Comparative in vitro activity of ciprofloxacin and five other quinoline derivatives against gram-negative isolates

A total of 375 Gram-negative bacterial strains were isolated from midstream urine specimens of the same number of patients affected by urinary tract infections. All bacteria were identified by standard bacteriological methods and their susceptibility to six quinoline derivatives (ciprofloxacin, cinoxacin, norfloxacin, oxolinic acid, pipemidic acid, nalidixic acid) was studied by determining the MICs and MBCs for each compound using a miniaturized dilution broth method in microtitre plates and twofold dilutions of each drug from 256 to 0.12 mcg/ml. Ciprofloxacin, a new quinoline carboxylic acid compound structurally related to nalidixic acid, showed a much higher antibacterial activity against all bacterial strains under examination, including Pseudomonas, than the other compounds, except for norfloxacin. The MIC90 and MBC90 of ciprofloxacin never exceeded 1 mcg/ml with any of the bacterial species; and MBC/MIC ratios were very low, which represents an important clinical advantage. Only norfloxacin showed comparable effectiveness. No bacterial strain showed resistance to the drug and the MIC90 and MBC90 never exceeded 8 mcg/ml.     

In vitro antibacterial activity of E-3604, a new 6-fluoroquinolone, on clinical isolates

From a series of pyrrol-containing antibacterial agents, E-3604 was selected for development and compared with nalidixic acid, norfloxacin and ciprofloxacin against strains of clinical isolates. The in vitro activity of E-3604 was greater than that of nalidixic acid, similar to that of norfloxacin and lower than that of ciprofloxacin, except in the case of Staphylococcus where E-3604 showed the best in vitro activity of all the studied compounds, with a MIC range of 0.25-0.03 mg/ml. E-3604, like the other quinolones, presented a pH-dependent variation of activity, greater activity being observed in slightly acidic pH values.     

Norfloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Norfloxacin is one of the new 4-quinolone antibacterial agents. A fluorinated piperazinyl-substituted congener of nalidixic acid, it demonstrates a much wider in vitro antibacterial spectrum and greater potency than the parent compound. Its antibacterial activity against most Gram-negative pathogens is enhanced in comparison to nalidixic acid, but is similar to that of some of the other new 4-quinolones like enoxacin, and slightly less than that of ciprofloxacin. Unlike nalidixic acid, norfloxacin is also active against Pseudomonas aeruginosa and some Gram-positive organisms. In acute or uncomplicated urinary tract infections, norfloxacin has repeatedly been shown to be as effective as co-trimoxazole. Single studies have demonstrated a significantly better bacteriological cure rate with norfloxacin than with pipemidic acid, and similar cure rates with norfloxacin and both a nalidixic acid/sodium citrate mixture and amoxycillin. Similar results were found in a few studies comparing norfloxacin to pipemidic acid or amoxycillin in patients with chronic and/or complicated urinary tract infections. Norfloxacin is as effective as spectinomycin in gonorrhoea due to penicillin-resistant N. gonorrhoeae, and cures bacterial gastroenteritis caused by several gastrointestinal pathogens. Norfloxacin appears to be well tolerated and may have a low propensity to select for bacterial resistance during clinical use, although the latter needs further confirmation.     

In vitro antibacterial activity of irloxacin (E-3432) on clinical isolates

Irloxacin (E-3432) is a new quinolone derivative. In this study, the activity of irloxacin was compared with that of nalidixic acid, norfloxacin and ciprofloxacin against strains of clinical isolates. Irloxacin showed greater in vitro activity than nalidixic acid, similar activity to norfloxacin and lower activity than ciprofloxacin. Against Staphylococcus, the MIC range of E-3432 was 0.06-1 mg/l, better than the other compounds studied.     

Research on antibacterial and antifungal agents. VII. Synthesis of (1-pyrryl)methylquinolines acids

Some (1-pyrryl)methyl derivatives of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were synthetized by the standard procedure involving Gould-Jacobs and Lappin reactions. The above derivatives were tested microbiologically as nalidixic acid analogs and compared with some clinically useful 4-oxopyridine-3-carboxylic acids (nalidixic acid, pipemidic acid, norfloxacin, enoxacin and ciprofloxacin). Their antibacterial activities were very weak.     

Susceptibility of recent clinical isolates to temafloxacin (A-63004) and other antimicrobial agents.

In vitro susceptibility of 1008 strains of recent clinical isolates was determined against the new aryl fluoroquinolone temafloxacin (T-167, A-63004) ciprofloxacin, norfloxacin, ampicillin, piperacillin, cephalothin, cefoxitin, ceftazidime, gentamicin, amikacin, oxacillin and vancomycin. The minimum inhibitory concentrations (MICs) of temafloxacin in micrograms/ml required for > or = 90% isolates were 0.13-0.5 for enterobacter, 0.03-0.25 for Escherichia coli, 0.12-0.5 for Klebsiella, 0.5-1.0 for Proteus mirabilis, 0.12-0.5 for Morganella morganii, 0.03-0.12 for Salmonella, 0.25-1.0 for Serratia marcescens, 0.03-0.12 for Shigella, 0.06-4.0 for Pseudomonas aeruginosa, 0.06-0.12 for Aeromonas hydrophila, 0.12-0.5 for Staphylococcus aureus, 0.12-1.0 for coagulase negative staphylococci and 4.0-8.0 for enterococci. The antibacterial activity of temafloxacin was comparable or superior to other drugs tested against most organisms. However, Xanthomonas malthophilia was relatively more susceptible to ciprofloxacin and norfloxacin, and temafloxacin had significantly high antibacterial activity against enterococci as compared to other fluoroquinolones.     

Influence of pH and human urine on the antibacterial activity of ciprofloxacin, norfloxacin and ofloxacin

The influence of pH on the antibacterial activity of ciprofloxacin, norfloxacin and ofloxacin was studied in broth and pooled human urine by microdilution susceptibility tests. Selected strains of E. coli, Staphylococcus aureus and Pseudomonas aeruginosa were used as test organisms. The results show that cultivation at pH 5.7 in urine increased the MIC values for all three quinolones 8, 16 and 32-fold compared with broth at pH 7.1. Killing curves show that in urine with 10 mcg/ml ciprofloxacin, rapid killing of E. coli and Pseudomonas aeruginosa occurred, whereas ofloxacin and especially norfloxacin were less effective.     

Rufloxacin (MF-934): in vitro and in vivo antibacterial activity

Rufloxacin (MF-934) is a new quinolone which shows in vitro antibacterial activity against E. coli, Salmonella, Klebsiella, Proteus and Staphylococcus spp. Lower in vitro activity was observed with Pseudomonas, Serratia, Enterobacter and the streptococci group D. The antimicrobial activity of MF-934 in vitro is higher than that of nalidixic acid but lower than that of ciprofloxacin, ofloxacin, pefloxacin or norfloxacin. The protective effects of MF-934 in systemic infections in mice are lower than those of ciprofloxacin and ofloxacin. In respiratory infections in rats and in subcutaneous infections in guinea-pigs, the protective effects of MF-934 are of the same order as ciprofloxacin and ofloxacin. This is probably due to the pharmacokinetic properties of MF-934, i.e. the long half-life and tissue concentrations higher than plasma levels.     

In vitro effect of pH and glucose concentration on the antibacterial activity of norfloxacin in urine

The in vitro effect of pH and glucose concentration on the antibacterial activity of norfloxacin in urine was studied. Norfloxacin effectively inhibited the growth of four gram-negative pathogens in urine in vitro at pH values of 6.0, 7.0, and 8.0. The antibacterial activity of norfloxacin in urine was reduced severalfold at pH 6, but minimum inhibitory concentrations (MICs) at this pH remained clinically significant. Glucose at concentrations of 200 mg/dl and 400 mg/dl (simulating glucosuria of diabetes) did not significantly affect the antibacterial activity of norfloxacin when tested against clinical isolates of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, or Pseudomonas aeruginosa. Norfloxacin appears to be a highly effective antibiotic in vitro under conditions which simulate normal and diabetic states.     

Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent

Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives, 8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ JC-2.     

In vitro evaluation of lomefloxacin

Lomefloxacin (1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4- oxoquinoline-3-carboxylic acid monohydrochloride, SC-47111) is a broad-spectrum antibiotic of the 4-quinolone group. In this comparative study the antimicrobial in-vitro activity of lomefloxacin was tested against 863 gram-negative and 415 gram-positive strains from fresh clinical isolates. As comparative agents ciprofloxacin, norfloxacin and ofloxacin were used. The minimal inhibitory concentrations were determined by means of a serial dilution with the agar-dilution procedure. Lomefloxacin showed an antibacterial efficacy comparable to other quinolones. Ciprofloxacin in general was two-fold dilutions more active. No cross-resistance with beta-lactamase producing-methicillin resistant or aminoglycoside-, tetracycline-, chloramphenicol- and co-trimoxacol-resistant strains could be found. Lomefloxacin showed in this study a broad antimicrobial activity. The clinical utilities of this new fluoroquinolone will depend on the pharmacokinetic properties and the adverse event profile.     

喹诺酮类抗菌药物的研究XV.6—氯—1（2,4—二氟苯基）—7—（1—？…

合成了12个6-氯-1-(2,4-二氟苯基)-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,并测定了它们的体外抗菌活性。结果表明,其中4Ab对金葡菌-9的活性是环丙沙星的12倍、诺氟沙星的50倍。     

Novel amino-substituted 3-quinolinecarboxylic acid antibacterial agents: synthesis and structure-activity relationships

A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antibacterial potency is greatest when the 1-substituent is methylamino and the 7-substituent is either 4-methyl-1-piperazinyl, 16, or 1-piperazinyl, 21. Derivatives 16 and 21, the 1-methylamino analogues of pefloxacin and norfloxacin, respectively, show comparable in vitro and in vivo antibacterial potency to these two known agents. The activity (vs. Escherichia coli Vogel) of 16 (amifloxacin) is the following: in vitro MIC (microgram/mL) = 0.25; in vivo (mice) PD50 (mg/kg) = 1.0 (po), 0.6 (sc).     

吡酮酸类抗菌药物的研究 XII.6-氯-1-环丙基-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

合成了１６个６氯１环丙基７（１哌嗪基）１，４二氢４氧代喹啉３羧酸及其类似物，并测定了抗菌活性，结果表明，化合物１１Ｃａ及１１Ｃｃ对金葡菌１５的活性是环丙沙星的４倍，对大肠杆菌２２和绿脓杆菌２９的活性与环丙沙星相当     

Antibacterial evaluation of a collection of norfloxacin and ciprofloxacin derivatives against multiresistant bacteria

The objective of this study was to analyse an array of ciprofloxacin and norfloxacin derivatives in order to determine those with good activity against bacteria that already present fluoroquinolone resistance associated with mutations in the gyrA and/or parC genes. Four norfloxacin and 20 ciprofloxacin derivatives were synthesised and tested against quinolone-susceptible and -resistant Escherichia coli, Acinetobacter baumannii, Stenotrophomonas maltophilia and Staphylococcus aureus strains using a microdilution test. Among the derivatives, the 4-methyl-7-piperazine ciprofloxacin derivative showed a minimum inhibitory concentration for 50% of the organisms that was 16- and 8-fold lower than ciprofloxacin for A. baumannii and S. maltophilia, respectively. When the methyl group at position 4 in the piperazine ring was substituted by ethyl, butyl or heptyl groups, activity against A. baumannii steadily decreased. The 7-(4-methyl)-piperazine ciprofloxacin derivative (UB-8902) showed very good activity against these multiresistant microorganisms including A. baumannii and S. maltophilia.     

妥舒沙星的体内外抗菌作用研究

测定妥舒沙星的体内外抗菌活性。以同类氟喹诺酮类及其他抗菌药物为对照,测定了６８９株临床分离菌对药物的敏感性,结果显示,妥舒沙星对需氧革兰氏阳性球菌（除ＭＲＳＡ外）均有良好的抗菌作用,对金葡球菌、肺炎球菌和溶血性链球菌的抗菌活性高;妥舒沙星对需氧革兰氏阴性菌具强大的抗菌作用,对肠杆菌科细菌、流感杆菌和淋球菌的抗菌作用尤强;妥舒沙星对脆弱拟杆菌等厌氧菌亦具良好抗菌作用。妥舒沙星对需氧革兰氏阳性球菌及厌氧菌的作用明显优于环丙沙星、氧氟沙星和诺氟沙星,对需氧革兰氏阴性杆菌的作用与其他受试氟喹诺酮类相仿。妥舒沙星对小鼠实验性细菌感染具有明显保护作用,口服或静注妥舒沙星对金葡球菌的体内抗菌作用明显优于环丙沙星;对大肠埃希氏菌的抗菌作用优于或与环丙沙星相似;对铜绿假单胞菌的作用与环丙沙星相似。     

Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials.

A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.     

In vivo activity of ciprofloxacin, ofloxacin, norfloxacin and pipemidic acid against Escherichia coli infections in mice

The therapeutic efficacy of four quinolones, i.e. ciprofloxacin, ofloxacin, norfloxacin and pipemidic acid, was investigated in experimental infections in mice caused by pipemidic acid-susceptible and -resistant E. coli. For intraperitoneal infections caused by E. coli strain 444 and 23, the efficacy of ciprofloxacin, ofloxacin and norfloxacin was superior to that of pipemidic acid. Furthermore, ciprofloxacin and ofloxacin had higher activity than norfloxacin and pipemidic acid in urinary tract and uterine infections. Serum and uterus levels of ciprofloxacin and ofloxacin in normal mice were higher and more durable than those of norfloxacin.     

In vitro activity of seven gyrase inhibitors of a group of heterocyclic carbonic acids against nonfermenting gram negative rods (nonfermenters)

MIC (minimal inhibitory concentration) determinations for nalidixic acid, cinoxacin, pipemidic acid, norfloxacin, enoxacin, and ciprofloxacin were done by agar dilution on isosensitest agar (oxoid). Bacterial strains investigated were 189 Pseudomonas aeruginosa, 164 Acinetobacter lwoffii, 4 Ps. maltophilia, 3 Ps. putrefaciens and 3 Ps. odorans. The results in summary are: Ciprofloxacin is the most active gyrase inhibitor against Ps. aeruginosa as well as against other nonfermentative gram-negative rods, versus Ps. aeruginosa norfloxacin is a little more active than ofloxacin, against nonfermentative gram-negative rods other than Ps. aeruginosa norfloxacin is markedly less active than ofloxacin. Problems concerning cross-resistance of new gyrase inhibitors are discussed.     

吡酮酸类抗菌药物的研究 XII.6-氯-1-环丙基-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

合成了16个6-氯-1-环丙基-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,并测定了抗菌活性,结果表明,化合物11Ca及11Cc对金葡菌-15的活性是环丙沙星的4倍,对大肠杆菌-22和绿脓杆菌-29的活性与环丙沙星相当。