Archive for July 15, 2015

Reviving old antibiotics

Journal of Antimicrobial Chemotherapy August 2015 V.70 N.8 P.2177-2181

Editor’s Choice

Ursula Theuretzbacher, Françoise Van Bambeke, Rafael Cantón, Christian G. Giske, Johan W. Mouton, Roger L. Nation, Mical Paul, John D. Turnidge, and Gunnar Kahlmeter

1Center for Anti-Infective Agents, Vienna, Austria

2Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium

3Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Biomédica (IRYCIS), Madrid, Spain

4Clinical Microbiology, L2:02, Karolinska University Hospital, Solna, Stockholm, Sweden

5Department of Laboratory Medicine (LABMED), Division of Clinical Microbiology, Karolinska Institutet, Huddinge, Sweden

6Department of Medical Microbiology and Infectious Diseases Erasmus MC, Rotterdam, The Netherlands

7Department of Medical Microbiology, Radboudumc Radboud University, Nijmegen, The Netherlands

8Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

9Division of Infectious Diseases, Rambam Health Care Campus and Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

10School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

11Department of Clinical Microbiology, Central Hospital, Växjö, Sweden

12Department of Medical Sciences, Division of Clinical Bacteriology, Uppsala University, Uppsala, Sweden

*Corresponding author. Center for Anti-Infective Agents, Eckpergasse 13, 1180 Vienna, Austria. Tel: +43-14797024; E-mail: utheuretzbacher@cefaia.com

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed.

One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents.

Strategies are urgently needed to ‘re-develop’ these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside.

Without a systematic approach to re-developing these old drugs and rigorously testing them according to today’s standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance.

This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

PDF

http://jac.oxfordjournals.org/content/70/8/2177.full.pdf+html

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July 15, 2015 at 8:33 am

Within-host diversity of MRSA antimicrobial resistances

Journal of Antimicrobial Chemotherapy August 2015 V.70 N.8 P.2191-2198

Kinga I. Stanczak-Mrozek, Anusha Manne, Gwenan M. Knight, Katherine Gould, Adam A. Witney, and Jodi A. Lindsay

1Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK

2Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK

*Corresponding author. Tel: +44-(0)208-725-0445; E-mail: jlindsay@sgul.ac.uk

Objectives

MRSA is a major antimicrobial resistance (AMR) pathogen. The reservoir of infecting isolates is colonization, which is the site of evolutionary selection. The aim was to identify if AMRs in colonizing MRSA populations diversified and potential mechanisms of resistance gene transfer in vivo.

Methods

Nasal swabs from 38 MRSA carriers admitted to hospital were plated and 20 individual colonies from each patient tested for phenotypic antibiotic susceptibility and genetically for lineage, carriage of four prophages and three plasmid families. Free bacteriophages were detected in swabs as well as their capacity for transducing resistance genes.

Results

Nine (24%) patients carried phenotypic AMR variants and 24 (63%) carried prophage and plasmid variants. If a single colony was selected for testing, the probability of detecting all AMR in that patient was 87%. Sixty-four different AMR and mobile genetic element (MGE) profiles were detected, mostly in the MRSA CC22 background (where CC stands for clonal complex), with up to 8 profiles per patient. Nearly half of the patients carried detectable free bacteriophages and phages successfully transduced resistance genes between laboratory and patient isolates in vitro. WGS showed MRSA core genomes were stable, while AMR and MGEs varied.

Conclusions

‘Clouds’ of MRSA variants that have acquired or lost AMR and MGEs are common in nasal colonizing populations and bacteriophages may play an important role in gene transfer. Accurate estimation of AMR and genetic variability has implications for diagnostics, epidemiology, antimicrobial stewardship and understanding the evolutionary selection of AMR in colonizing populations.

PDF

http://jac.oxfordjournals.org/content/70/8/2191.full.pdf+html

 

July 15, 2015 at 8:31 am

Parallel evolutionary pathways to antibiotic resistance selected by biocide exposure

Journal of Antimicrobial Chemotherapy August 2015 V.70 N.8 P.2241-2248

Mark A. Webber, Rebekah N. Whitehead, Manuella Mount, Nick J. Loman, Mark J. Pallen, and Laura J. V. Piddock

1Antimicrobials Research Group, School of Immunity and Infection and Institute for Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK

2School of Bioscience and Institute for Microbiology & Infection, College of Life and Environmental Sciences, University of Birmingham, Birmingham B15 2TT, UK

3Division of Microbiology and Infection, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK

*Corresponding author. Tel: +0121-414-2859; E-mail: m.a.webber@bham.ac.uk

Objectives

Biocides are widely used to prevent infection. We aimed to determine whether exposure of Salmonella to various biocides could act as a driver of antibiotic resistance.

Methods

Salmonella enterica serovar Typhimurium was exposed to four biocides with differing modes of action. Antibiotic-resistant mutants were selected during exposure to all biocides and characterized phenotypically and genotypically to identify mechanisms of resistance.

Results

All biocides tested selected MDR mutants with decreased antibiotic susceptibility; these occurred randomly throughout the experiments. Mutations that resulted in de-repression of the multidrug efflux pump AcrAB-TolC were seen in MDR mutants. A novel mutation in rpoA was also selected and contributed to the MDR phenotype. Other mutants were highly resistant to both quinolone antibiotics and the biocide triclosan.

Conclusions

This study shows that exposure of bacteria to biocides can select for antibiotic-resistant mutants and this is mediated by clinically relevant mechanisms of resistance prevalent in human pathogens.

PDF

http://jac.oxfordjournals.org/content/70/8/2241.full.pdf+html

July 15, 2015 at 8:28 am

Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial

Journal of Antimicrobial Chemotherapy August 2015 V.70 N.8 P.2369-2375

Editor’s Choice

Fekade Bruck Sime, Michael S. Roberts, Ing Soo Tiong, Julia H. Gardner, Sheila Lehman, Sandra L. Peake, Uwe Hahn, Morgyn S. Warner, and Jason A. Roberts

1School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

2Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia

3Therapeutics Research Centre, School of Medicine, University of Queensland, Brisbane, Australia

4Department of Haematology/Oncology, The Queen Elizabeth Hospital, Adelaide, Australia

5SA Pathology and the University of Adelaide, Adelaide, Australia

6Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, Australia

7Royal Brisbane and Women’s Hospital, Herston, Brisbane, Queensland, Australia

8Burns, Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane, Queensland, Australia

9Institute of Translational Medicine, University of Liverpool, Liverpool, UK

*Corresponding author. Tel: +614-1218-1027; E-mail: fekade.sime@mymail.unisa.edu.au

Objectives

The objectives of this study were to describe piperacillin exposure in febrile neutropenia patients and determine whether therapeutic drug monitoring (TDM) can be used to increase the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets.

Methods

In a prospective randomized controlled study (Australian New Zealand Registry, ACTRN12615000086561), patients were subjected to TDM for 3 consecutive days. Dose was adjusted in the intervention group to achieve a free drug concentration above the MIC for 100% of the dose interval (100% fT>MIC), which was also the primary outcome measure. The secondary PK/PD target was 50% fT>MIC. Duration of fever and days to recovery from neutropenia were recorded.

Results

Thirty-two patients were enrolled. Initially, patients received 4.5 g of piperacillin/tazobactam every 8 h or every 6 h along with gentamicin co-therapy in 30/32 (94%) patients. At the first TDM, 7/32 (22%) patients achieved 100% fT>MIC and 12/32 (38%) patients achieved 50% fT>MIC. Following dose adjustment, 11/16 (69%) of intervention patients versus 3/16 (19%) of control patients (P=0.012) attained 100% fT>MIC, and 15/16 (94%) of intervention patients versus 5/16 (31%) of control patients (P=0.001) achieved 50% fT>MIC. After the third TDM, the proportion of patients attaining 100% fT>MIC improved from a baseline 3/16 (19%) to 11/15 (73%) in the intervention group, while it declined from 4/16 (25%) to 1/15 (7%) in the control group. No difference was noted in the duration of fever and days to recovery from neutropenia.

Conclusions

Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization.

PDF

http://jac.oxfordjournals.org/content/70/8/2369.full.pdf+html

July 15, 2015 at 8:26 am


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