Past Issue
Vol. 7, No. 3
May–Jun 2001
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Letter
Will Avilamycin Convert Ziracine into Zerocine?
Read original letter, http://www.cdc.gov/ncidod/eid/vol6no5/courvalin_letter.htm
Read reply to this letter, http://www.cdc.gov/ncidod/eid/vol7no3/courvalin_letter.htm
To the Editor: Dr. Courvalin urges that avilamycin be prospectively banned as an antibiotic growth promoter to prevent the development of bacteria
cross-resistant to the potential human-use product evernimicin (1). Elanco Animal Health, the manufacturer of
avilamycin, would like to clarify the
situation with respect to avilamycin and everninimicin. It should be noted that there is incomplete cross-resistance in that enterococci resistant to
avilamycin exhibit only decreased susceptibility, not complete resistance, to evernimicin
(2). Dr. Courvalin's recommendation has become moot, since
Schering-Plough has discontinued clinical development of Ziracin, as announced in early May 2000, "because the balance between efficacy and safety
did not justify further development of the product" (www.sch-plough.com/news/research/2000/050500.html). Thus, avilamycin actually remains
in compliance with the Swann principles. In addition, the Scientific Committee on Animal Nutrition, which advises the European Union Commission,
released its assessment of the potential impact from cross-resistance in late April 2000
(www.europa.eu.int/comm/food/fs/sc/scan/out48_en.pdf)
and concluded that, although transfer of resistant bacteria-and presumably resistance genes-from animal to human bacteria is possible, the magnitude
of the transfer with avilamycin resistance was not possible to predict. In part, this conclusion reflected the early developmental status of Ziracin and a
few reports of clinical experience. An extensive survey of Ziracin showed that 100% of 4,208 enterococcal isolates from patients in 27 European
countries were susceptible (3). Another survey of Ziracin showed that 99.5%-100% of 6,030 isolates of
methicillin-resistant Staphylococcus aureus/epidermidis, enterococci, streptococci, and pneumococci from 33 laboratories around the world were susceptible
(4). Avilamycin has been used in animal
production in many of the countries from which these clinical isolates originated. To fairly balance a preemptive precautionary action against a
currently marketed animal use product and a human clinical candidate, the World Health Organization Global Principles recommended that such an
action be initiated only when the human clinical candidate dossier is submitted for regulatory approval, to ensure that the candidate will indeed enter
the marketplace. (Use of antimicrobial growth promoters that belong to classes of antimicrobial agents used or submitted for approval in humans and
animals should be terminated or rapidly phased out in the absence of risk-based evaluations.)
[www.who.int/emc/diseases/zoo/who_global_principles.html#Purpose]). This recommendation also acknowledges, in accordance with the Swann Principles, that antimicrobial agents intended for
nonhuman use can be used in animal production. The modification by the pharmaceutical industry of older classes of antimicrobials for human
clinical use, with counterparts previously developed by animal health companies for use as growth promoters, has become common. Dr. Aarestrup of
the Danish Veterinary Laboratory commented that "it will be necessary in the future to either totally avoid the use of antimicrobials for growth
promotion or, once antimicrobials have been approved for growth promotion, to reserve these classes for growth promotion and search for therapeutic
options among other classes" (2). With respect to avilamycin, this latter option is the better one, now that evernimicin (and perhaps the entire
orthosomycin class by extension) has been demonstrated to be unsafe for parenteral or injectable use in humans, because it allows animal producers to
use a product that poses no resistance threat to public health. Finally, other unique antibiotics for treatment of serious gram-positive infections in
humans (with no animal use counterparts) are in the pharmaceutical pipeline (e.g., LY333328 and
daptomycin) or have recently been approved (e.g., linezolid). We hope that a fair balance can be achieved by the human medical and the animal health and production communities with regard to the
types of antimicrobial agents that can be used in each sector.
Thomas R. Shryock
Elanco Animal Health, Greenfield, Indiana, USA
References
- Courvalin P. Will avilamycin convert ziracine into
zerocine? Emerg Infect Dis 2000;6:558.
- Aarestrup FM. Association between decreased susceptibility to a new antibiotic for treatment of human disease, everninomicin
(SCH 27899), and
resistance to an antibiotic used for growth promotion in animals, avilamycin. Microb Drug Resist 1998;4:137-41.
- Schouten MA, Voss A, Hoogkamp-Korstanje JAA, and the European VRE Study Group.
Antimicrobial susceptibility patterns of enterococci
causing infections in Europe. Antimicrob Agents Chemother 1999;43:2542-6.
- Jones RN, Hare RS, Sabatelli FJ, Ziracin Susceptibility Testing Group. In vitro gram-positive antimicrobial activity of evernimicin
(SCH 27899), a
novel oligosaccharide, compared with other antimicrobials: a multicentre international trial. J Antimicrob Chemother 2001;47:15-25.
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