Pleuromutilins: use in food-producing animals in the European Union, development of resistance and impact on human and animal health

Abstract

Pleuromutilins (tiamulin and valnemulin) are antimicrobial agents that are used mainly in veterinary medicine, especially for swine and to a lesser extent for poultry and rabbits. In pigs, tiamulin and valnemulin are used to treat swine dysentery, spirochaete-associated diarrhoea, porcine proliferative enteropathy, enzootic pneumonia and other infections where Mycoplasma is involved. There are concerns about the reported increases in the MICs of tiamulin and valnemulin for porcine Brachyspira hyodysenteriae isolates from different European countries, as only a limited number of antimicrobials are available for the treatment of swine dysentery where resistance to these antimicrobials is already common and widespread. The loss of pleuromutilins as effective tools to treat swine dysentery because of further increases in resistance or as a consequence of restrictions would present a considerable threat to pig health, welfare and productivity. In humans, only one product containing pleuromutilins (retapamulin) is authorized currently for topical use; however, products for oral and intravenous administration to humans with serious multidrug-resistant skin infections and respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA), are being developed. The objective of this review is to summarize the current knowledge on the usage of pleuromutilins, resistance development and the potential impact of this resistance on animal and human health.

Mutations Associated with Decreased Susceptibility to Seven Antimicrobial Families in Field and Laboratory-Derived Mycoplasma bovis Strains

“…Cross-resistance between macrolides and lincomycin has long been described (35,48), and cross-resistance was also reported between macrolides, pleuromutilins, lincomycin, and florfenicol (39,41). In the present study, the valnemulin-resistant MYC53 harboring mutations at positions 2035, 2060, 2500, and 2611 had elevated MICs to all of the tested 50S inhibitors.…”

“…The mutations at positions 2500 and 2506 found in the present study are closely related to the ribosomal binding sites of phenicols and pleuromutilins (39,41). In M. gallisepticum mutation A2503U leads to decreased susceptibility to phenicols and lincomycin beside pleuromutilins (39) and alteration of nucleotides 2498, 2499 2503 and 2504 causes resistance to pleuromutilins or florfenicol in different bacterial species (41,47). Alteration of position 2448 in tiamulin resistant MYC53 lead to decreased susceptibility to florfenicol and pleuromutilins, and the importance of position 2447 in pleuromutilin resistance was previously described in M. gallisepticum.…”

“…Mutants harboring A2063T substitution had eight times higher MIC values to florfenicol than their parental strains, suggesting the impact of this position in florfenicol resistance. The mutations at positions 2500 and 2506 found in the present study are closely related to the ribosomal binding sites of phenicols and pleuromutilins (39,41). In M. gallisepticum mutation A2503U leads to decreased susceptibility to phenicols and lincomycin beside pleuromutilins (39) and alteration of nucleotides 2498, 2499 2503 and 2504 causes resistance to pleuromutilins or florfenicol in different bacterial species (41,47).…”

“…This antimicrobial group binds to the peptidyl transferase center and also inhibits the peptide bond formation and protein synthesis. Pleuromutilin resistance commonly derives from chromosomal mutations in the 23S rRNA and rplC genes and emerges relatively slowly in a stepwise fashion (41). In the present study, slow evolution of valnemulin resistance was observed in the mutant MYC52 and MYC53 strains, whereas PG45 obtained resistance within three passages.…”

Antibiotic susceptibility profiles of Mycoplasma sp. 1220 strains isolated from geese in Hungary

“…To date, the use of pleuromutilins in humans is limited, as only one commercially available product is authorized containing this active substance. However, bacterial strains resistant to pleuromutilins have already been described and these strains also show multidrug resistance, which warrants the prudent use of these antibiotic agents [25]. …”