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PubMed1986

Inhibition of Micrococcus luteus DNA gyrase by norfloxacin and 10 other quinolone carboxylic acids.

The ability of norfloxacin, amifloxacin, cinoxacin, ciprofloxacin, flumequine, nalidixic acid, ofloxacin (OFL), oxolinic acid, perfloxacin, pipemidic acid, and rosoxacin to inhibit the in vitro supercoiling activity of Micrococcus luteus DNA gyrase was compared with the ability of each drug to inhibit the growth of the M. luteus strain from which the gyrase was purified. The potency of the quinolones as DNA gyrase inhibitors did not always correlate with antimicrobial potency. For example, OFL was a less potent inhibitor of gyrase than rosoxacin, yet the MIC of OFL was 16-fold lower than that of rosoxacin. Similarly, the MICs of norfloxacin and ciprofloxacin (the most potent of the antibiotics tested in these assays) were several hundredfold lower than the MIC of nalidixic acid (the least potent of these antibiotics), but the inhibition of purified gyrase by these two quinolones was only 8- to 16-fold lower than that of nalidixic acid. These results suggest that factors in addition to inhibition of gyrase supercoiling activity are important in determining the potency of these drugs. Further studies indicated that the uptake of norfloxacin, OFL, and amifloxacin by M. luteus cells may not account for the large differences in MICs observed for these drugs (MICs of 0.8, 2.0, and 128 micrograms/ml, respectively).

Anti-Bacterial Agents↗

PubMed1970

Control of initiation of DNA synthesis in Escherichia coli B-r.

The pattern of new growing forks in the Escherichia coli genome after a period of inhibition of DNA synthesis has been examined. Synchronous cultures of E. coli B/r were treated with nalidixic acid to stop DNA synthesis for various lengths of time. After removal of the nalidixic acid the location of active growing forks was determined by measuring the reversion rate of a histidine requirement induced by the "growing-point mutagen," nitrosoguanidine. It was found that the ability to initiate a new round of DNA synthesis upon release from the nalidixic acid block was attained at the cell age at which a new round of replication would have been initiated had DNA synthesis not been blocked. However, if the nalidixic acid was removed before the normal initiation age, the initiation of the next round of synthesis was delayed past the normal time, which indicates that initiation of new rounds is not completely independent of DNA synthesis.

Centrifugation, Density Gradient↗

PubMed1998

In vitro study of cytotoxicity of quinolones on rabbit tenocytes.

Tendinitis and tendon rupture complicating fluoroquinolone therapy have been reported recently, especially affecting men over 60 years. These new quinolones are more potent antimicrobial agents than older nonfluorinated compounds like nalidixic acid. We compared the effects of one quinolone (nalidixic acid) and two fluoroquinolones (norfloxacin and pefloxacin) on cultured rabbit Achilles tendon cells. First, we examined their effects on cell viability, mitochondrial succinate dehydrogenase and global activity, mitochondrial activity using microtitration methods. Pefloxacin and norfloxacin were more cytotoxic than nalidixic acid according to IC50 values. These results confirm that mitochondria represent a biological target of fluoroquinolones. Moreover, the extracellular matrix was studied by molecular hybridization. After a 72 h treatment, the level of type I collagen transcripts was not modified with any of the three antimicrobial agents, whereas mRNA encoding decorin was decreased with 10(-4) mol/L pefloxacin only. The decrease of transcripts encoding decorin suggests that this matrix component is another target of pefloxacin and modification of decorin seems to be an early event (before mitochondrion alteration) which may contribute to the explanation of tendon rupture.

Animals↗

PubMed2005

Biodegradable polymer releasing antibiotic developed for drainage catheter of cerebrospinal fluid: in vitro results.

The authors developed a biodegradable polymer that releases an antibiotic (nalidixic acid) slowly and continuously, for prevention of catheter-induced infection during drainage of cerebrospinal fluid. We investigated the in vitro antibiotic releasing characteristics and bacterial killing effects of the new polymer against E. coli. The novel fluoroquinolone polymer was prepared using diisopropylcarbodiimide, poly (e-capro-lactone) diol, and nalidixic acid. FT-IR, mass spectrometry, and elemental analysis proved that the novel antibacterial polymer was prepared successfully without any side products. Negative MS showed that the released drug has a similar molecular weight (M.W.=232, 350) to pure drug (M.W.=232). In high pressure liquid chromatography, the released drug and drug-oligomer showed similar retention times (about 4.5-5 min) in comparison to pure drug (4.5 min). The released nalidixic acid and nalidixic acid derivatives have antibacterial characteristics against E. Coli, Staphylococcus aureus, and Salmonella typhi, of more than 3 months duration. This study suggests the possibility of applying this new polymer to manufacture drainage catheters that resist catheter-induced infection, by delivering antibiotics for a longer period of more than 1 month.

Anti-Bacterial Agents↗

PubMed2000

Quinolone resistance among Salmonella enterica from cattle, broilers, and swine in Denmark.

This study was conducted to determine the susceptibility to nalidixic acid and fluoroquinolones of Salmonella Dublin, S. Enteritidis, and S. Typhimurium isolates from cattle, broilers, and pigs over time in Denmark and to characterise the gyrA, gyrB, and parC genes in quinolone-resistant isolates. A total of 584 S. Typhimiurium and 573 S. Dublin isolates from cattle during 1984 through 1999, and 241 S. Enteritidis and 131 S. Typhimurium from broilers and 452 S. Typhimurium from pigs isolated during 1997-1999 were tested. All isolates from cattle from the period 1984 through 1992 were susceptible to quinolones. A single (1.1%) S. Typhimurium isolate from 1995 and three (5.9%) from 1998 were resistant to nalidixic acid. Six (9.0%) S. Dublin isolates from 1996, four (4.2%) from 1997, and one (1.7%) from 1998 were resistant to nalidixic acid. Resistance was not observed among isolates from cattle in 1999. All broiler isolates from 1997 except for one were susceptible to nalidixic acid, whereas seven (6.2%) S. Enteritidis and two (6.3%) of the S. Typhimurium isolates from 1998 and 9 S. Enteritidis (26.5%) from 1999 were resistant. Among isolates from pigs, four isolates from 1997, three from 1998, and one from 1999 were resistant to nalidixic acid. All the nalidixic acid-resistant isolates had reduced susceptibility to fluoroquinolones. Sequence analysis of the gyrA gene in 37 nalidixic-resistant isolates identified two different base substitutions at codon serine-83 and two at aspartate-87. The base substitutions in serine-83 were TCC (Ser)-->TAC (Tyr), and TCC (Ser)-->TTC (Phe). The base substitutions in aspartic-87 were GAC (Asp)-->AAC (Asn), and GAC (Asp)-->GGC (Gly). Sequence analysis of the gyrB and parC genes revealed no mutations in 27 selected isolates. This study showed that quinolone-resistant isolates have emerged in recent years among food-producing animals, especially among S. Enteritidis from broilers in Denmark, and that the resistance mainly is associated with mutations in gyrA.

4-Quinolones↗

PubMedDate not supplied

Antimicrobial susceptibility of nontyphoidal Salmonella isolated from humans in Belgium.

Human nontyphoidal Salmonella infections are the primary cause of foodborne disease in developed countries, resulting in considerable morbidity and occasionally death, especially in immunocompromised patients. Strains of Salmonella that are resistant to antimicrobial agents have become a world-wide health problem. Fluoroquinolones are drugs of choice for treatment of human invasive salmonellosis, and have been useful for the treatment of infections caused by multi-resistant strains. However, strains resistant to ciprofloxacin have been noted. A random sample of 378 Salmonella strains of human origin was collected during 1998. Their susceptibility to 11 antimicrobial agents was determined by the agar dilution method according to NCCLS standards. In total, 38 serotypes were represented of which S. Enteritidis (20.4%), S. Typhimurium (20.4%), S. Hadar (9.0%), S. Brandenburg (7.9%), S. Infantis (7.7%), and S. Virchow (5.3%) were the most common. All strains were susceptible to ceftriaxone and ciprofloxacin. For nalidixic acid the rate of resistance was 19.0%. Of the 72 strains resistant to nalidixic acid, 31 were S. Hadar, and thus 91.2% (31/34) of the S. Hadar isolates showed resistance to nalidixic acid. Most of the S. Hadar strains were also resistant to ampicillin, tetracycline and sulphamethoxazole, and an elevated MIC50 (0.25 microgram/ml) and MIC90 (1 microgram/ml) was observed for ciprofloxacin. The high rate of resistance to nalidixic acid can be a first step towards the development of resistance to ciprofloxacin.

Anti-Bacterial Agents↗

PubMed2003

Patterns of mutations in target genes in septicemia isolates of Escherichia coli and Klebsiella pneumoniae with resistance or reduced susceptibility to ciprofloxacin.

Thirty-two Escherichia coli and 21 Klebsiella pneumoniae septicemia isolates with varying degrees of resistance to ciprofloxacin were analyzed for the presence of point mutations within the quinolone-resistance target genes. The number of mutations observed in the resistant isolates agreed with the level of ciprofloxacin resistance in both species. Such isolates were also resistant to nalidixic acid. Isolates with borderline susceptibility to ciprofloxacin, on the other hand, behaved differently in the two species. In E. coli all the isolates harbored at least one mutation and these isolates were also resistant to nalidixic acid, while no mutations were detected in the K. pneumoniae isolates, and susceptibility to nalidixic acid was unpredictable. Therefore, nalidixic acid cannot be used as a class representative. Time-kill curve studies on an isolate with borderline susceptibility from each species showed higher degrees of resistance to ciprofloxacin in comparison to that of the wild-type E. coli. A previously unreported parC mutation, S57-->T, was detected in a resistant E. coli isolate and might expand the QRDR of this gene. Normalized resistance interpretations of histograms confirmed the setting of microbiological zone breakpoints for ciprofloxacin testing.

Anti-Infective Agents↗

PubMed1982

Bactericidal effect of 5-azacytidine on Escherichia coli carrying EcoRII restriction-modification enzymes.

5-Azacytidine was found to be bactericidal to Escherichia coli carrying plasmids specifying EcoRII restriction-modification systems, but not to the same strains lacking these plasmids. Of other base analogs tested, only 5(beta-D-ribofuranosyl)isocytidine had similar, although weaker, effects. Plasmids that had lost the EcoRII restriction-modification system did not confer sensitivity to 5-azacytidine. Mutants defective in the restriction function remained sensitive to the toxic effects of the drug; however, a mutant defective in the modification function lost most of the sensitivity to 5-azacytidine. For the bactericidal effect to be seen, the cells had to be growing; cells in the stationary phase of growth were not killed by the drug. The drug inhibited the methylase enzyme, and an inhibitor of the enzyme could be detected in vitro in extracts of cells that had been treated with 5-azacytidine. This nalidixic acid inhibited its formation. Coumermycin but not nalidixic acid antagonized the bactericidal effect of the drug; however, coumermycin was more effective in preventing the inhibition of the methylase by 5-azacytidine than was nalidixic acid.

Azacitidine↗

PubMed2005

Susceptibility of Campylobacter hyointestinalis subsp. hyointestinalis to antimicrobial agents and characterization of quinolone-resistant strains.

OBJECTIVES: To study the susceptibility of Campylobacter hyointestinalis subsp. hyointestinalis to several antimicrobial agents and to investigate the mechanisms of nalidixic acid and ciprofloxacin resistance. METHODS: The disc diffusion method was employed to study the susceptibility of 49 C. hyointestinalis subsp. hyointestinalis strains of reindeer and bovine origin to 12 different antimicrobial agents. In addition, the MICs of nalidixic acid and ciprofloxacin were determined. The nucleotide sequence of a 270 bp fragment of the gyrA gene was determined in ciprofloxacin-susceptible and -resistant strains. The effect of a multidrug efflux pump inhibitor Phe-Arg-beta-naphthylamide (PA beta N) on the MICs of ciprofloxacin and nalidixic acid was also studied. RESULTS: The only decreased susceptibility for antimicrobial agents of this study was observed for sulphonamide compound and streptomycin (24% and 32% of the strains, respectively), and this phenomenon was observed exclusively in the bovine strains. In sequence studies, a Thr-86-->Ile change was found in strains with MICs of ciprofloxacin of > or = 64 mg/L, but this mutation was absent in strains with lower resistance levels. The use of PA beta N did not affect the MIC of ciprofloxacin but decreased the MIC of nalidixic acid 2-4-fold. CONCLUSIONS: The Finnish C. hyointestinalis subsp. hyointestinalis strains are susceptible to a majority of the antimicrobials of veterinary importance. The mechanism of ciprofloxacin resistance at lower levels (< or = 32 mg/L) is not associated with a specific mutation in the quinolone resistance-determining region of the gyrA gene. Finally, there are distinct differences in the mechanisms of ciprofloxacin resistance compared with nalidixic acid resistance within the studied species.

Animals↗

PubMed1992

Transcriptional regulation of Mn-superoxide dismutase gene (sodA) of Escherichia coli is stimulated by DNA gyrase inhibitors.

The expression of manganese-containing superoxide dismutase (sodA) in Escherichia coli using sodA::lacZ gene fusion was found to be stimulated by DNA gyrase inhibitors, nalidixic acid, or coumermycin A1. Aerobically, the gyrase inhibitors increased the expression of sodA::lacZ in the presence or absence of either paraquat or the iron chelator 2,2'-dipyridyl. The concentrations of the inhibitors used were found to reduce DNA supercoiling. Treatment of wild-type cells (sodA+) with nalidixic acid increased the transcription of MnSOD mRNA. Anaerobically, the expression of sodA::lacZ in wild-type cells was not affected by nalidixic acid. However, nalidixic acid had a stimulatory effect on the anaerobic expression of sodA::lacZ in cells preinduced by the iron chelator as well as in mutants derepressed in sodA expression by virtue of their lacking the trans-acting repressor proteins or the cis-acting regulatory elements needed for sodA regulation. The results indicate that the effect of DNA gyrase inhibitors is secondary to the cis- and trans-regulatory elements of sodA and suggest that changes in DNA topology may affect transcriptional regulation of sodA.

2,2'-Dipyridyl↗

PubMedDate not supplied

Mutation rate of avian intestinal coliform bacteria when pressured with fluoroquinolones.

The purpose of this study was to determine the rate at which resistance developed in avian coliform bacteria when exposed to nalidixic acid, sarafloxacin, or enrofloxacin. In in vitro studies, the rates of mutation of avian isolates of Escherichia coli and Salmonella were determined following nalidixic acid, sarafloxacin, or enrofloxacin pressure. The rates of mutation were similar for nalidixic acid and sarafloxacin, whereas a lower rate of mutation was seen after enrofloxacin pressure. In in vivo studies, the quinolones were administered in the drinking water to broiler chickens at a concentration of 40 ppm for five consecutive days. Samples of feces were inoculated onto appropriate media and the frequency of resistance was determined. The frequency rates of resistance to nalidixic acid and sarafloxacin were similar. Enrofloxacin-medicated birds did not develop enrofloxacin-resistant coliform bacteria. The in vitro and in vivo data appear to correlate.

Animals↗

PubMed1985

Cross resistance of quinolone derivatives in gram-negative bacteria.

A total of 127 Gram-negative bacteria resistant to nalidixic acid were isolated from as many patients affected by urinary tract infections and hospitalized in the first Clinic of Infectious Diseases, University of Naples. Enterobacteria were identified by Enterotube system (Roche) and API 20 system (Ayerst). Non-fermentative bacteria were identified by OXI/FERM system (Roche). The following bacteria were collected: Escherichia coli 50, Proteus spp. 35, Enterobacter agglomerans 12, Serratia sp. 5, Pseudomonas aeruginosa 25. The in vitro antibacterial activity of nalidixic acid and three other quinoline derivatives (pipemidic acid, oxolinic acid and ciprofloxacin) were studied by determining the MICs by a miniaturized dilution broth method. The MICs were compared to evaluate the eventual cross resistance to the drugs under examination within each bacterial species. The results showed that 23% of bacteria were resistant to nalidixic acid, pipemidic acid and oxolinic acid; 49.6% to nalidixic and pipemidic acid and 0.7% to nalidixic acid and oxolinic acid. On the other hand none of the bacteria were resistant to ciprofloxacin. The last showed very low MICs against all the bacteria under examination, including Pseudomonas and Serratia. The high antibacterial activity of ciprofloxacin even against bacteria highly resistant to the other quinolines could be due to a greater affinity of the target sites or to the better permeability of resistant strains to the newer drug or because it is unaffected until now by mutations of genes responsible for cross resistance.

Ciprofloxacin↗

PubMedDate not supplied

Short courses of ofloxacin for the treatment of enteric fever.

Typhoid fever continues to be a major public health problem in tropical countries, exacerbated in recent years by the spread of multi-drug resistant strains of Salmonella typhi. Short treatment courses of fluoroquinolones are effective, and have the advantage of reduced cost and increased compliance, but the optimal length of treatment is unknown. In an open, randomized comparison, 107 adults with uncomplicated enteric fever (95 of whom had positive blood cultures for S. typhi and 5 for S. paratyphi) were treated with oral ofloxacin, 15 mg/kg/d for 2 d or 10 mg/kg/d for 3 d. Mean fever clearance times were the same in the 2 treatment groups (97 h). There were 7 treatment failures, one in the 2 d group and 6 in the 3 d group (P = 0.07). Three of the 5 patients infected with nalidixic acid resistant strains of S. typhi had treatment failures, compared with 4 of 90 with nalidixic acid sensitive isolates (P < 0.0001; relative risk 13.5, 95% confidence interval 4.1-43%). Treatment with ofloxacin for 2 or 3 d is equally effective in adults with uncomplicated enteric fever caused by nalidixic acid sensitive strains of S. typhi. The epidemiology and management of nalidixic acid resistent typhoid needs further investigation.

Adult↗

PubMed1986

[Summarized results of clinical phase II and III studies with ofloxacin (HOE 280) in Europe].

Ofloxacin is a new quinolone-carboxylic acid derivative with a broad spectrum of activity, excellent bioavailability after oral administration and insignificant metabolisation. The serum elimination half-life is six to eight hours. 879 patients were treated with ofloxacin in therapeutic comparative studies monitored by the Department of Clinical Research, Hoechst AG. Of the original isolates 91 to 100% were susceptible to ofloxacin, 67 to 84% to co-trimoxazole, 73 to 98% to a fixed combination of amoxycilline plus clavulanic acid (AMC), 74% to nalidixic acid, 77% to nitrofurantoin, and 79% to pipemidic acid in previous in vitro tests. In the therapeutic studies which included only patients with pathogens susceptible to the antimicrobial agent used, the following cure rates (clinical and bacteriological) were obtained for uncomplicated infections of the lower urinary tract: ofloxacin (single dose treatment) 78% and 83%, co-trimoxazole 62%, nalidixic acid 72%. A three-day course with ofloxacin compared to a three to four-day treatment with co-trimoxazole or seven-day treatment with the other comparative compounds resulted for lower urinary tract infections in the following cure rates: ofloxacin 89%, co-trimoxazole 84%; ofloxacin 71%, AMC 33%; ofloxacin 64%, nitrofurantoin 56%; ofloxacin 56%, pipemidic acid 36%. The unfavourable results after treatment with AMC or pipemidic acid were caused by a high rate of superinfections. The combined cure rate in infections of the upper urinary tract was 73% for ofloxacin and 65% for co-trimoxazole or 81% for ofloxacin and 57% for AMC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Infective Agents↗

PubMed1987

Membrane permeability of Pseudomonas aeruginosa to 4-quinolones.

The outer membrane-disorganizing agent polymyxin B nonapeptide sensitized Pseudomonas aeruginosa strains 2-40fold to ciprofloxacin, norfloxacin, and ofloxacin, and 80-200fold to nalidixic acid. Sensitized P. aeruginosa strains were nearly as susceptible to nalidixic acid as Escherichia coli strains. The data suggest that the outer membrane permeability is of critical importance for the antipseudomonal activity of 4-quinolones. The low penetration of the outer membrane is the major cause of the nalidixic acid resistance of P. aeruginosa.

Anti-Bacterial Agents↗

PubMed2005

Validation of a novel HPLC sorbent material for the determination of ten quinolones in human and veterinary pharmaceutical formulations.

A novel sorbent material of ultrapure silica gel provided with novel State of the Art Bonding- and Endcapping Technology commercially available under the name PerfectSil Target (250 x 4 mm, ODS-3, 5 microm, by MZ-Analysentechnik, Germany) was used and validated for the sensitive HPLC determination of ten quinolone antibiotics: enoxacin, ofloxacin, norfloxacin, ciprofloxacin, danofloxacin (DAN), enrofloxacin (ENR), sarafloxacin, oxolinic acid (OXO), nalidixic acid (NAL), and flumequine. The analytical column validation was performed in terms of separation efficiency, precision, and peak asymmetry. The separation was achieved at ambient temperature using a mobile phase of TFA (0.1%)-CH3OH-CH3CN delivered under the optimum gradient program, at a flow rate of 1.2 mU/min. Photodiode array detection was used and eluant was monitored at 275 nm. For the quantitative determination caffeine (7.5 ng/microL) was used as internal standard. The achieved LODs were 0.03 ng/microL per 50 microL injected volume for OXO, 0.1 ng/microL for DAN, ENR, and NAL, and 0.2 ng/microL for the remaining six studied quinolones. The method was validated in terms of interday (n = 6) and intraday (n = 5) precision and accuracy. The proposed method was successfully applied to the analysis of pharmaceutical formulations destined either for human or for veterinary use.

Absorption↗

PubMed1999

Comparative in vitro activity of quinolones against Stenotrophomonas maltophilia.

The susceptibility of 109 Stenotrophomonas maltophilia isolates, all characterized by pulsed-field gel electrophoresis, to nine quinolones was studied. Grepafloxacin, trovafloxacin, and moxifloxacin displayed similar intrinsic activities (MIC90, 0.5 microg/ml), which were lower than those of ofloxacin and ciprofloxacin (MIC90, 4 microg/ml), norfloxacin (MIC90, 64 microg/ml), and nalidixic acid (MIC90, 32 microg/ml). Nalidixic acid was generally one- to twofold dilutions more active than norfloxacin. According to the criteria of the National Committee for Clinical Laboratory Standards (NCCLS), the percentage of isolates susceptible to ciprofloxacin (breakpoint < or = 1 microg/ml) was 76.1%. Using the NCCLS breakpoint for comparative purposes, the percentage of isolates susceptible to grepafloxacin, moxifloxacin, and trovafloxacin was 95.4, 96.4, and 96.4%, respectively. These results indicate that new quinolones may potentially be used for the management of Stenotrophomonas maltophilia infections.

4-Quinolones↗

PubMed1992

Two independent amsacrine-resistant human myeloid leukemia cell lines share an identical point mutation in the 170 kDa form of human topoisomerase II.

Cloning and sequencing of cDNA segments of human TOP2 gene encoding the 170 kDa form of human DNA topoisomerase II show that Arg486 of the enzyme has been mutated to a lysine in the enzyme from two human leukemia cell lines HL-60/AMSA and KBM-3/AMSA, which were independently selected for resistance to the antitumor drug amsacrine (4'-[9-acridinylamino]-methanesulfon-m-anisidide, mAMSA). Sequence identity comparisons between eukaryotic DNA topoisomerase II and bacterial gyrase (bacterial DNA topoisomerase II) indicate that the position of the common mutation observed in mAMSA-resistant human TOP2 corresponds to that of the point mutation nal-31 in the Escherichia coli gyrase B gene, which confers resistance to nalidixic acid. Because mAMSA and nalidixic acid are known to act on their respective targets by a common mechanism of trapping the covalent enzyme-DNA intermediates, these results provide strong evidence that the 170 kDa form of human DNA topoisomerase II is a major cellular target of mAMSA, and that Arg486 of this enzyme is involved in mAMSA-mediated trapping of the covalent enzyme-DNA complex.

Amino Acid Sequence↗