Will Avilamycin Convert Ziracine into Zerocine?

To the Editor: Avilamycin and evernimicin (Ziracine), which belong to the everninomicin class of drugs, are oligosaccharide antibiotics active against numerous gram-positive bacteria, including emerging pathogens such as glycopeptide-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant pneumococci (1,2). The two drugs share the same mode of action--inhibition of translation--by binding to the same target in the large 50S ribosomal subunit (3). As a result, they also display cross-resistance: bacteria resistant to avilamycin are resistant to evernimicin (and vice versa), but not to other classes of drugs (4). Two mechanisms of resistance to this class of drugs are amino-acid substitution in ribosomal protein L16 (5) and mutations in the peptidyltransferase domain of 23S ribosomal RNA (6).

Avilamycin has been used in Europe for several years as a growth promoter for food animals, particularly pigs. Enterococci resistant to everninomycins have been isolated from animals receiving avilamycin as a food additive (4). Evernimicin is being evaluated as a human therapeutic agent. Indirect evidence indicates that the use as growth promoters of antibiotics that display cross-resistance with those used in human therapy contributes to antibiotic resistance in bacteria responsible for human infections (7). As early as 1969, a recommendation was published in the United Kingdom that antibiotics used to treat infections in humans not be used as animal food additives (8). In 1999, four antibiotics were banned as food additives in the European community.

Antibiotic resistance in human pathogens has become a major health issue, complicated by the fact that no new class of drugs has been introduced for human therapy in the last 25 years. Since the use of avilamycin in animals has favored selection of enterococcal strains that are cross-resistant to evernimicin (4), these bacteria can colonize the human gut or form a pool of resistance genes that can spread to human commensals or pathogens (9). The continued use of avilamycin as a growth promoter is likely to diminish the effectiveness of evernimicin if Ziracine or any member of the class is used for human therapy. Since everninomicins will be prescribed mainly for infections due to multiresistant gram-positive cocci, avilamycin should be prospectively banned as an animal growth promoter.

References

1. Weinstein MJ, Luedemann GM, Oden EM, Wagman GH. Everninomicin, a new antibiotic complex from Micromonospora carbonacea. Antimicrob Agents Chemother 1965;9:24-32.
2. Jones RN, Barrett MS. Antimicrobial activity of everninomicin (evernimicin), an oligosaccharide antimicrobial with a potent Gram-positive spectrum. Clin Microbiol Infect 1995;1:35-43.
3. McNicholas PM, Najarian DJ, Mann PA, Hesk D, Hare RS, Shaw KJ, et al. Evernimicin binds exclusively to the 50S ribosomal subunit and inhibits translation in cell free systems derived from both gram-positive and gram-negative bacteria. Antimicrob Agents Chemother 2000;44:1121-6.
4. Aarestrup FM. Association between decreased susceptibility to a new antibiotic for treatment of human diseases, everninomicin (SCH 27899), and resistance to an antibiotic used for growth promotion in animals, avilamycin. Microb Drug Resist 1998;4:137-41.
5. Adrian PV, Zhao W, Black TA, Shaw KJ, Hare RS, Klugman KP. Mutations in ribosomal protein L16 conferring reduced susceptibility to evernimicin (SCH27899): implications for mechanism of action. Antimicrob Agents Chemother 2000;44:732-8.
6. Adrian PV, Mendrick C, Loebenberg D, Shaw KJ, Klugman KP, Hare RS, et al. Ziracin (SCH27899) inhibits a novel ribosome target site: an analysis of 23S rRNA mutants. Abstract no. 845. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1999; San Francisco.
7. Wegener HC, Aarestrup FM, Jensen LB, Hammerum AM, Bager F. Use of antimicrobial growth promoters in food animals and Enterococcus faecium resistance to therapeutic antimicrobial drugs in Europe. Emerg Infect Dis 1999;5:329-35.
8. Swann MM. Report of the joint committee on the use of antibiotics in animal husbandry and veterinary medicine. London: Her Majesty's Stationery Office; 1969.
9. Simonsen GS, Haaheim H, Dahl KH, Kruse H, Løvseth A, Olsvik Ø, et al. Transmission of VanA-type vancomycin-resistant enterococci and vanA resistance elements between chicken and humans at avoparcin-exposed farms. Microb Drug Resist 1998;4:313-8.

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