Publications by authors named "Alasdair P MacGowan"

57 Publications

Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study.

Open Forum Infect Dis 2021 Dec 18;8(12):ofab573. Epub 2021 Dec 18.

National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, London, UK.

This healthy volunteer study aimed to explore phenoxymethylpenicillin (penicillin-V) pharmacokinetics (PK) to support the planning of large dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentrations were determined, and a base population PK model was fitted to the data.
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http://dx.doi.org/10.1093/ofid/ofab573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684501PMC
December 2021

Limited phylogenetic overlap between fluoroquinolone-resistant Escherichia coli isolated on dairy farms and those causing bacteriuria in humans living in the same geographical region.

J Antimicrob Chemother 2021 11;76(12):3144-3150

School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.

Background: Our primary aim was to test whether cattle-associated fluoroquinolone-resistant (FQ-R) Escherichia coli found on dairy farms are closely phylogenetically related to those causing bacteriuria in humans living in the same 50 × 50 km geographical region suggestive of farm-human sharing. Another aim was to identify risk factors for the presence of FQ-R E. coli on dairy farms.

Methods: FQ-R E. coli were isolated during 2017-18 from 42 dairy farms and from community urine samples. Forty-two cattle and 489 human urinary isolates were subjected to WGS, allowing phylogenetic comparisons. Risk factors were identified using a Bayesian regularization approach.

Results: Of 489 FQ-R human isolates, 255 were also third-generation-cephalosporin-resistant, with strong genetic linkage between aac(6')Ib-cr and blaCTX-M-15. We identified possible farm-human sharing for pairs of ST744 and ST162 isolates, but minimal core genome SNP distances were larger between farm-human pairs of ST744 and ST162 isolates (71 and 63 SNPs, respectively) than between pairs of isolates from different farms (7 and 3 SNPs, respectively). Total farm fluoroquinolone use showed a positive association with the odds of isolating FQ-R E. coli, while total dry cow therapy use showed a negative association.

Conclusions: This work suggests that FQ-R E. coli found on dairy farms have a limited impact on community bacteriuria within the local human population. Reducing fluoroquinolone use may reduce the on-farm prevalence of FQ-R E. coli and this reduction may be greater when dry cow therapy is targeted to the ecology of resistant E. coli on the farm.
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http://dx.doi.org/10.1093/jac/dkab310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598280PMC
November 2021

Trade-Offs between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamases by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting.

Antimicrob Agents Chemother 2021 07 16;65(8):e0241220. Epub 2021 Jul 16.

School of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom.

Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the family , NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show that consistently confers meropenem resistance in wild-type , but does not. The reason is higher expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of -positive . In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a mutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.
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http://dx.doi.org/10.1128/AAC.02412-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284430PMC
July 2021

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents.

Clin Pharmacokinet 2020 10;59(10):1195-1216

University of Queensland Centre for Clinical Research, Faculty of Medicine and Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.
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http://dx.doi.org/10.1007/s40262-020-00924-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385074PMC
October 2020

Methodological features of clinical pharmacokinetic-pharmacodynamic studies of antibacterials and antifungals: a systematic review.

J Antimicrob Chemother 2020 06;75(6):1374-1389

Bristol Centre for Antimicrobial Research & Evaluation, Infection Sciences, Pathology Science Quarter, North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.

Background: Pharmacokinetic (PK)-pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK-PD studies aim to correlate PK-PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK-PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings.

Objectives: To describe the methodological features of clinical antibacterial and antifungal PK-PD studies that reported the relationship between PK-PD indices and clinical or microbiological responses.

Methods: Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted.

Results: We identified 85 publications containing 97 PK-PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK-PD-outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK-PD index and outcome. Target values of PK-PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression.

Conclusions: Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.
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http://dx.doi.org/10.1093/jac/dkaa005DOI Listing
June 2020

Characterization of cefotaxime-resistant urinary Escherichia coli from primary care in South-West England 2017-18.

J Antimicrob Chemother 2020 01;75(1):65-71

School of Cellular & Molecular Medicine, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK.

Objectives: Third-generation cephalosporin-resistant Escherichia coli from community-acquired urinary tract infections are increasingly reported worldwide. We sought to determine and characterize the mechanisms of cefotaxime resistance employed by urinary E. coli obtained from primary care, over 12 months, in Bristol and surrounding counties in South-West England.

Methods: Cefalexin-resistant E. coli isolates were identified from GP-referred urine samples using disc susceptibility testing. Cefotaxime resistance was determined by subsequent plating onto MIC breakpoint plates. β-Lactamase genes were detected by PCR. WGS was performed on 225 isolates and analyses were performed using the Center for Genomic Epidemiology platform. Patient information provided by the referring general practices was reviewed.

Results: Cefalexin-resistant E. coli (n=900) isolates were obtained from urines from 146 general practices. Following deduplication by patient approximately 69% (576/836) of isolates were cefotaxime resistant. WGS of 225 isolates identified that the most common cefotaxime-resistance mechanism was blaCTX-M carriage (185/225), followed by plasmid-mediated AmpCs (pAmpCs) (17/225), AmpC hyperproduction (13/225), ESBL blaSHV variants (6/225) or a combination of both blaCTX-M and pAmpC (4/225). Forty-four STs were identified, with ST131 representing 101/225 isolates, within which clade C2 was dominant (54/101). Ciprofloxacin resistance was observed in 128/225 (56.9%) of sequenced isolates, predominantly associated with fluoroquinolone-resistant clones ST131 and ST1193.

Conclusions: Most cefalexin-resistant E. coli isolates were cefotaxime resistant, predominantly caused by blaCTX-M carriage. The correlation between cefotaxime resistance and ciprofloxacin resistance was largely attributable to the high-risk pandemic clones ST131 and ST1193. Localized epidemiological data provide greater resolution than regional data and can be valuable for informing treatment choices in the primary care setting.
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http://dx.doi.org/10.1093/jac/dkz397DOI Listing
January 2020

Pharmacodynamics of plazomicin and a comparator aminoglycoside, amikacin, studied in an in vitro pharmacokinetic model of infection.

Int J Antimicrob Agents 2019 Nov 9;54(5):626-632. Epub 2019 Jul 9.

Bristol Centre for Antimicrobial Research & Evaluation (BCARE), Severn Infection Sciences Partnership, Southmead Hospital, Bristol BS10 5NB, UK. Electronic address:

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 ≥ 0.8302; amikacin R ≥ 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.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.07.001DOI Listing
November 2019

Antibacterial effect of imipenem/relebactam on aerobic Gram-negative bacilli: in vitro simulations of 7 or 14 day human exposures.

J Antimicrob Chemother 2019 07;74(7):1945-1951

Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Department of Infection Sciences, Pathology Sciences Building - Phase 2, Science Quarter, Southmead Hospital, Westbury-on-Trym, Bristol, UK.

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.
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http://dx.doi.org/10.1093/jac/dkz114DOI Listing
July 2019

Doxycycline in UK guidelines for hospital-acquired pneumonia: where is the evidence base?-authors' response.

J Antimicrob Chemother 2019 06;74(6):1767

Southmead Hospital, North Bristol NHS Trust, Bristol, UK.

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http://dx.doi.org/10.1093/jac/dkz105DOI Listing
June 2019

Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE's STAT-Net.

Clin Infect Dis 2018 11;67(12):1922-1931

Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Switzerland.

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.
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http://dx.doi.org/10.1093/cid/ciy516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260160PMC
November 2018

Doxycycline in UK guidelines for hospital-acquired pneumonia: where is the evidence base?

J Antimicrob Chemother 2018 11;73(11):3212-3215

British Society for Antimicrobial Chemotherapy, Birmingham, UK.

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http://dx.doi.org/10.1093/jac/dky306DOI Listing
November 2018

Antibacterial effect of ceftolozane/tazobactam in combination with amikacin against aerobic Gram-negative bacilli studied in an in vitro pharmacokinetic model of infection.

J Antimicrob Chemother 2018 09;73(9):2411-2417

Bristol Centre for Antimicrobial Research & Evaluation, North Bristol NHS Trust, Department of Infection Sciences, Pathology Sciences Building Phase 2, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.

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.
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http://dx.doi.org/10.1093/jac/dky225DOI Listing
September 2018

Pharmacodynamics of inhaled amikacin (BAY 41-6551) studied in an in vitro pharmacokinetic model of infection.

J Antimicrob Chemother 2018 05;73(5):1305-1313

Bristol Centre for Antimicrobial Research & Evaluation (BCARE), Severn Infection Sciences Partnership, Southmead Hospital, Bristol BS10 5NB, UK.

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.
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http://dx.doi.org/10.1093/jac/dky002DOI Listing
May 2018

Prediction of Fluoroquinolone Susceptibility Directly from Whole-Genome Sequence Data by Using Liquid Chromatography-Tandem Mass Spectrometry To Identify Mutant Genotypes.

Antimicrob Agents Chemother 2018 03 23;62(3). Epub 2018 Feb 23.

School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom

Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis, using transformation and mutant selection, of the relative importance of each of these mechanisms for fluoroquinolone nonsusceptibility using as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in clinical isolates. Key to the success of this predictive process was the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquinolone susceptibility.
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http://dx.doi.org/10.1128/AAC.01814-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826109PMC
March 2018

Pharmacodynamics of minocycline against Acinetobacter baumannii studied in a pharmacokinetic model of infection.

Int J Antimicrob Agents 2017 Dec 10;50(6):715-717. Epub 2017 Jul 10.

Bristol Centre for Antimicrobial Research & Evaluation (BCARE), Department of Infection Sciences, Pathology Sciences, North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK. Electronic address:

Minocycline (MNO) is an old antibiotic that may have an important role in the treatment of multidrug-resistant Gram-negative bacterial infections as the burden of such infections increases. In this study, a single-compartment dilutional pharmacokinetic model was used to determine the relationship between MNO exposure and antibacterial effect, including the risk of resistance emergence, against strains of Acinetobacter baumannii. The mean ± standard deviation area under the unbound drug concentration-time curve to minimum inhibitory concentration ratio (fAUC/MIC) associated with a 24-h bacteriostatic effect was 16.4 ± 2.6 and with a -1 log reduction in bacterial load at 24 h was 23.3 ± 3.7. None of the strains reached a -2 log reduction over 48 h. Changes in population profiles were noted for two of the three strains studied, especially at fAUC/MIC ratios of >5-15. A reasonable translational pharmacodynamic target for MNO against A. baumannii could be an fAUC/MIC of 20-25. However, if maximum standard 24-h doses of intravenous MNO are used (400 mg/day), many strains would be exposed to MNO concentrations likely to change population profiles and associated with the emergence of resistance. Either MNO combination therapy or an increased MNO dose (>400 mg/day) should be considered when treating A. baumannii infections.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.06.026DOI Listing
December 2017

Towards better antimicrobial susceptibility testing: impact of the Journal of Antimicrobial Chemotherapy.

J Antimicrob Chemother 2017 02;72(2):323-329

Welsh Antimicrobial Resistance Programme, Public Health Wales, University Hospital of Wales, Cardiff CF14 4XW, UK.

Susceptibility testing of bacteria is one of the most important tests performed in a clinical microbiology laboratory. Improvements in laboratory techniques, especially the move towards standardized susceptibility testing, has provided better consistency and accuracy of testing. When used in conjunction with the most recently developed interpretative criteria, the result is better prediction of the outcome of antimicrobial therapy for infected patients. Throughout the last four decades this Journal has published numerous articles evidencing improvements and new techniques, a valuable source of information for microbiology laboratories.
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http://dx.doi.org/10.1093/jac/dkw494DOI Listing
February 2017

A review of the pharmacokinetics and pharmacodynamics of aztreonam.

J Antimicrob Chemother 2016 10 21;71(10):2704-12. Epub 2016 Jun 21.

Department of Medical Microbiology, Southmead Hospital, Bristol Centre for Antimicrobial Research and Evaluation, Severn Infection Sciences Partnership, Westbury-on-Trym, Bristol BS10 5NB, UK.

The monobactam aztreonam is currently being re-examined as a therapeutic agent in light of the global spread of carbapenem resistance in aerobic Gram-negative bacilli and aztreonam's stability to Ambler class B metallo-β-lactamases. Of particular interest are the pharmacokinetic and pharmacodynamic properties of aztreonam alone and in combination with β-lactamase inhibitors. The choice of inhibitor may vary depending on the spectrum of β-lactamases produced by Enterobacteriaceae. The monobactam ring is also being used to produce new developmental monobactams. Thus, a greater understanding of aztreonam pharmacokinetics and dynamics is of great relevance in drug development. This review summarizes the pharmacokinetic profile of aztreonam in man and its pharmacodynamics in human and pre-clinical studies when studied alone and with β-lactamase inhibitors.
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http://dx.doi.org/10.1093/jac/dkw231DOI Listing
October 2016

Early warning score: a dynamic marker of severity and prognosis in patients with Gram-negative bacteraemia and sepsis.

Ann Clin Microbiol Antimicrob 2016 Apr 12;15:23. Epub 2016 Apr 12.

Lead Public Health Microbiologist-South West of England, North Bristol NHS Trust, University of Bristol, Southmead Hospital, Westbury-on-Trym, Bristol, BS10 5ND, UK.

Background: Early Warning Score (EWS) is a physiological composite score of six bedside vital parameters, routinely used in UK hospitals. We evaluated the prognostic ability of EWS in Gram-negative bacteraemia causing sepsis.

Methods: We prospectively evaluated EWS as a marker of severity and prognosis in adult patients with Gram-negative bacteraemia. All adult patients with Gram-negative bacteraemia admitted to our tertiary Teaching hospital of the National Health Service in England were enrolled over 1 year period. The highest daily EWS score was recorded from 7 days before to 14 days after the date of onset of bacteraemia. The primary outcome was 28-day mortality.

Main Results: A total of 245 consecutive adult patients with Gram-negative bacteraemia with sepsis were enrolled. On multivariate analysis, following variables were associated with death for every single unit change (odds ratio in the brackets): higher age (1.05), lower mean arterial pressure (1.03), lower serum bicarbonate (1.08), higher EWS (1.27), higher SOFA score (1.36), hospital-onset of infection (5.43) and need for vasopressor agents (16.4). EWS on day 0, 1, 2, and average 14-day score were significantly higher in patients who died by 28 days from the onset of bacteraemia [95 % CI 0.4-0.6] p < 0.001. A stepwise rise in EWS and failure of improvement in EWS by 2 points 48 h after the onset of bacteraemia were associated with poor outcome.

Conclusion: EWS is a simple and cost-effective bedside tool for the assessment of severity and prognosis of sepsis caused by Gram-negative bacteraemia.
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http://dx.doi.org/10.1186/s12941-016-0139-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830018PMC
April 2016

Differences in the pharmacodynamics of ceftaroline against different species of Enterobacteriaceae studied in an in vitro pharmacokinetic model of infection.

J Antimicrob Chemother 2016 May 3;71(5):1270-8. Epub 2016 Feb 3.

Bristol Centre for Antimicrobial Research & Evaluation, Department of Medical Microbiology, Lime Walk Building, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.

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.
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http://dx.doi.org/10.1093/jac/dkv480DOI Listing
May 2016

Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection.

Antimicrob Agents Chemother 2016 01 9;60(1):515-21. Epub 2015 Nov 9.

Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom

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.
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http://dx.doi.org/10.1128/AAC.00727-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704154PMC
January 2016

A non-fatal case of hantavirus cardiopulmonary syndrome imported into the UK (ex Panama), July 2014.

J Clin Virol 2015 Jun 8;67:52-5. Epub 2015 Apr 8.

Research Department, Microbiology Services Division, Public Health England, Porton Down, Salisbury, United Kingdom; National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, United Kingdom.

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http://dx.doi.org/10.1016/j.jcv.2015.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451477PMC
June 2015

Ceftaroline in the management of complicated skin and soft tissue infections and community acquired pneumonia.

Ther Clin Risk Manag 2015 7;11:565-79. Epub 2015 Apr 7.

Department of Medical Microbiology, North Bristol NHS Trust, Southmead Hospital, Bristol, England.

Ceftaroline is a new parenteral cephalosporin approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of complicated skin and soft tissue infections (cSSTIs) including those due to methicillin-resistant Staphylococcus aureus (MRSA), and community-acquired pneumonia (CAP). Ceftaroline has broad-spectrum activity against gram-positive and gram-negative bacteria and exerts its bactericidal effects by binding to penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell wall synthesis. It binds to PBP 2a of MRSA with high affinity and also binds to all six PBPs in Streptococcus pneumoniae. In in vitro studies, ceftaroline demonstrated potent activity against Staphylococcus aureus (including MRSA and vancomycin-intermediate isolates), Streptococcus pneumoniae (including multidrug resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, and many common gram-negative pathogens, excluding extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and Pseudomonas aeruginosa. In Phase II and Phase III clinical trials, ceftaroline was noninferior to its comparator agents and demonstrated high clinical cure rates in the treatment of cSSTIs and CAP. It demonstrated favorable outcomes in patients treated for both regulatory-approved indications and unlicensed indications in a retrospective analysis. Ceftaroline is a safe and effective option for treatment in specific patient populations in which its efficacy and safety have been proven. This article reviews the challenges in the treatment of cSSTI and CAP, ceftaroline and its microbiology, pharmacology, efficacy, and safety data which support its use in treatment of cSSTIs and CAP.
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http://dx.doi.org/10.2147/TCRM.S75412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396454PMC
April 2015

In memoriam: William A. Craig.

Antimicrob Agents Chemother 2015 20;59(6):2971. Epub 2015 Apr 20.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1128/AAC.00849-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432111PMC
February 2016

Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection.

Antimicrob Agents Chemother 2013 Jun 4;57(6):2451-6. Epub 2013 Mar 4.

Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Lime Walk Building, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.

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.
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http://dx.doi.org/10.1128/AAC.01386-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716170PMC
June 2013

Pharmacodynamics of the antibacterial effect of and emergence of resistance to doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an in vitro pharmacokinetic model.

Antimicrob Agents Chemother 2012 Oct 19;56(10):5009-15. Epub 2012 Jun 19.

Bristol Centre for Antimicrobial Research & Evaluation, North Bristol NHS Trust.

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.
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http://dx.doi.org/10.1128/AAC.06111-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457408PMC
October 2012

Pharmacodynamics of razupenem (PZ601) studied in an in vitro pharmacokinetic model of infection.

Antimicrob Agents Chemother 2011 Apr 24;55(4):1436-42. Epub 2011 Jan 24.

BCARE, Department of Medical Microbiology, Lime Walk Building, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom.

Simulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in an in vitro pharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains of Staphylococcus aureus (one methicillin-sensitive S. aureus [MSSA] strain [MIC, 0.015 μg/ml] and five methicillin-resistant S. aureus [MRSA] strains [MIC range, 0.09 to 3 μg/ml]) and five strains of Enterobacteriaceae (three Escherichia coli strains [two containing extended-spectrum β-lactamases {ESBLs}] and two Enterobacter sp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 μg/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2× MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 μg/ml) and at 120 h with strain 27706 (MIC, 1.5 μg/ml). Against E. coli and Enterobacter spp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 μg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except for Enterobacter strain 34425 (MIC, 6.0 μg/ml), where colonies were recovered from media containing 2×, 4×, and 8× MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% ± 1.4%, and that for a 1-log-unit reduction in count was 12.5% ± 5.8%. Population profiles indicated growth on 2× MIC recovery medium at fT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments with Enterobacteriaceae, the fT>MIC for a 24-h bacteriostatic effect was 34.2% ± 7.6% and that for a 1-log-unit reduction in count was 42.5% ± 7.8%. Population analysis profiles indicated growth on recovery media with 2×, 4×, and 8× MIC at fT>MICs in the range of 1 to 69% but rarely at values of ≥ 70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of ≤ 3.0 μg/ml and Enterobacteriaceae with MICs of ≤ 0.4 μg/ml. fT>MIC targets of ≥ 35% for MRSA and ≥ 70% for Enterobacteriaceae should provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.
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http://dx.doi.org/10.1128/AAC.00936-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067199PMC
April 2011

Pharmacodynamics of telavancin studied in an in vitro pharmacokinetic model of infection.

Antimicrob Agents Chemother 2011 Feb 15;55(2):867-73. Epub 2010 Nov 15.

Bristol Centre for Antimicrobial Research and Evaluation (BCARE), Department of Medical Microbiology, University of Bristol, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.

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.
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http://dx.doi.org/10.1128/AAC.00933-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028790PMC
February 2011

Bacterial strain-to-strain variation in pharmacodynamic index magnitude, a hitherto unconsidered factor in establishing antibiotic clinical breakpoints.

Antimicrob Agents Chemother 2009 Dec 5;53(12):5181-4. Epub 2009 Oct 5.

Bristol Centre for Antimicrobial Research and Evaluation, University of Bristol, North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.

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.
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http://dx.doi.org/10.1128/AAC.00118-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786373PMC
December 2009

Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection.

J Antimicrob Chemother 2009 Nov 16;64(5):1044-51. Epub 2009 Sep 16.

Bristol Centre for Antimicrobial Research and Evaluation, Department of Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, UK.

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.
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http://dx.doi.org/10.1093/jac/dkp289DOI Listing
November 2009
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