25 results on '"Noel, Alan R."'
Search Results
2. Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.
- Author
-
MacGowan AP, Attwood MLG, Noel AR, Barber R, Aron Z, Opperman TJ, Grimsey E, Stone J, Ricci V, and Piddock LJV
- Subjects
- Drug Resistance, Multiple, Bacterial, Anti-Bacterial Agents pharmacology, Ciprofloxacin pharmacology, Microbial Sensitivity Tests, Drug Resistance, Bacterial, Escherichia coli genetics, Chlorpromazine pharmacology
- Abstract
Background: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown., Methods: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine β naphthylamide (PAβN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS., Results: The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAβN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5-1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaβN with CIP AUC, 0.6 mg·h/L PaβN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5-0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA, gyrB or marR., Conclusions: AUC was the pharmacodynamic driver for chlorpromazine and PAβN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAβN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA, gyrB and marR were detected., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
3. Antibacterial effect of seven days exposure to ceftolozane-tazobactam as monotherapy and in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa with ceftolozane-tazobactam MICs at or above 4 mg/l in an in vitro pharmacokinetic model.
- Author
-
Attwood M, Griffin P, Noel AR, Albur M, and Macgowan AP
- Subjects
- Humans, Pseudomonas aeruginosa, Tobramycin pharmacology, Tobramycin therapeutic use, Anti-Bacterial Agents therapeutic use, Cephalosporins therapeutic use, Tazobactam pharmacokinetics, Microbial Sensitivity Tests, Fosfomycin pharmacology, Fosfomycin therapeutic use, Pseudomonas Infections drug therapy, Pseudomonas Infections microbiology
- Abstract
Objectives: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L)., Methods: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h., Results: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin., Conclusions: The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
4. A pilot observational study of CSF vancomycin therapeutic drug monitoring during the treatment of nosocomial ventriculitis.
- Author
-
Arkell P, Wilson R, Antcliffe DB, Gilchrist M, Noel AR, Wilson M, Barnes SC, Watkins K, Holmes A, and Rawson TM
- Subjects
- Anti-Bacterial Agents therapeutic use, Drug Monitoring, Humans, Vancomycin therapeutic use, Cerebral Ventriculitis drug therapy, Cross Infection drug therapy, Encephalitis
- Abstract
Competing Interests: Declaration of Competing Interest TMR has received honoraria from Sandoz (2020), bioMerieux (2021–2022), Roche Diagnostics Ltd (2021). MG has received honoraria from Sandoz (2020), Pfizer (2021). All other authors have no conflicts of interest to declare.
- Published
- 2022
- Full Text
- View/download PDF
5. Comparative bactericidal activity of representative β-lactams against Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa.
- Author
-
Noel AR, Attwood M, Bowker KE, MacGowan AP, and Albur M
- Subjects
- Anti-Bacterial Agents pharmacology, Aztreonam pharmacology, Carbapenems, Ceftazidime pharmacology, Cephalosporins pharmacology, Escherichia coli, Klebsiella pneumoniae, Meropenem pharmacology, Microbial Sensitivity Tests, Monobactams, Piperacillin pharmacology, Pseudomonas aeruginosa, Tazobactam, beta-Lactams pharmacology, Acinetobacter baumannii
- Abstract
Background: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of β-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way., Objectives: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa., Methods: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu·h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded., Results: Against E. coli and K. pneumoniae meropenem had a maximal ABE at ≥MIC × 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at ≥MIC × 4 and aztreonam at ≥MIC × 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8×/16 × MIC. Other β-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at ≥MIC × 4, concentration changes in population profiles were least apparent with E. coli., Conclusions: β-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of β-lactam to another is not justified., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
6. Lessons from isavuconazole therapeutic drug monitoring at a United Kingdom Reference Center.
- Author
-
Borman AM, Hughes JM, Oliver D, Fraser M, Sunderland J, Noel AR, and Johnson EM
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Sex Factors, United Kingdom, Young Adult, Antifungal Agents therapeutic use, Drug Monitoring, Drug-Related Side Effects and Adverse Reactions, Mycoses drug therapy, Nitriles blood, Nitriles therapeutic use, Pyridines blood, Pyridines therapeutic use, Serum chemistry, Triazoles blood, Triazoles therapeutic use
- Abstract
We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks., (© Crown copyright 2020.)
- Published
- 2020
- Full Text
- View/download PDF
7. Pharmacodynamics of plazomicin and a comparator aminoglycoside, amikacin, studied in an in vitro pharmacokinetic model of infection.
- Author
-
Noel AR, Attwood M, Bowker KE, Kim A, Krause KM, and MacGowan AP
- Subjects
- Bacterial Load drug effects, Drug Resistance, Multiple, Bacterial physiology, Escherichia coli Infections drug therapy, Humans, Klebsiella Infections drug therapy, Microbial Sensitivity Tests, Sisomicin pharmacokinetics, Sisomicin pharmacology, Amikacin pharmacokinetics, Amikacin pharmacology, Anti-Bacterial Agents pharmacokinetics, Escherichia coli drug effects, Klebsiella pneumoniae drug effects, Sisomicin analogs & derivatives
- Abstract
The new aminoglycoside plazomicin shows in vitro potency against multidrug-resistant Enterobacteriales. The exposure-response relationship of plazomicin and the comparator aminoglycoside amikacin was determined for Escherichia coli, while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic model was used. Five E. coli strains (two meropenem-resistant) and five K. pneumoniae strains (two meropenem-resistant) with plazomicin MICs of 0.5-4 mg/L were used. Antibacterial effect was assessed by changes in bacterial load and bacterial population profile. The correlation between change in initial inoculum after 24 h of drug exposure and the AUC/MIC ratio was good (plazomicin R
2 ≥ 0.8302; amikacin R2 ≥ 0.9520). Escherichia coli plazomicin AUC/MIC ratios for 24-h static, -1, -2 and -3 log drop were 36.1 ± 18.4, 39.3 ± 20.9, 41.2 ± 21.9 and 44.8 ± 24.3, respectively, and for amikacin were 49.5 ± 12.7, 55.7 ± 14.8, 64.1 ± 19.2 and 73.3 ± 25.3. Klebsiella pneumoniae plazomicin AUC/MIC ratios for 24-h static, -1, -2 and -3 log drop were 34.0 ± 15.2, 46.8 ± 27.8, 67.4 ± 46.5 and 144.3 ±129.8. Plazomicin AUC/MIC ratios >66 and amikacin AUC/MIC ratios >57.7 were associated with suppression of E. coli growth on 4 × or 8 × MIC recovery plates. The equivalent plazomicin AUC/MIC to suppress resistance emergence with K. pneumoniae was >132. The plazomicin AUC/MIC for 24-h static effect and -1 log reduction in E. coli and K. pneumoniae bacterial load was in the range 30-60. Plazomicin AUC/MIC targets aligned with those of amikacin for E. coli., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
8. Antibacterial effect of imipenem/relebactam on aerobic Gram-negative bacilli: in vitro simulations of 7 or 14 day human exposures.
- Author
-
Noel AR, Bowker KE, Attwood M, and MacGowan AP
- Subjects
- Computer Simulation, Dose-Response Relationship, Drug, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology, Humans, Microbial Sensitivity Tests, Time Factors, Anti-Bacterial Agents pharmacology, Azabicyclo Compounds pharmacology, Gram-Negative Bacteria drug effects, Imipenem pharmacology
- Abstract
Objectives: We assessed the antibacterial effect of human simulations of dosing with imipenem/relebactam (with or without amikacin) on Enterobacteriaceae or Pseudomonas aeruginosa over 7 or 14 day antibiotic exposures., Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and population profiles., Results: Imipenem/relebactam produced an initial >4 log drop in viable counts followed by suppression for 7 days for Enterobacteriaceae whether the strain was WT, produced KPC enzymes or produced an AmpC enzyme with porin loss. Similarly, with the P. aeruginosa strains, there was an initial >4 log clearance over the first 24 h irrespective of whether the strain was WT, hyperexpressed AmpC or had OprD mutation with porin loss. However, with three of four strains there was modest regrowth over the 7 days. There were no changes in imipenem/relebactam MICs over the 7 days. Addition of amikacin in 7 day simulations resulted in more suppression of pseudomonal growth. In 14 day simulations with P. aeruginosa there was regrowth to 8 log10 by 14 days with imipenem/relebactam alone and associated increases in MICs. Addition of amikacin resulted in clearance from the model and prevented changes in population profiles., Conclusions: Imipenem/relebactam was highly effective at reducing the bacterial load of Enterobacteriaceae and there was no emergence of resistance. Against P. aeruginosa, the initial bacterial burden was also rapidly reduced, but there was subsequent regrowth, especially after 7 days of exposure. Addition of amikacin increased the clearance of P. aeruginosa and prevented emergence of resistance., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
9. Antibacterial effect of ceftolozane/tazobactam in combination with amikacin against aerobic Gram-negative bacilli studied in an in vitro pharmacokinetic model of infection.
- Author
-
Noel AR, Bowker KE, Attwood M, and MacGowan AP
- Subjects
- Amikacin pharmacokinetics, Amikacin pharmacology, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Bacterial Load, Cephalosporins pharmacokinetics, Cephalosporins pharmacology, Drug Therapy, Combination methods, Gram-Negative Bacteria growth & development, Meropenem administration & dosage, Meropenem pharmacokinetics, Meropenem pharmacology, Microbial Sensitivity Tests, Microbial Viability drug effects, Models, Theoretical, Tazobactam pharmacokinetics, Tazobactam pharmacology, beta-Lactamase Inhibitors pharmacokinetics, beta-Lactamase Inhibitors pharmacology, Amikacin administration & dosage, Anti-Bacterial Agents administration & dosage, Cephalosporins administration & dosage, Gram-Negative Bacteria drug effects, Gram-Negative Bacterial Infections drug therapy, Tazobactam administration & dosage, beta-Lactamase Inhibitors administration & dosage
- Abstract
Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa., Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL·h) and growth on 4 × MIC recovery plates were the co-primary outcome measures., Results: Simulations of ceftolozane/tazobactam at 1 g/0.5 g or 2 g/1 g q8h or meropenem 2 g q8h all produced a >4 log reduction in bacterial load of Escherichia coli. Meropenem had smaller AUBKC values, indicating greater reduction in bacterial load than ceftolozane/tazobactam. Meropenem was also more effective than ceftolozane/tazobactam against Klebsiella pneumoniae strains. All regimens were equally effective in reducing P. aeruginosa bacterial load measured by AUBKC but growth on 4 × MIC recovery plates and changes in population profiles were only seen with meropenem. Addition of amikacin at 15 mg/kg q24h or 7.5 mg/kg q12h to 2 g/1 g of ceftolozane/tazobactam produced greater reductions in bacterial load but generated changes in amikacin population profiles with the 7.5 mg/kg q12h amikacin simulation., Conclusions: The doses of ceftolozane/tazobactam simulated were highly effective in reducing the bacterial load of E. coli (MIC ≤0.25 mg/L), but less so for K. pneumoniae (MIC 4 mg/L). For both species, meropenem produced an overall greater reduction in pathogen load. Ceftolozane/tazobactam and meropenem were equally effective as monotherapy against P. aeruginosa but emergence of resistance occurred with meropenem. Addition of amikacin to ceftolozane/tazobactam reduced the bacterial load of P. aeruginosa at the expense of emergence of resistance to amikacin.
- Published
- 2018
- Full Text
- View/download PDF
10. Pharmacodynamics of inhaled amikacin (BAY 41-6551) studied in an in vitro pharmacokinetic model of infection.
- Author
-
Bowker KE, Noel AR, Tomaselli S, Attwood M, and MacGowan AP
- Subjects
- Administration, Inhalation, Amikacin administration & dosage, Anti-Bacterial Agents administration & dosage, Escherichia coli drug effects, Humans, Klebsiella pneumoniae drug effects, Microbial Sensitivity Tests, Models, Statistical, Models, Theoretical, Pseudomonas aeruginosa drug effects, Amikacin pharmacokinetics, Amikacin pharmacology, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology
- Abstract
Background: The pharmacodynamics of inhaled antimicrobials are poorly studied. Amikacin is being developed for inhalational therapy as BAY 41-6551., Objectives: We employed an in vitro pharmacokinetic model to study the pharmacokinetics/pharmacodynamics of amikacin., Methods: A dose-ranging design was used to establish fAUC/MIC and fCmax/MIC targets for static, -1 log drop and -2 log drop effects for strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. We then modelled epithelial lining fluid (ELF) concentration associated with inhaled amikacin (400 mg every 12 h), over 5 days using mean human concentrations., Results: The 24 h static effect fAUC/MIC targets and -1 log drop targets were 51.0 ± 26.7 and 71.6 ± 27.6 for all species of aerobic Gram-negative bacilli. fAUC/MIC targets for static effect, -1 log drop or -2 log drop were smaller than the 24 h values at 12 h and larger at 48 h. Emergence of resistance occurred maximally with E. coli in the fAUC/MIC range 12-60; K. pneumoniae 0-60 (48 h) and P. aeruginosa 12-80. When human ELF concentrations were modelled for strains with MIC ≤8 mg/L, there was rapid clearance and no regrowth. For strains with MIC ≥32 mg/L, there was initial clearance followed by regrowth. If MIC values were related to bacterial clearance then at least a static effect or -1 log drop in count would be expected for bacterial strains with MICs of ≤180 mg/L (static effect) or ≤148 mg/L (-1 log drop effect)., Conclusions: An fAUC/MIC amikacin target of 50-80 is appropriate for aerobic Gram-negative bacilli and mean ELF concentrations of BAY 41-6551 would produce a static to -1 log clearance with strains up to 128 mg/L.
- Published
- 2018
- Full Text
- View/download PDF
11. Differences in the pharmacodynamics of ceftaroline against different species of Enterobacteriaceae studied in an in vitro pharmacokinetic model of infection.
- Author
-
Bowker KE, Noel AR, Tomaselli S, and MacGowan AP
- Subjects
- Anti-Bacterial Agents administration & dosage, Cephalosporins administration & dosage, Colony Count, Microbial, Enterobacteriaceae Infections microbiology, Humans, Microbial Sensitivity Tests, Microbial Viability drug effects, Models, Biological, Models, Theoretical, Ceftaroline, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Cephalosporins pharmacokinetics, Cephalosporins pharmacology, Enterobacteriaceae drug effects, Enterobacteriaceae Infections drug therapy
- Abstract
Objectives: Dose-ranging experiments were performed to study the pharmacodynamics of ceftaroline against Enterobacteriaceae., Methods: A range of fT>MIC values (0%-100%) were simulated over 96 h using a single-compartment dilutional in vitro pharmacokinetic model using Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter koseri and Serratia marcescens (n = 16). Antibacterial effect was assessed by change in viable count and population profiles by growth on ceftaroline MIC ×2, ×4 and ×8 agar plates. The fT>MIC (%) was related to antibacterial effect using a sigmoid Emax model., Results: The 24 h bacteriostatic effect fT>MIC was 39.7% ± 15.7% and 43.2% ± 15.6% for a -1 log drop for all strains. E. coli required lower exposures than K. pneumoniae, i.e. 24 h fT>MIC for a -3 log drop in viable count was 40.0% ± 9.6% and 84.8% ± 15.2% for K. pneumoniae. Similarly at 96 h, fT>MIC was >100% for K. pneumoniae (for four of five strains), 27.2%-66.2% for E. coli and 16.2%-86.6% for P. mirabilis. Strain-to-strain variation within species in the fT>MIC for static and cidal effect was marked; the 24 h bacteriostatic range was 14.1%-73.4% for P. mirabilis, 34.2%-44.6% for E. coli and 42.2%-62.5% for K. pneumoniae. Changes in ceftaroline population analysis profiles were observed with E. coli, K. pneumoniae and C. koseri, especially at fT>MIC values just below the bacteriostatic effect exposures., Conclusions: The pharmacodynamics of ceftaroline against the species within the Enterobacteriaceae group are different. K. pneumoniae requires higher drug exposures than E. coli, and P. mirabilis strains are highly variable, which may have important clinical correlates. Translational extrapolations from preclinical observations using E. coli to other Enterobacteriaceae species may not be optimal., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
12. Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection.
- Author
-
MacGowan AP, Noel AR, Tomaselli SG, Nicholls D, and Bowker KE
- Subjects
- Anti-Bacterial Agents pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bioreactors, Cephalosporins pharmacology, Chromatography, High Pressure Liquid, Colony Count, Microbial, Computer Simulation, Escherichia coli enzymology, Escherichia coli genetics, Gene Expression, Half-Life, Infusion Pumps, Microbial Sensitivity Tests, Penicillanic Acid pharmacokinetics, Penicillanic Acid pharmacology, Porins genetics, Porins metabolism, Pseudomonas aeruginosa enzymology, Pseudomonas aeruginosa genetics, Tazobactam, beta-Lactamases genetics, beta-Lactamases metabolism, Anti-Bacterial Agents pharmacokinetics, Cephalosporins pharmacokinetics, Escherichia coli drug effects, Models, Statistical, Penicillanic Acid analogs & derivatives, Pseudomonas aeruginosa drug effects
- Abstract
Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam-β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC β-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
13. Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection.
- Author
-
MacGowan AP, Noel AR, Tomaselli S, and Bowker KE
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Cephalosporins pharmacology, Cephalosporins therapeutic use, Colony Count, Microbial, Humans, Methicillin pharmacology, Methicillin-Resistant Staphylococcus aureus growth & development, Microbial Sensitivity Tests, Models, Biological, Staphylococcus aureus growth & development, Ceftaroline, Anti-Bacterial Agents pharmacokinetics, Cephalosporins pharmacokinetics, Methicillin-Resistant Staphylococcus aureus drug effects, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects
- Abstract
An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT(MIC)) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a -1-log-unit drop, and one of 32.1% ± 8.1% was associated with a -2-log-unit drop. The MSSA and MRSA strains had similar fT(MIC) values. fT(MIC) values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT(MIC). fT(MIC)s of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of ≤ 2 μg/ml. An fT(MIC) of 25 to 30% would make a suitable pharmacodynamic index target, but fTMIC values of ≥ 50% are needed to suppress the emergence of resistance and require clinical evaluation.
- Published
- 2013
- Full Text
- View/download PDF
14. Pharmacodynamics of the antibacterial effect of and emergence of resistance to doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an in vitro pharmacokinetic model.
- Author
-
Bowker KE, Noel AR, Tomaselli SG, Elliott H, and Macgowan AP
- Subjects
- Doripenem, Microbial Sensitivity Tests, Acinetobacter baumannii drug effects, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Carbapenems pharmacokinetics, Carbapenems pharmacology, Pseudomonas aeruginosa drug effects
- Abstract
An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(MIC)s) required for doripenem to produce a 24-h bacteriostatic effect and a -2-log-unit reduction in viable count were 25% ± 11% and 35% ± 13%, respectively, for P. aeruginosa (MIC range, 0.24 to 3 mg/liter) and 20% ± 11% and 33% ± 12%, respectively, for Acinetobacter spp. (MIC range, 0.45 to 3.0 mg/liter). A T(MIC) of >40 to 50% produced a maximum response with both species at 24 h or 48 h of exposure. After 24 h of exposure to doripenem at a T(MIC) in the range of 12.5 to 37.5%, P. aeruginosa and A. baumannii population profiles revealed mutants able to grow on 4× MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targeting T(MIC)s of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain of P. aeruginosa indicated that changes in population profiles were greatest with multiple exposures at T(MIC) targets of 12.5 or 25%. In contrast, multiple exposures at 37.5% T(MIC) most effectively suppressed total bacterial counts and changes in population profiles. Simulations of human doses of doripenem of 500 mg, 1,000 mg, 2,000 mg, and 3,000 mg every 8 h over 96 h showed marked initial killing up to 6 h but growback thereafter. Changes in population profiles occurred only in the regimen of 500 mg every 8 h against P. aeruginosa but occurred with all dose regimens for A. baumannii strains. A doripenem T(MIC) of ≥40 to 50% is maximally effective in killing P. aeruginosa or A. baumannii and suppressing changes in population profiles in short-term experiments for up to 48 h; however, a T(MIC) of 12.5 to 25% amplifies population changes, especially with exposures every 8 h. In longer-term experiments, up to 96 h, even doripenem doses of 4 to 6 times those used in human studies proved incapable of pathogen eradication and prevention of changes in population profiles. The association of a T(MIC) of 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting.
- Published
- 2012
- Full Text
- View/download PDF
15. Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model.
- Author
-
Baines SD, Noel AR, Huscroft GS, Todhunter SL, O'Connor R, Hobbs JK, Freeman J, Lovering AM, and Wilcox MH
- Subjects
- Acetamides pharmacology, Anti-Bacterial Agents pharmacology, Clostridioides difficile isolation & purification, Clostridium Infections microbiology, Feces microbiology, Humans, In Vitro Techniques, Linezolid, Metronidazole pharmacology, Microbial Sensitivity Tests, Oxazolidinones pharmacology, Acetamides administration & dosage, Anti-Bacterial Agents administration & dosage, Clostridioides difficile drug effects, Clostridium Infections drug therapy, Gastrointestinal Tract microbiology, Oxazolidinones administration & dosage
- Abstract
Objectives: Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI., Methods: MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations., Results: Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing., Conclusions: Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.
- Published
- 2011
- Full Text
- View/download PDF
16. Pharmacodynamics of telavancin studied in an in vitro pharmacokinetic model of infection.
- Author
-
MacGowan AP, Noel AR, Tomaselli S, Elliott HC, and Bowker KE
- Subjects
- Aminoglycosides pharmacology, Anti-Bacterial Agents pharmacology, Culture Media, Enterococcus classification, Enterococcus drug effects, Enterococcus growth & development, Gram-Positive Bacterial Infections drug therapy, Gram-Positive Bacterial Infections microbiology, Humans, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus growth & development, Microbial Sensitivity Tests methods, Staphylococcus aureus drug effects, Staphylococcus aureus growth & development, Teicoplanin administration & dosage, Teicoplanin pharmacokinetics, Teicoplanin pharmacology, Vancomycin administration & dosage, Vancomycin pharmacokinetics, Vancomycin pharmacology, Aminoglycosides administration & dosage, Aminoglycosides pharmacokinetics, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Gram-Positive Cocci drug effects, Models, Biological
- Abstract
The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S. aureus [VISA] strain) and three Enterococcus sp. strains (1 Enterococcus faecalis strain, 1 Enterococcus faecium strain, and 1 vancomycin-resistant E. faecium [VREF] strain) were compared using an in vitro pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus (VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC(24)) and 48 h (AUBKC(48)) in comparison to vancomycin or teicoplanin (P < 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P < 0.05). Against the three Enterococcus spp. tested, telavancin was superior to vancomycin in terms of its AUBKC(24), AUBKC(48), and greater early bactericidal effect (P < 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcus strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcus spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcus spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both S. aureus and Enterococcus spp.
- Published
- 2011
- Full Text
- View/download PDF
17. Bacterial strain-to-strain variation in pharmacodynamic index magnitude, a hitherto unconsidered factor in establishing antibiotic clinical breakpoints.
- Author
-
MacGowan AP, Reynolds R, Noel AR, and Bowker KE
- Subjects
- Anti-Bacterial Agents pharmacology, Area Under Curve, Aza Compounds pharmacology, Fluoroquinolones, Humans, Microbial Sensitivity Tests, Models, Theoretical, Moxifloxacin, Quinolines pharmacology, Staphylococcus aureus drug effects, Anti-Bacterial Agents pharmacokinetics, Aza Compounds pharmacokinetics, Quinolines pharmacokinetics
- Abstract
Antibiotic pharmacodynamic modeling allows variations in pathogen susceptibility and human pharmacokinetics to be accounted for when considering antibiotic doses, potential bacterial pathogen targets for therapy, and clinical susceptibility breakpoints. Variation in the pharmacodynamic index (area-under-the-concentration curve to 24 h [AUC(24)]/MIC; maximum serum concentration of drug in the serum/MIC; time the serum concentration remains higher than the MIC [T > MIC]) is not usually considered. In an in vitro pharmacokinetic model of infection using a dose-ranging design, we established the relationship between AUC(24)/MIC and the antibacterial effect for moxifloxacin against 10 strains of Staphylococcus aureus. The distributions of AUC(24)/MIC targets for 24-h bacteriostatic effect and 1-log, 2-log, and 3-log drops in bacterial counts were used to calculate potential clinical breakpoint values, and these were compared with those obtained by the more conventional approach of taking a single AUC(24)/MIC target. Consideration of the AUC(24)/MIC as a distribution rather than a single value resulted in a lower clinical breakpoint.
- Published
- 2009
- Full Text
- View/download PDF
18. Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection.
- Author
-
Bowker KE, Noel AR, and MacGowan AP
- Subjects
- Anti-Bacterial Agents pharmacokinetics, Daptomycin pharmacokinetics, Humans, Methicillin-Resistant Staphylococcus aureus isolation & purification, Microbial Sensitivity Tests methods, Microbial Viability, Models, Theoretical, Staphylococcal Infections microbiology, Teicoplanin pharmacokinetics, Vancomycin pharmacokinetics, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Teicoplanin pharmacology, Vancomycin pharmacology, Vancomycin Resistance
- Abstract
Objectives: To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint., Methods: Five clinical MRSA isolates held at Southmead Hospital were used (SMH 15841, SMH 40289, SMH 40275, SMH 33922 and SMH 33024) together with a VRSA isolate (SMH 19898); inocula of 10(6) and 10(8) cfu/mL were used. Daptomycin (6 mg/kg once daily), vancomycin (1 g twice daily) and teicoplanin (400 mg once daily) regimens were simulated. ABEs were measured using the 24 h area-under-the-bacterial kill curve (AUBKC) and log change in viable count at 24 h (Delta24). For daptomycin, dose escalation was used to determine the relationship between ABE and AUC/MIC., Results: Daptomycin was bactericidal against the MRSA strains. Daptomycin and vancomycin were active against the VRSA strain; teicoplanin had a static effect. The higher inoculum reduced the ABEs. Analysis of variance (ANOVA) indicated that daptomycin had a superior ABE to teicoplanin and vancomycin. Daptomycin fAUC/MIC was related to AUBKC and Delta24; the fAUC/MIC ratios for a static effect and 1 log and 3 log drop were 37.2 +/- 16.5, 40.6 +/- 17.8 and 49.8 +/- 19.2, respectively., Conclusions: These data define the fAUC/MIC sizes for daptomycin for bacteriostatic and bactericidal ABEs and indicate that a 6 mg/kg dose of daptomycin is superior to vancomycin and teicoplanin against MRSA and VRSA strains.
- Published
- 2009
- Full Text
- View/download PDF
19. Pharmacodynamics of minocycline against Staphylococcus aureus in an in vitro pharmacokinetic model.
- Author
-
Bowker KE, Noel AR, and Macgowan AP
- Subjects
- Area Under Curve, Colony Count, Microbial, Drug Therapy, Combination, Humans, Methicillin-Resistant Staphylococcus aureus growth & development, Microbial Sensitivity Tests standards, Rifampin pharmacokinetics, Rifampin pharmacology, Vancomycin pharmacokinetics, Vancomycin pharmacology, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Minocycline pharmacokinetics, Minocycline pharmacology
- Abstract
Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log(10)-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P < 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r(2) of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and -1-log-unit, -2-log-unit, and -3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.
- Published
- 2008
- Full Text
- View/download PDF
20. Pharmacodynamics of the antibacterial effect and emergence of resistance to tomopenem, formerly RO4908463/CS-023, in an in vitro pharmacokinetic model of Staphylococcus aureus infection.
- Author
-
MacGowan AP, Bowker KE, and Noel AR
- Subjects
- Colony Count, Microbial, Humans, Methicillin pharmacology, Methicillin Resistance, Microbial Sensitivity Tests methods, Microbial Sensitivity Tests standards, Vancomycin administration & dosage, Vancomycin pharmacokinetics, Vancomycin therapeutic use, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents therapeutic use, Carbapenems administration & dosage, Carbapenems pharmacokinetics, Carbapenems therapeutic use, Drug Resistance, Bacterial, Staphylococcus aureus drug effects, Staphylococcus aureus growth & development
- Abstract
The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillin-sensitive S. aureus [MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using S. aureus at a standard inoculum of 10(6) CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10(8) CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10(8) CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (P < 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% +/- 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% +/- 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC24 as ABE was 24.9% +/- 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2x and 4x the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.
- Published
- 2008
- Full Text
- View/download PDF
21. Pharmacodynamics of dalbavancin studied in an in vitro pharmacokinetic system.
- Author
-
Bowker KE, Noel AR, and MacGowan AP
- Subjects
- Anti-Bacterial Agents therapeutic use, Area Under Curve, Dose-Response Relationship, Drug, Drug Resistance, Bacterial, Humans, Microbial Sensitivity Tests, Staphylococcus aureus growth & development, Teicoplanin pharmacokinetics, Teicoplanin pharmacology, Teicoplanin therapeutic use, Vancomycin pharmacology, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Staphylococcus aureus drug effects, Teicoplanin analogs & derivatives
- Abstract
Objectives: The antibacterial effect of dalbavancin was studied against Staphylococcus aureus using stepwise declining concentrations designed to model a range of free drug concentrations observed in human serum., Methods: Initial concentrations ranged from 0.6 to 21 mg/L and experiments were conducted over 240 h. Three vancomycin-susceptible and one vancomycin-intermediate strain of S. aureus were used., Results and Conclusions: Dalbavancin showed non-concentration-dependent killing against the three vancomycin-susceptible strains in the range 3-21 mg/L and the vancomycin-intermediate strain at 15 and 21 mg/L. AUC/MIC could be related to antibacterial effect. The AUC/MIC for a bacteriostatic effect was 36 at 24 h, 55 at 120 h and 100 at 240 h. A larger AUC/MIC was required to produce a 2 log reduction in counts, being 214 at 24 h, 195 at 120 h and 331 at 240 h.
- Published
- 2006
- Full Text
- View/download PDF
22. Pharmacodynamics of moxifloxacin against anaerobes studied in an in vitro pharmacokinetic model.
- Author
-
Noel AR, Bowker KE, and Macgowan AP
- Subjects
- Anti-Bacterial Agents pharmacology, Area Under Curve, Aza Compounds pharmacology, Bacteria, Anaerobic genetics, Bacteroides fragilis drug effects, Clostridium perfringens drug effects, Computer Simulation, Escherichia coli drug effects, Fluoroquinolones, Microbial Sensitivity Tests, Monte Carlo Method, Moxifloxacin, Quinolines pharmacology, Anti-Bacterial Agents pharmacokinetics, Aza Compounds pharmacokinetics, Bacteria, Anaerobic drug effects, Quinolines pharmacokinetics
- Abstract
The antibacterial effects of moxifloxacin against Bacteroides fragilis, Clostridium perfringens, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with Escherichia coli. The AUC/MIC ratios for 50% and 90% effects, using a log CFU drop at 24 h as the antibacterial effect measure, were 34 and 59, respectively, aerobic and 54 and 96, respectively, anaerobic. These values are not significantly different. Dose ranging at AUC/MIC ratios of 9 to 216 against the anaerobes indicated a differing AUC/MIC ABE pattern, and the AUC/MICs for 50% and 90% effects were lower: for B. fragilis, they were 10.5 and 25.7, respectively; for C. perfringens, they were 8.6 and 16.2; and for GPAC, they were 7.3 and 17.4. The maximum-effect log drops were as follows: for B. fragilis, -3.2 +/- 0.2 logs; for C. perfringens, -3.7 +/- 0.1 logs; and for GPAC, -2.5 +/- 0.1 logs. Although the anaerobes were not eradicated, there was no emergence of resistance. Comparison of the ABE of moxifloxacin to that of ertapenem against B. fragilis indicated that moxifloxacin was superior at 24 h and 48 h. In contrast, ertapenem was superior to moxifloxacin against GPAC at 24 h and 48 h and against C. perfringens at 48 h. Both drugs performed equivalently against C. perfringens at 24 h. Monte Carlo simulations using human serum AUC data and an AUC/MIC anaerobe target of 7.5 suggests a >90% target achievement at MICs of <2 mg/liter. This divides the B. fragilis wild-type MIC distribution. The pharmacodynamic properties of moxifloxacin against anaerobes are different than those against aerobic species. The clinical implications of these differences need further exploration.
- Published
- 2005
- Full Text
- View/download PDF
23. Pharmacodynamics of ceftazidime plus the serine beta-lactamase inhibitor AM-112 against Escherichia coli containing TEM-1 and CTX-M-1 beta-lactamases.
- Author
-
Bowker KE, Noel AR, Walsh TR, Rogers CA, and MacGowan AP
- Subjects
- Ceftazidime administration & dosage, Ceftazidime pharmacokinetics, Colony Count, Microbial, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Escherichia coli enzymology, Half-Life, Lactams administration & dosage, Lactams pharmacokinetics, Ceftazidime pharmacology, Enzyme Inhibitors pharmacology, Escherichia coli drug effects, Lactams pharmacology, beta-Lactamase Inhibitors, beta-Lactamases metabolism
- Abstract
A strain of Escherichia coli containing TEM-1 and CTX-M-1 was tested in an in vitro pharmacokinetic model against ceftazidime with and without AM-112, a serine beta-lactamase inhibitor. Ceftazidime alone was less effective than ceftazidime plus AM-112, and a single dose was more effective than three fractionated doses.
- Published
- 2004
- Full Text
- View/download PDF
24. Antibacterial effects of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae strains for which MICs are high, in an in vitro pharmacokinetic model.
- Author
-
MacGowan AP, Noel AR, Rogers CA, and Bowker KE
- Subjects
- Amoxicillin-Potassium Clavulanate Combination pharmacokinetics, Chemistry, Pharmaceutical, Colony Count, Microbial, Culture Media, Drug Resistance, Bacterial, Drug Therapy, Combination pharmacokinetics, Microbial Sensitivity Tests, Amoxicillin-Potassium Clavulanate Combination pharmacology, Drug Therapy, Combination pharmacology, Haemophilus influenzae drug effects, Streptococcus pneumoniae drug effects
- Abstract
The antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection. Five strains of Streptococcus pneumoniae and two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used. The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (Delta24). A high 10(8) CFU/ml and low 10(6) CFU/ml initial inocula were used. Employing the Delta24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC(50)) for S. pneumoniae was in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum. For H. influenzae, the T>MIC EC(50) was 28 to 37%, and the 80% maximum response was 32 to 48% for the Delta24 measure and 20 to 48% for AUBKC. The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula. The S. pneumoniae data were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect. Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs. This is explained by the greater T>MICs of the enhanced formulation. Although resistant to amoxicillin-clavulanate by conventional breakpoints, S. pneumoniae and H. influenzae strains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate.
- Published
- 2004
- Full Text
- View/download PDF
25. Activity of AZD2563, a novel oxazolidinone, against Staphylococcus aureus strains with reduced susceptibility to vancomycin or linezolid.
- Author
-
Howe RA, Wootton M, Noel AR, Bowker KE, Walsh TR, and MacGowan AP
- Subjects
- Drug Resistance, Bacterial genetics, Humans, Linezolid, Microbial Sensitivity Tests, Staphylococcal Infections microbiology, Staphylococcus aureus genetics, Acetamides pharmacology, Anti-Infective Agents pharmacology, Oxazolidinones pharmacology, Staphylococcus aureus drug effects, Vancomycin Resistance genetics
- Abstract
The susceptibilities of clinical vancomycin-intermediate Staphylococcus aureus (VISA), heterogeneous VISA, and laboratory-generated linezolid-resistant S. aureus strains to the new oxazolidinone AZD2563 were assessed by agar dilution MIC determination. All clinical strains were susceptible to linezolid, and the linezolid MICs for them were equal to or twofold higher than those of AZD2563. Cross-resistance with linezolid was seen in laboratory-generated mutants, and for these strains the MIC of AZD2563 was twofold higher than that of linezolid.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.