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PubMed2003

Mutant prevention concentration of nalidixic acid, ciprofloxacin, clinafloxacin, levofloxacin, norfloxacin, ofloxacin, sparfloxacin or trovafloxacin for Escherichia coli under different growth conditions.

OBJECTIVES: We used two different strains of Escherichia coli, E.coli ATCC 25922 and a recent urinary isolate from a clinical sample, to investigate in vitro how the MIC and mutant prevention concentration (MPC) are affected by different temperatures (37 or 20 degrees C) or oxygen tension (aerobic or anaerobic atmosphere; MIC, MIC(an); MPC, MPC(an)). MATERIALS AND METHODS: MIC and MPC for E.coli ATCC 25922 and the clinical isolate were determined on agar containing ciprofloxacin or levofloxacin, and for the ATCC strain on agar supplemented with nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin or clinafloxacin. RESULTS: Results for the ATCC strain and the clinical strain for ciprofloxacin or levofloxacin were similar. The MPC values for E.coli ATCC 25922 were 2 x MIC (trovafloxacin), 4 x MIC (ciprofloxacin, norfloxacin, ofloxacin), 8 x MIC (clinafloxacin, levofloxacin), 16 x MIC (sparfloxacin) and 32 x MIC (nalidixic acid) at 37 degrees C and under aerobic conditions. Generally, a 37 degrees C aerobic atmosphere was associated with the highest MPC values. As an exception, both the MIC and the MPC of ciprofloxacin were higher under anaerobic versus aerobic conditions (MIC(an) approximately 8 x MIC; MPC(an) = 4 x MPC) for both E.coli isolates. Irrespective of the quinolone or growth conditions, the MIC for mutants was 1-256 x wild-type MIC. Calculated from published serum half-lives and the MPC values from this study, a putative selection period, in which resistant mutants might be selected, was calculated to be 14 h for nalidixic acid, 16 h for norfloxacin and ciprofloxacin, 28 h for ofloxacin, 30 h for trovafloxacin, 35 h for levofloxacin, 40 h for clinafloxacin, and 120 h for sparfloxacin. CONCLUSIONS: As calculated from our model in respect to the length of the selection period, long serum half-lives of recently developed compounds could not be compensated for by a more favourable activity in terms of MPC. Higher concentrations of ciprofloxacin may be required under an anaerobic atmosphere to prevent the emergence of resistant mutants among 10(10) cfu.

Anti-Bacterial Agents↗

PubMed1992

Effects of fluorodeoxyuridine and nalidixic acid on the activity of topoisomerase I in plasmodia of Physarum polycephalum.

1. A regulatory coupling between the rate of cellular transcription and the activity of topoisomerase I was investigated in plasmodia of Physarum polycephalum treated with fluorodeoxyuridine or nalidixic acid. 2. Fluorodeoxyuridine at concentrations above 40 micrograms/ml lowered both the incorporation of [3H]uridine and the activity of topoisomerase I to 10% of corresponding control values. 3. Nalidixic acid, in the range of concentrations between 20-50 micrograms/ml did not inhibit the incorporation of [3H]uridine but lowered the activity of topoisomerase I by about half. 4. It is suggested that a coupling between the level of transcription and the activity of topoisomerase I in Physarum plasmodia involves only about a half of the topoisomerase I activity and is limited to transcription occurring on ribosomal genes.

Animals↗

PubMed1985

Mutation affecting resistance of Escherichia coli K12 to nalidixic acid.

A new mutation, nalD, determining resistance of Escherichia coli to nalidixic acid (NAL) is reported. The nalD mutant described is resistant to NAL at 37 degrees C but sensitive at 30 degrees C. It is defective in penetration of NAL and glycerol through the outer membrane at 37 degrees C. The nalD mutation is located half-way between 89 and 89.5 min on the E. coli genetic map.

Biological Transport↗

PubMed1999

Separation and simultaneous determination of nalidixic acid, hydroxynalidixic acid and carboxynalidixic acid in serum and urine by micellar electrokinetic capillary chromatography.

Separation in capillary electrophoresis is governed by various factors, including buffer type, buffer concentration, pH, temperature, voltage and micelles. Through proper adjustment of these parameters, nalidixic acid and its two major metabolites, 7-hydroxynalidixic and 7-carboxynalidixic, could be separated by micellar electrokinetic capillary chromatography using an electrophoretic electrolyte consisting of 50 mM borate buffer (pH 9) containing 25 mM sodium dodecyl sulphate and 10% acetonitrile. A linear relationship between concentration and peak area for each compound was obtained in the concentration range 0.15-100 micrograms ml-1, with a correlation coefficient greater than 0.999 and detection limits in the 0.2-0.7 ng ml-1 range. Intra- and inter-day precision values of about 0.8-1.2% RSD (n = 11) and 1.3-2.0% RSD (n = 30), respectively, were obtained. The method has been applied to the analysis of nalidixic acid and its two major metabolites in serum and urine with limits of sensitivity lower than 0.8 ng ml-1.

Chromatography, Micellar Electrokinetic Capillary↗

PubMed1981

Nalidixic acid kinetics after single and repeated oral doses.

The kinetics of nalidixic acid (NA) and its two metabolites, 7-hydroxynalidixic acid (HNA) and 7-carboxynalidixic acid (CNA) were studied after a single oral dose and after two doses a day for 7 days. Total unconjugated NA, HNA, and CNA concentrations in plasma and urine samples were assayed by a new high-pressure liquid chromatographic (HPLC) technique. NA was rapidly absorbed and hydroxylated to HNA. Both were rapidly excreted in urine with an apparent elimination half-life (t1/2) of 6 to 7 hr. CNA was never detected in the plasma, although it accounted for about 25% of total urinary NA and metabolites. No major sex-related differences in the kinetics and the metabolic pattern were observed. During the 7-day treatment there was no significant cumulation of NA and HNA. The study demonstrated that the concentration of the active compounds, unconjugated NA and HNA, was more than five times the minimum bacteria inhibiting concentration for 8 hr after drug and slightly above this concentration during the next 4 hr.

Adult↗

PubMed1965

NALIDIXIC ACID (NEGGRAM) IN THE TREATMENT OF URINARY INFECTIONS.

In a bacteriologic and clinical assessment of nalidixic acid (NegGram), 95% of Gramnegative urinary pathogens tested in vitro (with the exception of Pseudomonas pyocyanea) were sensitive to therapeutically attainable levels. The antibacterial spectrum of this agent was surpassed only by parenteral kanamycin, which is potentially ototoxic. Of 70 patients treated with 0.5-1.0 g. every six hours for from two weeks to two months, 61 underwent a full course of treatment and could be assessed. In 42 the infection cleared up, in 15 the original organism disappeared and a new resistant organism emerged, and in four the original organisms became resistant. These four were treated with 0.5 g. every six hours, which suggests that the higher dose may be necessary to prevent development of resistance. In only three of 13 patients with nausea did the drug have to be discontinued. Two patients developed drug rashes and one diarrhea. The drug is a valuable addition to the therapeutic agents used for urinary infections.

Ampicillin↗

PubMed1988

Failure of single-dose metronidazole prophylaxis in colorectal surgery. No benefit from high dosage or combination with nalidixic acid.

In an open prospective study of postoperative infectious complications, patients undergoing elective colorectal surgery were randomly allocated to one of three groups receiving parenteral single-dose antimicrobial prophylaxis (1 g or 3 g metronidazole or 1 g metronidazole + 3 g nalidixic acid). Because of an unacceptably high rate of surgical infection in all three groups (36%, 29% and 39%, p greater than 0.1) among the first 103 evaluable patients, the study was discontinued. Nalidixic acid--though effective in in vitro tests of bacterial susceptibility--thus was found to be of little or no value as prophylaxis against Gram-negative infection. As the observed infection rate when metronidazole was given at the start of operation was seven-fold that previously found in the same department when 1 g metronidazole was administered 3-4 hours preoperatively (28/103 vs. 2/50, p less than 0.01), the timing of metronidazole prophylaxis was assumed to be potentially important for its ability to protect also against aerobic postoperative infection.

Adult↗

PubMed1984

Norfloxacin, amoxycillin, cotrimoxazole and nalidixic acid. A summary of 3-day and 7-day therapy studies in the treatment of urinary tract infections.

The results of clinical trials in which norfloxacin was used for 7 days compared with amoxycillin or cotrimoxazole, or for 3 days compared with citrated nalidixic acid, are presented. Additionally, the results of a concurrent open study of 3 days of norfloxacin in the management of simple urinary tract infections are discussed. Resistance to norfloxacin was only encountered in 0.2% of pathogens isolated. Norfloxacin was as effective in eradicating bacteriuria as amoxycillin, cotrimoxazole or citrated nalidixic acid. The response to 3 days of norfloxacin was similar to that seen after 7 days therapy with this compound, or to 7 days of cotrimoxazole. The incidence of adverse experiences to norfloxacin in 758 patients was below 10%.

Amoxicillin↗

PubMed1990

Nalidixic acid in diarrhoea.

In a private practice set-up from June 21, 1982 to December 31, 1984, 109 children who were admitted to the hospital with acute bacterial diarrhoea diagnosed on the basis of clinical findings and faecal leucocytes over 10/high power field, were treated with nalidixic acid 55 mg/kg in 4 divided doses to find out its effectiveness. The youngest in this study group was of 18 days, the oldest was of 16 years and the mean age was 2.61 years. In this group 72 were male children and 37 female. The average duration of stay in hospital was 2.71 days. Before admission 40 children (36%) had prior antimicrobial treatment elsewhere. These children were re-evaluated 14 hours after treatment and clinical improvement was observed in most of the cases. It was found that nalidixic acid was an effective and safe antimicrobial agent in acute infectious diarrhoea. It cut down the days of hospitalisation and cost. It was well tolerated even in children less than 3 months.

Acute Disease↗

PubMed1987

Problems in identification of Campylobacter jejuni associated with acquisition of resistance to nalidixic acid.

In a patient with campylobacteriosis, we observed development of resistance to nalidixic acid and norfloxacin under adequate treatment with the latter antibiotic. Isolates before and after treatment differed in their total protein profile but were otherwise identical with respect to enzymatic activity, serotype, crude membrane protein profiles, and other phenotypic characteristics.

Adult↗

PubMed1981

Nalidixic acid, oxolinic acid, and novobiocin inhibit yeast glycyl- and leucyl-transfer RNA synthetases.

Nalidixic acid and novobiocin inhibit the aminoacylation and pyrophosphate exchange activities of glycyl- and leucyl-transfer RNA synthetases from bakers' yeast. Similar types of inhibition are observed for both enzymes, suggesting similar mechanisms. The potency of these inhibitors is comparable to that observed for their inhibition of in vivo DNA synthesis in eukaryotic cells.

Amino Acyl-tRNA Synthetases↗

PubMed1986

Penetration of nalidixic acid in the cell cycle of Escherichia coli K-12.

Diffusion of nalidixic acid (NAL), DNA synthesis and filamentation of Escherichia coli K-12 cells induced by the drug were investigated in the division cycle. It was found that in nonsynchronous culture and within the range of sublethal NAL concentrations the length of the filaments depends on the dose or the time of action of the drug. In synchronous culture differences are observed in the values of measured parametres between samples from the successive culture phases. Maximum [3H] NAL penetration and DNA synthesis inhibition caused by the drug were noted in the period proceeding directly division. The extent of NAL penetration into the cell in the sample is correlated with the change in length of the NAL-induced filamentous cells.

Cell Division↗

PubMed1976

Toxicity of nalidixic acid on candida albicans, Saccharomyces cerevisiae, and Kluyveromyces lactis.

The antibacterial drug nalidixic acid (Nal) can suppress the growth of Candida albicans at levels of the drug normally found in urine. Growth suppression increases as drug levels are increased, and Nal also causes a similar proportional inhibition of the synthesis of all cellular macromolecules. However, growth temperature (25 versus 37 C) and the divalent cations Mg(2+) and Mn(2+) can increase C. albicans resistance to Nal. Also, nitrogen depletion of Candida shows that Nal-treated and untreated cells exhibit no difference in leucine uptake during readaptation to nitrogen. In Nal-treated, nitrogen-starved cells, ribonucleic acid and deoxyribonucleic acid (DNA) biosynthesis are less affected than in unstarved Nal-treated cells, but of the two nucleic acids DNA synthesis is the most affected. Nal-resistant strains of C. albicans exhibit a slight toxicity for macromolecular synthesis. Nal treatment of a synchronized population of Saccharomyces cerevisiae results in an increase in the culture mean doubling time of, at most, 20%, but Nal causes the loss of synchronous cell division. With a synchronized population of Kluyveromyces lactis, Nal causes an increase in the mean doubling time of upwards of 300%, with synchrony of cell division being maintained. It is known that S. cerevisiae asynchronously synthesizes mitochondrial DNA during the cell cycle, whereas with K. lactis it is synchronous. Thus, with C. albicans Nal toxicity is dependent both on the dose and the physiological state of the cell. Furthermore, Nal inhibits growth of yeast with synchronous mitochondrial DNA synthesis more adversely than yeast with asynchronous mitochondrial DNA synthesis.

Ascomycota↗

PubMed1994

Fluctuation analysis of mutations to nalidixic acid resistance in Escherichia coli.

Mutations of Escherichia coli from sensitivity to nalidixic acid resistance were studied by fluctuation analysis. The mutant distributions in replicate cultures were not significantly affected either by the age of the carbon-starved preculture used for inocula or by the inoculum size. The data from 23 fluctuation tests (48 cultures each) were pooled. The mean number of mutations per culture was estimated to be 0.71 from the fraction of cultures without mutants or 0.74 and 0.77 by maximum-likelihood estimation based on the two models under consideration. When the pooled data were compared with the theoretical expectations, the fits were unsatisfactory (P < 0.005). The lack of fit was caused mainly by too high a frequency of cultures with between 17 and 32 mutants and too high a frequency of cultures with more than 128 mutants. Possible reasons for the lack of fit and its implications with respect to estimation of mutation rates from fluctuation tests are discussed.

Chi-Square Distribution↗

PubMed1983

Inhibition of retrovirus RNA-dependent DNA polymerase by novobiocin and nalidixic acid.

Inhibitors of bacterial DNA gyrase and eukaryotic DNA topoisomerase (novobiocin and nalidixic acid) were investigated with respect to their effect on the activity of RNA-dependent DNA polymerases from murine and avian retroviruses. Purified RNA-dependent DNA polymerase from AKR virus was inhibited more than 90% by 0.3 mg/ml and almost completely by 1 mg/ml of the drugs when poly(A) X oligo(dT)12-18 was used as a template-primer. In contrast to the enzyme from AKR virus, purified enzyme from avian myeloblastosis virus was less sensitive, i.e. nearly 50% activity remained even in the presence of 1 mg/ml of the drugs with the same template-primer. RNA-dependent DNA polymerase activity in AKR virus particles was inhibited, but was resistant to low concentrations of the drugs. The inhibition was not due to specific interaction between drugs and the template-primer or labelled precursor, since RNA-dependent DNA polymerase was inhibited by the drugs with activated calf thymus DNA or poly(C) X oligo(dG)12-18 as the template. Endogenous DNA synthesis by AKR virus particles was inhibited by novobiocin to the same extent.

AKR murine leukemia virus↗

PubMedDate not supplied

Induced and photoinduced DNA damage by quinolones: ciprofloxacin, ofloxacin and nalidixic acid determined by comet assay.

Quinolones are degraded by light with loss of their antimicrobial activity, generating active species or radicals. Evidence exists that some fluoroquinolones (lomefloxacin, fleroxacin and enoxacin) induce damage to the cellular membrane and DNA cleavage by photosensitization. In this study, the genotoxic potential of the quinolones ofloxacin, nalidixic acid and ciprofloxacin (three antimicrobials frequently used in therapy) was evaluated upon irradiation with UV light by using the comet assay on cells of the Jurkat line. The results demonstrate that there are significant differences between the control groups (positive control with 50 microM H2O2, negative controls without drug and with and without irradiation) and the groups of irradiated quinolones (ofloxacin 2.76 x 10(-5) M, nalidixic acid 2.15 x 10(-4) M and ciprofloxacin 2.01 x 10(-5) M), indicating that, at the dose of irradiation employed (necessary to produce 50% photodegradation), the photodecomposition of the quinolones enhanced DNA damage. The unirradiated drugs also exhibited genotoxicity significantly different from that of the negative control.

Cell Membrane↗

PubMed1986

Population analysis of susceptibility to ciprofloxacin and nalidixic acid in Staphylococcus, Pseudomonas aeruginosa, and Enterobacteriaceae.

Susceptibility to ciprofloxacin (Cfl) and nalidixic acid (Nal) was tested in vitro by means of the population analysis technique against six strains of Staphylococcus, one strain of Pseudomonas aeruginosa, and seven strains from five genera of Enterobacteriaceae. All strains of Staphylococcus were uniformly resistant to Nal as was the Pseudomonas aeruginosa strain, all bacteria being resistant to 250- less than 500 micrograms/ml. The Enterobacteriaceae were heterogeneous as regards susceptibility to Nal. With some strains minority populations of highly-resistant bacteria could be detected with frequencies of about 10(-6.3). The MIC for Cfl for the staphylococci varied between 0.25 and 0.50 microgram/ml. There were no differences in MIC of penicillinase-producing and penicillin-susceptible strains, either in Staphylococcus aureus or in Staphylococcus epidermidis. The MIC for Cfl in the enterobacteria varied between 0.004 and 0.03 microgram/ml. The MIC for Cfl in the Pseudomonas aeruginosa was 0.25 microgram/ml. MIC for Cfl increased in all strains when the parental strains were compared to bacteria selected from the plates with the highest concentration permitting growth, indicating heterogeneity against Cfl. But while the MIC of the selected enterobacteria were lower than one fourth of the level obtainable in serum, the MIC of the selected staphylococci and Pseudomonas aeruginosa were either exceeding the level obtainable in serum or were only a little lower than this level. While Cfl thus seems to be a promising antimicrobial agent in the treatment of infections caused by enterobacteria, the suitability for infections caused by staphylococci and Pseudomonas aeruginosa should be further explored.

Ciprofloxacin↗

PubMed2000

[Experimental resistance of Vibrio cholerae el tor to nalidixic acid and fluoroquinolones].

It was shown that sensitivity of Vibrio cholerae eltor P-5879 to tetracycline, levomycetin, furazolidone, trimethoprim/sulfamethoxazole, aminoglycosides, beta-lactams, rifampicin, quinolones in vitro correlated with drugs efficacy in the treatment of experimental cholera of albino mice. Mutants of V. cholerae eltor P-5879 Nalr resistant to nalidixic acid (MIC 160-200 mg/l) formed with frequency 10(-9)-110(-8) had no cross resistance to fluoroquinolones. But the efficacy of ofloxacin, lomefloxacin, norfloxacin against these mutants in vivo reduced, though it was not changed in vitro. Mutants of V. cholerae eltor P-5879 resistant to fluoroquinolones and selected after culturing in the presence of the drugs had cross resistance to all quinolones studied. Infection caused by Cpfr mutant could not be treated with nalidixic acid and fluoroquinolones, therapeutic efficacy of rifampicin and beta-lactams, also reduced though sensitivity in vitro was not changed. The results of investigation proves the necessity of quinolones use for cholerae treatment as it is recommended for other severe enteric infections.

Animals↗