A while back I posted about how awful it would be for the FDA to approve the use of cefquinome, an antibiotic similar to the medically important drug cefepime. I even coauthored a letter about it. Well, it turns out the IDSA wrote a letter about cefquinome too (the whole letter, in pdf). There’s good and bad things about the letter. First, the bad–the IDSA proposals about what to do if cefquinome is approved:
1. Limit the marketing status to prescription only.
2. Prohibit extra-label use of the product.
3. Limit the extent of use to “low,” meaning that the drug will be administered only to individual animals rather than groups or pens of animals.
4. Require post-approval surveillance for resistance in NARMS and provide sufficient funding to include the new drug in the NARMS panel.
5. Require the manufacturer to report the volume of product sold or distributed in the United States each calendar year. FDA should establish standard criteria for reporting. As a minimum, volume should be reported separately for use in poultry, cattle, and swine, as well as total volume sold for use in all food-producing animals. These data should be publicly available to support epidemiologic and microbiologic research on the impact of 4th generation cephalosporin use in food-producing animals.
6. Provide funding for molecular epidemiology studies to evaluate the impact of cefquinome use in livestock and the associated risk of CTX-M transmission to human pathogens and commensal flora through the food supply.
Proposal #1 is fine. But the rest aren’t very good, or, more accurately, are completely unrealistic. With regard to proposals #2 and #3, preventing off-label use and herd-wide prophylaxis are laudable goals which will never happen. I was at an agricultural meeting in Toronto about antibiotic resistance. One of the speakers reported that five percent of dairy farmers in Washington (the state) had used enrofloxacin to treat mastitis in cattle. The jaws of the FDA guys sitting at the table next to me all simultaneously hit the floor: not only is that off-label use of enrofloxacin, but it’s explicitly illegal (during the Q & A, words like prosecution were mentioned). So, like I said in the earlier posts, if cefquinome is approved, it will certainly be misused.
Then there are proposals #4 and #6. For those of you who don’t know what NARMS (the National Antimicrobial Resistance Monitoring System) is, NARMS is an interagency program that tracks antibiotic resistance from the farm and the slaughterhouse, to the supermarket, and then into sick people. It’s also been cut tremendously. In what parallel funding universe does NARMS realistically have the funding to do this?
Then there’s proposal #5, which would require sale and use reporting. That kind of regulation would be super, but it would also be a first. Does anyone think that the Bush administration would do this?
[crickets, sun rises, sun sets]
I don’t think so either. They’re nice proposals, but not reality based. Ultimately, they would just be used as a way to get the drug approved. Then, magically, the regulatory apparatus would disappear (and NARMS really needs another political motivation to cut it). I’m not sure what IDSA was thinking.
However, there is some good. The scientific explanation is very good and jibes with what my coauthors and I wrote in our letter:
Resistance to 3rd and 4th generation cephalosporins is mediated by extended spectrum beta-lactamases, or ESBLs, in gram negative organisms. ESBLs are an important cause of treatment failure in patients receiving cephalosporins. A specific family of ESBL, known as cefotaximases, or CTX-M, has rapidly expanded in the past decade to include Europe, Africa, Asia, and Latin America (1). The CTX-M gene is located on plasmids, allowing rapid and efficient spread of CTX-M mediated resistance (2). Even more concerning is the fact that CTX-M-producing isolates often exhibit coresistance to other drug classes, including fluoroquinolones. For example, ciprofloxacin resistance was strongly associated (odds ratio = 14) with the presence of CTX-M in a recent Canadian study (3). In the United Kingdom, surveillance for CTX-M producing isolates from outpatient and inpatient sources identified an epidemic strain with multiple resistance to fluoroquinolones, trimethoprim, tetracycline, and aminoglycosides (4).
Most ESBL-mediated resistance has been reported from hospitalized patients, but there is growing evidence that ESBL-producing organisms, and CTX-M producers in particular, represent an emerging problem in the community (5). For example, data from Spain indicate that the rates of ESBL-producing isolates increased significantly in both hospitalized patients and outpatients between 1991 and 2003 (6). In this study, CTX-M enzymes accounted for over 60% of the ESBL isolates. Despite the rapid emergence of CTX-M in Europe and other regions, CTX-M producing organisms appear to be uncommon in the United States. We are not aware of any published reports of community-onset disease caused by CTX-M producing organisms in this country, and there has been only a single report of 9 E. coli isolates with CTX-M from patients in five states (1, 7).
ESBL-producing E. coli with CTX-M genes have recently been detected in foodproducing animals in the United Kingdom, Denmark, and Spain (8-10). CTX-M genes have also been found in Salmonella enterica isolates from food-producing animals in Spain (11). There is a legitimate concern that food producing animals may serve as a reservoir for ESBL-producing human pathogens, and that resistance genes may be transferred to humans through the food supply and ultimately cause treatment failure in patients receiving cephalosporin therapy for serious infections….
The overall risk estimate is derived from 3 components: release assessment, exposure assessment, and consequence assessment. For the exposure assessment, the probability of human exposure is determined by the prevalence of Salmonella and Campylobacter contamination in various food commodities and the amount of the food commodity consumed by the general public. Using this framework, cefquinome is best classified as ‘medium risk’ for human exposure to resistant Salmonella or Campylobacter in beef. Since 4th generation cephalosporins are classified as ‘highly important’ for treating human infections, the overall level of risk is most appropriately ranked as medium….
IDSA supports… the overall FDA risk assessment approach. However, we note that in this case it fails to consider the human risk posed by horizontal gene transfer or clonal spread of ESBL-producing E. coli. In Europe, resistant E. coli with CTX-M have been detected on farms where 4th generation cephalosporins were administered to livestock (8, 10). The risk to human health has not been defined, but the potential for selection and horizontal transfer of CTX-M from food-producing animals to human pathogenic bacteria must be taken seriously.
We also note that many infectious disease specialists would consider 4th generation cephalosporins to be ‘critically important’ rather than ‘highly important’ for treating human infections. The 4th generation cephalosporins fail to meet the FDA criteria for ‘critically important’ only because they are not routinely recommended for treating enteric pathogens that cause foodborne disease. However, IDSA guidelines recommend 3rd and 4th generation cephalosporins for complicated, high-severity intra-abdominal infections, as well as for other serious infections in people at risk for multidrug resistant infections. Extended spectrum cephalosporins are also important for treating invasive Salmonella infections in humans. We therefore believe the FDA should re-evaluate the criteria used to classify the importance of cephalosporins for human health.
I’m surprised because IDSA is usually a little more savvy than this.