The in vitro and in vivo activities of T-3811ME, a novel des-F(6)-quinolone, were evaluated in comparison with those of some fluoroquinolones, including a newly developed one, trovafloxacin. T-3811, a free base of T-3811ME, showed a wide range of antimicrobial spectra, including activities against Chlamydia trachomatis, Mycoplasma pneumoniae, andMycobacterium tuberculosis. In particular, T-3811 exhibited potent activity against various gram-positive cocci, with MICs at which 90% of the isolates are inhibited (MIC90s) of 0.025 to 6.25 μg/ml. T-3811 was the most active agent against methicillin-resistant Staphylococcus aureus and streptococci, including penicillin-resistant Streptococcus pneumoniae (PRSP). T-3811 also showed potent activity against quinolone-resistant gram-positive cocci with GyrA and ParC (GrlA) mutations. The activity of T-3811 against members of the familyEnterobacteriaceae and nonfermentative gram-negative rods was comparable to that of trovafloxacin. In common with other fluoroquinolones, T-3811 was highly active against Haemophilus influenzae, Moraxella catarrhalis, andLegionella sp., with MIC90s of 0.0125 to 0.1 μg/ml. T-3811 showed a potent activity against anaerobic bacteria, such as Bacteroides fragilis and Clostridium difficile. T-3811 was the most active agent against C. trachomatis (MIC, 0.008 μg/ml) and M. pneumoniae(MIC90, 0.0313 μg/ml). The activity of T-3811 againstM. tuberculosis (MIC90, 0.0625 μg/ml) was potent and superior to that of trovafloxacin. In experimental systemic infection with a GrlA mutant of S. aureus and experimental pneumonia with PRSP in mice, T-3811ME showed excellent therapeutic efficacy in oral and subcutaneous administrations.
T-3761, a new quinolone derivative, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.20 to 100 ,Lg/ml against gram-positive bacteria, including members of the genera Staphylococcus, Streptococcus, and Enterococcus; 0.025 to 3.13 ,ug/ml against gram-negative bacteria, including members of the family Enterobacteriaceae and the genus Haemophilus; 0.05 to 50 p,g/ml against glucose nonfermenters, including members of the genera Pseudomonas, Xanthomonas, Acinetobacter, Alcaligenes, and MoraxeUa; 0.025 ,g/ml against Legionella spp.; and 6.25 to 25 ±g/ml against anaerobes, including Bacteroides fragilis, Clostridium difJicile, and Peptostreptococcus spp. The in vitro activity of T-3761 against these clinical isolates was comparable to or 2-to 32-fold greater than those of ofloxacin and norfloxacin and 2-to 16-fold less and 1-to 8-fold greater than those of ciprofloxacin and tosufloxacin, respectively. When administered orally, T-3761 showed good efficacy in mice against systemic, pulmonary, and urinary tract infections with gram-positive and gram-negative bacteria, including quinolone-resistant Serratia marcescens and Pseudomonas aeruginosa. The in vivo activity of T-3761 was comparable to or greater than those of ofloxacin, ciprofloxacin, norfloxacin, and tosufloxacin against most infection models in mice. The activities of T-3761 were lower than those of tosufloxacin against gram-positive bacterial systemic and pulmonary infections in mice but not against infections with methicillin-resistant Staphylococcus aureus. The activities of T-3761 against systemic quinolone-resistant Serratia marcescens and Pseudomonas aeruginosa infections in mice were 2-to 14-fold greater than those of the reference agents.
The in vitro interactions of four 1-lactam antibiotics and five antineoplastic agents were examined with 100 clinically isolated strains of four species of gramnegative bacilli. Generally, by the checkerboard dilution method, 3-lactam antibiotics, when tested in combination with mitomycin C, bleomycin, or 5-fluorouracil, showed synergistic action, whereas when tested in combination with carboquone, they showed antagonistic action. Almost no combinations of adriamycin showed the interactions. Among 3-lactam antibiotics, piperacillin was more frequently synergistic than cefoperazone, cefazolin, or carbenicillin when tested in combination with each antineoplastic agent against various species.The course of patients undergoing cancer therapy is apt to be complicated by infection; therefore, combination therapy with antimicrobial agents and antineoplastic agents is given in many cases. Manten and Terra (9), Jacobs et al. In the present study, we investigated the in vitro interactions of two new 3-lactam antibiotics, cefoperazone and piperaciflin, with a broad antibacterial spectrum and antineoplastic agents (mitomycin C, bleomycin, adriamycin, 5-fluorouracil, and carboquone) against gram-negative bacilli, using cefazolin and carbenicillin as controls. MATERIALS AND METHODSIsolates. Twenty-five fresh clinical isolates each of Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were used.Drugs. The ,B-lactam antibiotics studied were cefoperazone (Toyama Chemical Co.), cefazolin (Fujisawa Pharmaceutical Co.), piperacillin (Toyama Chemical Co.), and carbenicillin (Fujisawa Pharmaceutical Co.). The antineoplastic agents studied were mitomycin C (Sankyo Co.), bleomycin (Nihon Kayaku Co.), adriamycin (Kyowa Hakko Co.), 5-fluorouracil (Fuji Chemical Co.), and carboquone (Sankyo Co.
The antibacterial activity of 5-fluorouracil, an antineoplastic agent, was found to be enhanced by piperacillin, a jS-lactam antibiotic, resulting in a synergism. It was considered that the synergism was caused by an increase of 5-fluorouracil uptake into the bacterial cell. On the other hand, amount of piperacillin bound to penicillin binding protein (PBP) did not change when 5-fluorouracil was added. The morphological change of the cell was due to the 5-fluorouracil when synergism appeared between 5-fluorouracil and piperacillin.5-Fluorouracil, an anti-neoplastic agent, has been reported to have antibacterial activity against Gram-negative bacterial). This activity is considered to be due to an inhibitory action against thymidylate synthetase2). Further, as reported previously3), some antineoplastic agents exhibited synergism with piperacillin, a i3-lactam antibiotic. In this study, regarding to 5-fluorouracil particularly, we observed that the incorporation of 5-fluorouracil into the bacterial cell is promoted by piperacillin. Materials and MethodsChemicals 5-Fluorouracil (Fuji Chemical Co., Ltd.) and piperacillin (Toyama Chemical Co., Ltd.), as well as 5-fluoro[6-3H]uracil (Amersham International, England, 2.1 Ci/mmol) and benzyl[14C]penicillin potassium (Amersham, 58.9 mCi/mmol) were used.Bacterial Strains Escherichia coli TK-54, Klebsiella pneumoniae Y-40, Pseudoinonas aeruginosa S-340, and P. aeruginosa S-344 were used. These strains were clinical isolates.Antibacterial Activity and Synergy Studies Minimal inhibitory concentrations (MICS) of piperacillin, 5-fluorouracil, and these drugs in combination were determined by the 2-fold dilution method using Mueller-Hinton agar (Eiken Co., Ltd.). The bacteria were cultured overnight in Mueller-Hinton broth (Difco Laboratories) at 37°C, and one loopful of diluted pre-culture (1/100) was inoculated on the agar plate (approximately 104 cfu). After overnight incubation at 37°C, the MICs were determined. To compare the combination effect, we calculated the fractional inhibitory concentration (FIC) index for each strain according to the following formulas4.1). FIC=MIC of the drug in combination/MIC of the drug alone. FIC index= the sum of the FICs for each drug in combination. Synergy was defined as an FIC index <0.5, and antagonism as an FIC index >2. Incorporation of 5-Fluoro[3H]uracil into the Bacterial CellThe strains were grown in Brain-Heart Infusion broth (Eiken Co., Ltd.) at 37°C for 18 hours.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.