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Biomedical subjects

C S Lewin

Publications and source records attributed to C S Lewin.

At least 19 recordsLinked to original sources
PubMed1993

Mechanisms of antimicrobial resistance and implications for epidemiology.

The development of antibacterial agents has provided a means of treating bacterial diseases which were, previously, often fatal in both man and animal and thus represents one of the major advances of the 20th century. However, the efficacy of these agents is increasingly being compromised by the development of bacterial resistance to the drugs currently available for therapeutic use. Bacterial resistance can be combated in two ways. New drugs to which bacteria are susceptible can be developed and policies to contain the development and spread of resistance can be implemented. Both strategies require an understanding of the mechanisms of drug resistance, its epidemiology and the role of environmental factors in promoting resistance. Over the past thirty years our knowledge of bacterial resistance has increased dramatically mainly due to new technology that has become available. Bacteria are able to resist antibacterials by a variety of mechanisms: for example, altering the target to decrease susceptibility to the antibacterial, inactivating or destroying the drug, reducing drug transport into the cell or metabolic bypass. These drug resistance determinants are mediated via one of two distinct genetic mechanisms, a mutation in the bacterial chromosome or by a transmissible element; either a plasmid or a transposon. Significant differences exist between these two types of drug resistance as transmissible resistance, which is mainly plasmid-mediated, permits intraspecies and even interspecies transfer to occur. In contrast, chromosomal resistance can only be passed on to progeny. Transmissible antibacterial resistance is the major cause of concern as it can lead to the rapid spread of antibacterial resistance and has proven difficult, if not impossible, to eradicate. Furthermore, plasmids and transposons can code for multiple antibiotic resistance as well as virulence genes. Antibacterials for which transferable resistance has been identified include most commonly used antibacterials such as beta-lactams, aminoglycosides, macrolides, sulphonamides, tetracyclines, chloramphenicol and trimethoprim. One notable exception is the 4-quinolones for which plasmid-mediated resistance has yet to be identified.

Anti-Bacterial Agents↗
PubMed1992

The bactericidal activity of sparfloxacin.

Sparfloxacin was found to display a biphasic response against Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis in nutrient broth. Its optimum bactericidal concentration was found to be identical for all three species which contrasts with other clinically available fluoroquinolones that are more active against E. coli than against staphylococci. Bacterial protein and RNA synthesis as well as cell division were not found to be essential for all the lethality of sparfloxacin, which hence displays bactericidal mechanism B. However, sparfloxacin was unable to kill bacteria in absence of oxygen.

Anti-Infective Agents↗
PubMed1992

Antibacterial activity of a 1,8-naphthyridine quinolone, PD 131628.

A new 1,8-naphthyridine quinolone antimicrobial, PD131628, was found to be as, or more active than ciprofloxacin or ofloxacin against Escherichia coli and considerably more active than the two 4-quinolone agents against staphylococci in terms of both MIC and OBC (the optimum bactericidal concentration, at which the rate of kill is greatest). In common with ciprofloxacin and ofloxacin, the rate of kill of PD131628 against Enterococcus faecalis was considerably slower than against the other three species tested. Bacterial protein synthesis, RNA synthesis and cell division were not required for the bactericidal activity of PD131628 against E. coli or the staphylococci, although the lethality of PD131628 in the absence of these activities was reduced.

Anti-Infective Agents↗
PubMed1992

The effect of thymidine on the antibacterial and antiviral activity of zidovudine.

The effect of thymidine and deoxyadenosine on the antiviral and antibacterial effect of zidovudine was studied in human immunodeficiency virus type 1 (HIV-1) Escherichia coli and Salmonella typhimurium. In quantitative assays, 10 micrograms mL-1 thymidine was shown to increase the 50% inhibitory concentration (IC50) of zidovudine for HIV-1 by approximately 100-fold and to reduce zidovudine (1 microM)-induced protection of C8166 cells from 2.04 to 0.18 log syncytial-forming units. Thymidine also antagonized the antibacterial effect of zidovudine for two E. coli and three S. typhimurium species in a dose-dependent manner; 10 micrograms mL-1 of thymidine increased the minimum inhibitory concentration of zidovudine for E. coli strains by 10-40-fold and for S. typhimurium strains by three-fold. Deoxyadenosine reduced the minimum inhibitory concentration of zidovudine against all five bacterial strains but had no effect on the IC50 of zidovudine for HIV-1, nor did it significantly reverse the antagonism of the antibacterial and antiviral activity of thymidine. The induction of the SOS response in E. coli was reversed in a dose-dependent manner by thymidine while the presence of deoxyadenosine increased induction of the SOS response by zidovudine at suboptimal concentrations.

Deoxyadenosines↗
PubMed1991

The mode of action of quinolones: the paradox in activity of low and high concentrations and activity in the anaerobic environment.

All 4-quinolones that have been examined display rapid bactericidal activity which is biphasic. At concentrations above the MIC, the lethality of the drugs increases until a concentration known as the optimum bactericidal concentration (OBC) beyond which the bactericidal activity then declines. The biphasic response appears to be due to the inhibition of RNA synthesis at concentrations above the OBC, as RNA synthesis is required for the full bactericidal activity of the 4-quinolones. However, differences in the biphasic response are observed as some fluoroquinolones are still able to kill bacteria in the absence of bacterial protein or RNA synthesis, thus reducing the inhibition of bactericidal activity at concentrations above the OBC. It has been proposed that this ability to kill bacteria in the absence of protein or RNA synthesis is due to the possession of an additional bactericidal mechanism by these fluoroquinolones. Oxygen also appears to be essential for the lethality of the clinically available 4-quinolones although it is not required for the drugs to inhibit bacterial multiplication. Therefore these drugs are not bactericidal under anaerobic conditions.

4-Quinolones↗
PubMed1991

Protein- and RNA-synthesis independent bactericidal activity of ciprofloxacin that involves the A subunit of DNA gyrase.

Ciprofloxacin, unlike nalidixic acid, can kill Escherichia coli cells in the absence of synthesis of protein or RNA. Hence, chloramphenicol or rifampicin do not abolish the bactericidal activity of ciprofloxacin against wild-type E. coli. Protein and RNA synthesis were not required for the bactericidal activity of ciprofloxacin against nalB, nalC and nalD mutants of E. coli. However, the addition of chloramphenicol or rifampicin abolished the bactericidal activity of ciprofloxacin against a nalA mutant in nutrient broth. It is concluded that the ability of ciprofloxacin to kill E. coli in the absence of protein or RNA synthesis involves the A subunit of DNA gyrase.

Cell Membrane Permeability↗
PubMed1991

The role of the SOS response in bacteria exposed to zidovudine or trimethoprim.

Trimethoprim was more potent than zidovudine as an inducer of the SOS response in Escherichia coli. The level of induction by each compound initially increased with rising drug concentration and then fell; this effect was less marked with zidovudine than with trimethoprim. The SOS response did not appear to be involved in the inhibition of bacterial multiplication as the MICs of trimethoprim or zidovudine for recA430 and lexA3 mutants, which are unable to induce the SOS response, were identical to the MICs for the parent strains. However, the bactericidal activity of each compound against strains deficient in the SOS response was reduced. This suggest that induction of the DNA repair system contributes to the bactericidal activity of the drugs.

Cell Survival↗
PubMed1991

4-Quinolone interactions with gyrase subunit B inhibitors.

In studies which have involved determination of fractional inhibitory concentrations, synergy has been described between the 4-quinolones, which inhibit the A subunit of DNA gyrase, and either coumermycin or novobiocin, which inhibit the B subunit of the same enzyme. In this study, fixed concentrations of ciprofloxacin or ofloxacin were combined with varying concentrations of coumermycin or novobiocin and vice versa in nutrient broth. The bactericidal activities of the different mixtures against either Staphylococcus aureus E3T or S. warneri were determined and found to be less than those of equivalent concentrations of either 4-quinolone alone. The observation that gyrase B subunit inhibitors antagonised the bactericidal activity of 4-quinolones is in accordance with the report previously made by others that ciprofloxacin combined with coumermycin was less effective than ciprofloxacin alone in treating staphylococcal endocarditis in rats. Our results indicate that both inhibitory and bactericidal activity should be taken into account when assessing possible interactions in vivo between 4-quinolones and other antimicrobial agents.

Aminocoumarins↗
PubMed1991

The fluoroquinolones exert a reduced rate of kill against Enterococcus faecalis.

The bactericidal activities of ciprofloxacin, ofloxacin and DR-3355 have been investigated against Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis over 24 h. The three fluoroquinolones were found to be rapidly bactericidal against the staphylococci, killing over 99% of the bacteria during the first 3 h of exposure with a further reduction in viability of approximately one logarithm occurring over the next 21 h. In contrast, the fluoroquinolones displayed a much slower rate of kill against E. faecalis, as little or no bactericidal activity was detected over the first 3 h for both E. faecalis ATCC19433 and a clinical isolate. At 6 h all three of the drugs were bactericidal against the enterococci although the amount of kill was not as great as against the staphylococci. However, at 24 h the amount of kill obtained with all three drugs was similar to that obtained for staphylococci exposed to these drugs. Ciprofloxacin, ofloxacin and DR-3355 were not active against E. faecalis ATCC19433 in phosphate buffered saline and therefore require cell division for their bactericidal activity against this species.

Anti-Infective Agents↗
PubMed1991

In vitro susceptibility of the fish pathogen Aeromonas salmonicida to flumequine.

The activity of the fluoroquinolone flumequine was investigated against the fish pathogen Aeromonas salmonicida and was compared with that of oxolinic acid. Flumequine was more active than oxolinic acid in terms of its MIC against oxolinic acid-resistant isolates of A. salmonicida and was as active as oxolinic acid against susceptible isolates. In contrast to oxolinic acid, flumequine was bactericidal, with only 1% of the bacteria surviving 6 h of exposure to the drug at concentrations slightly above the MIC. Mutation to resistance to flumequine was found to occur at a lower frequency than that to oxolinic acid. Hence, in vitro, flumequine appears to possess some advantages over oxolinic acid against this fish pathogen.

Aeromonas↗
PubMed1990

Cross resistance between oxytetracycline and oxolinic acid in Aeromonas salmonicida associated with alterations in outer membrane proteins.

Oxytetracycline resistant mutants of Aeromonas salmonicida isolated from mutation frequency experiments showed decreased susceptibility to oxolinic acid. Outer membrane preparations of these resistant mutant strains revealed a major protein, with a molecular mass of approximately 37 kDa, which was not present in significant quantities in the parent strain.

Aeromonas↗