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Biomedical subjects

J T Smith

Publications and source records attributed to J T Smith.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effects of temperature on the bactericidal activities of ciprofloxacin and levofloxacin against Escherichia coli and Pseudomonas aeruginosa.

The bactericidal activities of the 4-quinolones ciprofloxacin and levofloxacin against Escherichia coli and Pseudomonas aeruginosa in nutrient broth were drastically reduced as the temperature of incubation was decreased from 37 to 30 to 25 to 20 degrees C. With E. coli a biphasic response was observed with either 4-quinolone at any one of the four temperatures tested. At the optimum bactericidal concentrations (OBCs) of ciprofloxacin or levofloxacin against E. coli the activity at 20 degrees C was 68- and 56-fold less than at 37 degrees C, respectively. As expected, with P. aeruginosa biphasic responses were not observed so OBC values could not be estimated. At the peak serum concentrations of ciprofloxacin or levofloxacin the bactericidal activity against P. aeruginosa was reduced by 61- or 50-fold, respectively, as temperature was decreased from 37 to 20 degrees C. This was similar in scale to the reductions in bactericidal activity observed with E. coli at its OBC values.

Ciprofloxacin↗
PubMed1994

Effects of temperature on the bactericidal activities of ciprofloxacin and levofloxacin against Staphylococcus aureus and Staphylococcus epidermidis.

The bactericidal activities of the 4-quinolones ciprofloxacin and levofloxacin against Staphylococcus aureus and Staphylococcus epidermidis in nutrient broth were dramatically reduced when the temperature of incubation was decreased from 37 to 20 degrees C. For S. aureus the relative reduction in the activities was 86- and 46-fold with ciprofloxacin or levofloxacin, respectively. For S. epidermidis the corresponding reduction in activities was 82- and 19-fold, respectively. At infectious sites which are at lower-than-body temperature the reduced activity of 4-quinolones may contribute to clinical failure and/or the development of resistance. Levofloxacin was more bactericidal than ciprofloxacin against either of the staphylococci at every temperature tested. These results tend to suggest that levofloxacin may be preferable to ciprofloxacin for staphylococcal infections especially at skin and soft-tissue sites.

Body Temperature↗
PubMed1994

The importance of oxygen in the killing of bacteria by ofloxacin and ciprofloxacin.

There is an inoculum size effect associated with the bactericidal potency of 4-quinolones. This phenomenon has previously been attributed to anaerobic conditions at high initial inoculum sizes. The level of anaerobicity present with Escherichia coli and Staphylococcus aureus at varying initial inoculum size was analysed by measuring dissolved oxygen concentrations and redox potentials. Such measurements confirmed that conditions at high initial inoculum sizes are more anaerobic than conditions at low initial inoculum sizes. The precise concentration of oxygen at which 4-quinolones are no longer able to kill bacteria could not be deduced by either method. The results suggest that extremely low oxygen levels are needed to antagonise 4-quinolone kill. This explains why very stringent conditions are required to render media anaerobic enough to prevent the bactericidal activity of 4-quinolones against bacteria at low initial inoculum sizes.

Ciprofloxacin↗
PubMed1994

Antagonism between bactericidal activities of 4-quinolones and coumarins gives insight into 4-quinolone killing mechanisms.

At concentrations exceeding their MICs, novobiocin and coumermycin antagonised the bactericidal activities of nalidixic acid, ciprofloxacin, ofloxacin and norfloxacin against Escherichia coli KL16. The sensitivities to killing by ciprofloxacin of four mutant derivatives of KL16 carrying gyrA, nalB, nal24 or nal31 alleles were also antagonised by novobiocin. The activities of drug combinations were tested in nutrient broth, which allowed expression of 4-quinolone killing mechanisms A, B and C. They were also tested in nutrient broth plus rifampicin to inhibit mechanisms A and C of the 4-quinolones, and in phosphate-buffered saline, which inhibited mechanism A. Results showed that novobiocin antagonised mechanism C, but not B, of both ciprofloxacin and ofloxacin, but did not antagonise mechanism C of norfloxacin. A review of these and other data indicates that mechanism B may result from the activities of SOS error-prone DNA repair on an irreversibly-bound drug-gyrase-DNA complex, and that mechanism C is mediated via drug interaction with the B subunit of DNA gyrase.

Aminocoumarins↗
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↗
PubMed1993

The association between preterm newborn hypotension and hypoxemia and outcome during the first year.

Ninety-eight newborn infants, less than 34 weeks at birth, were studied to examine the relationship between newborn hypotension and hypoxemia and brain damage. Heart rate, blood pressure and oxygen tension were recorded continuously during the 96 h following delivery. Outcome measures included neuropathology in children who died, and motor and cognitive development at one year corrected age in children who survived. There were 22 children with a minor and 27 with a major abnormal outcome. There was a relationship between newborn hypotension, newborn hypoxemia and low birth weight, and a major abnormal outcome. The probability of a major abnormal outcome increased from 8% in newborns with no hypotension or hypoxemia, to 53% in children with both hypotension and hypoxemia. These findings support the contention that combinations of sustained newborn hypotension and hypoxemia are important factors in the development of brain damage, accounting for a major abnormal outcome.

Acidosis↗
PubMed1993

Function of the SOS process in repair of DNA damage induced by modern 4-quinolones.

The recA13 mutant of Escherichia coli strain K-12, which lacks recombination and SOS error-prone DNA repair is hypersensitive to nalidixic acid and to the newer 4-quinolones ciprofloxacin, norfloxacin and ofloxacin. However, whereas recombination-proficient but SOS repair-deficient strains, such as those carrying the lexA3 or recA430 alleles are no more sensitive to nalidixic than the lexA+ recA+ parent, they are more sensitive to the newer quinolones, although not as sensitive as the recA13 derivative. Nalidixic acid possesses only bactericidal mechanism A (which requires RNA and protein synthesis and is only effective on actively dividing cells), whereas the newer 4-quinolones exhibit additional mechanisms B (which does not require RNA and protein synthesis and is effective on bacteria unable to multiply) and C (which requires RNA and protein synthesis but does not depend on cell division). Results obtained with bacteria suspended in phosphate-buffered saline, which inhibits mechanism A, and with bacteria suspended in nutrient broth plus rifampicin, which inhibits mechanisms A and C, showed that the lexA3 mutant was still more sensitive than the lexA+ parent under these conditions. The results suggest that, unlike bactericidal mechanism A, DNA damage that results from bactericidal mechanisms B and C of the newer 4-quinolones is subject to SOS error-prone (mutagenic) repair.

Anti-Infective Agents↗
PubMed1993

Contributions of post-antibiotic lag and repair-recovery to the post-antibiotic effects of ciprofloxacin on Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pyogenes.

A viable counting technique was used to determine the post-antibiotic effect (PAE) of ciprofloxacin against four bacterial species, treated with either one or four times the minimum inhibitory concentration for 1 or 3 h. PAE were demonstrated with Escherichia coli, Staphylococcus aureus or Streptococcus pyogenes after exposure to either concentration for both times. No clear PAE was demonstrated for Klebsiella pneumoniae after any treatment. In some cases, PAE was due to an increased post-treatment lag phase, which was followed by nearly normal multiplication, whereas in other cases a long lag was followed by abnormally rapid cell division, with the generation times of treated cultures being much less than those of the corresponding drug-free controls. This is evidence of recovery of cells that have completed DNA repair. S. aureus, E. coli and K. pneumoniae all exhibited evidence of this type of repair even though K. pneumoniae gave no significant PAE. However, the post-treatment generation times of S. pyogenes, which produced the greatest PAE, gave no evidence of such repair. It is concluded that PAEs may result from a variety of factors.

Ciprofloxacin↗
PubMed1993

4-Quinolone bactericidal mechanisms.

The bactericidal activity of nalidixic acid against Escherichia coli strain KL16 in nutrient broth was abolished by the addition of rifampicin. Cells suspended in phosphate-buffered normal saline (PBS) were also not killed by nalidixic acid. Experiments with modern 4-quinolones showed their activities varied according to the conditions under which they were tested. Rifampicin did not affect the concentration at which ofloxacin became bactericidal in nutrient broth, but did limit the extent of ofloxacin-induced death. However, rifampicin produced a 10-fold increase in the concentration at which ciprofloxacin became bactericidal in nutrient broth, and completely abolished the bactericidal activity of norfloxacin. Unlike nalidixic acid all of the modern 4-quinolones killed cells suspended in PBS. Based on these results it was possible to differentiate 3 processes by which 4-quinolones induced death. Mechanism A was only active against dividing bacteria and required RNA and protein synthesis; it was therefore not active against bacteria suspended in PBS and was inhibited in nutrient broth by the addition of rifampicin. Mechanism B required neither RNA nor protein synthesis and was also active against non-dividing bacteria; it was therefore not inhibited by rifampicin nor by suspending bacteria in PBS. Mechanism C killed non-dividing bacteria, but required protein and RNA synthesis: it therefore functioned in PBS, but was inhibited by rifampicin.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Quinolones↗
PubMed1993

Studies on mutational cross-resistance between ciprofloxacin, novobiocin and coumermycin in Escherichia coli and Staphylococcus warneri.

Nalidixic acid resistant mutants of Escherichia coli KL16 were tested against ciprofloxacin, coumermycin and novobiocin. The mutants gyrA, nalB and nal-24 were more resistant than KL16 to ciprofloxacin, whereas the nal-31 strain was hypersensitive. Only the nalB mutant was more resistant to novobiocin than KL16, but gyrA, nal-31 and nal-24 mutants were more sensitive to coumermycin than KL16. Newly-isolated novobiocin-resistant mutants of KL16 were not cross-resistant to coumermycin or ciprofloxacin. Some coumermycin-resistant mutants were cross-resistant to novobiocin but not ciprofloxacin, whereas mutants resistant to novobiocin and ciprofloxacin were isolated at higher coumermycin concentrations. Two types of Staphylococcus warneri mutant were isolated on media containing novobiocin or coumermycin. Each was resistant to both coumarins, but one was highly resistant to novobiocin and the other to coumermycin. High level resistance to both coumarins was unstable. E. coli mutants differed in susceptibility to bactericidal concentrations of ciprofloxacin, and S. warneri mutants behaved similarly. These results suggest the modes of action of the coumarins are not identical.

Aminocoumarins↗
PubMed1993

Middle cerebral artery blood flow velocity in the newborn following delivery.

Ninety-five normally grown term and preterm newborns were examined to determine the means and prediction limits of cerebral blood flow velocity following delivery and to examine the relationship of systemic blood pressure to cerebral blood flow velocity. Doppler blood flow velocity was observed during the four days following delivery. Continuous measures of blood pressure and heart rate were recorded concurrently. Mean peak systolic and end diastolic blood flow velocity immediately following delivery was 43.2 and 9.3 cm/sec for term newborn, and 31.8 and 3.3 cm/sec for preterm newborn. During the 24 h following delivery there was no change of peak systolic blood flow velocity but a two to three fold increase of end diastolic blood flow velocity in the term and preterm newborn. The reference limits for peak systolic and end diastolic blood flow velocity provide criteria to define abnormal increases and decreases of blood flow velocity. During the 24 h following delivery, increasing diastolic blood pressure was associated with increasing end diastolic blood flow velocity independent of birth weight and time following delivery. Also there was a significant correlation between systemic pressure pulsatile index and middle cerebral artery blood flow velocity pulsatile index. Thus systemic blood pressure pulsatility must be recognized as distinct from other intracerebral influences on cerebral blood flow velocity regulation in the newborn.

Blood Flow Velocity↗
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

Development of physical fitness standards for Canadian Armed Forces younger personnel.

The purpose of this study was to develop minimum physical fitness standards based on common task criteria for personnel younger than 35 years of age in the Canadian Armed Forces. A random sample of 66 men and 144 women performed the Exercise Prescription (EXPRES) test and five physically demanding tasks that simulated common military tasks. Common cutting scores were selected as the point at which 75% of the total weighted sample passed each task. Since there were significant differences between the sexes in task performance and technique execution, the groups were analyzed separately. Results indicated a range in variance of 14 to 48% between military task performance and physical fitness test score, thus suggesting that fitness measures are a poor predictor of task performance. Because of the low variance observed the passing group of each task was treated as a representative sample of subjects whose fitness profiles were indicative of those able to meet task criteria. The 5th percentile fitness scores of the passing group were proposed as the minimum fitness standard. These conditions resulted in fitness standards that were physically more demanding for women than for men.

Adult↗
PubMed1992

Hypotension and hypoxemia in the preterm newborn during the four days following delivery identify infants at risk of echosonographically demonstrable cerebral lesions.

This prospective study of 130 preterm newborns at less than 34 weeks gestational age has examined the predictive value of abnormalities in continuously recorded newborn blood pressure, heart rate, and oxygen tension during the 4 d following delivery for echosonographically demonstrable cerebral lesions (EDCL) identified in the infant by six months corrected age. EDCL consisting of intraventricular hemorrhage, ventriculomegaly, or hyperechoic parenchymal lesions in the brain were identified in 44 preterm newborns (34%). The incidence of EDCL in preterm newborns with no hypotension or hypoxemia was 13%. The incidence of EDCL was significantly increased in preterm newborns with either hypotension or hypoxemia. The probability of EDCL exceeded 50% when the total exposure to either hypotension or hypoxemia during the 4 d exceeded 50 mmHg-hours, or when newborn hypotension and hypoxemia occurred concurrently. No relationship to hypertension, bradycardia, or tachycardia was detected. These findings indicate that hypotension and hypoxemia in the preterm newborn during the 4 d following delivery are useful risk markers of EDCL.

Brain Diseases↗
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↗