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PubMed2005

Nalidixic acid screening test in detection of decreased fluoroquinolone susceptibility in Salmonella typhi isolated from blood.

OBJECTIVE: To determine the validity of nalidixic acid screening test in the detection of high MICs of fluoroquinolone against Salmonella(S.) typhi isolated from blood and correlate zone diameters of ofloxacin with that of MIC value for nalidixic acid sensitive and resistant strains. DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Clinical Microbiology Laboratory of the Aga Khan Hospital, Karachi from January 2002 to December 2003. PATIENTS AND METHODS: Two hundred S. typhi isolates from blood were included for nalidixic acid screening and ofloxacin susceptibility. Antibiotic susceptibilities for both the antibiotics were obtained by disc diffusion method whereas MICs were determined by standard agar dilution method as recommended by NCCLS guidelines. Sensitivity, specificity and correlation between both antimicrobial susceptibility methods were calculated and results expressed as scattergrams. RESULTS: The results broadly classify S. typhi isolates into nalidixic acid resistant strains with no zone of inhibition around 30 mug nalidixic acid disc and nalidixic acid sensitive strains with mean zone of inhibition of 24.9 mm. All S. typhi isolates with ofloxacin MIC of capital ZHE, Cyrillic 0.125 microg/ml were found to be nalidixic acid resistant (MIC capital ZHE, Cyrillic32 microg/ml) whereas the isolates with ofloxacin MIC 0.06 microg/ml were nalidixic acid sensitive (MIC 8 microg/ml). Screening for nalidixic acid resistance was found to be 100% sensitive and 97% specific in identifying S. typhi strains with reduced susceptibility to fluoroquinolone (MIC capital ZHE, Cyrillic 0.125 microg/ml). CONCLUSION: Nalidixic acid resistance as a screening method is proved to be significant in identifying S. typhi isolates with reduced susceptibility to fluoroquinolones. It is also suggested that inhibition zone of 25 mm around 5 microg ofloxacin disc is appropriate as a selection criterion to detect S. typhi isolates with reduced susceptibility to fluoroquinolones.

Anti-Infective Agents↗
PubMed1965

MECHANISM OF ACTION OF NALIDIXIC ACID ON ESCHERICHIA COLI.II. INHIBITION OF DEOXYRIBONUCLEIC ACID SYNTHESIS.

Goss, William A. (Sterling-Winthrop Research Institute, Rensselaer, N.Y.), William H. Deitz, and Thomas M. Cook. Mechanism of action of nalidixic acid on Escherichia coli. II. Inhibition of deoxyribonucleic acid synthesis. J. Bacteriol. 89:1068-1074. 1965.-Nalidixic acid was shown to inhibit specifically the synthesis of deoxyribonucleic acid (DNA) in Escherichia coli. Slight effects on protein and ribonucleic acid (RNA) synthesis were observed only at higher levels of drug or after prolonged incubation. The inhibition of DNA synthesis in E. coli 15TAU, as measured by incorporation of C(14)-labeled thymine, was observed after exposure to nalidixic acid for 10 min. Inhibition of the incorporation of C(14)-labeled uracil into RNA and C(14)-labeled l-arginine into protein (21 and 28% inhibition, respectively) was observed only after 60 min of exposure. When cultures of E. coli 15TAU were exposed to 3.0 mug/ml of nalidixic acid (slightly greater than the minimal growth inhibitory concentration), the incorporation of C(14)-labeled thymidine was inhibited 30 to 40% after 90 min. Nalidixic acid at 10 mug/ml, a lethal concentration, inhibited thymidine incorporation 72% during this period. Nalidixic acid at 1.0 mug/ml had no apparent effect on the incorporation of C(14)-labeled adenine or C(14)-labeled uracil into RNA of cultures of E. coli 198, a wild-type strain. However, incorporation of both bases into DNA was strongly inhibited after 60 min of exposure (66 and 69%, respectively). Nalidixic acid inhibited DNA replication during a single round of synthesis. In contrast with "thymineless death," nalidixic acid was not lethal to E. coli 15TAU during restricted RNA and protein synthesis (i.e., in a medium containing thymine but lacking arginine and uracil). We have shown also that this chemotherapeutic agent has little effect on the synthesis of protein or RNA required to initiate DNA replication. After 75 min of inhibition, the capacity of E. coli 15TAU to synthesize DNA in a medium containing thymine, arginine, and uracil may be restored by a simple filtration and washing process, indicating that the drug is not firmly bound. These studies leave little doubt that a primary action of nalidixic acid is the inhibition of the synthesis of DNA in E. coli.

Adenine↗
PubMed1969

Mechanism of action of nalidixic acid on Escherichia coli. Vi. Cell-free studies.

The effects of nalidixic acid in vitro on deoxyribonucleic acid (DNA)- polymerase (deoxyribonucleosidetriphosphate: DNA deoxynucleotidyltransferase, EC 2.7.7.7), deoxyribonucleotide kinases (ATP: deoxymono- and diphosphate phosphotransferases), and deoxyribosyl transferase (nucleoside: purine deoxyribosyltransferase, EC 2.4.2.6) were examined employing partially purified and crude extracts of Escherichia coli ATCC 11229 and E. coli 15TAU. Nalidixic acid had no inhibitory effect on the DNA-polymerase of the wild-type strain E. coli ATCC 11229 at concentrations of 1.4 x 10(-3) to 2.8 x 10(-3)m. No inhibition of deoxyribonucleotide kinase activity was observed at concentrations of nalidixic acid ranging from 2 x 10(-3) to 8.6 x 10(-3)m. Nalidixic acid (0.43 x 10(-4) to 0.43 x 10(-3)m) had no inhibitory effect on the deoxyribosyl transferase activity of crude extracts obtained from E. coli ATCC 11229 or E. coli 15TAU. Analytical CsCl density gradient centrifugation demonstrated that the DNA obtained after treatment of E. coli 15TAU with nalidixic acid was not cross-linked. These results suggest that the prevention of DNA synthesis in vivo by nalidixic acid is not attributable to inhibition of DNA polymerase, deoxyribonucleotide kinase, deoxyribosyl transferase, or to cross-linking of the DNA of treated cells.

Carbon Isotopes↗
PubMed1976

Resistance to nalidixic acid. A misconception due to underdosage.

The clinical impression of inordinate selection of resistant mutants to nalidixic acid cannot be substantiated on close scrutiny when sensitive infections are treated at a full dosage of 4 gm/day. When 27 consecutive patients were treated with 4 gm of nalidixic acid per day, resistance developed in the bacteriuric population in only 7%. Moreover, resistance in the fecal reservoir was surprisingly minimal and much less than that reported for sulfonamides, tetracyclines, and ampicillin. The observation is important because multiply-resistant Enterobacteriaceae maintain their sensitivity to nalidixic acid since extrachromosomal R-factor resistance to nalidixic acid has never been demonstrated and cannot be transferred from one organism to another. In vitro data on 100 sensitive strains of Enterobacteriaceae show that the developmental of resistance to nalidixic acid is inversely proportional to the concentration of nalidixic acid regardless of whether the inoculum size is 10(5) or 10(8) bacteria per milliliter. Underdosage (less than 4 gm/day) with nalidixic acid is the probable cause of excessive resistance.

Aged↗
PubMed1989

Reversible suppression by nalidixic acid of anchorage-independent growth of mouse cells transformed by 3-methylcholanthrene or an activated c-Ha-ras gene.

Effects of nalidixic acid and its derivatives were investigated on mouse cells transformed by methylcholanthrene or an activated c-Ha-ras oncogene. Our findings were as follows. Nalidixic acid preferentially suppressed growth in soft agar of transformed Balb/3T3 mouse cells induced by methylcholanthrene. The suppressive effect of nalidixic acid on growth in soft agar was reversible. Nalidixic acid reversibly reduced saturation density of these transformed cells. Oxolinic acid and pipemidic acid, which are derivatives of nalidixic acid, were less effective than nalidixic acid in suppressing growth in soft agar. Nalidixic acid suppressed growth in soft agar of NIH/3T3 mouse cells transformed by an activated c-Ha-ras, without affecting the amount of ras p21 proteins as detected by an immunoblotting analysis using a monoclonal antibody. These results show that nalidixic acid reversibly suppressed the expression of transformed phenotypes that were already being expressed.

Animals↗
PubMed1993

Pharmacokinetics, bioavailability, plasma protein binding and disposition of nalidixic acid in rainbow trout (Oncorhynchus mykiss).

1. The pharmacokinetics, disposition and bioavailability of nalidixic acid were examined in Rainbow Trout following i.v. and per os administration (5 mg/kg). 2. Nalidixic acid was biexponentially eliminated from plasma following i.v. dosing (t1/2 alpha = 0.06 h, t1/2 beta = 23.0 h). The volume of distribution (Vss) and total body clearance (Clb) were 964.7 ml/kg and 31.5 ml/kg/h, respectively. 3. In vitro plasma protein binding was specific and saturable over a range of concentrations from 0.43 microM to 20.0 mM. Binding was approx. 26% at kinetically relevant plasma concentrations. 4. Apparent oral bioavailability was determined to be > 100%, suggesting that nalidixic acid was largely bioavailable and non-linear pharmacokinetics were evoked. 5. Oral studies demonstrated the highest 14C nalidixic acid equivalent concentrations in bile, intestine and liver. Muscle contained intermediate concentrations but among all organs accounted for the greatest total amount of drug (12.2% of dose). Mass balance studies demonstrated composite values for per cent of dose administered of 23.7, 18.8, 8.5, 10.0, 7.4 and 2.3% for 1, 2, 3, 6, 9 and 15 days, respectively. 6. A glucuronic acid conjugate of nalidixic acid was identified by n.m.r. and mass spectral analysis as the single primary metabolite.

Administration, Oral↗
PubMed1975

Nalidixic acid: intrarenal distribution and its effect upon para-aminohippurate excretion.

Studies performed on the intrarenal distribution of nalidixic acid in dogs show that this weak organic acid is indeed accumulated in the kidney, the highest concentration being attained in the cortex and followed in order by the outer medulla, papillae, and inner cortex. Our results also show that nalidixic acid produces significant changes in the para-aminohippuric concentration and on the filtered load, secretion and clearance of para-aminohippuric acid. Stop-flow experiments confirmed the inhibitory effect of nalidixic acid upon para-aminohippuric acid secretion. It is plausible that nalidixic acid may inhibit the secreted moiety of creatinine. This inhibitory effect is localized in the proximal tubule, where para-aminohippuric acid is known to be secreted. Based on our data it is suggested that nalidixic acid competes with para-aminohippuric acid for the same transport system or that the decreased secretory para-aminohippuric acid activity after nalidixic acid may be caused by a direct inhibition produced by the latter.

Aminohippuric Acids↗
PubMed1982

Determination of norfloxacin, a new nalidixic acid analog, in human serum and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the analysis of norfloxacin (MK-366) [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)3-quinolinecarboxylic acid], a new nalidixic acid analog, in human serum and urine is described. A statistical evaluation of the assay data showed acceptable accuracy and precision for 0.1 to 10.0 micrograms of MK-366 per ml of serum and for 1.0 to 500 micrograms of MK-366 per ml of urine. MK-366 was extracted from serum and urine at pH 7.5 with methylene chloride and back-extracted with sodium hydroxide solution. Chromatography was performed on an anion-exchange column with acetonitrile-phosphate buffer as the mobile phase; UV absorbance was monitored at 273 nm. The method was used to measure MK-366 in clinical specimens.

Anti-Infective Agents↗
PubMed1978

Mode of incomplete cross-resistance among pipemidic, piromidic, and nalidixic acids.

Spontaneous mutants with various patterns of resistance to pipemidic acid (PPA), piromidic acid (PA), and nalidixic acid (NAL) were isolated from Escherichia coli K-12. Most mutants were less resistant to PPA than to PA and NAL, and some mutants resistant to PA and NAL were hypersusceptible to PPA. As for the mutants tested, resistance to the drugs was conferred by mutations at nalA and new nal genes designated as nalC and nalD, both of which were located at about 82 min on the recalibrated map. Resistance to PA and NAL was due to decreased sensitivity of the bacterial DNA synthesizing system to them and insufficient drug transport, whereas resistance to PPA was only due to the former.

Chromosome Mapping↗
PubMedDate not supplied

Photophysics and photochemistry of nalidixic acid.

The photophysics and photochemistry of nalidixic acid (NA) were studied as function of pH and solvent properties. The ground state of NA exhibits different protonated forms in the range of pH 1.8-10.0. Fluorescence studies showed that the same species exist at the lowest singlet excited state. Absorption experiments were carried out with NA and with the methylated analog of nalidixic acid (MNE) in different organic solvents and water pH 3, where the main species corresponds to that protonated at the carboxylic group. These studies and the DFT calculation of torsional potential energy profiles suggest that the most stable conformation of the NA in nonprotic solvents corresponds to a closed structure caused by the existence of intramolecular hydrogen bond. Absorption and fluorescence spectra were studied in sulfuric acid solution. The pK value (Ho -1.0) found in these conditions was attributed to the protonation of the 4' keto oxygen atom of the heterocyclic ring. Theoretical calculations (DFT/B3LYP/6-311G*) of the energies of the different monoprotonated forms of the NA and Fukui indexes (f(x)-) showed that the species with the proton attached to 4' keto oxygen atom is the most stable of all the cationic forms. MNE and enoxacin also showed the protonation of the 4' keto oxygen atom with similar pK values. The photodecomposition of NA is dependent on the medium properties. Faster decomposition rates were obtained in strong acid solution. In nonprotic solvents, a very slow decomposition rate was observed.

Anti-Infective Agents↗
PubMed1992

Influence of E. coli infection on the disposition kinetic of nalidixic acid in broiler chickens.

The pharmacokinetic data of nalidixic acid were investigated in normal and E. coli infected chickens. The highest serum concentration were reached after 2 hours with t0.5 (ab) of (1.706 +/- 0.1 min in normal and 2.030 +/- 0.11 min in diseased) and (1.72 +/- 0.11 min in normal and 1.416 +/- 0.044 in diseased chickens) following oral and intramuscular administration, respectively. The elimination half-life t0.5 (beta) were (2.514 in normal and 2.35 hr in diseased) and (2.567 hr in normal and 2.672 hr in diseased) respectively. Following intravenous injection the kinetic of nalidixic acid followed two compartments open model with t0.5 of (6.27 and 9.15 hr), Vd (0.45 and 0.79 L/kg), Cltot (8.86 and 13.32 ml/kg/min) in normal and E. coli infected chickens, respectively. Administration of nalidixic acid twice daily for 5 successive days in a dose level of 25 mg/kg b. wt. by oral and intramuscular routes showed a cumulative behaviour.

Administration, Oral↗
PubMed1987

Direct inhibition of u.v.-induced DNA excision repair in human cells by novobiocin, coumermycin and nalidixic acid.

In permeable human fibroblasts, novobiocin, coumermycin and nalidixic acid completely inhibit u.v.-induced DNA repair synthesis, with 50% inhibition occurring at 500, 24 and 8800 microM respectively. Novobiocin also inhibits damage-specific incision of DNA in u.v.-irradiated permeable human fibroblasts by at least 75%. It has been suggested that effects of novobiocin on DNA excision repair result from changes in ATP pools; this explanation is not applicable to our data because excision repair in the permeable cell system is entirely dependent on exogenous ATP. It has also been suggested that novobiocin-induced inhibition of repair is mediated by alterations of chromatin structure recognizable by electron microscopy as gross chromatin clumping. There were no ultrastructural alterations, however, in the nuclei of permeable cells that had been incubated with 1 mM novobiocin. We conclude that, in human cells, novobiocin, coumermycin, and nalidixic acid directly inhibit the excision repair of u.v. damage to DNA, and that one locus of inhibition lies at or before the incision step. Because 1 mM novobiocin completely abolishes u.v.-induced repair synthesis in permeable cells, but inhibits damage-specific incision by only 75%, there seems to be a second site of inhibition following the incision step. The similarity between the concentrations of novobiocin, nalidixic acid and coumermycin required to inhibit u.v.-induced excision repair and the concentrations required to inhibit human DNA polymerase alpha suggest that the distal locus of inhibition may be DNA polymerase alpha-mediated repair patch synthesis. The proximal inhibitory site may be a type II DNA topoisomerase.

Aminocoumarins↗
PubMed1983

In vitro comparison of norfloxacin with nalidixic acid, cinoxacin and oxolinic acid.

1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbo xylic acid (Norfloxacin, MK-0366), a new nalidixic acid analog was shown to be significantly more active against Enterobacteriaceae than nalidixic acid and cinoxacin and about four times as active as oxolinic acid. The compound was highly effective against Pseudomonas aeruginosa (MIC less than or equal to 1 microgram/ml). In contrast to the other compounds, norfloxacin inhibited group B and D streptococci, whereas against staphylococci, both norfloxacin and oxolinic acid were shown to be active. The new compound proved to be bactericidal at minimum inhibitory concentrations. Nalidixic acid-resistant strains of various species were less sensitive to norfloxacin than nalidixic acid-sensitive bacteria, although the MICs for these strains remained well within therapeutically obtainable levels. Variants with decreased sensitivity could easily be obtained in vitro with all compounds; however, high-level resistance was not observed with norfloxacin in contrast to the other three compounds.

Anti-Bacterial Agents↗
PubMed1969

Effect of nalidixic acid on deoxyribonucleic acid synthesis in bacteriophage SPO1-infected Bacillus subtilis.

The effect of nalidixic acid on deoxyribonucleic acid (DNA) synthesis in Bacillus subtilis cells infected with bacteriophage SPO1 was studied. Nalidixic acid had little inhibitory effect on SPO1 DNA synthesis at concentrations that drastically inhibited B. subtilis DNA synthesis. Inhibition of DNA synthesis, appropriate to the concentration used, was imposed within 1 min after addition of nalidixic acid, suggesting that it acts directly on DNA synthesis in both infected and uninfected cells. The SPO1 DNA synthesized in the presence of high concentrations of nalidixic acid had a density characteristic of normal SPO1 DNA and was packaged into viable progeny phage particles, but its rate of synthesis was reduced and bacterial lysis was delayed.

Adenine↗
PubMed1993

Novel gyrA point mutation in a strain of Escherichia coli resistant to fluoroquinolones but not to nalidixic acid.

We have previously described a clinical isolate of Escherichia coli (Q2) that is highly resistant to fluoroquinolones (MIC of ciprofloxacin, 16 micrograms/ml) but susceptible to nalidixic acid (MIC of nalidixic acid, 4 micrograms/ml) (N. Moniot-Ville, J. Guibert, N. Moreau, J.F. Acar, E. Collatz, and L. Gutmann, Antimicrob. Agents Chemother. 35:519-523, 1991). Transformation of strain Q2 with a plasmid carrying the wild-type gyrA gene from E. coli K-12(pAFF801) resulted in a 32-fold decrease in the MIC of ciprofloxacin, suggesting that at least one mutation in gyrA was involved in the resistance of Q2. Intragenic gyrA fragments of 668 and 2,500 bp from strain Q2 were amplified by the polymerase chain reaction. We sequenced the 668-bp fragment and identified a single novel point mutation (transition from G to A at position 242), leading to an amino acid substitution (Gly-81 to Asp) in the gyrase A subunit. We constructed hybrid plasmids by substituting either the 668-bp fragment or the 2,500-bp fragment from Q2 DNA, both of which contained the gyrA point mutation, for the corresponding fragments in wild-type gyrA (2,625 bp) of E. coli K-12. When introduced into E. coli KNK453 (gyrA temperature sensitive), both plasmids conferred an eightfold increase in the MIC of ciprofloxacin, but only a twofold increase in the MIC of nalidixic acid. When introduced into E. coli Q2, neither plasmid conferred any change in the MICs of ciprofloxacin or nalidixic acid, suggesting that only the point mutation found in gyrA was involved in the resistance that we observed.

Anti-Infective Agents↗