Here’s the letter:
Andrew C. von Eschenbach, M.D.
U.S. Food and Drug Administration
5600 Fishers Lane,
Rockville MD 20857-000
Dear Acting Commissioner von Eschenbach,
We are writing to support the recommendation of the VMAC to reject and not approve the use of cefquinome, a fourth-generation cephalosporin antibiotic, for use in animal agriculture. One area that is critical in assessing the potential effects of cefquinome use is the exposure of non-target organisms, including opportunistic pathogens such as Escherichia coli.
Cefquinome exposure can result in resistance to other cephalosporin antibiotics, including the medically-important antibiotic cefepime. Decreased cefepime sensitivity and resistance is due, in large part, to extended-spectrum beta-lactamases (ESBLs), including CTM-X-15. These genetically mobile genes have been observed at clinically significant frequencies in many countries, and are increasing in frequency in the U.S. Cefquinome use in agriculture, especially with no specific limitations on off-label use, will increase the prevalence of these powerful antibiotic resistance genes.
Since many disease-causing bacteria are both pathogens as well as components of the normal microbiota in animals and people (e.g., E. coli), cefquinome use will accelerate the replacement of older, less effective beta-lactamases with newer beta-lactamases that confer resistance to cefepime. These resistant bacteria then can either cause infections directly or serve as a reservoir of resistance genes which can then be transferred into other bacterial species. Evidence outside of the U.S. strongly indicates that this has already happened. For example, CTM-X-15 ESBLs have been isolated from Salmonella in Ireland and E. coli in Mexico. In Australia, resistance to older cephalosporins has occurred by a two-step process. First, an ESBL is acquired through gene transfer, and then followed by a very simple change in the bacterium’s ability to take up the antibiotic. There is no reason to think this will not occur with cefquinome (and thus cefepime). The history of antibiotic resistance, in fact, suggests that if cefquinome is approved, cefquinome resistance will evolve. It would fly in the face of over a half-century’s worth of scientific observation to conclude otherwise.
Another disturbing trend associated with cefepime resistance in non-target organisms is the correlation between cefepime resistance and resistance to other antibiotics. Resistance to cefepime in conjuction with resistance to other antibiotics can also lead to increased treatment failure, since many cefepime-resistant organisms are multidrug resistant. Consequently, we think it is premature to conclude that there will always be other options for treatment. Cefquinome/cefepime resistance will require that antibiotics of last resort be used for treatment of human infections. This will have tragic consequences for the mortality and morbidity associated with these infections, and it will also increase the economic burden of treatment.
Now is the time to take action before these ESBLs become established in similar bacterial populations in the U.S., not when it is already too late, particularly in light of the slowing discovery of novel antibiotics for human therapeutic use. We strongly urge you to follow the recommendation of the expert advisory panel and not release cefquinome for agricultural use, so that we may preserve the power of these life-saving drugs.
[Mike the Mad Biologist and His Heroic Comrades in the Glorious Struggle Against Antibiotic Resistance]