate vancomycin therapy S. haemolyticus demonstrated stepwise increases in vancomycin MICs, the final MIC being of intermediate resistance (14). Similarly, S. haemolyticus isolates in vitro have demonstrated stepwise resistance to vancomycin; the resistant strains demonstrated cross-resistance with teicoplanin but were susceptible to LY146032 (14).In this study, we investigated the propensity of strains of pneumococci, enterococci, and coagulase-positive and -negative staphylococci to develop resistance to LY146032 in vitro. MATERIALS AND METHODSOrganisms. The bacterial strains used were clinical isolates obtained from patients attending the Johannesburg, Hillbrow, and Baragwaneth hospitals. The isolates were stored in liquid nitrogen until required.Antimicrobial agent. Standard LY146032 reference powder was obtained from Eli Lilly & Co., Indianapolis, Ind.Selection of resistant organisms. Organisms resistant to LY146032 were selected for by two methods. Firstly, a gradient plate technique was used to screen for resistant mutants (15). Briefly, plates were poured with two layers of agar. The bottom layer consisted of 20 ml of antibiotic-free nutrient agar (Oxoid Ltd., Basingstoke, England), which was allowed to harden with the plate slanted sufficiently so that the entire bottom was just covered. The plate was returned to the horizontal position, and a further 20 ml of agar containing the appropriate concentration of LY146032 was added. The plates were inoculated with approximately 0.15 ml of suspensions of the organisms, for which the LY146032 MICs were known, at various inoculum sizes and...
The attachment of Actinomyces naeslundii ATCC 12104 to human buccal epithelial cells pre-treated with neuraminidase (sialidase) was evaluated. Both commercial clostridial neuraminidase and neuraminidase preparations from the test strain of A. naeslundii enhanced attachment. The results suggest that the A. naeslundii beta-galactoside-seeking ligand involved in hemagglutination and interbacterial coaggregation also mediates one type of binding to human buccal epithelial cells.
The in vitro activities of two new carboxyquinolones, A-56619 (difloxacin) and A-56620, were compared with those of ciprofloxacin, norfloxacin, and ofloxacin against genital tract pathogens. All the quinolones were highly active against Neisseria gonorrhoeae. A-56619 had the lowest MICs against Chlamydia trachomatis (MIC range, 0.125 to 0.25 ,ug/ml) and Haemophilus ducreyi (MIC for 90% of isolates tested, 0.1 ,ug/ml).The newer quinolone antimicrobial agents have been shown to have excellent activity in vitro against gonococci, including ,B-lactamase-producing strains (3,11,13,16,18), and moderate activity in vitro against Chlamydia trachomatis (2,10,14).We compared the activities of A-56619 (difloxacin), A-56620, ciprofloxacin, norfloxacin, ofloxacin, and antimicrobial agents now used for the treatment of genital infections against clinical isolates of Neisseria gonorrhoeae, Haemophilus ducreyi, Gardnerella vaginalis, Ureaplasma urealyticum, and C. trachomatis.Antimicrobial reference standards and sources were as follows: A-56619, A-56620, and erythromycin, Abbott Lab of M. hominis and 2-day-old broth cultures of U. urealyticum were inoculated into 100 ,ul of twice the required final concentration of each of the antibiotic dilutions in U-well microtiter plates. Controls containing medium only, medium plus antimicrobial agent, and medium plus M. hominis or U. urealyticum were included. The microtiter plates were sealed and incubated at 37°C until the indicator in the Mycoplasma-Ureaplasma control well changed color. The MIC was defined as the lowest concentration of antimicrobial agent which prevented color change.MIC testing of C. trachomatis was performed by a modification of a previously described method (15). Inocula of a 1-ml suspension of C. trachomatis in Eagle minimum essential medium supplemented with fetal bovine serum (10% vol/vol), glutamine (1% [vol/vol] of stock solution of 30 mg/ml), and vitamins (1% vol/vol), containing approximately 1.6 x 108 inclusion-forming units per ml, were added to flat-bottomed plastic tubes containing a cover slip monolayer of cycloheximide-treated McCoy cells. After centrifugation at 3,500 x g at 35°C for 60 min, the medium was replaced with 1 ml of supplemental Eagle medium containing the antimicrobial agents tested. The tubes were incubated at 35°C for 48 h. The cover slips were removed, fixed with methanol, stained with iodine, and examined by bright-field illumination for the presence of inclusions. The MIC was defined as the lowest concentration of antimicrobial agent which prevented the appearance of any inclusion bodies.The MICs of the antimicrobial agents tested against isolates of N. gonorrhoeae, H. ducreyi, U. urealyticum, G. vaginalis, and C. trachomatis are shown in Tables 1 and 2. The quinolones, cefotaxime, and ceftazidime were highly active against gonococci, including P-lactamase-producing isolates. A-56619 and A-56620 were the most active quinolones against H. ducreyi. A-56619 was the most active quinolone against both the lymphogranuloma venereum and o...
The Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) prime human neutrophils for enhanced, stimulus-activated release of superoxide and myeloperoxidase (MPO), respectively. In the present study, the modulatory potentials of the antimicrobial agents clindamycin, eythromycin, and roxithromycin (10 and 20 ,ug/ml) on the prooxidative interactions of pyocyanin and 1-hp (12.5 FM) with human neutrophils have been investigated. Clindamycin, erythromycin, and especially roxithromycin caused dose-related inhibition of the generation of superoxide by both untreated and pyocyanin-treated neutrophils during activation with either the synthetic chemotactic tripeptide N-formyl-Lmethionyl-L-leucyl-L-phenylalanine (FMLP) or the calcium ionophore A23187. The antimicrobial agents also inhibited the generation of reactive oxidants by the MPO-H202-halide system during activation of both untreated and 1-hp-treated neutrophils by FMLP. These effects appeared to be due to drug-related interference with membrane-associated oxidative metabolism, since none of the antimicrobial agents inhibited the release of MPO by activated neutrophils, nor did they possess oxidant-scavenging properties. These data demonstrate that clindamycin, erythromycin, and especially roxithromycin antagonize the proinflammatory interactions of pyocyanin and 1-hp with neutrophils and indicate a possible therapeutic role for these antimicrobial agents in the prevention of tissue damage in diseases characterized by P. aeruginosa infection.The Pseudomonas aeruginosa-derived phenazine pigment pyocyanin, at pathologically relevant concentrations, primes human neutrophils for increased oxygen consumption and increased generation of superoxide when the cells are subsequently exposed to stimuli of membrane-associated oxidative metabolism (25,31). The prooxidative potential of pyocyanin is amplified by its degradation product, 1-hydroxyphenazine (1-hp), which is also synthesized byP. aeruginosa and which primes neutrophils for enhanced release of myeloperoxidase (MPO) (31). Pigment-neutrophil interaction during P. aeruginosa infection may cause reactive oxidantmediated damage to host tissues, particularly during chronic colonization of the bronchial tree in bronchiectasis. In this situation, damage to the bronchial epithelium may be inflicted by prolonged exposure to oxidants and proteases released by chronically activated phagocytes (6,7,21). Moreover, in patients with P. aeruginosa pneumonia, pulmonary parenchymal destruction might also be related to the release of oxidants and granule enzymes by pigment-primed hyperactive neutrophils (9,17,28).Broad-spectrum antibiotic treatment with currently available agents is insufficient to eradicate P. aeruginosa from the bronchial tree of patients with bronchiectasis and cystic fibrosis once colonization has occurred (19). Inhibition of the reactive-oxidant component of neutrophil-induced chronic bronchial inflammation might therefore introduce a new * Corresponding author.strategy to preve...
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