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PubMed1995

Effect of dietary protein content on nalidixic acid disposition in chickens.

The effect of a diet high in protein (HP) (26%) or low protein (LP) (15%) content on kidney function and pharmacokinetic of nalidixic acid was studied in chickens. Nalidixic acid was given intravenously and orally in a dose of 25 mg/kg b. wt. with 15 days rest period between treatments. Nalidixic acid was determined by microbiological assay. The serum nalidixic acid concentrations were consistently higher in chickens that received a LP diet. The intravenous pharmacokinetics could be described by two compartments model with a t0.5(alpha) 0.13 +/- 0.008 hours and 0.17 +/- 0.008 hours; t0.5(beta) 3.07 +/- 0.07 hours and 2.56 +/- 0.05 hours; Cltot. 0.51 +/- 0.005 ml/kg/min and 0.59 +/- 0.01 ml/kg/min; Vdss 0.349 +/- 0.008 L/kg and 0.462 +/- 0.01 L/kg in LP and HP respectively. This suggests that the protein content of the diet modifies the distribution of body water and kidney function. Also, the results cleared higher recoveries of nalidixic acid in HP chickens.

Administration, Oral↗

PubMed1993

Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid. A pilot experiment.

The aim of this pilot study was to demonstrate the possible inhibitory effect of probenecid on the renal glucuronidation and on the renal clearance of nalidixic acid in a human volunteer. Under acidic urine conditions, hardly any nalidixic acid is excreted unchanged (0.2%). It is excreted as acyl glucuronide (53.4%), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide 30.9%, and 7-carboxynalidixic acid (4.2%). Under probenecid co-medication the renal glucuronidation of nalidixic acid is reduced from 53% to 16%; the renal clearance of both nalidixic acid and 7-hydroxymethylnalidixic acid are reduced (p < 0.001); the intrinsic t1/2 of the metabolite 7-hydroxymethylnalidixic acid increased from 0.48 h to 4.24 h. The amount of acyl glucuronidation of 7-hydroxymethylnalidixic acid was not altered. The in vitro protein binding of both acyl glucuronides was increased, while no effect on the unconjugated compounds was seen. Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide.

Depression, Chemical↗

PubMed1966

Bactericidal action of nalidixic acid on Bacillus subtilis.

Cook, Thomas M. (Sterling-Winthrop Research Institute, Rensselaer, N.Y.), Karen G. Brown, James V. Boyle, and William A. Goss. Bactericidal action of nalidixic acid on Bacillus subtilis. J. Bacteriol. 92:1510-1514. 1966.-Nalidixic acid at moderate concentrations exerts a bactericidal action upon the gram-positive bacterium Bacillus subtilis. The synthesis of deoxyribonucleic acid (DNA) in B. subtilis is selectively inhibited by nalidixic acid at concentrations approximating the minimal growth inhibitory concentration. Higher concentrations (25 mug/ml) result in a 30 to 35% degradation of DNA. After extended exposure to nalidixic acid, protein synthesis is also depressed. Cells of B. subtilis treated with nalidixic acid exhibit characteristic morphological abnormalities including cell elongation and development of gram-negative areas. From the results presented, it can be concluded that the mode of action of nalidixic acid upon susceptible bacteria is similar for both gram-positive and gram-negative species.

Anti-Bacterial Agents↗

PubMed1989

Protein binding of quinolonecarboxylic acids. II. Spectral changes on the interaction of cinoxacin, nalidixic acid and pipemidic acid with human and rat albumins.

The interaction of cinoxacin (CINX), nalidixic acid (NA), and pipemidic acid (PPA) with human and rat serum albumins (HSA and RSA) was studied by UV difference absorption and circular dichroism (CD) spectroscopy. CINX and NA bound to the albumins and generated difference absorption and induced CD (ICD) spectra. The difference absorption spectral data explained reasonably our previous observations that CINX bound to HSA more weakly than NA, but to RSA as strongly as NA. We used a quantity delta epsilon/epsilon, designated as relative molar difference absorbance, at positions corresponding to the longest wavelength peaks in the difference spectra. The quantity was found to correlate linearly with percent bound to both HSA and RSA, but with different slopes, from which the binding site for CINX and NA in RSA was supposed to provide a much more nonpolar environment than that in HSA. The magnitude of ICD bands observed at 371 nm for CINX and at 342-348 nm for NA corresponded to the binding degrees of these drugs to both albumins. Anisotropy factors for the ICD bands at 350-271 nm for CINX and 320-348 nm for NA were approximately similar between HSA and RSA, suggesting a similar ability to generate the ICD spectra in these wavelength regions upon binding to the albumins. Spectral results for PPA in albumin solutions showed little or no binding of this drug to HSA and RSA. PPA existed as a betaine form in neutral solution and its positively charged group acted as an unfavorable factor for binding to both albumins.

Animals↗

PubMed1968

Effect of nalidixic acid and hydroxyurea on division ability of Escherichia coli fil+ and lon- strains.

Short periods of incubation in medium containing nalidixic acid or hydroxyurea, followed by a return to normal growth conditions, induced filament formation in Escherichia coli B (fil(+)) and AB1899NM (lon(-)) but not in B/r (fil(-)) and AB1157 (lon(+)). These drugs reversibly stopped deoxyribonucleic acid (DNA) synthesis with little or no effect on ribonucleic acid (RNA) synthesis or mass increase. The initial imbalance caused by incubation in these drugs was the same for B and B/r as was macromolecular synthesis following a return to normal growth conditions. DNA degradation caused by nalidixic acid was measured and found to be the same for B and B/r. Hydroxyurea caused no DNA degradation in these two strains. Survival curves as determined under various conditions by colony formation suggested that the property of filament formation was responsible for the extrasensitivity of fil(+) and lon(-) strains to either nalidixic acid or hydroxyurea. E. coli B was more sensitive to either drug than was B/r or B(s-1). Pantoyl lactone or liquid holding treatment aided division and colony formation of nalidixic acid-treated B but had no effect on B/r. Likewise, the filament-former AB1899NM was more sensitive to nalidixic acid than was the non-filament-former AB1157. The sensitivity of B/r and B(s-1) to nalidixic acid was nearly the same except at longer times in nalidixic acid, when B(s-1) appeared more resistant. Even though nalidixic acid, hydroxyurea, and ultraviolet light may produce quite different molecular alterations in E. coli, they all cause a metabolic imbalance resulting in a lowered ratio of DNA to RNA and protein. We propose that it is this imbalance per se rather than any specific primary chemical or photochemical alterations which leads to filament formation by some genetically susceptible bacterial strains such as lon(-) and fil(+).

Bacterial Proteins↗

PubMed1973

Bactericidal effect of combinations of nalidixic acid and various antibiotics on Enterobacteriaceae.

The activity of nalidixic acid combined with each of 10 other antimicrobial agents on 95 strains of Enterobacteriaceae was studied. Synergism was found less often than antagonism, and the commonest outcome was indifference. Combinations of nalidixic acid with kanamycin, gentamicin, or colistin were more often synergistic than antagonistic, whereas with the other antibiotics the combination was more often antagonistic than synergistic. Synergistic effects were more common with Shigella than with other genera. In vitro examination for synergism or antagonism appears to be advisable before nalidixic acid is used therapeutically in combination with other antimicrobial agents.

Anti-Bacterial Agents↗

PubMed2005

Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents.

In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN).

Adult↗

PubMed1966

Mechanism of action of nalidixic acid on Escherichia coli. 3. Conditions required for lethality.

Deitz, William H. (Sterling-Winthrop Research Institute, Rensselaer, N.Y.), Thomas M. Cook, and William A. Goss. Mechanism of action of nalidixic acid on Escherichia coli. III. Conditions required for lethality. J. Bacteriol. 91:768-773. 1966.-Nalidixic acid selectively inhibited deoxyribonucleic acid (DNA) synthesis in cultures of Escherichia coli 15TAU. Protein and ribonucleic acid synthesis were shown to be a prerequisite for the bactericidal action of the drug. This action can be prevented by means of inhibitors at bacteriostatic concentrations. Both chloramphenicol, which inhibits protein synthesis, and dinitrophenol, which uncouples oxidative phosphorylation, effectively prevented the bactericidal action of nalidixic acid on E. coli. The lethal action of nalidixic acid also was controlled by transfer of treated cells to drug-free medium. DNA synthesis resumed immediately upon removal of the drug and was halted immediately by retreatment. These studies indicate that nalidixic acid acts directly on the replication of DNA rather than on the "initiator" of DNA synthesis. The entry of nalidixic acid into cells of E. coli was not dependent upon protein synthesis. Even in the presence of an inhibiting concentration of chloramphenicol, nalidixic acid prevented DNA synthesis by E. coli 15TAU.

Anti-Bacterial Agents↗

PubMed1982

Interactions of antimicrobial drugs and combined phagocytic/serum bactericidal activity of defibrinated human blood against Serratia marcescens. I. Cotrimoxazole, nalidixic acid, nitrofurantoin, and trimethoprim.

Minimal bactericidal concentrations of trimethoprim, nalidixic acid, and nitrofurantoin revealed effective intraphagolysosomal bactericidal activity against several assay strains of Serratia marcescens as determined with phenylbutazone-treated (2 mg/ml) fresh defibrinated human blood (55 vol%), following killing of extraphagocytic test bacteria with group A (phage tail) bacteriocins of S. marcescens. The degree of intraphagocytic killing activity of trimethoprim, nalidixic acid, and nitrofurantoin approximated that of rifampin. Inhibitory and subinhibitory concentrations of cotrimoxazole or trimethoprim combined with 55 vol% of defibrinated blood, respectively, yielded additive effects against all test strains of S. marcescens. However, combinations of nalidixic acid and nitrofurantoin with blood, respectively, resulted in essentially indifferent effects against S. marcescens.

Anti-Bacterial Agents↗

PubMed1994

Comparison of pivmecillinam and nalidixic acid in the treatment of acute shigellosis in children.

The efficacy of oral pivmecillinam was compared with nalidixic acid in the treatment of acute shigellosis in children 1-8 years of age. In a double-blind trial we studied 80 comparable children with bloody diarrhoea of less than 3 days' duration. Shigella spp. was isolated in 71 children. Patients were randomly assigned to receive either pivmecillinam, 50 mg/kg.day, or nalidixic acid, 60 mg/kg.day, both given orally for 5 days. The stool frequency decreased progressively in both treatment groups. Nalidixic acid failed to eradicate Shigella species in 10 patients, compared with three in the pivmecillinam group (p = 0.04). Similarly, clinical failure was observed in 11 of 37 patients receiving nalidixic acid and in 2 of 26 patients infected with nalidixic acid-susceptible strains as against none in the group receiving pivmecillinam. The results suggest that pivmecillinam given orally was, in fact, more effective than nalidixic acid in the treatment of acute shigellosis in children, particularly when the resistant strains are taken into account.

Acute Disease↗

PubMed2006

Validity of nalidixic acid screening in fluoroquinolone-resistant typhoid salmonellae.

OBJECTIVE: To validate the screening of low-level fluoroquinolone resistance in typhoid salmonellae by using nalidixic acid (30 mg) disk providing an acceptable zone of inhibition. DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: The Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan from July 2002 to June 2003. MATERIALS AND METHODS: Antimicrobial susceptibility of 225 clinical isolates of S. typhi (n=126) and S. paratyphi A (n=99) against nalidixic acid and ciprofloxacin was determined by the modified Kirby-Bauer disk diffusion and agar dilution techniques of NCCLS. The relationship between the zone sizes and the MICs of the two quinolones was plotted in the form of scattergrams and nalidixic acid MICs and zone of inhibition sizes were correlated with those of ciprofloxacin by regression analysis. RESULTS: One hundred and ninety-five isolates were nalidixic acid-susceptible (MIC <16 microg/mL) and approximately 30 were nalidixic acid-resistant (MIC >32 microg/mL). All the nalidixic acid-susceptible isolates had ciprofloxacin MIC of <0.064 microg/mL. Among the nalidixic acid-resistant isolates approximately 20 had ciprofloxacin MIC > or =0.125 microg/mL and approximately 10 had ciprofloxacin MIC < or =0.03-0.064 microg/mL. The diameter of inhibition zone around a 30 mg nalidixic acid disk of nalidixic acid-resistant isolates was < or =13 mm (range 6-16 mm, mean 10.3 mm + SD 3.5 mm), while among nalidixic acid-susceptible isolates it ranged from 14 to 30 mm (mean 23.8 mm + SD 2.2 mm). The diameter of inhibition zone around a 5mg ciprofloxacin disk of nalidixic acid-resistant isolates ranged from 26 to 35 mm (mean 29.8 mm + SD 3.1 mm), while in nalidixic acid-susceptible isolates it ranged from 32 to 42 mm (mean 36.6 mm + SD 1.9 mm). With ciprofloxacin MIC > or =0.125 microg/mL taken as a breakpoint, a zone of <or =33 mm around a 5 microg ciprofloxacin disk to detect low susceptibility strains had a sensitivity of 100% and a specificity of 82%. Screening for nalidixic acid resistance (inhibition zone diameter of < or =13 mm) in isolates with ciprofloxacin MIC 0.125 microg/mL using a 30 microg nalidixic acid disk yielded a sensitivity of 100% and a specificity of 95%. CONCLUSION: Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method for detection of low-level fluoroquinolone resistance in typhoid salmonellae.

Anti-Infective Agents↗

PubMed1979

Evaluation of colistin and nalidixic acid in Todd-Hewitt broth for selective isolation of group B streptocci.

Todd-Hewitt broth (THB) containing colistin and nalidixic acid was compared with four other media with respect to efficacy of isolation of group B streptocci. It was effective as plain THB, THB with gentamicin and nalidixic acid and blood, and THB with colistin, nalidixic acid, and blood. THB with gentamicin and nalidixic acid, but without blood, was inhibitory to group B streptocci. The value of THB with colistin and nalidixic acid lies in its ability to successfully inhibit gram-negative organisms and still promote group B streptococcal growth without the addition of blood. This greatly reduces the time and expense of media preparation and permits early determination of bacterial growth, so that other means of rapidly identifying group B streptocci can be applied at the earliest possible time.

Animals↗

PubMedDate not supplied

Experiences on the efficacy and safety of nalidixic acid, oxolinic acid, cinoxacin and norfloxacin in the treatment of urinary tract infections (UTI).

The purpose of this study was to determine the effectiveness and tolerability of norfloxacin, cinoxacin and oxolinic acid in the treatment of urinary tract infections (UTI) in comparison to nalidixic acid. 125 patients were given the drugs in the appropriate doses for 10-14 days and 30 patients were treated for six weeks. Clinical, bacteriological, hematological and chemical checks were made on all patients before and after treatment. It was found that norfloxacin, cinoxacin and oxolinic acid are safe and effective against Escherichia coli, Klebsiella and Proteus, the commonly encountered organisms in urinary tract infections. The cure rate for norfloxacin was 93%, for cinoxacin 83%, for oxolinic acid 80% and for nalidixic acid 70% in the short course. However, these differences were not statistically significant. Oxolinic acid, cinoxacin and norfloxacin have the advantage over nalidixic acid of being administered only twice daily.

Adolescent↗

PubMedDate not supplied

Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers.

The oral bioavailability of nalidixic acid (NA) is low due to its poor solubility and slow dissolution. Solid dispersions of NA containing varying concentrations of polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starch glycolate (SSG) were prepared by solvent evaporation technique in an attempt to improve dissolution rate of NA. Physical characterization of NA, physical mixtures (PM) and solid dispersions were investigated by a variety of analytical methods including scanning electron microscopy (SEM), infrared (IR) spectroscopy and powder X-ray diffraction (XRD). SEM was useful in the verification of possible nalidixic acid inclusion in the dispersion system by studying its surface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the solid dispersions. The degree of crystallinity of nalidixic acid decreased and also differed with the dispersion systems of different carriers. Disolution studies indicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. The relative potency of the carriers to enhance the dissolution rate of nalidixic acid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in the solid dispersions was faster when the ration of the drug to carrier was smaller. F-test suggests that first order model may be used for explaining the kinetics of drug release from all the solid dispersion systems.

Drug Carriers↗

PubMed1977

Antimicrobials commonly used for urinary tract infection: sulfonamides, trimethoprim-sulfamethoxazole, nitrofurantoin, nalidixic acid.

Sulfonamides, trimethoprim-sulfamethoxazole, nitrofurantoin, and nalidixic acid are excreted in the urine in high concentration and, with the exception of Pseudomonas aeruginosa and Serratia marcescens, are all active in vitro against usual aerobic gram-negative bacteria. They are useful for treatment of uncomplicated lower urinary tract infections in an outpatient setting but are probably not indicated for acute upper tract infections, especially in the hospitalized patient. Trimethoprim-sulfamethoxazole is a very effective combination agent in vitro, has appealing pharmacokinetic properties, and is usually well tolerated by patients. However, it is more expensive than the sulfonamides and is ordinarily not indicated for initial treatment. A sulfonamide is in our view still the agent of first choice, with either nitrofurantoin or nalidixic acid as an alternative if sulfonamides cannot be tolerated.

Anti-Infective Agents, Urinary↗

PubMed1964

MECHANISM OF ACTION OF NALIDIXIC ACID ON ESCHERICHIA COLI.

Goss, William A. (Sterling-Winthrop Research Institute, Rensselaer, N.Y.), William H. Dietz, and Thomas M. Cook. Mechanism of action of nalidixic acid on Escherichia coli. J. Bacteriol. 88:1112-1118. 1964.-Nalidixic acid was lethal for proliferating cultures of Escherichia coli. Associated with this lethal effect was the formation of elongated, serpentine forms. Cultures treated with nalidixic acid were osmotically stable; lethality was observed in the presence of stabilizers. Although it was possible to demonstrate leakage of intracellular components from treated cells, this effect occurred only after 99% of the cells were nonviable. Nalidixic acid had little or no effect on respiration with glucose as substrate. If cellular growth was restricted by suboptimal temperature or nutritional deficiencies, the drug was not lethal. Chemical analysis of cellular constituents revealed that lipid, protein, and ribonucleic acid levels were of the same order of magnitude in control and drug-treated cells. Only deoxyribonucleic acid (DNA) levels were markedly lowered in drug-treated cells. These facts are consistent with the view that nalidixic acid interferes with the synthesis of E. coli DNA.

Bacterial Proteins↗

PubMed2006

Sorption of acetaminophen, 17alpha-ethynyl estradiol, nalidixic acid, and norfloxacin to silica, alumina. and a hydrophobic medium.

Two pure minerals and a hydrophobic medium were selected to study sorption of pharmaceuticals. The sorption of four pharmaceuticals, acetaminophen (analgesic), 17alpha-ethynyl estradiol (synthetic hormone), nalidixic acid (antibiotic), and norfloxacin (antibiotic), was evaluated with silica, alumina, and Porapak P (a hydrophobic medium). Alumina and silica were selected to represent positively charged and negatively charged aquifer mineral surfaces at neutral pH, respectively, while Porapak P was selected to represent the hydrophobic organic content of an aquifer medium. At neutral pH, acetaminophen, the least hydrophobic pharmaceutical, showed no significant sorption to any of the media, while 17alpha-ethynyl estradiol, the most hydrophobic pharmaceutical, showed significant sorption to Porapak P. Nalidixic acid, which has a carboxyl functional group that is anionic at neutral pH, showed significant adsorption to the positively charged alumina. Norfloxacin, with both a carboxyl (anionic) and a piperazynyl (cationic) group, can exist in four forms (neutral, cationic, anionic, and zwitterionic) depending on the aqueous pH. Norfloxacin also showed significant adsorption than nalidixic acid. Both nalidixic acid and norfloxacin adsorbed to silica and Porapak P to a much lower extent. The pH dependence of nalidixic acid and norfloxacin adsorption to silica and alumina was also studied by varying the pH between 4 and 11. The maximum adsorption of nalidixic acid to alumina occurred near its pKa (pH approximately 6), where the combination of cationic alumina and anionic nalidixic produced maximum adsorption. The maximum adsorption of norfloxacin to alumina was observed at pH approximately 7, which was the region where the zwitterionic form dominated. This research demonstrates that the adsorption of ionizable pharmaceuticals is strongly dependent on the system pH, the pharmaceutical properties (pKa and hydrophobicity), and the nature of the surface charge (point of zero charge). For pharmaceuticals that are uncharged at environmentally relevant pH values, the main sorption factor is their solubility or hydrophobicity; for charged forms, ion exchange is also an important adsorption mechanism.

Acetaminophen↗

PubMed1973

Effect of nalidixic acid on DNA replication by toluene-treated Escherichia coli.

Nalidixic acid inhibits DNA synthesis in toluene-treated E. coli, strain B/r, as it is well known to do in vivo. Both semiconservative and repair syntheses are affected, though to different degrees. Density-transfer experiments indicate that chromosomal replication is reinitiated when nalidixic acid is removed from toluene-treated cells after exposure to the acid for one generation in vivo. For cells in vivo or after toluene-treatment, reinitiation is not seen in asynchronous cultures exposed briefly to nalidixic acid or in cells prevented from synthesizing proteins during their exposure to the acid. Reinitiation occurs at the chromosomal origin but, unlike the effect seen in vivo, replication at the old site persists.

Carbon Isotopes↗