- Email: [email protected]
Effects of antimicrobial usage on the development of antimicrobial resistance
The Veterinary Journal 198 (2013) 307–308
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Effects of antimicrobial usage on the development of antimicrobial resistance Histomoniasis (‘blackhead’), caused by Histomonas meleagridis, is a major problem in turkey rearing. There are few therapeutic options for treatment of this disease and vaccination is still in the experimental phase (Liebhart et al., 2013; Nguyen Pham et al., 2013). Medication with the aminoglycoside antibiotic paromomycin may play a role in the control of histomoniasis, but also has the potential to select for resistant bacteria. Evaluating the effects of antimicrobial agents on the selection of resistance in experimental models has always been difficult. It requires a major research effort, including large groups of animals and numerous samples; few such studies have been performed. Most studies on selection for resistance rely on epidemiological data through surveillance studies, in which consumption of antibiotics is correlated with the occurrence of resistance. However, evaluating data from such studies has proven to be difficult, since resistance is not only driven by the use of antimicrobial agents, but is also related to the dynamics of the bacterial population and mobile genetic element(s) on which genes encoding resistance are located. Selection for resistance in Enterococcus spp. has been demonstrated through the use of avoparcin, a glycopeptide antibiotic that is cross-resistant with vancomycin, as well as for other growth promoting antibiotics (Butaye et al., 1999, 2001). An epidemiological study demonstrated co-resistance selection of vancomycin-resistant enterococci (VRE) with macrolide antibiotics, causing an unusual high prevalence of VRE in pigs, even after a ban on avoparcin was introduced (Aarestrup et al., 2000; Bager et al., 1999; Butaye et al., 1999). In this issue of The Veterinary Journal, Dr Isabelle Kempf of the Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES) and colleagues have published an interesting field study examining the effects of the use of paromomycin on selection of resistance in the intestinal microbiota of turkeys (Kempf et al., 2013). They studied the evolution of resistance in Escherichia coli, Enterococcus faecium and Staphylococcus aureus in 24 turkey flocks for a period of 180 days and demonstrated the selective effect of paromomycin, as well as selection for coresistance against other antibiotics. However, this was not equal for all the bacterial species investigated, since selection for coresistance could only be demonstrated in E. coli. The effect persisted after treatment, although the frequency of resistance decreased in both groups. This study is of general interest because it shows that resistance mechanisms can be present in normal intestinal bacterial populations that are selected for through the use of an antimicrobial agent. The study also demonstrates that resistance can persist even after cessation of use of the antibiotic. There is considerable debate about the effects of the use of antimicrobial agents for prevention (rather than treatment) of disease on the selection of antimicrobial resistance in bacteria. Growth promoting antibiotics, now banned in the EU, are a typical example 1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.06.024
of the use of antibiotics for purposes other than therapy; these antibiotics are administered at low doses (Butaye et al., 2003). Similar to the effects of paromomycin, these antibiotics also induce shifts in the bacterial microbiota (Hafez et al., 2010), favouring or discouraging certain bacterial species, indirectly indicating that these antibiotics might select for the less susceptible (resistant) bacteria. Even at low doses, selection for resistance is evident in vivo, as shown for the growth promoting antibiotic avilamycin, in which the relative proportions of resistant and susceptible isolates was an indicator of selection for resistance (Butaye et al., 2005). Similar to the trial by Kempf et al. (2013) with paromomycin, this resistance persisted after treatment with avilamycin had been discontinued, although the frequency of resistance had diminished by the end of the trial in all groups (Butaye et al., 2005). As such, the use of any antibiotics, even at concentrations far below therapeutic level, should be regarded as capable of selecting for resistance, albeit perhaps at different rates. A major problem of selected resistances is that they do not seem to disappear rapidly; cross-resistance and co-resistance selection may be involved in this persistence. In selection for co-resistance, the location of the resistance gene on specific mobile genetic elements is of utmost importance, resulting in spread even without selective pressure (Smet et al., 2011). Integrons and complex genetic structures within genomic islands lead to an accumulation of resistance genes, linked to each other, increasing the selective power of one antibiotic to multiple unrelated antibiotics. Next to extended cross-resistance, single resistance elements are circulating that encode resistance against multiple unrelated antibiotics, for example the modified aac(60 )-Ib-cr gene (encoding resistance against fluoroquinolones and certain aminoglycosides) and the cfr gene (encoding resistance to lincosamides, phenicols, pleuromutilins, streptgramin A and selected 16-membered macrolides, and the oxazolidinone linezolid). As for paromomycin, selection for co-resistance by other aminoglycoside antibiotics, such as neomycin and kanamycin, is also of importance. The study by Kempf et al. (2013) also shows that the gene encoding paromomycin is transferrable and, in most cases, there was co-transfer of tetracycline, amoxicillin and sulphonamide–trimethoprim resistance. As such, care should be taken not to compromise antibacterial therapy by the long-term use of paromomycin in the prevention of histomoniasis in turkeys. It is clear that we must manage antimicrobial agents carefully. Resistance is an ever increasing problem, with some worrisome new developments, including an increase in multi-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum b-lactamase (ESBL) carrying Enterobacteriaceae and carbapenem resistance in E. coli and Salmonella spp. (Fischer et al., 2012, 2013). On the other hand, veterinarians need antibiotics for therapy. These factors should be taken into account when
308
Guest Editorial / The Veterinary Journal 198 (2013) 307–308
approving the use of particular antibiotics and evaluating the ‘pros and cons’ of the usage of antimicrobial agents; sometimes, it is like ‘balancing on a tightrope’. We should also bear in mind that few new antibiotics are in the ‘pipeline’ and there is a need to look for alternatives to antibiotics. Patrick Butaye Department of Bacteriology and Immunology Veterinary and Agrochemical Research Centre VAR-CODA-CERVA, Groeselenberg 99 B-1180 Ukkel, Belgium Department of Pathology, Bacteriology and Poultry Diseases Faculty of Veterinary Medicine, Ghent University Salisburylaan 133, 9820 Merelbeke, Belgium E-mail address: [email protected]
References Aarestrup, F.M., Seyfarth, A.M., Emborg, H.D., Pedersen, K., Hendriksen, R.S., Bager, F., 2000. Chracterization of glycoppetide-resistant Enterococcus faecium (GRE) from broilers and pigs in denmark: genetic evidence that persistance of GRE in pig hers is associated with co-selection by resistance to macrolides. Journal of CLinical Microbiology 38, 2774–2777. Bager, F., Aarestrup, F.M., Madsen, M., Wegener, H.C., 1999. Glycopeptide resistance in Enterococcus faecium from broilers and pigs following discontinued use of avoparcin. Microbial Drug Resistance 5, 53–56.
Butaye, P., Devriese, L.A., Goossens, H., Ieven, M., Haesebrouck, F., 1999. Enterococci with acquired vancomycin resistance in pigs and chickens of different age groups. Antimicrobial Agents and Chemotherapy 43, 365–366. Butaye, P., Devriese, L.A., Haesebrouck, F., 2001. Differences in antibiotic resistance patterns of Enterococcus faecalis and Enterococcus faecium strains isolated from pet and farm animals. Antimicrobial Agents and Chemotherapy 45, 1347–1378. Butaye, P., Devriese, L.A., Haesebrouck, F., 2003. Antimicrobial growth promoters used in animal feed: Effects of less well known antibiotics on Gram-positive bacteria. Clinical Microbiology Reviews 16, 175–188. Butaye, P., Devriese, L.A., Haesebrouck, F., 2005. Effect of avilamycin fed to chickens on E. faecium counts and on the selection of avilamycin-resistant E. faecium populations. Microbial Drug Resistance 11, 170–177. Fischer, J., Rodríguez, I., Schmoger, S., Friese, A., Roesler, U., Helmuth, R., Guerra, B., 2013. Salmonella enterica subsp. enterica producing VIM-1 carbapenemase isolated from livestock farms. Journal of Antimicrobial Chemotherapy 68, 478– 480. Fischer, J., Rodríguez, I., Schmoger, S., Friese, A., Roesler, U., Helmuth, R., Guerra, B., 2012. Escherichia coli producing VIM-1 carbapenemase isolated on a pig farm. Journal of Antimicrobial Chemotherapy 67, 1793–1795. Hafez, H.M., Hauck, R., Gad, W., De Gussem, K., Lotfi, A., 2010. Pilot study on the efficacy of paromomycin as a histomonostatic feed additive in turkey poults experimentally infected with Histomonas meleagridis. Archives of Animal Nutrition 64, 77–84. Kempf, I., Le Roux, A., Perrin-Guyomard, A., Mourand, G., Le Dendec, L., Bougeard, S., Richez, P., Le Poittier, G., Eterradossi, N., 2013. Effect of in-feed paromomycin supplementation on antimicrobial resistance of enteric bacteria in turkeys. The Veterinary Journal 198, 398–403. Liebhart, D., Sulejmanovic, T., Grafl, B., Tichy, A., Hess, M., 2013. Vaccination against histomonosis prevents a drop in egg production in layers following challenge. Avian Pathology 42, 79–84. Nguyen Pham, A.D., De Gussem, J.K., Goddeeris, B.M., 2013. Intracloacally passaged low-virulent Histomonas meleagridis protects turkeys from histomonosis. Veterinary Parasitology. http://dx.doi.org/10.1016/j.vetpar.2013.03.008. Smet, A., Rasschaert, G., Martel, A., Persoons, D., Dewulf, J., Butaye, P., Catry, B., Haesebrouck, F., Herman, L., Heyndrickx, M., 2011. In situ ESBL conjugation from avian to human Escherichia coli during cefotaxime administration. Journal of Applied Microbiology 110, 541–549.
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Effects of antimicrobial usage on the development of antimicrobial resistance Histomoniasis (‘blackhead’), caused by Histomonas meleagridis, is a major problem in turkey rearing. There are few therapeutic options for treatment of this disease and vaccination is still in the experimental phase (Liebhart et al., 2013; Nguyen Pham et al., 2013). Medication with the aminoglycoside antibiotic paromomycin may play a role in the control of histomoniasis, but also has the potential to select for resistant bacteria. Evaluating the effects of antimicrobial agents on the selection of resistance in experimental models has always been difficult. It requires a major research effort, including large groups of animals and numerous samples; few such studies have been performed. Most studies on selection for resistance rely on epidemiological data through surveillance studies, in which consumption of antibiotics is correlated with the occurrence of resistance. However, evaluating data from such studies has proven to be difficult, since resistance is not only driven by the use of antimicrobial agents, but is also related to the dynamics of the bacterial population and mobile genetic element(s) on which genes encoding resistance are located. Selection for resistance in Enterococcus spp. has been demonstrated through the use of avoparcin, a glycopeptide antibiotic that is cross-resistant with vancomycin, as well as for other growth promoting antibiotics (Butaye et al., 1999, 2001). An epidemiological study demonstrated co-resistance selection of vancomycin-resistant enterococci (VRE) with macrolide antibiotics, causing an unusual high prevalence of VRE in pigs, even after a ban on avoparcin was introduced (Aarestrup et al., 2000; Bager et al., 1999; Butaye et al., 1999). In this issue of The Veterinary Journal, Dr Isabelle Kempf of the Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES) and colleagues have published an interesting field study examining the effects of the use of paromomycin on selection of resistance in the intestinal microbiota of turkeys (Kempf et al., 2013). They studied the evolution of resistance in Escherichia coli, Enterococcus faecium and Staphylococcus aureus in 24 turkey flocks for a period of 180 days and demonstrated the selective effect of paromomycin, as well as selection for coresistance against other antibiotics. However, this was not equal for all the bacterial species investigated, since selection for coresistance could only be demonstrated in E. coli. The effect persisted after treatment, although the frequency of resistance decreased in both groups. This study is of general interest because it shows that resistance mechanisms can be present in normal intestinal bacterial populations that are selected for through the use of an antimicrobial agent. The study also demonstrates that resistance can persist even after cessation of use of the antibiotic. There is considerable debate about the effects of the use of antimicrobial agents for prevention (rather than treatment) of disease on the selection of antimicrobial resistance in bacteria. Growth promoting antibiotics, now banned in the EU, are a typical example 1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.06.024
of the use of antibiotics for purposes other than therapy; these antibiotics are administered at low doses (Butaye et al., 2003). Similar to the effects of paromomycin, these antibiotics also induce shifts in the bacterial microbiota (Hafez et al., 2010), favouring or discouraging certain bacterial species, indirectly indicating that these antibiotics might select for the less susceptible (resistant) bacteria. Even at low doses, selection for resistance is evident in vivo, as shown for the growth promoting antibiotic avilamycin, in which the relative proportions of resistant and susceptible isolates was an indicator of selection for resistance (Butaye et al., 2005). Similar to the trial by Kempf et al. (2013) with paromomycin, this resistance persisted after treatment with avilamycin had been discontinued, although the frequency of resistance had diminished by the end of the trial in all groups (Butaye et al., 2005). As such, the use of any antibiotics, even at concentrations far below therapeutic level, should be regarded as capable of selecting for resistance, albeit perhaps at different rates. A major problem of selected resistances is that they do not seem to disappear rapidly; cross-resistance and co-resistance selection may be involved in this persistence. In selection for co-resistance, the location of the resistance gene on specific mobile genetic elements is of utmost importance, resulting in spread even without selective pressure (Smet et al., 2011). Integrons and complex genetic structures within genomic islands lead to an accumulation of resistance genes, linked to each other, increasing the selective power of one antibiotic to multiple unrelated antibiotics. Next to extended cross-resistance, single resistance elements are circulating that encode resistance against multiple unrelated antibiotics, for example the modified aac(60 )-Ib-cr gene (encoding resistance against fluoroquinolones and certain aminoglycosides) and the cfr gene (encoding resistance to lincosamides, phenicols, pleuromutilins, streptgramin A and selected 16-membered macrolides, and the oxazolidinone linezolid). As for paromomycin, selection for co-resistance by other aminoglycoside antibiotics, such as neomycin and kanamycin, is also of importance. The study by Kempf et al. (2013) also shows that the gene encoding paromomycin is transferrable and, in most cases, there was co-transfer of tetracycline, amoxicillin and sulphonamide–trimethoprim resistance. As such, care should be taken not to compromise antibacterial therapy by the long-term use of paromomycin in the prevention of histomoniasis in turkeys. It is clear that we must manage antimicrobial agents carefully. Resistance is an ever increasing problem, with some worrisome new developments, including an increase in multi-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum b-lactamase (ESBL) carrying Enterobacteriaceae and carbapenem resistance in E. coli and Salmonella spp. (Fischer et al., 2012, 2013). On the other hand, veterinarians need antibiotics for therapy. These factors should be taken into account when
308
Guest Editorial / The Veterinary Journal 198 (2013) 307–308
approving the use of particular antibiotics and evaluating the ‘pros and cons’ of the usage of antimicrobial agents; sometimes, it is like ‘balancing on a tightrope’. We should also bear in mind that few new antibiotics are in the ‘pipeline’ and there is a need to look for alternatives to antibiotics. Patrick Butaye Department of Bacteriology and Immunology Veterinary and Agrochemical Research Centre VAR-CODA-CERVA, Groeselenberg 99 B-1180 Ukkel, Belgium Department of Pathology, Bacteriology and Poultry Diseases Faculty of Veterinary Medicine, Ghent University Salisburylaan 133, 9820 Merelbeke, Belgium E-mail address: [email protected]
References Aarestrup, F.M., Seyfarth, A.M., Emborg, H.D., Pedersen, K., Hendriksen, R.S., Bager, F., 2000. Chracterization of glycoppetide-resistant Enterococcus faecium (GRE) from broilers and pigs in denmark: genetic evidence that persistance of GRE in pig hers is associated with co-selection by resistance to macrolides. Journal of CLinical Microbiology 38, 2774–2777. Bager, F., Aarestrup, F.M., Madsen, M., Wegener, H.C., 1999. Glycopeptide resistance in Enterococcus faecium from broilers and pigs following discontinued use of avoparcin. Microbial Drug Resistance 5, 53–56.
Butaye, P., Devriese, L.A., Goossens, H., Ieven, M., Haesebrouck, F., 1999. Enterococci with acquired vancomycin resistance in pigs and chickens of different age groups. Antimicrobial Agents and Chemotherapy 43, 365–366. Butaye, P., Devriese, L.A., Haesebrouck, F., 2001. Differences in antibiotic resistance patterns of Enterococcus faecalis and Enterococcus faecium strains isolated from pet and farm animals. Antimicrobial Agents and Chemotherapy 45, 1347–1378. Butaye, P., Devriese, L.A., Haesebrouck, F., 2003. Antimicrobial growth promoters used in animal feed: Effects of less well known antibiotics on Gram-positive bacteria. Clinical Microbiology Reviews 16, 175–188. Butaye, P., Devriese, L.A., Haesebrouck, F., 2005. Effect of avilamycin fed to chickens on E. faecium counts and on the selection of avilamycin-resistant E. faecium populations. Microbial Drug Resistance 11, 170–177. Fischer, J., Rodríguez, I., Schmoger, S., Friese, A., Roesler, U., Helmuth, R., Guerra, B., 2013. Salmonella enterica subsp. enterica producing VIM-1 carbapenemase isolated from livestock farms. Journal of Antimicrobial Chemotherapy 68, 478– 480. Fischer, J., Rodríguez, I., Schmoger, S., Friese, A., Roesler, U., Helmuth, R., Guerra, B., 2012. Escherichia coli producing VIM-1 carbapenemase isolated on a pig farm. Journal of Antimicrobial Chemotherapy 67, 1793–1795. Hafez, H.M., Hauck, R., Gad, W., De Gussem, K., Lotfi, A., 2010. Pilot study on the efficacy of paromomycin as a histomonostatic feed additive in turkey poults experimentally infected with Histomonas meleagridis. Archives of Animal Nutrition 64, 77–84. Kempf, I., Le Roux, A., Perrin-Guyomard, A., Mourand, G., Le Dendec, L., Bougeard, S., Richez, P., Le Poittier, G., Eterradossi, N., 2013. Effect of in-feed paromomycin supplementation on antimicrobial resistance of enteric bacteria in turkeys. The Veterinary Journal 198, 398–403. Liebhart, D., Sulejmanovic, T., Grafl, B., Tichy, A., Hess, M., 2013. Vaccination against histomonosis prevents a drop in egg production in layers following challenge. Avian Pathology 42, 79–84. Nguyen Pham, A.D., De Gussem, J.K., Goddeeris, B.M., 2013. Intracloacally passaged low-virulent Histomonas meleagridis protects turkeys from histomonosis. Veterinary Parasitology. http://dx.doi.org/10.1016/j.vetpar.2013.03.008. Smet, A., Rasschaert, G., Martel, A., Persoons, D., Dewulf, J., Butaye, P., Catry, B., Haesebrouck, F., Herman, L., Heyndrickx, M., 2011. In situ ESBL conjugation from avian to human Escherichia coli during cefotaxime administration. Journal of Applied Microbiology 110, 541–549.