Antimicrobial synergy between carprofen and doxycycline against methicillin-resistant Staphylococcus pseudintermedius ST71

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Abstract

Background

New therapeutic strategies are needed to face the rapid spread of multidrug-resistant staphylococci in veterinary medicine. The objective of this study was to identify synergies between antimicrobial and non-antimicrobial drugs commonly used in companion animals as a possible strategy to restore antimicrobial susceptibility in methicillin-resistant Staphylococcus pseudintermedius (MRSP).

Results

A total of 216 antimicrobial/non-antimicrobial drug combinations were screened by disk diffusion using a clinical MRSP sequence type (ST) 71 strain resistant to all six antimicrobials tested (ampicillin, ciprofloxacin, clindamycin, doxycycline, oxacillin and trimethoprim/sulfamethoxazole). The most promising drug combination (doxycycline-carprofen) was further assessed by checkerboard testing extended to four additional MRSP strains belonging to ST71 or ST68, and by growth inhibition experiments.

Seven non-antimicrobial drugs (bromhexine, acepromazine, amitriptyline, clomipramine, carprofen, fluoxetine and ketoconazole) displayed minimum inhibitory concentrations (MICs) ranging between 32 and >4096 mg/L, and enhanced antimicrobial activity of one or more antimicrobials. Secondary screening by checkerboard assay revealed a synergistic antimicrobial effect between carprofen and doxycycline, with the sum of the fractional inhibitory concentration indexes (ΣFICI) ranging between 0.3 and 0.5 depending on drug concentration. Checkerboard testing of multiple MRSP strains revealed a clear association between synergy and carriage of tetK, which is a typical feature of MRSP ST71. An increased growth inhibition was observed when MRSP ST71 cells in exponential phase were exposed to 0.5/32 mg/L of doxycycline/carprofen compared to individual drug exposure.

Conclusions

Carprofen restores in vitro susceptibility to doxycycline in S. pseudintermedius strains carrying tetK such as MRSP ST71. Further research is warranted to elucidate the molecular mechanism behind the identified synergy and its linkage to tetK.

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Most cited references 20

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Combination approaches to combat multidrug-resistant bacteria.

Christian Melander, Kenneth R Worthington (2013)

The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Tetracyclines: nonantibiotic properties and their clinical implications.

Allen Sapadin, Raul Fleischmajer (2006)

Tetracyclines are broad-spectrum antibiotics that act as such at the ribosomal level where they interfere with protein synthesis. They were first widely prescribed by dermatologists in the early 1950s when it was discovered that they were effective as a treatment for acne. More recently, biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched. The therapeutic effects of tetracycline and its analogues in various diseases have also been investigated. These include rosacea, bullous dermatoses, neutrophilic diseases, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorders such as rheumatoid arthritis and scleroderma. We review the nonantibiotic properties of tetracycline and its analogues and their potential for clinical application.

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Is Open Access

Antibiotics used most commonly to treat animals in Europe

N. De Briyne, J Atkinson, L. Pokludová … (2014)

The Heads of Medicines Agencies and the Federation of Veterinarians of Europe undertook a survey to gain an insight into European prescribing of antibiotics for animals, in particular to highlight the diseases for which antibiotics are most commonly said to be prescribed and which different classes, including human critically important antibiotics (CIAs). The survey was completed by 3004 practitioners from 25 European countries. Many older antibiotics (eg, penicillins, tetracyclines) are cited most frequently as the prescribed classes to treat the main food producing species. The frequency of citation of non-CIAs predominates. CIAs are mostly frequently cited to be prescribed for: urinary diseases in cats (62 per cent), respiratory diseases in cattle (45 per cent), diarrhoea in cattle and pigs (respectively 29 per cent and 34 per cent), locomotion disorders in cattle (31 per cent), postpartum dysgalactia syndrome complex in pigs (31 per cent) and dental disease in dogs (36 per cent). Clear ‘preferences’ between countries can be observed between antibiotic classes. The use of national formularies and guidance helps to drive responsible use of antibiotics and can significantly reduce the extent of use of CIAs. A more widespread introduction of veterinary practice antibiotic prescribing policies and monitoring obedience to these should ensure more widespread compliance with responsible use guidelines.

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Author and article information

Contributors

Rikke Prejh Brochmann: rpb@sund.ku.dk

Alexandra Helmfrid: alexandra.helmfrid@gmail.com

Bimal Jana: bimal@sund.ku.dk

Zofia Magnowska: zofia@sund.ku.dk

Luca Guardabassi: +1 869 4654161 x401-1329 , lguardabassi@rossvet.edu.kn

Journal

Journal ID (nlm-ta): BMC Vet Res

Journal ID (iso-abbrev): BMC Vet. Res

Title: BMC Veterinary Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1746-6148

Publication date (Electronic): 24 June 2016

Publication date PMC-release: 24 June 2016

Publication date Collection: 2016

Volume: 12

Electronic Location Identifier: 126

Affiliations

[ ]Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Denmark

[ ]Department of Biomedical Sciences, Ross School of Veterinary Medicine, Basseterre, St Kitts West Indies

Article

Publisher ID: 751

DOI: 10.1186/s12917-016-0751-3

PMC ID: 4921001

PubMed ID: 27342694

SO-VID: 51b653c1-dedf-49dd-aea1-c750a17c7306

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 February 2016

Date accepted : 16 June 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001734, Københavns Universitet;

Award ID: NA

Award Recipient : Luca Guardabassi

Funded by: Zoetis

Award ID: NA

Award Recipient : Luca Guardabassi

Custom metadata

ScienceOpen disciplines: Veterinary medicine

Keywords: veterinary antimicrobial therapy,non-steroidal anti-inflammatory drugs,multidrug resistance,dogs

Data availability:

ScienceOpen disciplines: Veterinary medicine

Keywords: veterinary antimicrobial therapy, non-steroidal anti-inflammatory drugs, multidrug resistance, dogs

Antimicrobial synergy between carprofen and doxycycline against methicillin-resistant Staphylococcus pseudintermedius ST71

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Most cited references 20

Combination approaches to combat multidrug-resistant bacteria.

Tetracyclines: nonantibiotic properties and their clinical implications.

Antibiotics used most commonly to treat animals in Europe

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