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.     

Responsiveness of genetically epilepsy-prone rats to aminophylline-induced seizures and interactions with quinolones.

The authors sought to determine whether different responsiveness to seizures induced by aminophylline existed between the genetically epilepsy-prone and normal rats. It was found that the seizure latency was consistently shorter in the genetically epilepsy-prone rats than in normal ones. A different pattern of response was observed in the progression to tonic seizures. In addition, seizures appeared to be more marked in genetically epilepsy-prone than in normal rats. A pretreatment with some quinolones (nalidixic acid, pipemidic acid, ciprofloxacin, norfloxacin, ofloxacin and enoxacin) significantly increased the convulsant properties of aminophylline. These studies demonstrated that the order of proconvulsant activity was ciprofloxacin greater than enoxacin greater than ofloxacin greater than norfloxacin greater than nalidixic acid greater than pipemidic acid. In addition, the present results showed that quinolones, having a fluorine atom showed the most marked proconvulsant activity.     

Penetrability of ofloxacin into cultured epithelial cells and macrophages

It is well known that the penetration of drugs into host cells is the minimal requirement to exhibit their efficacy against infections with intracellular bacteria. Thus the penetrability of new quinolones including ofloxacin, norfloxacin and ciprofloxacin was evaluated by comparing their intracellular and extracellular activities by the use of cell infection systems in vitro. It was evidenced that the new quinolones tested were penetrable into both epithelial cells and macrophages, however, ofloxacin was more penetrable than norfloxacin and ciprofloxacin into both types of cells which serve the nest for proliferation of intracellular bacteria.     

In-vitro activity of antifungal agents in combination with four quinolones

The antifungal activity of amphotericin B (AMB), mepartricin (MEPA), 5-fluorocytosine (5FC) and three imidazoles was tested in combination with each of four quinolones against 60 clinical yeast isolates. The inhibitory activity of AMB and MEPA was marginally enhanced by the azaquinolones, nalidixic acid (NAL) and enoxacin (ENO), but there was antagonism when combined with the fluorinated quinolones ciprofloxacin (CIP) and norfloxacin (NOR). All quinolones except NAL partially antagonised 5FC. Miconazole (MCZ), ketoconazole (KTZ) and itraconazole (ITZ) were each found to be synergistic with low concentrations of the quinolones, and also with high concentrations of NAL and ENO, but were strongly antagonised by high concentrations of CIP and NOR.     

Pharmacological evaluation of garenoxacin,a novel des-F(6)-quinolone antimicrobial agent: effects on the central nervous system

The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 micrograms/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.     

Quantitative determination of ofloxacin, ciprofloxacin, norfloxacin and pefloxacin in serum by high pressure liquid chromatography

A simple sensitive HPLC method for the analysis of ciprofloxacin, norfloxacin, ofloxacin and pefloxacin in serum is described. The quinolones were extracted using dichloromethane under neutral conditions, followed by drying under nitrogen and dissolving in mobile phase before Chromatographic analysis. The stationary phase consisted of a stainless steel column with Nucleosil C18 (5 m), and a mobile phase of 0.04M phosphoric acid, tetrabutylammoniumiodide as ion-pairing reagent and methanol (pH 2.2). UV absorbance was used for detection. The method was shown to be linear, quantitative and reproducible in the therapeutic range of each of these quinolones. Serum levels of ofloxacin and ciprofloxacin were determined and compared to those found by a microbiological assay. Good correlation was found for the assay of ciprofloxacin as well as for ofloxacin.     

Update on quinolone drug interactions

Concurrent administration of both ciprofloxacin and norfloxacin with sucralfate leads to a decrease in quinolone bioavailability. It is unknown whether this decrease is clinically significant because studies have focused primarily on pharmacokinetics and not therapeutic outcomes. A reasonable recommendation may be to avoid using sucralfate and norfloxacin concurrently, or avoid administration of norfloxacin and ciprofloxacin within two hours of sucralfate administration. Magnesium- and aluminum-containing antacids may also interfere with quinolone absorption. Calcium carbonate and H2 receptor antagonists do not appear to interact with quinolones and may be considered as an alternative to sucralfate or magnesium- and aluminum-containing antacids when quinolones are administered. Concurrent administration of ciprofloxacin and theophylline may precipitate theophylline toxicity if not monitored carefully. Some clinicians recommend a 30% empiric reduction in theophylline dosage when ciprofloxacin therapy is initiated. Because the drug interaction is not completely predictable, the patient's theophylline levels should be monitored and signs and symptoms of toxicity noted, adjusting the dose as needed. Decreased theophylline clearance may persist for as long as five days following discontinuation of ciprofloxacin. Some potential for slight increases in serum theophylline concentrations secondary to norfloxacin administration may exist. However, it is unlikely to be clinically significant, based on currently available information.     

Pharmacokinetic determination of relative potency of quinolone inhibition of caffeine disposition

Summary Quinolone is reported to interact with caffeine, often resulting in an increase both in the plasma half-life and AUC, a decrease in total plasma clearance, and little change in the absorption rate constant and maximum plasma level. These complex changes in the pharmacokinetics of caffeine were analyzed experimentally and from published reports in order to determine the nature of the interaction, which is thought to be due to inhibition of caffeine metabolism by quinolones. A simple pharmacokinetic model for the caffeine-quinolone interaction was developed, which provides a unified method for evaluation and comparison of the effect of quinolones on the disposition of caffeine. The model is applicable to other methylxanthines, such as theophylline. The relative potency of the interactions of quinolones with caffeine in humans has been established as enoxacin (100), pipemidic acid (29), ciprofloxacin (11), norfloxacin (9) and ofloxacin (0).     

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.     

Quinolones in vitro

The first quinolone compound, nalidixic acid, showed activity against a limited number of Gram-negative micro-organisms. ‘One step’ resistance developed hiin vitro and during treatment. Resistance was not mediated by transfer of R-plasmids, which is a characteristic of all quinolones. Newer quinolones like oxolinic acid, piromidic acid, cinoxacin and pipemidic acid exhibit an extended spectrum of activity against Gram-negative bacteria at lower MIC values. In recent years fluorinated quinolones were introduced like ciprofloxacin, norfloxacin, pefloxacin, ofloxacin, enoxacin and amifloxacin. These compounds exhibitin vitro a broad spectrum of activity against Gram-negative and Gram-positive bacteria at MIC values seventy to four hundred times less than those for nalidixic acid. Thein vitro activity of these compounds has been investigated in a large study of uncomplicated urinary tract infections in general practice (PINISU). No resistance was found. The fluorinated quinolones are very promising antimicrobial agents for a limited number of indications.     

新喹诺酮类抗菌药合成路线概述

概述了国外文献上喹诺酮类抗菌药物的主要合成方法。对氟哌酸和丙氟哌酸的合成工艺予较详细叙述,并作简要分析比较。     

Place of quinolones in the therapeutic armoury

On the basis of antimicrobial activity, resistance development, pharmacokinetics, side effects and pre-clinical results, the applicability of the quinolones ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin is assessed. These quinolones seem especially useful in infections in hospitalized patients, in gonococcal infections and in urinary tract infections. Also salmonellosis and shigellosis might be indications for quinolones.     

The new quinolones

The new quinolones are reviewed. These drugs are fluorinated derivatives of nalidixic acid, like ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, and others. The following aspects are discussed: microbiology, modes of action and of resistance, the pharmacologic properties, the adverse reactions, the interactions with other drugs, and the principal clinical applications.     

The place of quinolones in antibacterial therapy in hospitals

A comparative evaluation is made on activity, resistance problems and side effects of nine quinolones. These data and the information on clinical experiences are used to outline the author's view on the present position of these compounds in treatment policies. The following indications seem appropriate: norfloxacin or pipemidic acid in lower urinary tract infection, secondary to nitrofurantoin and sulfonamides; one of the more active quinolones, like ciprofloxacin, in case of therapy failure or multiple resistance; application for gonorrhoea appears attractive, but data on long-term effects and resistance are needed; in antibacterial combinations for selective bowel decontamination. Comparative clinical trials are essential before other indications for quinolones in clinical policies can be defined.     

Selective in-vitro inhibition of hepatic oxidative metabolism by quinolones: 7-ethoxyresorufin and caffeine as model substrates.

The in-vitro inhibition of several metabolic pathways has been studied in 3-methylcholanthrene-treated rats. The specificity of the 7-ethoxyresorufin O-de-ethylase reaction has been determined in the presence and absence of ciprofloxacin, enoxacin, norfloxacin, ofloxacin, nalidixic acid, oxolinic acid and pipemidic acid. For the caffeine N3-demethylation reaction, enoxacin and pipemidic acid were used. Enoxacin (IC50 = 105 microM, Ki = 65 microM) and pipemidic acid (IC50 = 115 microM, Ki = 160 microM) significantly inhibited 7-ethoxyresorufin O-de-ethylase reaction and caffeine N3-demethylation (IC50 = 60 microM for enoxacin and IC50 = 185 microM for pipemidic acid) by a competitive mechanism. Other quinolones had lower or no (ofloxacin) inhibitory capacity. The order of inhibitory activity observed is in agreement with results obtained previously from in-vivo studies in man. No activity was detected towards ethylmorphine N-demethylation.     

三种国产喹诺酮类药物对高接种量志贺氏菌的抗菌活性

测试了吡哌酸、氟哌酸和环丙氟哌酸等三种国产喹诺酮类药物对60株志贺氏菌高接种量(10~7CFU/ml)和标准接种量(10~5CFU/ml)的抗菌活性。结果表明,高接种量与标准接种量相比,药物最小抑菌浓度(MIC)增大16～256倍,氨苄青霉素和庆大霉素高接种量与标准接种量相比,MIC仅增高2倍。氨苄青霉素是对其敏感的志贺氏菌所致的重型菌痢较好的首选药物。而喹诺酮类药物如使用不当,不仅不能杀死志贺氏菌,反而诱导选择出耐药菌,给治疗带来新问题。     

Susceptibility of Brucella melitensis to fluoroquinolones

In vitro activity of four fluoroquinolones and four other antibacterial agents was tested against clinical isolates of Brucella melitensis. Initially all the 146 isolates studied were inhibited by 0.06-0.5 mg/l of ciprofloxacin and fleroxacin and 0.12-0.5 mg/l of pefloxacin or norfloxacin. One of these isolates developed resistance during therapy with ciprofloxacin, with a rise in MIC from 0.06 mg/l to more than 5.0 mg/l. This strain also showed cross-resistance to all other quinolones. All the isolates remained susceptible to tetracycline, gentamicin, rifampicin and trimethoprim-sulfamethoxazole. None of the quinolones showed in vitro synergy with other antibiotics.     

Central stimulating effect of the combination of the new quinolone group of antimicrobials and nonsteroidal anti-inflammatory drugs in mice]

Six new quinolones: enoxacin, norfloxacin, ofloxacin, ciproflosacin, lomefloxacin, and tosufloxacin and eight nonsteroidal anti-inflammatory drugs: fenbufen, flurbiprofen, ketoprofen, pranoprofen, ibuprofen, indomethacin, mefenamic acid and aspirin were tested for their ability to produce a central stimulating effect in mice. At 5 min after the oral administration of one of the nonsteroidal anti-inflammatory drugs, a new quinolone was administered orally. The combination of drugs induced convulsions in a dose-dependent manner, and some mice died as a result of the convulsions. The survival time was used as an index to measure the intensity of convulsions induced by the drug combination. The new quinolones in combination with fenbufen at 100 mg/kg produced convulsions in the following order of potencies: enoxacin greater than lomefloxacin greater than norfloxacin. In contrast, administration of fenbufen together with ofloxacin, ciprofloxacin, or tosufloxacin up to a dose of 1000 mg/kg caused no convulsions. Four nonsteroidal anti-inflammatory drugs combined with enoxacin at 100 mg/kg also caused convulsion dose-dependently. The order of potency in producing convulsion was as follows: fenbufen greater than flurbiprofen greater than ketoprofen = pranoprofen. However, no convulsions were produced by treatment of ibuprofen, indomethacin, mefenamic acid or aspirin together with enoxacin. From these results, the important chemical structures of the new quinolones particularly concerned with the appearance of convulsion were discussed.     

喹诺酮类药物对厌氧菌的体外抗菌活性研究

用６种喹诺酮类药物（氟罗沙星、诺氟沙星、依诺沙星、环丙沙星、洛美沙星、氧氟沙星）对９３株不同厌氧菌作体外抗菌活性研究，并与常用的抗厌氧菌药物克林霉素、甲硝唑比较，结果显示环丙沙星对厌氧菌的抗菌活性最强，与甲硝唑类似，优于克林霉素；其次为氧氟沙星和氟罗沙星；洛美沙星、依诺沙星、诺氟沙星效果较差。其中，革兰氏阳性厌氧菌对环丙沙星最敏感，其次为氟罗沙星和氧氟沙星；革兰氏阴性厌氧菌对环丙沙星最敏感，其次为