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Biomedical subjects

K E Bowker

Publications and source records attributed to K E Bowker.

At least 19 recordsLinked to original sources
PubMed2000

Use of meropenem 3 g once daily for outpatient treatment of infective exacerbations of bronchiectasis.

Meropenem administered as a single iv 3 g dose once every 24 h was used to treat nine ambulatory patients with infective exacerbations of bronchiectasis. Serum meropenem concentrations were measured before dosing and at 30 min after each 30 min infusion. Mean pre-dose concentrations were <0.1 mg/L and mean post-dose concentrations 93.9 +/- 29.5 mg/L (95% confidence interval (CI) 86. 2-101.6, n = 59). A pathogen was cultured from sputum in six patients and eradicated (<100 cfu/g sputum) in all but one by day 6 of therapy. Previous work on animals has shown that a bacteriostatic effect is seen with meropenem when t > MIC is greater than 20-30% of the dose interval. In these nine patients, this could be achieved and was associated with successful outcome for pathogens for which MICs are </= 0.5 mg/L. Therefore, once-a-day meropenem therapy may be a useful option for outpatient treatment for isolates for which MICs are </= 0.5 mg/L.

Aged↗
PubMed1999

Use of a clinical Escherichia coli isolate expressing lux genes to study the antimicrobial pharmacodynamics of moxifloxacin.

Escherichia coli isolate 16,906 expressing lux genes was used for real-time monitoring of moxifloxacin effects on bacterial metabolism compared with effects on cell replication. Viable counts showed concentration-dependent killing by moxifloxacin; real-time measurement of bioluminescence on the same cultures showed metabolic activity over 54 h, but with greater inhibition at 1 x MIC than with higher MIC multiples. Post-antibiotic effect was longer when determined using bioluminescence than by viable counts. The control-related effective regrowth time was consistent with both methods. Bioluminescent bacteria provide a rapid and sensitive means for measuring antimicrobial effects on bacterial metabolism.

Anti-Bacterial Agents↗
PubMed1999

In-vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and beta-haemolytic streptococci.

The in-vitro activity of HMR 3647 and seven comparators (azithromycin, clarithromycin, erythromycin A, roxithromycin, penicillin G, ciprofloxacin and levofloxacin) were tested against 207 Streptococcus pneumoniae and 200 beta-haemolytic streptococci. Ten comparators (azithromycin, clarithromycin, erythromycin A, roxithromycin, ampicillin, co-amoxiclav, cefuroxime, cefotaxime, ciprofloxacin and levofloxacin) were tested against 143 Haemophilus influenzae and 58 Moraxella catarrhalis. The MIC50 of HMR 3647 for S. pneumoniae was < or =0.008 mg/L, less than that for the macrolides or quinolones tested. Pneumococci with an erythromycin A MIC of 0.06 mg/L (n = 23) had an MIC50 of HMR 3647 < or =0.008 mg/L, whereas isolates with an erythromycin A MIC > or =1 mg/L (n = 34) had an MIC50 of HMR 3647 of 0.03 mg/L, a four-fold increase. In contrast, the difference in macrolide MIC50s for the two groups was > or =64-fold. The MIC50s foro beta-haemolytic streptococci, classified by Lancefield group, were in the range 0.015 to 0.06 mg/L for HMR 3647. H. influenzae were categorized into three groups according to cefuroxime MIC: <1 mg/L (n = 72); 2-4 mg/L (n = 29); and >4 mg/L (n = 42). The MIC50 of HMR 3647 increased two-fold with increasing cefuroxime MICs; beta-lactam MICs increased much more markedly. The MIC50 of HMR 3647 for M. catarrhalis was 0.03 mg/L. HMR 3647 has good activity against respiratory tract pathogens but in-vitro susceptibility is affected by erythromycin A susceptibility in S. pneumoniae and beta-haemolytic streptococci.

Anti-Bacterial Agents↗
PubMed1999

Comparison of in-vitro pharmacodynamics of once and twice daily ciprofloxacin.

The pharmacodynamics of ciprofloxacin were explored in an in-vitro continuous bacterial culture model of infection, by simulating two oral dosing regimens; 0.5 g 12-hourly (bd) and 1 g 24-hourly (od). Three strains of Escherichia coli (ciprofloxacin MICs 0.03, 0.5 and 2 mg/L); two strains of Pseudomonas aeruginosa (MICs 0.09 and 1.5 mg/L), two strains of Staphylococcus aureus (MICs 0.12 and 1 mg/L) and two strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L) were used. Three pharmacodynamic parameters, T > MIC, C(max)/MIC and AUC/MIC (T = time, C(max) = peak serum concentration, AUC = area under the curve), were compared with area under the bacterial-kill curve (AUBKC) (after transformation of the AUBKC) using a simple E(max) or sigmoidal E(max) model. AUBKC was taken to be the main antibacterial effect measure. The models were compared by inspection of residuals and Akaike information criterion. E(max) models adequately described the relationship between AUC/MIC and AUBKC and between C(max)/MIC and AUBKC, but not between T> MIC and AUBKC. All three pharmacodynamic parameters are related to each other but multiple regression analysis indicated that AUC/MIC was the best individual predictor of AUBKC. Despite this, comparison of od and bd regimens indicates some advantage to od in terms of early antibacterial effect. Serum concentration-time curve shape has some importance in determining antibacterial effect. These data indicate that for ciprofloxacin AUC/MIC ratio is not the sole determinant of antibacterial effect.

Anti-Infective Agents↗
PubMed1999

Exploration of the in-vitro pharmacodynamic activity of moxifloxacin for Staphylococcus aureus and Streptococci of lancefield groups A and G.

The serum concentrations associated with the oral administration of 400 mg moxifloxacin every 24 h over 48 h in man were simulated in an in-vitro dilutional, continuous bacterial culture model of infection. The initial inoculum was 5 x 10(7)-5 x 10(8) cfu/mL and all strains were tested on at least three occasions. Two strains of Staphylococcus aureus (one methicillin susceptible, the other resistant) with moxifloxacin MICs 0.14 mg/L and 0.06 mg/L and two strains of beta-haemolytic streptococci, Lancefield Group A, MIC 0. 16 mg/L and Group G, MIC 0.4 mg/L were used. In addition, two laboratory-generated mutants with raised moxifloxacin MICs were also employed: methicillin-sensitive S. aureus (MSSA) MIC 1.0 mg/L and Group A streptococcus MIC 1.8 mg/L. The antibacterial effect of moxifloxacin was judged by changes in viable count over time, and the area under the bacterial-kill curve (AUBKC) after 24 and 48 h. For S. aureus MIC 0.14 mg/L the AUBKC(24) (log cfu/mL.h) was 77.8 +/- 4.6 and AUBKC(48) 92.0 +/- 6.9. For its mutant, moxifloxacin MIC 1.0 mg/L, the AUBKC(24) was 116.1 +/- 15.6 and AUBKC(48) 211.9 +/- 23.1, indicating decreased killing. AUBKC(24) and AUBKC(48) values of 110.7 +/- 10.3 and 130.9 +/- 21.3, respectively, were noted for the MRSA strain. The Group A streptococcus, MIC 0.16 mg/L, had an AUBKC(24) of 91.4 +/- 19.4 and AUBKC(48) of 157.0 +/- 70.9. The mutant, MIC 1.8 mg/L, had an AUBKC(24) of 127.0 +/- 1.9 and AUBKC(48) of 205.1 +/- 6.4. Despite a lower MIC (0.4 mg/L) the single strain of Group G streptococcus tested was killed poorly, AUBKC(24) 139.9 +/- 3.6 and AUBKC(48) 252.3 +/- 18.6. The pharmacodynamic parameters AUC/MIC, T > MIC, (AUC > MIC)/MIC (AUC = area under the curve, T = time) and WAUC ((AUC/MIC) (T > MIC/100)) (WAUC = weighted area under the curve) were related to AUBKC(24) and AUBKC(48) using an inhibitory sigmoid E(max) model. T > MIC was poorly related to AUBKC (r = 0.36) while AUC/MIC, (AUC > MIC)/MIC and WAUC were strongly related to AUBKC(24) (r = 0.75-0.79) and AUBKC(48) (r = 0.78-0.84). The maximum antibacterial effect was achieved with an AUC/MIC ratio of 150-200. AUC-related pharmacodynamic parameters predicted antibacterial effect better than T > MIC.

Anti-Infective Agents↗
PubMed1999

Activity of moxifloxacin, administered once a day, against Streptococcus pneumoniae in an in vitro pharmacodynamic model of infection.

The antibacterial effect of moxifloxacin was studied by using an in vitro pharmacodynamic model of infection with dosing simulations of 400 mg every 24 h for 48 h. Streptococcus pneumoniae was tested by using four wild-type strains for which the moxifloxacin MICs were 0. 008, 0.12, 0.14, and 3.6 mg/liter. In addition, two isogenic mutants, generated from the strains for which the moxifloxacin MICs were </=0.12 mg/liter and for which the MICs were 1.0 and 1.6 mg/liter, were also used. Antibacterial efficacy was measured by the following indices: log change in viable count at 12, 24, 36, and 48 h; area under the bacterial kill curve (AUBKC); and time to kill 99.9% of the initial inoculum. With the three strains for which the moxifloxacin MICs were </=0.14 mg/liter, there was a marked reduction in viable count over 12 to 36 h; in contrast, with strains for which the MICs were >/=1.0 mg/liter, little killing occurred over 48 h. A sigmoid dose-response model indicated that the area under the curve/MIC ratio was strongly related to the log change in viable count at 24 and 48 h and to the AUBKC. These data indicate that moxifloxacin may have a role in management of S. pneumoniae infection.

Anti-Infective Agents↗
PubMed1998

Sequential antimicrobial therapy: pharmacokinetic and pharmacodynamic considerations in sequential therapy.

The pharmacodynamic factors important in sequential therapy are largely unknown. This is because most pharmacodynamic investigations concentrate on how bacterial populations respond to first antimicrobial exposures. However, it is likely that for B lactams T>MIC and for quinolones the antimicrobial AUC/MIC ratio will be important. Factors which reduce antimicrobial absorption will impact on these parameters and require further study.

4-Quinolones↗
PubMed1998

Comparison of the modified Stokes' method of susceptibility testing with results obtained using MIC methods and British Society of Antimicrobial Chemotherapy breakpoints.

The majority of clinical microbiology laboratories in the UK use comparative disc diffusion methods based on the Stokes' method to determine antibiotic susceptibility. The technical validity of the results obtained from the modified Stokes' method of disc testing and how they relate to MIC data are not known. We studied susceptibility testing using a modified Stokes' disc diffusion method for a wide range of clinical isolates against which MICs had been determined by collaborators not involved with the disc testing evaluation. Results indicated that for 1301 organism-antibiotic combinations the number of major errors (where resistant strains were reported as sensitive) was 21/468 (4.4%) and the number of minor errors (where sensitive strains were reported as resistant) was 14/713 (1.9%) using ciprofloxacin breakpoints of 0.5 and 2 mg/L. There was good correlation between the disc susceptibility test and the MIC for 119 isolates of Enterobacteriaceae tested with the exception of Serratia spp. Excluding Serratia spp. the number of major errors for Enterobacteriaceae was 1/200 (0.5%). Data revealed 2/25 (8%) major errors for Pseudomonas aeruginosa and 1/45 (2.2%) for Acinetobacter spp. Haemophilus influenzae showed a number of unexpected categorization errors. The modified Stokes' method performed accurately for Staphylococcus aureus and coagulase-negative staphylococci when tested for susceptibility to gentamicin, erythromycin, teicoplanin and vancomycin. No major errors were reported for Streptococcus pneumoniae and beta-haemolytic streptococci. Problems occurred with the detection of antibiotic resistance in Enterococcus spp. Major errors were seen for ampicillin (2/12 strains), teicoplanin (5/6 strains) and vancomycin (5/13 strains) using a 30 microg disc but only 1/13 strains using a 5 microg disc. Overall, from our data, the modified Stokes' disc diffusion antibiotic susceptibility test showed an unacceptable number of major errors but an acceptable number of minor errors.

Anti-Bacterial Agents↗
PubMed1998

Comparative pharmacodynamics of meropenem using an in-vitro model to simulate once, twice and three times daily dosing in humans.

An in-vitro pharmacokinetic model was used to study the antibacterial activity of meropenem. Strains of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were exposed to meropenem concentrations likely to be produced in an adult by rapid iv infusion of 3 g once a day (q24h regimen), 1.5 g twice a day (ql2h regimen) or 1 g three times a day (q8h regimen). Each of these three dosing regimens produced a rapid reduction in viable bacterial count over the first 16 h after dosing. There were no differences in the pattern of reduction in viable count with the q24h, q12h or q8h regimens with any of the three bacterial strains tested over the first 16 h. However, reduction in viable counts was poorer at 24 h with the q24h than q12h or q8h regimens. A simulation lasting 48 h of the q24h dosing regimen indicated a reduction in bacterial count below the limit of detection from the model with E. coli but not with P. aeruginosa or S. aureus. The time for which the meropenem concentration was higher than the MIC for the bacteria correlated best with the reduction in viable bacterial count at 24 h. The AUC for the bacterial time-kill curve, which may be a better measure of antibacterial efficacy, was not related to the length of time for which the concentration was above the MIC or the peak concentration/MIC ratio. The antibacterial effect of the conventional q8h dosing simulation was indistinguishable from that given by the q12h simulation, and both the q8h and q12h regimens offered minor advantages over a q24h regimen. Dosing of meropenem 12 hourly or 24 hourly in humans should be investigated.

Adult↗
PubMed1998

In vitro activities of Y-688, a new 7-substituted fluoroquinolone, against anaerobic bacteria.

The in vitro activities of Y-688, a new 7-substituted fluoroquinolone derivative, against 317 nonduplicate anaerobic isolates were determined. Eighty-five percent of the Bacteroides fragilis group (n = 89) were inhibited by < or = 2 mg of Y-688 per liter, while 78, 100, 89, and 98% of gram-negative bacilli (n = 135), gram-positive cocci (n = 59), and non-spore-forming (n = 58) and spore-forming (n = 51) gram-positive bacilli, respectively, were inhibited by < or = 1 mg of Y-688 per liter.

Anti-Infective Agents↗
PubMed1998

Continuous infusion of beta-lactam antibiotics.

There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins. Penicillins do not exert concentration-dependent killing in the therapeutic range but have a post-antibiotic effect (PAE) against Gram-positive cocci but not Gram-negative rods. Animal models indicate the time (T) during which the serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen [T > MIC] determines outcomes. Pharmacokinetic studies in humans indicate that continuous infusion with penicillins is possible but there are no clinical data on efficacy. Cephalosporins have similar pharmacodynamic properties to penicillins; T > MIC determines outcome. Data related to ceftazidime indicate that the drug concentration at steady-state (Css) should exceed the pathogen MIC by > 1-fold and perhaps by 4- to 5-fold or more. Human pharmacokinetics of ceftazidime administered by continuous infusion to a wide variety of patient groups indicates that Css of > 20 mg/L can easily be achieved using conventional daily doses. Clinical data indicate increased effectiveness of a continuous regimen in neutropenic patients with Gram-negative infection. Furthermore cefuroxime administration by continuous infusion has resulted in lower doses and shorter course durations. Little is known of the pharmacodynamics of monobactams and there are few clinical data on continuous infusion therapy. Carbapenems have different pharmacodynamics to other beta-lactams as they have concentration-dependent killing and a PAE with both Gram-positive and Gram-negative bacteria. While T > MIC has a role in determining outcomes, the proportion of the dosing interval for which serum drug concentrations should exceed the pathogen MIC is less than for other beta-lactams. In vitro models have shown that continuous infusion is effective, as is less frequent dosing. There are few data on continuous infusion of carbapenems but some patients have been treated with once-daily dosing. Clinically, continuous infusion therapy with penicillins and cephalosporins should be considered in patients infected with susceptible Gram-negative rods not responding to conventional therapy. As an approximation, the same total daily dose should be given but a bolus intravenous injection should be give at the start of continuous infusion to ensure Css is reached rapidly. The Css may be difficult to predict and determination of serum drug concentrations may be indicated. Ideally, the Css should be calculated based on the MIC of the potential pathogen and may be higher or lower than the Css achieved by a conventional daily dose.

Animals↗
PubMed1997

Salt tolerance of EMRSA-16 and its effect on the sensitivity of screening cultures.

The salt (NaCl) tolerance of methicillin-resistant Staphylococcus aureus (EMRSA)-16 was compared with 18 other MRSA isolates by an agar incorporation technique. The NaCl minimum inhibitory concentration (MIC) of EMRSA-16 was 7% which compared with an MIC50 of 7%, MIC90 of 10%, range (5.5-10.5%) for the other isolates. Study of the growth kinetics in broth containing NaCl at concentrations up to 10% indicated complete inhibition of growth by 7 and 10% NaCl and partial inhibition by 5%. Addition of EMRSA-16 at inocula of < or = 1 cfu/mL into salt broths revealed lower than expected EMRSA recovery from broths containing 5, 7.5 and 10% NaCl. Two and a half per cent NaCl broths were not inhibitory. Selective broth containing 2.5% NaCl should be considered for use when screening for EMRSA-16.

Culture Media↗
PubMed1997

A comparison of the penetration of cefuroxime and cephamandole into bone, fat and haematoma fluid in patients undergoing total hip replacement.

Twelve patients undergoing total hip anthroplasty received, at the induction of anaesthesia, cephamandole (1 g) and cefuroxime (1.5 g); further doses of cephamandole (1 g) and cefuroxime (750 mg) were given at 8 and 16 h after the operation. Routine total hip arthroplasty was performed and at timed intervals during operation samples of bone, fat and blood were collected for assay for HPLC analysis. Samples of the haematoma fluid that formed around the operation site and further blood samples were also collected at 7 and 15 h after the operation. Although considerable variation was observed in the bone and fat concentrations of both agents, the cefuroxime levels were substantially higher than those of cephamandole, with mean values for bone of cefuroxime 36.0 mg/L (95% CI 29.0-43.0 mg/L) and cephamandole 18.3 mg/L (95% CI 14.2-22.4 mg/L) and for fat of cefuroxime 15.0 mg/L (95% CI 11.1-18.9 mg/L) and cephamandole 11.2 mg/L (95% CI 7.2-15.2 mg/L). When corrected for blood concentrations the penetration of both agents was similar (bone, 43.6% cefuroxime and 37.8% cephamandole; fat, 16.0% cefuroxime and 19.2% cephamandole). Cefuroxime concentrations in haematoma drain fluid were higher than those of cephamandole 6-8 h after the operation (17.8 versus 8.3 mg/L) but lower at 14-16 h (7.7 versus 9.6 mg/L). We conclude that there are no significant differences between the bone, fat or haematoma penetration of cefuroxime and cephamandole and that any differences in the absolute levels of the two agents are due to differences in the total drug administered rather than their ability to penetrate into these sites. Time-kill curves for cefuroxime and cephamandole against five clinical isolates of Staphylococcus aureus failed to identify any significant differences between the rates of kill for the two agents at the concentrations seen in bone, fat or haematoma fluid. For both prophylaxis regimens antibiotic concentrations exceeded the MICs for potential pathogens for the duration of the operation and also in the haematoma which surrounds the operation site for up to 24 h after the operation.

Adipose Tissue↗