Aspoxicillin, a newly developed acylureido-penicillin with a long half-life in mouse serum of 55 min, induced postantibiotic effects (PAEs) against Staphylococcus aureus Smith of 1.7 h in vitro and 5.2 h in vivo in a thigh infection model in neutropenic mice. The long serum half-life meant that in order to evaluate the in-vivo PAE, it was necessary to examine the contribution of the drug at a sub-minimal inhibitory concentration (sub-MIC). Growth suppression by sub-MICs of aspoxicillin was examined in vitro using either previously unexposed bacterial cells or cells which had been pre-exposed to twice the MIC of aspoxicillin for 2 h. At each sub-MIC tested, the duration of growth suppression for pre-exposed cells was longer than that for unexposed cells. In an attempt to eliminate the sub-MIC effect in vivo, penicillinase was injected into mice at the time after administration when the aspoxicillin serum concentration approached the MIC. The in-vivo PAE decreased to 2.7 h when penicillinase was injected. It was concluded that aspoxicillin induced a PAE in vivo which was additional to the effect of sub-inhibitory residual drug, but that sub-MIC levels of the drug were simultaneously involved in suppressing bacterial regrowth after the drug concentration decreased below the MIC. Similar postantibiotic sub-MIC effects may also occur with other long half-life antibiotics.
The in vitro antibacterial activity of temafloxacin hydrochloride (TA-167 or A-62254) was evaluated against a wide variety of clinical isolates and compared with those of other fluoroquinolones. The potency (MIC90) of the compound against gram-positive aerobic bacteria was higher or comparable to those of ciprofloxacin, ofloxacin, and norfloxacin. Against most gram-negative enteric bacteria and Pseudomonas species, temafloxacin was less active than ciprofloxacin, but was generally as active as ofloxacin and norfloxacin, except against Proteus species and Morganella morganii. Against obligate anaerobes, it was more active than the reference quinolones. Temafloxacin was bactericidal for one strain each of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The compound inhibited E. coli DNA gyrase activity at a low concentration.
The serum concentrations, urinary and biliary excretions of six penicillin derivatives including aspoxicillin (ASPC)were studied in rats and the correlation between the values of pharmacokinetic parameters thus obtained and the Rmvalues measuredby meansof reversed phase TLCwere analyzed. Amongthe penicillins studied, the hydrophilicity of amoxicillin was the highest (the lowest Rmvalue), which was followed by those of ASPC, ampicillin, /7-hydroxypiperacillin, dehydroxyaspoxicillin and piperacillin in descending order. These Rmvalues were then correlated with the AUCvalues at 20 mg/kg of dosing, giving the results that more hydrophilic penicillins having a hydroxyl group show higher serum concentrations as well as greater AUC values. The studies of correlation between the Rmvalues and the urinary or biliary excretion revealed that hydrophilic penicillins were almost excreted into urine, but more hydrophobic ones were mainly eliminated into bile.From the above results, a hydroxyl group introduced to the phenyl group of ASPCwas considered to have a role that increases the hydrophilicity of ASPC,giving higher and longer persistency of the serum levels and increasing the excretion of drugs into urine.
The action of VA-2, the most active component of antibiotic M-92, against S. aureus is bactericidal but not bacteriolytic. The bactericidal action is markedly affected by incubation temperature, whether bacterial cells are prolific or resting.The bactericidal kinetics of VA-2 is biphasic, since addition of VA-2 caused rapid and straight decrease in viability curve and reached a plateau after several minutes. The bactericidal activity of VA-2 is blocked by 2,4-dinitrophenol.Alike to many membrane-active bacteriocins, VA-2 seems to exert its action through two stages.As reported previously" 2.1), antibacterial and anticancer antibiotic M-92 elaborated by Micromonospora verruculosa MCRL 0404 is a complex of several structurally related antibiotics having a quinoid nature. Among the six major components, VA-2 exhibited the most potent antibacterial activity, particularly against some Gram-positive bacteria (MICs: 0.000001-0.0001 ag/ml)". Such a potent activity urged us to examine the mechanism of interaction between VA-2 and bacterial cells, and also the mode of action on the target bacteria.The present paper concerns the characteristics of the interaction between VA-2 and the susceptible Staphylococcus aureus cells which suggest that interaction proceeds through two stages. In some parts of the present experiments, mitomycin C4' was used for comparison, because mitomycin C, an antitumor quinoid antibiotic, shows biological properties somewhat resembling to VA-2. Mode of action of VA-2 as a DNA synthesis inhibitor will be dealt with in the succeeding paper. Materials and MethodsAntibiotics and Chemicals VA-2 was separated and purified as described in the preceding paper'). Mitomycin C and other chemicals were obtained from commercial sources. Antibiotic solutions were prepared by dissolving the antibiotic in dimethylsulfoxide and then diluting with an appropriate amount of sterile deionized water. Microorganisms and MediaStaphylococcus aureus 209P JC-1 maintained in our laboratory was used. Nutrient broth (Difco) and Bacto-agar (Difco) were employed in the present study.Culture Conditions for Growth and Viability Tests A test strain was grown in double strength Nutrient broth (2NB) on a reciprocating shaker at 37°C. The bacterial growth was monitored by measuring absorbance at 600 nm. Bacterial cell cultures in an early exponential stage, whose absorbance at 600 nm reached to approximately 0.2, were used for the tests. Viability of cells was determined by counting the colony numbers grown on 2NB agar plates, which were prepared as follows. The cell suspensions were serially diluted with 0.9y. physiological
In vitro activities of M-4365 G2, a new basic 16-membered macrolide antibiotic, against a total 19 strains including human, bovine, porcine, rodent, avian and saprophytic mycoplasmas were compared with those of three other macrolide antibiotics, josamycin, erythromycin and tylosin. M-4365 G2 exhibited stronger activities than the other macrolide antibiotics against 11 strains of mycoplasma tested. Especially, its higher activities against M. pneumoniae Mac and FH, U. urealyticum T-960, M. mycoides PG-1 and M. gallisepticum Kp-13, PG-31 and 9-49A were to be noticed (final minimum inhibitory concentrations: 0.0001"0.049ttg/ml). Higher antimycoplasmal activity of M-4365 G1 than that of tylosin was also proved in experimental treatment of chickens intranasally inoculated with M. gallisepticum Kp-13 by feeding a diet containing the drug. M. gallisepticum Kp-13 was not isolated from the infected chickens fed a diet containing 0.0063 % or more of M-4365 G2.
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