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Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013
G Model
VETMIC-6510; No. of Pages 5 Veterinary Microbiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Veterinary Microbiology journal homepage: www.elsevier.com/locate/vetmic
Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013 Arshnee Moodley a,*, Peter Damborg a, Søren Saxmose Nielsen b a b
Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
A R T I C L E I N F O
Keywords: Antibiotic Commensal Clinical Dog Susceptibility
A B S T R A C T
Staphylococcus pseudintermedius is a commensal and a common opportunistic pathogen causing mainly infections of the integumentary system in dogs. The recent emergence of multidrug-resistant S. pseudintermedius isolates, in particular methicillin-resistant strains (MRSP) is a threat to small animal health and highlights the need for antimicrobial resistance surveillance to detect trends and potentially perform timeous interventions. We systematically reviewed 202 published articles to investigate temporal changes in antimicrobial resistance in clinical and commensal S. pseudintermedius isolated from dogs in 27 countries between 1980 and 2013. Resistance to the most common antimicrobials tested for in published studies and important for the treatment of staphylococcal infections in dogs were assessed separately for methicillin resistant (MRSP) and methicillin susceptible (MSSP) isolates. Stratified by MSSP and MRSP, no significant increases in antimicrobial resistance were observed over time, except for the penicillinase-labile penicillins (penicillin and ampicillin) among MSSP. However, in recent years, a few studies have reported higher-level of resistance to amikacin, gentamicin and enrofloxacin amongst MSSP. The review highlights inconsistencies between studies as a result of several factors, for example the use of different antimicrobial susceptibility testing methods and interpretation criteria. We recommend that data on susceptibility in important companion animal pathogens are collected and presented in a more harmonized way to allow more precise comparison of susceptibility patterns between studies. One way to accomplish this would be through systematic surveillance either at the country-level or at a larger scale across countries e.g. EU level. ß 2014 Elsevier B.V. All rights reserved.
1. Introduction Staphylococcus pseudintermedius is a commensal and the most common bacterial pathogen in dogs. Before the description of S. pseudintermedius in 2005 (Devriese et al.,
* Corresponding author. Tel.: +45 35 33 27 11. E-mail address: [email protected] (A. Moodley).
2005), any non-pigmented haemolytic, coagulase-positive staphylococci isolated from dogs were generally referred to as S. intermedius without further confirmation. For the purpose of this review, all S. intermedius and S. pseudintermedius isolated from dogs were referred to as S. pseudintermedius irrespective of molecular confirmation of species identification. The first phenotypic methicillin resistant S. pseudintermedius (MRSP) strains were isolated in France in the
http://dx.doi.org/10.1016/j.vetmic.2014.02.008 0378-1135/ß 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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VETMIC-6510; No. of Pages 5 2
A. Moodley et al. / Veterinary Microbiology xxx (2014) xxx–xxx
mid-1980s from healthy dogs and dogs with pyoderma (Pellerin et al., 1998). The first mecA positive strain was reported in 1999 in a canine pyoderma isolate from the US (Gortel et al., 1999) and in Europe in 2005 (Loeffler et al., 2007). Since these early reports of MRSP, they are now increasingly reported in veterinary clinics around the world, and are recognized as a serious canine health problem due to their multidrug resistance phenotype, limiting treatment options, and challenging infection control measures (Weese and van Duijkeren, 2010; van Duijkeren et al., 2011; Bannoehr and Guardabassi, 2012; Bond and Loeffler, 2012). Our objective was to investigate temporal changes of antimicrobial resistance in methicillin susceptible- and resistant S. pseudintermedius of canine origin by systematically reviewing published studies between 1980 and 2013. The study was limited to the following antimicrobials, which were most often tested for in published studies and represent the major classes for treatment of staphylococcal infections in veterinary medicine: aminoglycosides (amikacin and gentamicin), phenicols (chloramphenicol), fluoroquinolones (ciprofloxacin and enrofloxacin), macrolides (erythromycin), lincosamides (clindamycin), tetracycline, and trimethoprim/sulphonamides. For b-lactams, amongst MSSP only, we analysed resistance to penicillin and ampicillin, since resistance to amoxicillin/clavulanic acid and cephalosporins would indicate the presence of mecA (MRSP). 2. Identification and analysis of relevant literature The free electronic database PubMed was searched for all articles using the following search strings: ‘‘staphylococcus and pseudintermedius AND resistance OR resistant AND dog OR canine’’ and ‘‘staphylococcus and intermedius AND resistance OR resistant AND dog OR canine’’ until 30 June 2013. Papers were screened using six inclusion criteria: (i) full articles in English, (ii) dog specific antimicrobial resistance data could be extracted from the paper, (iii) not a case report, (iv) MRSP were confirmed to harbour mecA (see definition below), (v) antimicrobial resistance was reported separately for MSSP and MRSP, and (vi) the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards (NCCLS)) clinical breakpoints were used, independent of the publication year and whether they were specific for animals or humans. A data extraction form was used to obtain information from the relevant studies, which included general information of the article, study period, country of isolation, type of isolate (clinical or commensal), total number of S. pseudintermedius isolates, if strains were tested for oxacillin resistance and phenotypically resistant strains were confirmed by mecA PCR, antimicrobial susceptibility testing methods, interpretative breakpoints for resistance, and the number of isolates resistant to the selected antimicrobials. Intermediately resistant isolates were excluded from the analysis. If oxacillin resistance was tested, resistant isolates confirmed to carry mecA were called MRSP and included in the analysis. Oxacillin resistant isolates that were shown to
be mecA negative were called MSSP and also included in the analysis. Studies reporting oxacillin resistance without confirming the presence of mecA were excluded from the analysis. Antimicrobial resistance was summarised for the following antimicrobials (i) b-lactams (penicillin and ampicillin), (ii) tetracycline, (iii) trimethoprim/sulphonamides, (iv) phenicols (chloramphenicol), (v) macrolides (erythromycin), (vi) lincosamides (clindamycin), (vii) aminoglycosides (gentamicin and amikacin), and (viii) fluoroquinolones (ciprofloxacin and enrofloxacin). The prevalence of resistance reported in each study to the different antimicrobials were depicted in scatter plots for each antimicrobial type over time, and stratified by MRSP and MSSP. For each antimicrobial, a linear relationship of resistance prevalence with time was assessed, while weighing each observation (i.e. each original study) by the number of isolates included. The glm (generalized linear model) -function in R was used to assess if the prevalence of resistance increased or decreased over time (R Core Team, 2013). A linear trend line was added to the resulting plot if a statistical association (P < 0.05) was identified.
3. Description of relevant literature This is the first review systematically analysing temporal trends of phenotypic antimicrobial resistance in S. pseudintermedius isolated from geographically dispersed dogs over an extended time period, independent of infection type and methicillin resistance. Initially, 202 unique articles were identified through PubMed, and after the screening process, 57 articles that met all six inclusion criteria were included. References of all 57 included articles are listed in the supplementary material, which also includes the raw data, e.g. the number of isolates and resistance recorded in each study. The 145 articles were excluded for the reasons; (a) articles not in English (n = 3); (b) reviews, case reports or articles did not perform antimicrobial susceptibility testing, or did not include the antimicrobials of interest for this review (n = 71), (c) did not provide antimicrobial resistance data separately for S. pseudintermedius (n = 9), (d) dog specific antimicrobial resistance data could not be extracted either because of reporting errors or data was combined for all animal species (n = 31), (e) oxacillin resistance was reported but isolates were not confirmed to harbour mecA (n = 5), (f) provided combined MSSP and MRSP antimicrobial resistance data (n = 5), (g) did not use CLSI clinical breakpoints or did not provide information on which antimicrobial breakpoints were used (n = 21). 3.1. Penicillinase-labile penicillins Amongst MSSP, there was a significant increasing trend of resistance to the penicillinase-labile penicillins (Fig. 1). A significant increase in resistance to the penicillinaselabile penicillin and ampicillin was observed amongst MSSP, which is likely the result of dissemination of the narrow spectrum b-lactamase, blaZ (Kadlec and Schwarz, 2012). As a result of this widespread resistance, penicillin
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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Fig. 1. Percentage of penicillin/ampicillin resistance over time amongst methicillin susceptible S. pseudintermedius reported in the literature. There was a significantly increasing level of resistance with time (P = 0.006; R2 = 0.15). The total number of studies was 38 including 4384 isolates.
and ampicillin are not routinely used for treatment of staphylococcal infections in dogs.
4. Limitations to performing a systematic review of changes in antimicrobial resistance patterns
3.2. Non-b-lactam antimicrobial classes
We excluded many studies because of poor reporting and/or presentation of data in publications e.g. providing resistance data collectively for all staphylococci, or for all animal species combined, or combining MSSP and MRSP resistance data. Despite our critical selection of studies for this review there are some limitations that should be noted; (i) we were unable to standardize the interpretations of susceptibility across studies, despite including only studies using CLSI breakpoints, since there are several versions of the CLSI interpretive guidelines, and breakpoints are revised over time; (ii) the number of isolates from each country varied by study and by year. Thus some countries may be overrepresented in some years and vice versa. Therefore, apparent temporal changes may in fact reflect geographic variations of susceptibility patterns; and (iii) we did not consider the isolate origin e.g. commensal vs. clinical isolates. This could have an impact on the analyses, since dogs with pyoderma or ear infections, are likely to have received antibiotics before. Performing a comprehensive systematic review of changes in antimicrobial resistance patterns was challenging, and future meta-analyses in S. pseudintermedius would certainly benefit if susceptibility testing methods and interpretative guidelines were harmonized, and if authors followed a stringent structure for reporting antimicrobial resistance, which should be stratified based on oxacillin resistance and confirmation of mecA by PCR, species, country and other relevant factors. Mixing of data over several ecological niches is rarely ideal because future interpretation of the data may be impossible. Schwarz et al. (2010) published a guideline to assist authors on how antimicrobial testing should be performed, and how results should be presented to facilitate future comparisons.
Amongst the non-b-lactam antimicrobial classes (fluoroquinolones, tetracycline, aminoglycosides, macrolides, lincosamides, phenicols, and trimethoprim/sulphonamides) no significant temporal changes in resistance were observed for both MSSP and MRSP (Fig. 2). Only seven studies reported S. pseudintermedius fully susceptible to all tested antimicrobials, and they accounted for 8–50% of all isolates in those studies. Resistance to gentamicin, amikacin and fluoroquinolones was generally low amongst MSSP (4–6%), but a few studies have reported elevated levels of resistance amongst MSSP isolates; amikacin (56%, Casagrande Proietti et al., 2012), gentamicin (21–56%, Yoon et al., 2010; Youn et al., 2011; Casagrande Proietti et al., 2012; Gomez-Sanz et al., 2013), and fluoroquinolones (33–93%; Piriz et al., 1996; Descloux et al., 2008; Kawakami et al., 2010; Casagrande Proietti et al., 2012) (Fig. 2). This should be monitored since these antibiotics are important for the treatment of S. pseudintermedius infections. MRSP were generally more resistant than MSSP but it is well known that MRSP exhibit resistance to a multitude of non-b-lactam antibiotics (Ruscher et al., 2010; Perreten et al., 2010), and this was confirmed in the present study, since the prevalence of non-b-lactam resistance generally was higher in MRSP compared to MSSP (Fig. 2). This high prevalence of multi-resistance is likely related to the dissemination of dominant clones, e.g. MRSP belonging to the clonal lineage ST71. In a multi-centre study, 74% (76/ 103) of MRSP belonged to ST71, and of those 87% were resistant to at least six antimicrobial classes (Perreten et al., 2010).
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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Fig. 2. Percentage of resistance over time for fluoroquinolones (ciprofloxacin and enrofloxacin), tetracycline, gentamicin, amikacin, erythromycin, clindamycin, chloramphenicol, and trimethoprim/sulphonamides amongst MSSP (open circles) and MRSP (filled circles) reported in the literature. n = total number of isolates, s = number of included studies.
5. Conclusion There is limited evidence from our analyses of any significant increase or decrease in resistance except for the narrow spectrum b-lactams. Harmonization of testing methods, interpretation of susceptibility, and the choice of antibiotics tested are important factors in facilitating future comparisons, but may be difficult to implement due to geographic differences in the use of certain antibiotics as
well as economic resources. Antimicrobial surveillance in individual countries is advantageous to monitor trends, which can be used to guide local national antibiotic usage policies. Such surveillance data may be retrieved from diagnostic labs. A larger, regional surveillance initiative would also be beneficial, e.g. a common EU-coordinated surveillance in companion animals to obtain baseline antimicrobial resistance data on pathogens of clinical relevance to small animals (e.g. S. pseudintermedius) as well
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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as other bacteria with important multi-drug resistance phenotypes and zoonotic potential (e.g. Staphylococcus aureus and Escherichia coli). Conflict of interest None declared. Acknowledgements Arshnee Moodley is supported by grants from the Danish Research Council: Technology and Innovation, and the Sapere Aude Young Elite Researcher. The authors would like to thank Luca Guardabassi for constructive comments to the manuscript. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.vetmic.2014.02.008. References Bannoehr, J., Guardabassi, L., 2012. Staphylococcus pseudintermedius in the dog: taxonomy, diagnostics, ecology, epidemiology and pathogenicity. Vet. Dermatol. 23, 253–266, e51–2. Bond, R., Loeffler, A., 2012. What’s happened to Staphylococcus intermedius? Taxonomic revision and emergence of multi-drug resistance. J. Small Anim. Pract. 53, 147–154. Casagrande Proietti, P., Bietta, A., Coletti, M., Marenzoni, M.L., Scorza, A.V., Passamonti, F., 2012. Insertion sequence IS256 in canine pyoderma isolates of Staphylococcus pseudintermedius associated with antibiotic resistance. Vet. Microbiol. 157, 376–382. Devriese, L.A., Vancanneyt, M., Baele, M., Vaneechoutte, M., De Graef, E., Snauwaert, C., Cleenwerck, I., Dawyndt, P., Swings, J., Decostere, A., Haesebrouck, F., 2005. Staphylococcus pseudintermedius sp. nov., a coagulase-positive species from animals. Int. J. Syst. Evol. Microbiol. 55, 1569–1573. Descloux, S., Rossano, A., Perreten, V., 2008. Characterization of new staphylococcal cassette chromosome mec (SCCmec) and topoisomerase genes in fluoroquinolone- and methicillin-resistant Staphylococcus pseudintermedius. J. Clin. Microbiol. 46, 1818–1823. Gomez-Sanz, E., Torres, C., Ceballos, S., Lozano, C., Zarazaga, M., 2013. Clonal dynamics of nasal Staphylococcus aureus and Staphylococcus pseudintermedius in dog-owning household members. Detection of MSSA ST(398). PLoS ONE 8, e69337. Gortel, K., Campbell, K.L., Kakoma, I., Whittem, T., Schaeffer, D.J., Weisiger, R.M., 1999. Methicillin resistance among staphylococci isolated from dogs. Am. J. Vet. Res. 60, 1526–1530.
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Kadlec, K., Schwarz, S., 2012. Antimicrobial resistance of Staphylococcus pseudintermedius. Vet. Dermatol. 23, 276–282, e55. Kawakami, T., Shibata, S., Murayama, N., Nagata, M., Nishifuji, K., Iwasaki, T., Fukata, T., 2010. Antimicrobial susceptibility and methicillin resistance in Staphylococcus pseudintermedius and Staphylococcus schleiferi subsp. coagulans isolated from dogs with pyoderma in Japan. J. Vet. Med. Sci. 72, 1615–1619. Loeffler, A., Linek, M., Moodley, A., Guardabassi, L., Sung, J.M., Winkler, M., Weiss, R., Lloyd, D.H., 2007. First report of multiresistant, mecApositive Staphylococcus intermedius in Europe: 12 cases from a veterinary dermatology referral clinic in Germany. Vet. Dermatol. 18, 412– 421. Pellerin, J.L., Bourdeau, P., Sebbag, H., Person, J.M., 1998. Epidemiosurveillance of antimicrobial compound resistance of Staphylococcus intermedius clinical isolates from canine pyodermas. Comp. Immunol. Microbiol. Infect. Dis. 21, 115–133. Perreten, V., Kadlec, K., Schwarz, S., Gro¨nlund Andersson, U., Finn, M., Greko, C., Moodley, A., Kania, S.A., Frank, L.A., Bemis, D.A., Franco, A., Iurescia, M., Battisti, A., Duim, B., Wagenaar, J.A., van Duijkeren, E., Weese, J.S., Fitzgerald, J.R., Rossano, A., Guardabassi, L., 2010. Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study. J. Antimicrob. Chemother. 65, 1145–1154. Piriz, S., Valle, J., Mateos, E.M., de la Fuente, R., Cid, D., Ruiz-Santaquiteria, J.A., Vadillo, S., 1996. In vitro activity of fifteen antimicrobial agents against methicillin-resistant and methicillin-susceptible Staphylococcus intermedius. J. Vet. Pharmacol. Ther. 19, 118–123. R Core Team, 2013. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. , http://www.R-project.org/. Ruscher, C., Lu¨bke-Becker, A., Semmler, T., Wleklinski, C.G., Paasch, A., Soba, A., Stamm, I., Kopp, P., Wieler, L.H., Walther, B., 2010. Widespread rapid emergence of a distinct methicillin- and multidrugresistant Staphylococcus pseudintermedius (MRSP) genetic lineage in Europe. Vet. Microbiol. 144, 340–346. Schwarz, S., Silley, P., Simjee, S., Woodford, N., van Duijkeren, E., Johnson, A.P., Gaastra, W., 2010. Editorial: assessing the antimicrobial susceptibility of bacteria obtained from animals. J. Antimicrob. Chemother. 65, 601–604. van Duijkeren, E., Catry, B., Greko, C., Moreno, M.A., Pomba, M.C., Pyo¨ra¨la¨, S., Ruzauskas, M., Sanders, P., Threlfall, E.J., Torren-Edo, J., To¨rneke, K., Scientific Advisory Group on Antimicrobials (SAGAM), 2011. Review on methicillin-resistant Staphylococcus pseudintermedius. J. Antimicrob. Chemother. 66, 2705–2714. Weese, J.S., van Duijkeren, E., 2010. Methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius in veterinary medicine. Vet. Microbiol. 140, 418–429. Yoon, J.W., Lee, K.J., Lee, S.Y., Chae, M.J., Park, J.K., Yoo, J.H., Park, H.M., 2010. Antibiotic resistance profiles of Staphylococcus pseudintermedius isolates from canine patients in Korea. J. Microbiol. Biotechnol. 20, 1764–1768. Youn, J.H., Yoon, J.W., Koo, H.C., Lim, S.K., Park, Y.H., 2011. Prevalence and antimicrogram of Staphylococcus intermedius group isolates from veterinary staff, companion animals, and the environment in veterinary hospitals in Korea. J. Vet. Diagn. Invest. 23, 268– 274.
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
VETMIC-6510; No. of Pages 5 Veterinary Microbiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Veterinary Microbiology journal homepage: www.elsevier.com/locate/vetmic
Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013 Arshnee Moodley a,*, Peter Damborg a, Søren Saxmose Nielsen b a b
Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
A R T I C L E I N F O
Keywords: Antibiotic Commensal Clinical Dog Susceptibility
A B S T R A C T
Staphylococcus pseudintermedius is a commensal and a common opportunistic pathogen causing mainly infections of the integumentary system in dogs. The recent emergence of multidrug-resistant S. pseudintermedius isolates, in particular methicillin-resistant strains (MRSP) is a threat to small animal health and highlights the need for antimicrobial resistance surveillance to detect trends and potentially perform timeous interventions. We systematically reviewed 202 published articles to investigate temporal changes in antimicrobial resistance in clinical and commensal S. pseudintermedius isolated from dogs in 27 countries between 1980 and 2013. Resistance to the most common antimicrobials tested for in published studies and important for the treatment of staphylococcal infections in dogs were assessed separately for methicillin resistant (MRSP) and methicillin susceptible (MSSP) isolates. Stratified by MSSP and MRSP, no significant increases in antimicrobial resistance were observed over time, except for the penicillinase-labile penicillins (penicillin and ampicillin) among MSSP. However, in recent years, a few studies have reported higher-level of resistance to amikacin, gentamicin and enrofloxacin amongst MSSP. The review highlights inconsistencies between studies as a result of several factors, for example the use of different antimicrobial susceptibility testing methods and interpretation criteria. We recommend that data on susceptibility in important companion animal pathogens are collected and presented in a more harmonized way to allow more precise comparison of susceptibility patterns between studies. One way to accomplish this would be through systematic surveillance either at the country-level or at a larger scale across countries e.g. EU level. ß 2014 Elsevier B.V. All rights reserved.
1. Introduction Staphylococcus pseudintermedius is a commensal and the most common bacterial pathogen in dogs. Before the description of S. pseudintermedius in 2005 (Devriese et al.,
* Corresponding author. Tel.: +45 35 33 27 11. E-mail address: [email protected] (A. Moodley).
2005), any non-pigmented haemolytic, coagulase-positive staphylococci isolated from dogs were generally referred to as S. intermedius without further confirmation. For the purpose of this review, all S. intermedius and S. pseudintermedius isolated from dogs were referred to as S. pseudintermedius irrespective of molecular confirmation of species identification. The first phenotypic methicillin resistant S. pseudintermedius (MRSP) strains were isolated in France in the
http://dx.doi.org/10.1016/j.vetmic.2014.02.008 0378-1135/ß 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
G Model
VETMIC-6510; No. of Pages 5 2
A. Moodley et al. / Veterinary Microbiology xxx (2014) xxx–xxx
mid-1980s from healthy dogs and dogs with pyoderma (Pellerin et al., 1998). The first mecA positive strain was reported in 1999 in a canine pyoderma isolate from the US (Gortel et al., 1999) and in Europe in 2005 (Loeffler et al., 2007). Since these early reports of MRSP, they are now increasingly reported in veterinary clinics around the world, and are recognized as a serious canine health problem due to their multidrug resistance phenotype, limiting treatment options, and challenging infection control measures (Weese and van Duijkeren, 2010; van Duijkeren et al., 2011; Bannoehr and Guardabassi, 2012; Bond and Loeffler, 2012). Our objective was to investigate temporal changes of antimicrobial resistance in methicillin susceptible- and resistant S. pseudintermedius of canine origin by systematically reviewing published studies between 1980 and 2013. The study was limited to the following antimicrobials, which were most often tested for in published studies and represent the major classes for treatment of staphylococcal infections in veterinary medicine: aminoglycosides (amikacin and gentamicin), phenicols (chloramphenicol), fluoroquinolones (ciprofloxacin and enrofloxacin), macrolides (erythromycin), lincosamides (clindamycin), tetracycline, and trimethoprim/sulphonamides. For b-lactams, amongst MSSP only, we analysed resistance to penicillin and ampicillin, since resistance to amoxicillin/clavulanic acid and cephalosporins would indicate the presence of mecA (MRSP). 2. Identification and analysis of relevant literature The free electronic database PubMed was searched for all articles using the following search strings: ‘‘staphylococcus and pseudintermedius AND resistance OR resistant AND dog OR canine’’ and ‘‘staphylococcus and intermedius AND resistance OR resistant AND dog OR canine’’ until 30 June 2013. Papers were screened using six inclusion criteria: (i) full articles in English, (ii) dog specific antimicrobial resistance data could be extracted from the paper, (iii) not a case report, (iv) MRSP were confirmed to harbour mecA (see definition below), (v) antimicrobial resistance was reported separately for MSSP and MRSP, and (vi) the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards (NCCLS)) clinical breakpoints were used, independent of the publication year and whether they were specific for animals or humans. A data extraction form was used to obtain information from the relevant studies, which included general information of the article, study period, country of isolation, type of isolate (clinical or commensal), total number of S. pseudintermedius isolates, if strains were tested for oxacillin resistance and phenotypically resistant strains were confirmed by mecA PCR, antimicrobial susceptibility testing methods, interpretative breakpoints for resistance, and the number of isolates resistant to the selected antimicrobials. Intermediately resistant isolates were excluded from the analysis. If oxacillin resistance was tested, resistant isolates confirmed to carry mecA were called MRSP and included in the analysis. Oxacillin resistant isolates that were shown to
be mecA negative were called MSSP and also included in the analysis. Studies reporting oxacillin resistance without confirming the presence of mecA were excluded from the analysis. Antimicrobial resistance was summarised for the following antimicrobials (i) b-lactams (penicillin and ampicillin), (ii) tetracycline, (iii) trimethoprim/sulphonamides, (iv) phenicols (chloramphenicol), (v) macrolides (erythromycin), (vi) lincosamides (clindamycin), (vii) aminoglycosides (gentamicin and amikacin), and (viii) fluoroquinolones (ciprofloxacin and enrofloxacin). The prevalence of resistance reported in each study to the different antimicrobials were depicted in scatter plots for each antimicrobial type over time, and stratified by MRSP and MSSP. For each antimicrobial, a linear relationship of resistance prevalence with time was assessed, while weighing each observation (i.e. each original study) by the number of isolates included. The glm (generalized linear model) -function in R was used to assess if the prevalence of resistance increased or decreased over time (R Core Team, 2013). A linear trend line was added to the resulting plot if a statistical association (P < 0.05) was identified.
3. Description of relevant literature This is the first review systematically analysing temporal trends of phenotypic antimicrobial resistance in S. pseudintermedius isolated from geographically dispersed dogs over an extended time period, independent of infection type and methicillin resistance. Initially, 202 unique articles were identified through PubMed, and after the screening process, 57 articles that met all six inclusion criteria were included. References of all 57 included articles are listed in the supplementary material, which also includes the raw data, e.g. the number of isolates and resistance recorded in each study. The 145 articles were excluded for the reasons; (a) articles not in English (n = 3); (b) reviews, case reports or articles did not perform antimicrobial susceptibility testing, or did not include the antimicrobials of interest for this review (n = 71), (c) did not provide antimicrobial resistance data separately for S. pseudintermedius (n = 9), (d) dog specific antimicrobial resistance data could not be extracted either because of reporting errors or data was combined for all animal species (n = 31), (e) oxacillin resistance was reported but isolates were not confirmed to harbour mecA (n = 5), (f) provided combined MSSP and MRSP antimicrobial resistance data (n = 5), (g) did not use CLSI clinical breakpoints or did not provide information on which antimicrobial breakpoints were used (n = 21). 3.1. Penicillinase-labile penicillins Amongst MSSP, there was a significant increasing trend of resistance to the penicillinase-labile penicillins (Fig. 1). A significant increase in resistance to the penicillinaselabile penicillin and ampicillin was observed amongst MSSP, which is likely the result of dissemination of the narrow spectrum b-lactamase, blaZ (Kadlec and Schwarz, 2012). As a result of this widespread resistance, penicillin
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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VETMIC-6510; No. of Pages 5 A. Moodley et al. / Veterinary Microbiology xxx (2014) xxx–xxx
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Fig. 1. Percentage of penicillin/ampicillin resistance over time amongst methicillin susceptible S. pseudintermedius reported in the literature. There was a significantly increasing level of resistance with time (P = 0.006; R2 = 0.15). The total number of studies was 38 including 4384 isolates.
and ampicillin are not routinely used for treatment of staphylococcal infections in dogs.
4. Limitations to performing a systematic review of changes in antimicrobial resistance patterns
3.2. Non-b-lactam antimicrobial classes
We excluded many studies because of poor reporting and/or presentation of data in publications e.g. providing resistance data collectively for all staphylococci, or for all animal species combined, or combining MSSP and MRSP resistance data. Despite our critical selection of studies for this review there are some limitations that should be noted; (i) we were unable to standardize the interpretations of susceptibility across studies, despite including only studies using CLSI breakpoints, since there are several versions of the CLSI interpretive guidelines, and breakpoints are revised over time; (ii) the number of isolates from each country varied by study and by year. Thus some countries may be overrepresented in some years and vice versa. Therefore, apparent temporal changes may in fact reflect geographic variations of susceptibility patterns; and (iii) we did not consider the isolate origin e.g. commensal vs. clinical isolates. This could have an impact on the analyses, since dogs with pyoderma or ear infections, are likely to have received antibiotics before. Performing a comprehensive systematic review of changes in antimicrobial resistance patterns was challenging, and future meta-analyses in S. pseudintermedius would certainly benefit if susceptibility testing methods and interpretative guidelines were harmonized, and if authors followed a stringent structure for reporting antimicrobial resistance, which should be stratified based on oxacillin resistance and confirmation of mecA by PCR, species, country and other relevant factors. Mixing of data over several ecological niches is rarely ideal because future interpretation of the data may be impossible. Schwarz et al. (2010) published a guideline to assist authors on how antimicrobial testing should be performed, and how results should be presented to facilitate future comparisons.
Amongst the non-b-lactam antimicrobial classes (fluoroquinolones, tetracycline, aminoglycosides, macrolides, lincosamides, phenicols, and trimethoprim/sulphonamides) no significant temporal changes in resistance were observed for both MSSP and MRSP (Fig. 2). Only seven studies reported S. pseudintermedius fully susceptible to all tested antimicrobials, and they accounted for 8–50% of all isolates in those studies. Resistance to gentamicin, amikacin and fluoroquinolones was generally low amongst MSSP (4–6%), but a few studies have reported elevated levels of resistance amongst MSSP isolates; amikacin (56%, Casagrande Proietti et al., 2012), gentamicin (21–56%, Yoon et al., 2010; Youn et al., 2011; Casagrande Proietti et al., 2012; Gomez-Sanz et al., 2013), and fluoroquinolones (33–93%; Piriz et al., 1996; Descloux et al., 2008; Kawakami et al., 2010; Casagrande Proietti et al., 2012) (Fig. 2). This should be monitored since these antibiotics are important for the treatment of S. pseudintermedius infections. MRSP were generally more resistant than MSSP but it is well known that MRSP exhibit resistance to a multitude of non-b-lactam antibiotics (Ruscher et al., 2010; Perreten et al., 2010), and this was confirmed in the present study, since the prevalence of non-b-lactam resistance generally was higher in MRSP compared to MSSP (Fig. 2). This high prevalence of multi-resistance is likely related to the dissemination of dominant clones, e.g. MRSP belonging to the clonal lineage ST71. In a multi-centre study, 74% (76/ 103) of MRSP belonged to ST71, and of those 87% were resistant to at least six antimicrobial classes (Perreten et al., 2010).
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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Fig. 2. Percentage of resistance over time for fluoroquinolones (ciprofloxacin and enrofloxacin), tetracycline, gentamicin, amikacin, erythromycin, clindamycin, chloramphenicol, and trimethoprim/sulphonamides amongst MSSP (open circles) and MRSP (filled circles) reported in the literature. n = total number of isolates, s = number of included studies.
5. Conclusion There is limited evidence from our analyses of any significant increase or decrease in resistance except for the narrow spectrum b-lactams. Harmonization of testing methods, interpretation of susceptibility, and the choice of antibiotics tested are important factors in facilitating future comparisons, but may be difficult to implement due to geographic differences in the use of certain antibiotics as
well as economic resources. Antimicrobial surveillance in individual countries is advantageous to monitor trends, which can be used to guide local national antibiotic usage policies. Such surveillance data may be retrieved from diagnostic labs. A larger, regional surveillance initiative would also be beneficial, e.g. a common EU-coordinated surveillance in companion animals to obtain baseline antimicrobial resistance data on pathogens of clinical relevance to small animals (e.g. S. pseudintermedius) as well
Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008
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Please cite this article in press as: Moodley, A., et al., Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: Literature review from 1980 to 2013. Vet. Microbiol. (2014), http://dx.doi.org/10.1016/j.vetmic.2014.02.008