In vitro method for prediction of the phototoxic potentials of fluoroquinolones

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.     

Activity of eight fluoroquinolones against methicillin-resistant Staphylococcus aureus isolated from cutaneous infections

The in vitro susceptibility of methicillin-resistant Staphylococcus aureus to eight fluoroquinolones, norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, sparfloxacin and nadifloxacin, was evaluated. Methicillin-resistant S. aureus strains were isolated from 64 cutaneous infections from 1991 to 1993. Nadifloxacin exhibited the lowest MIC among all of the fluoroquinolones. In addition, there was no resistance to nadifloxacin. The MIC(50) of these drugs has been increasing in the past 3 years.     

Transient Relaxation of Plasmid DNA in Escherichia coli by Fluoroquinolones

We examined the influence of fluoroquinolones (norfloxacin, enoxacin, ofloxacin, levofloxacin, and sparfloxacin) on DNA supercoiling of plasmids in Escherichia coli cells by analysis with agarose gel electrophoresis in the presence of chloroquine. All the fluoroquinolones tested immediately induced DNA relaxation. The relaxed DNA was re-supercoiled, and the process was sensitive to chloramphenicol, suggesting that newly synthesized proteins participate in the reaction. The concentrations of fluoroquinolones required for DNA relaxation were much higher than those required for cell killing. The bactericidal effect of fluoroquinolones is apparently related to mechanisms other than DNA relaxation.     

我国西南地区2000年～2001年氟喹诺酮类药物用药分析

目的:调查分析2000年～2001年氟喹诺酮类药物在我国西南4省市医院中的用药情况,评估其现状和趋势。方法:对西南4省市共51家医院应用氟喹诺酮类药物的品种、用药金额、DDDs等进行统计分析。结果:2000年～2001年西南4省市51家医院共应用氟喹诺酮类药物10个品种;2000年与2001年的用药金额分别为74 208 227元和93 660 193元,年度增长26.21％,用药金额上升主要是左氧氟沙星、司帕沙星和依诺沙星的用量增加所致;2001年较2000年的DDDs减少17.58％,但平均DDD金额分别为21.54元和21.52元,无明显差异;两年中氧氟沙星、环丙沙星、诺氟沙星、洛美沙星滴眼液和滴鼻液用量较大。结论:氟喹诺酮类药物在西南地区是一类应用普遍的抗菌药物。一些较新的氟喹诺酮药物如左氧氟沙星和司帕沙星的用量增长迅速。     

6种氟喹诺酮类药物对临床分离金葡萄的抗菌活性比较

目的：观察临床分离金葡萄对6种氟喹诺酮类药物的耐药情况。方法：用琼脂稀释法测定诺氟沙星（NFLX）、氧氟沙星（OFLX）、氟罗沙星（FLRX）、环丙沙星（CPFX）、司帕沙星（SPFX）、托舒沙星（TFLX）6种2、3代氟喹诺桐类药物对成都地区155株临床分离金葡菌的体外抗菌活性。结果：金葡菌对6种药物的耐药率分别为诺氟沙星35.5%。氟罗沙星34.19%,环丙沙星27.75%,托舒沙星27.75% ,氧氟沙星25.81%,司帕沙星25.81%。结论：氟喹诺酮类药物的广泛应用已使细菌的耐药性明显增高,各药MIC90均超过16mg.L^-1,比以往文献报道的本地区金葡萄耐药性明显升高,提示要合理应用氟喹诺酮类药物,减少耐药菌株的增加。     

Activity of nine fluoroquinolones against strains of Bordetella bronchiseptica

Thirty-two strains of Bordetella bronchiseptica were tested for their antimicrobial susceptibilities to nine fluoroquinolones. The most active agents were fleroxacin, temafloxacin, ciprofloxacin (MIC₉₀ 1 μg/ml), ofloxacin, lomefloxacin and enoxacin (MIC₉₀ 2 μg/ml). Pefloxacin and norfloxacin were active only against 59.3 and 83.1%, respectively, of the strains tested, whereas rufloxacin lacked activity against all the strains of B. bronchiseptica tested.     

Permeability classification of representative fluoroquinolones by a cell culture method

This study was undertaken to categorize representative fluoroquinolone drug substance permeability based on the methods outlined in the Food and Drug Administration's biopharmaceutic classification system (BCS) Guidance for Industry. The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones drugs demonstrated concentration-dependent permeability, indicating active drug transport. In comparing absorptive versus secretive in vitro transport, the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to labetalol, the high permeability internal standard, ciprofloxacin was classified as a low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were classified as high permeability drugs. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance.     

氟喹诺酮类抗菌药物致药物不良反应205例调查分析

目的分析氟喹诺酮类抗菌药物(FQNS)药物不良反应(ADR)的特点,为临床合理用药提供依据。方法对2001-2010年某院门、急诊及住院部应用FQNS致ADR患者205例进行回顾性统计、分析。结果男性ADR发生率高于女性,31～40岁年龄段ADR发生率最高(31.2%);引起ADR的主要给药途径为静脉注射,共105例(51.2%);共涉及10种FQNS,不良反应主要表现在神经、循环、皮肤、泌尿、消化、呼吸、血液等系统,其中以神经系统、皮肤及消化系统症状较突出。结论 FQNS致ADR因素较多,临床使用时应注意ADR的监测,合理用药,以提高用药的安全性,减少ADR的发生。     

Quinolone pharmacokinetics

Fluoroquinolones have broad antibacterial spectra and are active against most Gram-negative and many Gram-positive species. They exhibit excellent oral bioavailability, extensive tissue penetration, low protein binding, and a long elimination half-life. This review compares and contrasts the pharmakonetics of some quinolone antibiotics - especially pefloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, fleroxacin and lomefloxacin - in terms of their adsorption, distribution, metabolism, elimination, and interactions with other drugs and with food. In addition, the pharmacokinetics of these agents in the elderly and in patients with renal or hepatic impairment is discussed. The fluoroquinolones are established as a major class of antibiotics in the treatment of infections but pharmacokinetics factors should be considered when deciding on the most appropriate of these agents to use in individual patients.     

Susceptibility of bacterial isolates from AIDS patients to six fluoroquinolones

The susceptibilities to ciprofloxacin, DR-3355 (S-(-)-ofloxacin), enoxacin, lomefloxacin, ofloxacin and PD127,391 of 69 significant bacterial isolates from HIV-positive patients at the City Hospital, Edinburgh have been determined. With the exception of the enterococci, most of the strains tested (including staphylococci, Escherichia coli and Pseudomonas aeruginosa) were susceptible to the fluoroquinolones. Ciprofloxacin was the most active of the clinically available drugs followed by ofloxacin, lomefloxacin and enoxacin. PD127,391 and DR-3355, the new fluoroquinolones tested, were at least as active as ciprofloxacin. Hence bacterial infections in AIDS patients should respond to fluoroquinolone therapy.     

Structure-phototoxicity relationship in Balb/c mice treated with fluoroquinolone derivatives, followed by ultraviolet-A irradiation

We examined the structure-phototoxicity relationship for fluoroquinolone antimicrobial agents (quinolones) using female albino Balb/c mice. First of all, to obtain an optimum dosage level for induction of phototoxicity, the prototype phototoxicant sparfloxacin was intravenously administered once at 10 mg/kg, 30 mg/kg or 100 mg/kg to female mice, followed immediately by ultraviolet-A (UVA) irradiation for 4 h (21.6J/cm2). The auricular thickness was measured at pre-dose (0 h), 4, 24, 48, 72 and 96 h post-dose, and then the histopathological examination of the auricle was performed. As results, the auricular thickness increased from 30 mg/kg, in conjunction with edema, cellular infiltration, epidermal necrosis and focal loss of the auricle. On the basis of these information, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, lomefloxacin, norfloxacin and ofloxacin were given intravenously to mice at a fixed dose of 100 mg/kg to compare their potential phototoxicities. Certain quinolones caused the auricular lesions in the following rank order (from lowest to highest): vehicle control (non-phototoxicity)=gatifloxacin=ofloxacin相似文献   

Mutagenesis induced by 12 quinolone antibacterial agents in Escherichia coli WP2uvrA/pKM101.

The mutagenic potential of 12 quinolone antibacterial agents (quinolones) was examined at concentrations of 3.91-1000 ng/plate with or without S9 mix in Escherichia coli WP2uvrA/pKM101. All quinolones showed mutagenic potential in the strain: the maximum numbers of revertant colonies were observed at 7.81 ng/plate for clinafloxacin and sitafloxacin; 15.63 ng/plate for ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin; and 31.25-500 ng/plate for enoxacin, lomefloxacin, norfloxacin and ofloxacin. The numbers for all quinolones were comparable between the groups with and without S9 mix. In all quinolones, bactericidal effects were observed at one or two higher concentrations than their mutagenic concentrations except for enoxacin without S9 mix. From these results, the WP2uvrA/pKM101 strain is proved to be highly sensitive to quinolones.     

Comparative in vitro activity of enoxacin and other fluoroquinolones against multi-resistant strains of Salmonella typhi.

The in vitro activities of enoxacin, lomefloxacin, norfloxacin, ofloxacin, and pefloxacin against 274 strains of Salmonella typhi isolated from suspected typhoid fever patients (137 multi-resistant strains and 137 strains sensitive to chloramphenicol, ampicillin and/or co-trimoxazole) were determined using disk diffusion and agar dilution techniques. In vitro, enoxacin was active against all tested strains with a MIC90 and inhibition zone size against multi-resistant strains of 0.12 mg/l and 34 mm diameter, respectively. Similar results were found with the other fluoroquinolones. Enoxacin and other fluoroquinolones may be the therapy of choice in cases of typhoid fever caused by organisms resistant to the standard therapy, chloramphenicol.     

Fluoroquinolone-induced renal failure.

Fluoroquinolones are generally well tolerated, clinically useful antimicrobials. This paper highlights rare, but potentially serious, adverse effects involving the kidney. Other antimicrobials have long been known to cause various forms of nephrotoxicity occurring as allergic interstitial nephritis, granulomatous interstitial nephritis, necrotising vasculitis, allergic tubular nephritis or a tubular necrosis. A Medline search (1985 to May 1999) of ciprofloxacin, norfloxacin, levofloxacin, ofloxacin, trovafloxacin, enoxacin, sparfloxacin, grepafloxacin, gatifloxacin, clinafloxacin and moxifloxacin was conducted to ascertain the incidence and features of fluoroquinolone nephrotoxicity. Unfortunately, the data primarily consist of case reports and temporally related events. The incidence of these adverse effects is hard to estimate, and the cause may be multifactorial. While the use of ciprofloxacin appears to increase the risk, this may be due to its longer and more widespread use when compared with the newer agents.     

Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG

Administration of certain fluoroquinolone antibacterials has been associated with prolongation of the QT interval on the electrocardiogram and, on rare occasions, ventricular arrhythmia. Blockade of the human cardiac K+ channel HERG often underlies such clinical findings. Therefore, we examined a series of seven fluoroquinolones for their ability to interact with this channel. Using patch-clamp electrophysiology, we found that all of the drugs tested inhibited HERG channel currents, but with widely differing potencies. Sparfloxacin was the most potent compound, displaying an IC50 value of 18 microM, whereas ofloxacin was the least potent compound, with an IC50 value of 1420 microM. Other IC50 values were as follows: grepafloxacin, 50 microM; moxifloxacin, 129 microM; gatifloxacin, 130 microM; levofloxacin, 915 microM; and ciprofloxacin, 966 microM. Block of HERG by sparfloxacin displayed a positive voltage dependence. In contrast to HERG, the KvLQT1/minK K+ channel was not a target for block by the fluoroquinolones. These results provide a mechanism for the QT prolongation observed clinically with administration of sparfloxacin and certain other fluoroquinolones because free plasma levels of these drugs after therapeutic doses approximate those concentrations that inhibit HERG channel current. In the cases of levofloxacin, ciprofloxacin, and ofloxacin, inhibition of HERG occurs at concentrations much greater than those observed clinically. The data indicate that clinically relevant HERG channel inhibition is not a class effect of the fluoroquinolone antibacterials but is highly dependent upon specific substitutions within this series of compounds. HERG channel affinity should be an important criterion for the development of newer fluoroquinolones.     

Febrile neutropenia in a bone marrow transplantation unit

A total of 119 strains of coagulase-negative staphylococci isolated from clinical specimens were speciated and tested for sensitivity to methicillin and four fluoroquinolones (ciprofloxacin, sparfloxacin, levofloxacin and ofloxacin). Resistance to fluoroquinolones was significantly more common in Staphylococcus haemolyticus (43%) than in Staphylococcus epidermidis (11%). Methicillin-resistant strains of S. haemolyticus were more often resistant to ciprofloxacin than were methicillin-resistant strains of S. epidermidis (P < 0.05). Sparfloxacin was the most active against fluoroquinolone-sensitive strains, and levofloxacin was twice as active as ofloxacin. There was cross-resistance between the four fluoroquinolones. Levofloxacin was the most active against resistant strains, but MICs obtained for all the compounds seemed to be outside the clinically useful range for the treatment of systemic infections.     

Comparative in vitro activity of enoxacin and other fluoro-quinolones against multi-resistant strains of Salmonella typhi

Summary

The in vitro activities of enoxacin, lomefloxacin, norfloxacin, ofloxacin, and pefloxacin against 274 strains of Salmonella typhi isolated from suspected typhoid fever patients (137 multi-resistant strains and 137 strains sensitive to chlor-amphenicol, ampicillin and/or co-trimoxazole) were determined using disk diffusion and agar dilution techniques. In vitro, enoxacin was active against all tested strains with a MIC₉₀ and inhibition zone size against multi-resistant strains of 0.12?mg/l and 34?mm diameter, respectively. Similar results were found with the other fluoroquinolones. Enoxacin and other fluoroquinolones may be the therapy of choice in cases of typhoid fever caused by organisms resistant to the standard therapy, chloramphenicol.     

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.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.