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[Gram negative bacillus septicemias. Results of treatment of 31 gram negative bacillus septicemias using intravenous nalidixic acid].

Enterobacteria multiresistant to usual antibiotics, often remain sensitive to nalidixic acid, sometimes as a result of synergy with polymixins. Use of the intravenous route makes it possible to obtain more than adequate serum levels. Pharmacological study has indicated appropriate doses in terms of renal function. Intravenous nalidixic acid has been used in the treatment of 31 cases of Gram negative septicaemia, with success in 22. These results are all the more significant given that the patients were all seriously ill, cultures having grown multiresistant organisms and that nalidixic acid was used only after other antibiotics had failed.

Anuria↗

Unusual association of a plasmid with nalidixic acid resistance in an epidemic strain of Shigella dysenteriae type 1 from Asia.

The association of a 20-MDa plasmid with nalidixic acid resistant (Nalr) strains of Shigella dysenteriae 1 has been examined. The plasmid, which is readily transferable, does not itself code for nalidixic acid resistance but offers a survival advantage to its host under nalidixic acid stress. The plasmid-containing cultures of S. dynsenteriae 1 produced Nalr mutants in vitro at a frequency 1000-fold higher than their plasmidless parent strains, after two exposures to nalidixic acid. Using a similar procedure, mutants resistant to other antibiotics such as chloramphenicol, tetracycline, or ciprofloxacin could not be isolated. The genome of S. dysenteriae 1 appears to carry a heavy load of the insertion sequence IS1. The propensity of the plasmid-containing strains to readily mutate to nalidixic acid resistance and its possible relevance to the observed association of the plasmid with Nalr clinical isolates is discussed.

Asia↗

Detection of decreased fluoroquinolone susceptibility in Salmonellas and validation of nalidixic acid screening test.

We evaluated 1,010 Salmonella isolates classified as fluoroquinolone susceptible according to the National Committee for Clinical Laboratory Standards guidelines for susceptibility to nalidixic acid and three fluoroquinolones. These isolates were divided into two distinct subpopulations, with the great majority (n = 960) being fully ciprofloxacin susceptible and a minority (n = 50) exhibiting reduced ciprofloxacin susceptibility (MICs ranging between 0.125 and 0.5 microg/ml). The less ciprofloxacin-susceptible isolates were uniformly resistant to nalidixic acid, while only 12 (1.3%) of the fully susceptible isolates were nalidixic acid resistant. A similar association was observed between resistance to nalidixic acid and decreased susceptibility to ofloxacin or norfloxacin. A mutation of the gyrA gene could be demonstrated in all isolates for which the ciprofloxacin MICs were >/= 0.125 microg/ml and in 94% of the nalidixic acid-resistant isolates but in none of the nalidixic acid-susceptible isolates analyzed. Identification of nalidixic acid resistance by the disk diffusion method provided a sensitivity of 100% and a specificity of 87.3% as tools to screen for isolates for which the MICs of ciprofloxacin were >/= 0.125 microg/ml. We regard it as important that microbiology laboratories endeavor to recognize these less susceptible Salmonella strains, in order to reveal their clinical importance and to survey their epidemic spread.

Anti-Infective Agents↗

Direct gradient reversed-phase HPLC analysis and preliminary pharmacokinetics of nalidixic acid, 7-hydroxymethylnalidixic acid, 7-carboxynalidixic acid, and their corresponding glucuronide conjugates in humans.

A gradient reversed-phase high pressure liquid chromatographic analysis was developed for the direct measurement of nalidixic acid with its acyl glucuronide, 7-hydroxymethylnalidixic acid with its acyl and ether glucuronides, and 7-carboxynalidixic acid in human plasma and urine. The glucuronides and 7-carboxynalidixic acid were not present in plasma after an oral dose of 1,000 mg nalidixic acid. The acyl glucuronides of 7-carboxynalidixic acid were not present in plasma and urine. The acyl glucuronides are stable in urine at pH 5.0-5.5. The subject's urine must therefore be acidified by the oral intake of 4 x 1 g of ammonium chloride per day. With acidic urine, hardly any nalidixic acid was excreted unchanged (0.2%). It was excreted as acyl glucuronide (53.4% of dose), 7-hydroxymethyl-nalidixic acid (10.0%), the latter's acyl glucuronide (30.9%), and 7-carboxynalidixic acid (4.2%).

Chromatography, High Pressure Liquid↗

Use of nalidixic acid for constructing the replication map of the Mycobacterium phlei chromosome.

Nalidixic acid was used for describing more accurately the terminal replication region of the Mycobacterium phlei chromosome. Cell division in synchronized cultures was not sensitive to this acid any more between 185-190 min, i.e. about 10 min after replication of the ser gene, the last of 24 genes of the replication map described so far. The replication of the chromosome was controlled by determining the position of the bac gene. Microscopic studies in phase contrast of the cells that were subjected for long time periods to nalidixic acid treatment at a bactericidal concentration showed elongated cells. The electronmicroscopic observation showed that a portion of the population influenced by nalidixic acid lyses, whereas other cells remain intact and resemble control cells.

Cell Division↗

The DNA gyrase inhibitors, nalidixic acid and oxolinic acid, prevent iron-mediated repression of catechol siderophore synthesis in Azotobacter vinelandii.

Low concentrations of nalidixic acid and oxolinic acid that were just inhibitory to Azotobacter vinelandii growth promoted the production of the catechol siderophores azotochelin and aminochelin, in the presence of normally repressive concentrations of Fe3+. There was a limited effect on the pyoverdin siderophore, azotobactin, where low concentrations of Fe3+ were rendered less repressive, but the repression by higher concentrations of Fe3+ was normal. These drugs did not induce high-molecular-mass iron-repressible outer-membrane proteins and similar effects on the regulation of catechol siderophore synthesis were not produced by novobiocin, coumermycin, or ethidium bromide. The timing of nalidixic acid and Fe3+ addition to iron-limited cells was critical. Nalidixic acid had to be added before iron-repression of catechol siderophore synthesis and before the onset of iron-sufficient growth. Continued production of the catechol siderophores, however, was not due to interference with normal iron uptake. These data indicated that nalidixic acid prevented normal iron-repression of catechol siderophore synthesis but could not reverse iron repression once it had occurred. The possible roles of DNA gyrase activity in the regulation of catechol siderophore synthesis is discussed.

Azotobacter↗

A comparative study of genotoxic effects in the treatment of trichomonas vaginalis infection: metronidazole or nalidixic acid.

We performed a prospective randomized study to compare the potential genotoxic effects of metronidazole and nalidixic acid which they are used in the treatment of Trichomonas vaginalis infection. 20 patients with Trichomonas vaginalis infections participated in this study. 14 patients with vaginal trichomoniasis were treated with therapeutic doses of metronidazole 250 mg 3 times/d and six patients were treated with nalidixic acid 400 mg twice a day for 10 d. The genotoxic potential of a variety of mutagenic and carcinogenic agents can be evaluated by sister-chromatid exchange (SCE) test as a rapid cytogenetic test. An increased number of exchanges in lymphocytes reflects the influence of mutagens. No significant difference was observed in the SCE frequency of metronidazole treated patient however, a statistically significant increase (P<0.05) after nalidixic acid treatment could be described. We conclude that in spite of wide use of nalidixic acid for Trichomonas vaginalis infection, because of its potential genotoxic effect its usage must be individualized especially for pregnant women and small babies.

Adult↗

Effect of nalidixic acid, pipemidic acid and cinoxacin on chondrocyte metabolism in explants of articular cartilage.

Explants of immature bovine articular cartilage were exposed to nalidixic acid, pipemidic acid and cinoxacin at one and ten times the human therapeutic plasma level for 7 days. Only nalidixic acid had significant effects on the chondrocyte metabolism. 20 micrograms/ml nalidixic acid caused an increase of 35S-sulfate incorporation into glycosaminoglycans at day 7. Two hundred micrograms/ml nalidixic acid inhibited the incorporation of 3H-thymidine into DNA. The incorporation of 35S-sulfate into glycosaminoglycans was decreased at day 0, while at day 7 the incorporation had returned to the control value. Pipemidic acid and cinoxacin had no significant effects on either the 3H-thymidine or the 35S-sulfate incorporation.

Animals↗

Hypersensitivity pneumonitis induced by nalidixic acid.

Interstitial pneumonitis developed in a patient one week after therapy with nalidixic acid was initiated. The causal association between the drug and the lung disease is based on the temporal relationship, an increased eosinophil count in both peripheral blood and fluid obtained by bronchoalveolar lavage, a positive migration inhibitory factor test with nalidixic acid, and exclusion of other causes. This is, to the best of our knowledge, the first report of a pulmonary hypersensitivity reaction to nalidixic acid.

Aged↗

The comparative in-vitro activity of eight newer quinolones and nalidixic acid.

The in-vitro antibacterial activity of nalidixic acid and the 4-quinolones, ciprofloxacin, norfloxacin, enoxacin, ofloxacin, pefloxacin, A-56619, A-56620 and CI-934 was assessed by determination of MICs. The 4-quinolones were all highly active against most isolates of Enterobacteriaceae, including nalidixic acid-resistant strains. Ciprofloxacin (MICs 0.002-2 mg/l) was the most active and A-56619 (MICs 0.008-32 mg/l) was the least active. A-56619, A-56620, ofloxacin, ciprofloxacin and CI-934 were highly active against Acinetobacter strains, pefloxacin and enoxacin were slightly less active, and a few strains were resistant to norfloxacin. All the compounds, including nalidixic acid, were active against Aeromonas strains (MICs 0.001-0.12 mg/l). Ciprofloxacin (MICs 0.06-1 mg/l) was the most active compound against Pseudomonas aeruginosa; A-56619 and CI-934 (MICs 1-16 mg/l) were the least active against this species. All the compounds were highly active against Haemophilus influenzae, Branhamella catarrhalis and Neisseria gonorrhoeae but the activity of all the compounds was poor against most isolates of Gardnerella vaginalis. All the 4-quinolones were active against staphylococci and CI-934 (MICs 0.03-0.25 mg/l) was the most active. CI-934 (MICs 0.06-2 mg/l) was also the most active compound against all streptococci. Most streptococci were sensitive also to ciprofloxacin (MICs 0.25-4 mg/l) but there were many isolates resistant to the other 4-quinolones. Against the anaerobic bacteria CI-934 was again the most active compound, particularly against the Gram-positive anaerobic cocci. Pefloxacin, enoxacin and norfloxacin had poor activity against most anaerobes. Ofloxacin, ciprofloxacin, A-56619 and A-56620 had good to moderate activity against all species of anaerobes except the Bacteroides fragilis group, against which none of the compounds was very active.

Acinetobacter↗

Gas chromatographic determination of nalidixic acid in tablets.

A gas chromatographic method has been established for the quantitative analysis of nalidixic acid. The method is based on the derivatization of nalidixic acid with diazomethane, and 5-alpha-cholestane is used as an internal standard. The sample is chromatographed on a glass column packed with 1% OV-1 on Chromosorb W. Quantitation is achieved by measuring peak-height ratios. The improved simplicity, specificity and accuracy of the method has been demonstrated for the quantitation of nalidixic acid in tablets.

Chromatography, Gas↗

[The pharmacokinetics of nalidixic acid administered parenterally. Towards rational use in severe infections (author's transl)].

Nalidixic acid is effective toward Gram negative infections but its short half-life and potential neurological toxicity explain that its parenteral use is hazardous. Interindividual variations of its pharmacokinetic parameters explain also the absolute necessity of a careful drug monitoring adapted to each patient. The study of plasma kinetics of a single dose of nalidixic acid injected by intravenous route, shows these metabolic variations. With this results, the predicted plasma drug concentrations show that classical dosage regimens are adapted only to a little number of patients. Advantages and inadequacies of a single daily intravenous infusion of nalidixic acid are next analysed.

Bacterial Infections↗

Effect of a three-day course of nalidixic acid in the frequency-dysuria syndrome with significant bacteriuria in women.

The effect of a 3-day course of nalidixic acid was studied in 82 women, presenting with the dysuria-frequency syndrome and significant bacteriuria, mostly Escherichia coli sensitive to nalidixic acid. 62/76 patients (82%) that could be evaluated about 1 week after initiation of therapy were subjectively cured. Negative urinary cultures were found in 64/76 patients (84%). Two patients (2.4%) developed resistance to nalidixic acid. Bacteriological cure rate was 76% of 71 patients that could be controlled 1 month after the initiation of therapy. Nalidixic acid in the used granulate preparation initiated only mild side-effects.

Adolescent↗

Emerging nalidixic acid and ciprofloxacin resistance in non-typhoidal Salmonella isolated from patients having acute diarrhoeal disease.

BACKGROUND: Non-typhoidal Salmonella are one of the key etiological agents of diarrhoeal disease. The appearance of multiple drug resistance along with resistance to quinolones in this bacterium poses a serious therapeutic problem. We determined the prevalence of nalidixic acid and ciprofloxacin resistance in non-typhoidal Salmonella isolated from faecal samples of patients with acute diarrhoeal disease attending the outpatient and inpatient department of a hospital in Saudi Arabia during the years 1999 to 2002. METHODS: Non-typhoidal Salmonella were isolated from faecal samples. Antimicrobial susceptibility was tested by the disc diffusion test. MICs to nalidixic acid and ciprofloxacin were determined by the agar dilution method. RESULTS: During the study period, 524 strains of non-typhoidal Salmonella were isolated. Strains belonging to serogroup C1 were the commonest (41.4%) followed by serogroups B and D (15.6% and 14.5%, respectively). Resistance to ampicillin was observed in 22.9% and to trimethoprim/sulfamethoxazole in 18.5% of the strains. Nalidixic acid resistance was encountered in 9.9% and ciprofloxacin resistance in 2.3% of the strains. Resistance to nalidixic acid significantly increased from 0.1% in 1999 to 5.5% in 2002 (P=0.0007) and ciprofloxacin resistance increased significantly from 0.1% in 1999 to 0.9% in 2002 (P=0.0001). MICs to nalidixic acid and ciprofloxacin were determined among 29 nalidixic acid-resistant strains of non-typhoidal Salmonella isolated during 2002. The MIC was >256 microg/mL to nalidixic acid and 8 to 16 microg/mL to ciprofloxacin. CONCLUSION: The increasing rates of antimicrobial resistance encountered among non-typhoidal Salmonella necessitate the judicious use of these drugs in humans. Moreover, these findings support the concern that the use of quinolones in animal feed may lead to an increase in resistance and should be restricted.

Acute Disease↗

Emerging nalidixic acid and ciprofloxacin resistance in non-typhoidal Salmonella isolated from patients having acute diarrhoeal disease.

BACKGROUND: Non-typhoidal Salmonella are one of the key etiological agents of diarrhoeal disease. The appearance of multiple drug resistance along with resistance to quinolones in this bacterium poses a serious therapeutic problem. We determined the prevalence of nalidixic acid and ciprofloxacin resistance in non-typhoidal Salmonella isolated from faecal samples of patients with acute diarrhoeal disease attending the outpatient and inpatient departments of a hospital in Saudi Arabia during the years 1999 to 2002. METHODS: Non-typhoidal Salmonella were isolated from faecal samples. Antimicrobial susceptibility was tested by the disc diffusion test. MICs to nalidixic acid and ciprofloxacin were determined by the agar dilution method. RESULTS: During the study period, 524 strains of non-typhoidal Salmonella were isolated. Strains belonging to serogroup C1 were the commonest (41.4%) followed by serogroups B and D (15.6% and 14.5%, respectively). Resistance to ampicillin was observed in 22.9% and to trimethoprim/sulfamethoxazole in 18.5% of the strains. Nalidixic acid resistance was encountered in 9.9% and ciprofloxacin resistance in 2.3% of the strains. Resistance to nalidixic acid significantly increased from 0.1% in 1999 to 5.5% in 2002 (P=0.0007) and ciprofloxacin resistance increased significantly from 0.1% in 1999 to 0.9% in 2002 (P=0.0001). MICs to nalidixic acid and ciprofloxacin were determined among 29 nalidixic acid-resistant strains of non-typhoidal Salmonella isolated during 2002. The MIC was >256 microg/mL to nalidixic acid and 8 to 16 microg/mL to ciprofloxacin. CONCLUSION: The increasing rates of antimicrobial resistance encountered among non-typhoidal Salmonella necessitate the judicious use of these drugs in humans. Moreover, these findings support the concern that the use of quinolones in animal feed may lead to an increase in resistance and should be restricted.

Acute Disease↗

Epidemiology of nalidixic acid resistance and TEM-1- and TEM-52-mediated ampicillin resistance of Shigella sonnei isolates obtained in Korea between 1980 and 2000.

The resistance to ampicillin and nalidixic acid in Shigella sonnei isolates obtained in Korea during the period 1998 to 2000 was characterized. Recently (J. Y. Oh, H. S. Yu, S. K. Kim, S. Y. Seol, D. T. Cho, and J. C. Lee, J. Clin. Microbiol. 41:421-423, 2003) ampicillin and nalidixic acid resistance was found in 49 and 70%, respectively, of the 67 S. sonnei isolates obtained during this period. We analyzed 138 S. sonnei isolates collected during the same period. Ampicillin and nalidixic acid resistance was found in 30 and 86% of the isolates, respectively. The ampicillin resistance was mediated by a TEM-1 beta-lactamase, and TEM-52 extended-spectrum beta-lactamase was identified in one sporadic S. sonnei isolate from 1999. bla(TEM-1) and bla(TEM-52) were located in conjugative R-plasmids. Tn3 was detected in 41% of the ampicillin-resistant isolates. The R-plasmids from the transconjugants that transferred resistance to ampicillin exhibited different restriction fragment length polymorphism patterns, and a bla(TEM-1) probe was hybridized with the different fragments. The nalidixic acid resistance was exclusively associated with an amino acid substitution, Ser83-->Leu (TCG-->TTG), in gyrA. These findings indicate that the genetically related S. sonnei strains readily acquire resistance to ampicillin, streptomycin, trimethoprim, and sulfamethoxazole but not nalidixic acid through conjugative R-plasmids from difference sources when confronted by antibiotic selective pressures.

Ampicillin Resistance↗

Predictive value of nalidixic acid resistance for detecting salmonellae with decreased ciprofloxacin susceptibility.

Seventy-three Salmonella isolates classified as ciprofloxacin susceptible when using the criteria of the National Committee for Clinical Laboratory Standards were studied for nalidixic acid (NA) resistance. The aim of the study was to determine the predictive value of nalidixic acid resistance in screening for decreased ciprofloxacin susceptibility. We observed that isolates with decreased ciprofloxacin susceptibility were all resistant to nalidixic acid. Identification of nalidixic acid resistance by the disk diffusion method provided 100% sensitivity and a specificity of 98.4% in strains with minimum inhibitory concentrations (MICs) >0.008 mg/l.

Anti-Infective Agents↗

Studies on the mechanism of action of nalidixic acid.

With three independent techniques (absorption spectrophotometry, measurement of the deoxyribonucleic acid [DNA] melting temperature, and equilibrium dialysis), no evidence has been found for the binding of nalidixic acid to purified DNA. Also, no evidence has been found to support the hypothesis that nalidixic acid is permanently modified to a new, active compound by the bacterial cell. By using an in vitro DNA replication system developed by Bonhoeffer and colleagues, soluble extracts from nalidixic acid-sensitive cells have been shown to confer nalidixic acid sensitivity on the DNA synthesis of lysates from nalidixic acid-resistant cells. The activity in the extracts is only present in sensitive cells and is nondialyzable and heat sensitive. Finally, two known nalidixic acid-resistant mutants of Escherichia coli, mapping at nal A and nal B, respectively, have been tested to determine whether either of them is a transport mutant. It has been shown that nal B(r) is a transport mutant whereas nal A(r) is not.

DNA Replication↗