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PubMed2001

Susceptibility patterns of enteroaggregative Escherichia coli associated with traveller's diarrhoea: emergence of quinolone resistance.

Enteroaggregative Escherichia coli (EAggEC) isolates were identified as a cause of traveller's diarrhoea in 50 (9%) of 517 patients and their antimicrobial susceptibility was determined. Molecular epidemiological characterisation and investigation of the mechanisms of acquisition of quinolone resistance among nalidixic acid-resistant EAggEC strains was performed. Seventeen (34%) of 50 patients needed antimicrobial therapy, because of persistence of symptoms in nine cases and the severity of symptoms in eight cases. Ampicillin and tetracycline resistance was high, whereas chloramphenicol and co-trimoxazole showed moderate activity and amoxicillin plus clavulanic acid, nalidixic acid and ciprofloxacin showed very good activity. Resistance to nalidixic acid was demonstrated in three isolates, two from patients who had travelled to India. In all three strains the resistance was linked to mutations in the gyrA gene alone or in both gyrA and parC genes. Although ciprofloxacin shows excellent in-vitro activity and could be useful in the treatment of traveller's diarrhoea in patients travelling abroad, it may not be useful in patients who have journeyed to India or to Mexico.

Anti-Bacterial Agents↗

PubMed1978

Activity of flumequine against Escherichia coli: in vitro comparison with nalidixic and oxolinic acids.

The in vitro activity of the new antibacterial agent, flumequine, against Escherichia coli was compared with those of oxolinic acid and nalidixic acid. As judged by turbidimetric criteria, flumequine was considerably more active than nalidixic acid and slightly less active than oxolinic acid against both nalidixic acid-susceptible and -resistant strains. Resistance to all three drugs could be easily induced in vitro. The comparative efficacy of flumequine, oxolinic acid, and nalidixic acid was also tested in an in vitro model of the treatment of bacterial cystitis. In this system, suppression of bacterial growth was obtained with markedly lower concentrations of flumequine and oxolinic acid than of nalidixic acid, but prevention of the emergence of bacterial populations that exhibited increased resistance to these compounds depended on the maintenance of adequate drug levels.

Chemical Phenomena↗

PubMed1982

In vitro and in vivo activity of DL-8280, a new oxazine derivative.

DL-8280, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido-(1,2,3-de)1,4-benzoxazine-6-carboxylic acid, is a new nalidixic acid analog with a broad spectrum of antibacterial activity against gram-negative and gram-positive bacteria, including obligate anaerobes. The activity of DL-8280 against Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae, and Clostridium perfringens was roughly comparable to that of norfloxacin and far exceeded that of pipemidic acid and nalidixic acid. DL-8280 had greater activity against Staphylococcus spp., Streptococcus spp., Pseudomonas maltophilia, Acinetobacter spp., and Bacteroides fragilis than did norfloxacin, pipemidic acid, and nalidixic acid. Nalidixic acid-resistant Enterobacteriaceae, ampicillin-resistant gonococci, and clindamycin-resistant obligate anaerobes were also susceptible to DL-8280. The activity of DL-8280 was affected very little by inoculum size, and its action was bactericidal at two times the minimal inhibitory concentrations at most. Administered orally to mice experimentally infected with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Serratia marcescens, or P. aeruginosa, DL-8280 was 2 to 7 times more effective than norfloxacin and 7 to more than 50 times more active than pipemidic acid.

Animals↗

PubMed1986

Chemotherapeutic effects of ofloxacin (HOE 280) and other quinolone-carboxylic derivates in the treatment of experimental lung infections due to Klebsiella pneumoniae DT-S in mice.

The chemotherapeutic activity of ofloxacin (HOE 280), a new pyridone-carboxylic acid derivative, was compared with that of other drugs in the same group, including norfloxacin, ciprofloxacin, enoxacin and in some cases pipemidic acid and nalidixic acid. The test model used was experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. In the treatment of pneumonic mice, ofloxacin was 4 to 18 times more effective than norfloxacin and enoxacin and in most cases slightly more effective than ciprofloxacin. Pipemidic acid and nalidixic acid showed only low activity or proved to be inactive. In studies on the bactericidal activity of the compounds in vivo, ofloxacin produced a more pronounced effect than ciprofloxacin. With norfloxacin and enoxacin, a bactericidal effect in the infected tissue of the animals was only observed during the first hours after treatment.

Animals↗

PubMed1986

Antibacterial activity of ofloxacin and its mode of action.

The antibacterial activity of ofloxacin against Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Branhamella catarrhalis, and Neisseria gonorrhoeae was comparable to norfloxacin and enoxacin, and far exceeded the activity of pipemidic acid and nalidixic acid. The activity of ofloxacin was two to eight times less than that of ciprofloxacin. Ofloxacin was more active against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Acinetobacter spp., Legionella spp., and Bacteroides fragilis, than norfloxacin, enoxacin, pipemidic acid and nalidixic acid, and the activity of ofloxacin was comparable to that of ciprofloxacin. Ofloxacin was two to seven times more effective than norfloxacin in systemic infections in mice with S. aureus, Escherichia coli, Serratia marcescens and P. aeruginosa. Ofloxacin strongly inhibited DNA supercoiling activity of DNA gyrase purified from E. coli KL-16. There is a parallel relationship between antibacterial activity of ofloxacin and its inhibitory action against DNA gyrases from ofloxacin-susceptible and ofloxacin-resistant clinical isolates of E. coli. These results indicate that the high bactericidal action of ofloxacin and the related new quinolone agents can be explained by their potent inhibitory activities against DNA gyrase in bacterial cells.

Animals↗

PubMed2004

Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity.

Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC(50)) was measured for 22 different quinolones, and values ranged from 2 to 3 microg/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 microg/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 microg/ml (for gatifloxacin) to 128 microg/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC(50)s (R(2) = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R(2) = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase.

Adenosine Triphosphate↗

PubMed1975

Pipemidic acid, a new antibacterial agent active against Pseudomonas aeruginosa: in vitro properties.

Pipemidic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido [2,3-d]pyrimidine-6-carboxylic acid, is a new derivative of piromidic acid. It is active against gram-negative bacteria including Pseudomonas aeruginosa as well as some gram-positive bacteria. Its potency is generally greater than that of piromidic acid and nalidixic acid. Cross-resistance is not observed between pipemidic acid and various antibiotics, and most of bacteria resistant to piromidic acid and nalidixic acid are moderately susceptible to pipemidic acid. The activity of pipemidic acid is scarcely affected by the addition of serum, sodium cholate, or change of medium pH, but is subject to the influence of inoculum size. Its action is bactericidal above minimal inhibitory concentrations.

Bacteria↗

PubMed1993

[Susceptibility in vitro to certain quinolines of gram-negative bacteria and gram-positive cocci causing urinary tract infections].

Susceptibility to norfloxacin, ofloxacin, pipemidic acid and nalidixic acid of 848 bacterial strains isolated from urine of patients treated in 1989-1992 in Wrocław hospitals was investigated. The study, performed by the disc diffusion methods, concerned 568 Enterobacteriaceae strains, 147 Gram-negative non-fermenting bacteria and 133 strains of staphylococci. Highest percentage (90-100%) of susceptibility to all used antimicrobial agents was detected among Escherichia, Proteus, Morganella and Citrobacter. Less frequent susceptibility (30-70%) was observed among Klebsiella, Enterobacter and Serratia. Among strains of P. aeruginosa susceptible to norfloxacin and ofloxacin were, respectively, 61.4 and 22.2% isolates. Over 95% of strains of P. aeruginosa were resistant to nalidixic acid. Among other non-fermenting Gram-negative bacteria, over 50% were resistant to norfloxacin and ofloxacin. Both S. aureus and S. epidermidis were susceptible to ofloxacin and norfloxacin in 81-93% of tested strains. They were 2-3 times less frequently susceptible to pipemidic and nalidixic acid.

4-Quinolones↗

PubMed2004

Reduced susceptibility to ciprofloxacin and gyra gene mutation in North Indian strains of Salmonella enterica serotype Typhi and serotype Paratyphi A.

The emergence of reduced susceptibility to ciprofloxacin among Salmonella enterica serotype Typhi and serotype Paratyphi A leading to clinical failure of treatment poses a great therapeutic challenge. The mechanism of fluoroquinolone resistance in clinical isolates of S. Typhi and S. Paratyphi A is not very well documented. The present study was carried out with the objective of molecular characterization of reduced quinolone susceptibility amongst the strains of S. Typhi and S. Paratyphi A isolated from the patients with enteric fever during January, 2000, to April, 2003, in a North Indian hospital. A total of 422 culture-positive cases of enteric fever were reported to the hospital during the period of study, of which S. Typhi was isolated from 350 cases and S. Paratyphi A from 72 cases. The antimicrobial susceptibility of these strains was determined by disk diffusion and agar dilution method according to NCCLS guidelines, and E-test method. A total of 140 randomly selected strains, isolated during the years 1993-1999, that were available from the laboratory stocks were also studied to compare with the present strains. To study the quinolone susceptibility, the strains were divided into nalidixic acid sensitive (NAS), nalidixic acid intermediate resistant, (NAI) and nalidixic acid resistant (NAR) on the basis of susceptibility to nalidixic acid. Clinical history was available from 174 patients, of which 93 needed hospitalization due to severe disease. Of these, 82 patients were infected with NAR strains and 22 patients had a documented evidence of clinical failure to ciprofloxacin therapy. The patients infected with NAR strains were younger and had a significantly longer duration of fever (p value < 0.05) than those infected with NAS strains. It was observed that the proportion of NAR strains increased gradually over the years. These strains had a significantly higher range of MIC of ciprofloxacin (0.023-1.0 microg/ml) as compared to the NAS strains (0.002-0.125 microg/ml) (p value < 0.05). The sequencing of quinolone resistance determining region (QRDR) of the gyrA gene showed the presence of mutation at either Ser 83 or at Asp 87 in all the NAR and NAI strains. None of the NAS strains had a mutation, suggesting that the gyrA gene mutation is sufficient to confer resistance to nalidixic acid and reduced susceptibility to ciprofloxacin. This mutation, although phenotypically expressed as decreased susceptibility to ciprofloxacin, goes undetected by the disk diffusion method using the present NCCLS guidelines. Hence, it can increase morbidity and mortality due to delay in appropriate antibiotic treatment.

Adolescent↗

PubMed1979

Modulation of gene expression by drugs affecting deoxyribonucleic acid gyrase.

Nalidixic acid (Nal), a drug which affects deoxyribonucleic acid gyrase activity, inhibits the expression of catabolite-sensitive genes: the three maltose operons, the lactose and galactose operons, and the tryptophanase gene. A correlation between the degree of sensitivity to Nal and that to catabolite repression has been observed. The expression of the threonine and tryptophan operons, insensitive to catabolite repression, is insensitive to Nal. The expression of the lacZ gene under the control of the IQ promoter is activated by Nal. Strains carrying a mutation in the nalA locus are resistant to these effects. Novobiocin, which inhibits the negative supercoiling activity of deoxyribonucleic acid gyrase, affects expression of the operons similarly to Nal. The involvement of promoters in Nal and novobiocin action, as well as a possible role of in vivo negative supercoiling in the selectivity of gene expression, are discussed.

DNA, Bacterial↗

PubMed1993

Mutator plasmid in a nalidixic acid-resistant strain of Shigella dysenteriae type 1.

A clinical isolate of Shigella dysenteriae from Kashmir, resistant to seven antibacterial agents including nalidixic acid, carried four plasmids, only one of which was transferable by conjugation. This plasmid, designated pYD1, conferred trimethoprim resistance and increased the frequency of mutation to nalidixic acid resistance in recipient strains. Thus, although nalidixic acid resistance was not carried on a transferable plasmid, the presence of pYD1 increased the frequency at which the strain mutated to nalidixic acid resistance.

Conjugation, Genetic↗

PubMed1975

Antibacterial activity of cinoxacin in vitro.

Cinoxacin is a new synthetic compound similar chemically and in antimicrobial activity to oxolonic acid and nalidixic acid. It is most effective against Escherichia coli and Proteus mirabilis, but at concentrations expected in the urine it is inhibitory for all species of Enterobacteriaceae. Relative to nalidixic acid, cinoxacin has slightly greater inhibitory and bactericidal activity, less inoculum effect probably due to less heterogeneity in the susceptibility of bacterial cells, and less inhibition by high concentrations of serum protein. Both drugs are more active in an acid than an alkaline medium. Glucose can specifically antagonize the inhibitory effect against P. mirabilis. In urine the bactericidal rate and effect are decreased. Resistance to cinoxacin can be developed quickly by serial transfers in vitro. Some nonresistant organisms remained viable in bactericidal drug concentrations. The in vivo importance of the favorable features of cinoxacin must be determined by clinical trials.

Anti-Bacterial Agents↗

PubMed1988

Mutagenicity of topoisomerase-active agents in bacteriophage T4.

Recently, the antitumor agent 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) was shown to revert a frameshift mutant of T4 (rFC11), and its mutagenicity was shown to be mediated by T4 DNA topoisomerase II [Ripley et al.: J Mol Biol 200: 665-680, 1988]. Here we report dose-response data on the mutagenicity and toxicity of m-AMSA in T4 rFC11. We find that m-AMSA is among the most potent frameshift mutagens observed in T4, inducing a 10-fold increase in mutant frequency in the absence of toxicity and a 500-fold increase in mutant frequency at 31% survival. In addition to m-AMSA, the topoisomerase-active agents ellipticine, oxolinic acid, and nalidixic acid also reverted rFC11; however, they required concentrations 10-100 times greater than those required by m-AMSA in order to be mutagenic, and they did not produce mutant frequencies as high as those produced by m-AMSA. Unlike m-AMSA, all three agents were mutagenic only at toxic doses. The other agents evaluated--actinomycin D, adriamycin, 9-aminoellipticine, 9-methoxyellipticine, teniposide (VM-26), and novobiocin--were toxic but not mutagenic to T4 rFC11. Thus, m-AMSA appears to be distinctly different from the other topoisomerase-active agents in exhibiting such potent mutagenic activity in T4 rFC11. Because E. coli DNA gyrase may substitute for T4 topoisomerase II, we examined the ability of two inhibitors of E. coli DNA gyrase, novobiocin and nalidixic acid, to inhibit m-AMSA's mutagenicity. Both agents substantially reduced the mutagenicity of m-AMSA in T4 rFC11, further suggesting that topoisomerase mediates the mutagenicity of m-AMSA.

Amsacrine↗

PubMed1984

Nalidixic acid-induced photosensitivity in mice: a model for pseudoporphyria.

Porphyria cutanea tarda (PCT)-like photosensitivity eruptions have occurred in patients treated with nalidixic acid, furosemide (Lasix), or tetracycline. An animal model for nalidixic acid photosensitivity was developed in young CF-1 female mice. The hair on the back was plucked from groups of animals that were injected i.p. each day with nalidixic acid or saline. The animals were exposed to black-lamp radiation for 12 h daily for 6 weeks, followed by a 2-week rest period, and then 4 more weeks of UV radiation exposure. The nalidixic acid-treated animals developed far greater gross and chronic inflammatory changes than the saline-treated animals; microscopically and ultrastructurally they showed blister formation beneath the basal lamina at the same level as that found in PCT. This model appears to be suitable for the study of PCT-like and other photosensitivity reactions.

Animals↗

PubMed1995

The interaction of trimethoprim and quinolones against gram-negative fish pathogens.

The effect of combination of trimethoprim with other non-sulphonamide antibacterial agents, in particular oxolinic acid and nalidixic acid, was evaluated against Gram-negative fish pathogens. The species included Aeromonas salmonicida, Yersinia ruckeri, some Vibrio spp. and Escherichia coli as a reference. The extent of synergy found by other workers with these substances against human Gram-negative bacteria was not apparent here. Some positive interaction between trimethoprim and oxolinic acid was found with Aer. salmonicida, Y. ruckeri and E. coli and between trimethoprim and nalidixic acid with Y. ruckeri in double disc diffusion tests but was not supported by fractional inhibitory concentration indices. The combinations were not effective in preventing emergence of resistance in passage on a drug gradient. Trimethoprim-resistant isolates of Aer. salmonicida were inhibited by low levels of oxolinic acid but the converse did not apply.

Animals↗

PubMed1987

Modulation of cell wall synthesis by DNA replication in Escherichia coli during initiation of cell growth.

Resting cells of Escherichia coli are able to initiate growth and murein biosynthesis in the presence of beta-lactam antibiotics binding to penicillin-binding proteins (PBPs) 1a and 1b (E. J. de la Rosa, M. A. de Pedro, and D. Vázquez, Proc. Natl. Acad. Sci. USA 82:5632-5635, 1985). Under these conditions, cells elongate normally until they approach the first doubling in mass, the time at which cell lysis starts. Assuming that coupling between DNA replication and cell division both in cells starting growth and in growing cells is essentially similar, triggering of the lytic response in the beta-lactam-treated cells coincides with the termination of the first round of DNA replication. This coincidence suggests that both events are interrelated. We investigated this possibility by studying the initiation of growth in cultures of wild-type strains and in cell division mutants treated with beta-lactams inhibiting PBPs 1a and 1b and with the DNA replication inhibitor nalidixic acid. Addition of nalidixic acid, even late in the first cell cycle, prevented the lytic response of the cells to the blockade of PBPs 1a and 1b. The effect of nalidixic acid is more likely due to its action on DNA replication itself than to its indirect inhibitory effect on cell division or to its ability to induce the SOS system of the cell. These observations favor the idea that the cell wall biosynthetic machinery might be modulated by DNA replication at precise periods during cell growth.

Bacterial Proteins↗

PubMed2005

New quinolone resistance phenomenon in Salmonella enterica: nalidixic acid-susceptible isolates with reduced fluoroquinolone susceptibility.

We describe the emergence of a new quinolone resistance pattern in Salmonella enterica isolates from Southeast Asia. These isolates are susceptible to nalidixic acid but exhibit reduced susceptibility to ciprofloxacin. The increase of such strains may threaten the value of the nalidixic acid disk test to screen for reduced fluoroquinolone susceptibility in salmonellas.

Anti-Infective Agents↗

PubMed1984

The assessment of antimicrobial activity in an in-vitro model of the treatment of bacterial cystitis.

In order to investigate the comparative activity of agents of the nalidixic acid series, cultures of nalidixic acid sensitive strains of E. coli were exposed to the drugs in an in-vitro model that simulates the hydrokinetic aspects of the treatment of bacterial cystitis. Intrinsic activity, as judged by the response to a single dose of drug and resistance as judged by response to a repeat dose, were investigated. All seven compounds tested in this way were able to inhibit bacterial growth for considerable periods of time even when the peak concentration achieved was as low as 10 mg/l. However, resistance emerged readily, particularly to nalidixic acid, pipemidic acid and piromidic acid. Norfloxacin was the most active of the seven compounds tested and was the only one to which resistance did not emerge at the concentrations tested. However, when two nalidixic acid resistant strains were tested in the bladder model, norfloxacin resistance was observed to emerge with one strain, but not with the other.

Anti-Infective Agents, Urinary↗