Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark

Abstract

From 1995 to 2000, a total of 673 Enterococcus faecium and 1,088 Enterococcus faecalis isolates from pigs together with 856 E. faecium isolates from broilers were isolated and tested for susceptibility to four classes of antimicrobial agents used for growth promotion as part of the Danish program of monitoring for antimicrobial resistance. The four antimicrobials were avilamycin, erythromycin, vancomycin, and virginiamycin. Major changes in the use of antimicrobial agents for growth promotion have occurred during the last 6 years in Denmark. The government banned the use of avoparcin in 1995 and of virginiamycin in 1998. Furthermore, the producers have voluntarily stopped all use beginning in 1999. The avoparcin ban in 1995 was followed by a decrease in the occurrence of glycopeptide-resistant E. faecium (GRE) in broilers, from 72.7% in 1995 to 5.8% in 2000. The occurrence of glycopeptide resistance among isolates from pigs remained constant at around 20% from 1995 to 1997. It was shown that, in GRE from pigs, the genes encoding macrolide and glycopeptide resistance were genetically linked and that, following the decrease in the use of tylosin during 1998 and 1999, the occurrence of GRE in pigs decreased to 6.0% in 2000. From 1995 to 1997 the occurrence of erythromycin resistance among E. faecium and E. faecalis isolates from pigs was almost 90%. Use of tylosin decreased considerably during 1998 and 1999, and this decrease was followed by decreases in the occurrence of resistance to 46.7 and 28.1% among E. faecium and E. faecalis isolates from pigs, respectively. Erythromycin resistance among E. faecium isolates from broilers reached a maximum of 76.3% in 1997 but decreased to 12.7% in 2000 concomitantly with more limited use of virginiamycin. Use of virginiamycin increased from 1995 to 1997 and was followed by an increased occurrence of virginiamycin resistance among E. faecium isolates in broilers, from 27.3% in 1995 to 66.2% in 1997. In January 1998 the use of virginiamycin was banned in Denmark, and the occurrence of virginiamycin resistance decreased to 33.9% in 2000. Use of avilamycin increased from 1995 to 1996 and was followed by an increase in avilamycin resistance among E. faecium isolates from broilers, from 63.6% in 1995 to 77.4% in 1996. Since 1996 avilamycin usage has decreased, followed by a decrease in resistance to 4.8% in 2000. Our observations show that it is possible to reduce the occurrence of antimicrobial resistance in a national population of food animals when the selective pressure is removed. Cases in which resistance to vancomycin was linked to resistance to erythromycin were exceptions. In such cases resistance did not decrease until the use of both avoparcin and tylosin was limited.

Erratum: Can landscape ecology untangle the complexity of antibiotic resistance?

“…Changes in resistance patterns over time are also often detected, but these changes are not always reflective of obvious changes in antibiotic usage 5,7,22 . A major challenge in this sort of study is to correctly characterize exposure to antibiotics and any other factor that might select for changes in antibiotic resistance.…”

“…Currently, resistance in a sample is based on the cultivation of specific bacteria, and categorizing the bacterial isolates into resistant and susceptible groups. If only one colony is analysed per sample, as is done in some surveillance systems 5,38,101 , then this is equivalent to saying that the entire sample is resistant or susceptible. However, all of the bacteria in a sample or at a given site can be under the same set of selection pressures, and therefore, the 'amount' of a resistance gene present in all of the bacteria in a sample might be a better predictor of the selection pressures being applied to that sample over short-and long-term timescales.…”

“…For example, as some countries have reduced the amount of antibiotic used in animal agriculture, specific resistance has persisted in the apparent absence of primary selection pressure 5,7,22 . A more thorough genetic analysis of these isolates reveals that linkages to other antibiotics 5,47 can partially explain this persistence. Commonly used disinfectants can also help explain certain patterns of antimicrobial resistance.…”

“…The presence of resistance was thought to exert a fitness cost on the organism: when the antibiotic was removed, the organism was expected to lose its resistance or else be competitively replaced by a susceptible organism with higher fitness. This assumption has been questioned [19][20][21] , and recent evidence demonstrates that, in the absence of selection pressure due to antibiotic use, resistance levels in bacterial populations are often slow to decline, if at all 5,7,22 . In fact, some organisms with antibiotic-resistant phenotypes and genotypes seem to be fitter than their susceptible counterparts [23][24][25][26] , and compensatory mutations have been observed that allow the resistant organism to retain its fitness level 27 .…”

“…The relationship between antibiotic use and the development of resistance has been studied extensively, with some of this research aimed at identifying antibiotic treatment strategies that minimize the maintenance of resistance genes and resistant bacterial strains. However, attempts to reduce resistance levels through changes in antibiotic use patterns have had variable success, leading us to question whether antibiotic use is the only (or even the predominant) selection pressure maintaining antibiotic resistance [1][2][3][4][5][6][7][8][9] .…”