Friday, July 2, 2010

Augean Stables

In June 2010 the FDA issued a "Draft Guidance" titled "The Judicious Use of Medically Important Antimicrobial Drugs in Food-producing Animals."

Basically, it recommends that farmers use antibiotics on food-producing animals only when the animal's health requires it. For many years, food-animal producers have used anitbiotics or anitmicrobials to increase the rate of weight gain and to improve feed efficiency.

It issued this recommendation because it had been determined that the "non-judicious" (euphemism for careless and abusive) use of antimicrobials was responsible for selectively evolving virulent antibiotic-resistant strains of bacteria that found their way into food, and into human bodies.

The FDA'a report provides some history and background which should be very embarrassing to it, the Centers for Disease Control and Prevention, the Department of Agriculture, and Congress.

In 1969, a  "Joint Comittee" in the U.K. explored the issue and presented the "Swann Report" to Parliament:

The report stated, “It is clear that there has been a dramatic increase over the years in the numbers of strains of enteric bacteria of animal origin which show resistance to one or more antibiotics. Further, these resistant strains are able to transmit this resistance to other bacteria. This resistance has resulted from the use of antibiotics for growth promotion and other purposes in farm livestock”. The report also noted, “There is ample and incontrovertible evidence to show that man may commonly ingest enteric bacteria of animal origin”.

A 1970 FDA "Task Force" came up with the following:

This task force acknowledged that the understanding at the time it conducted its study was that the use of antimicrobials in food-producing animals, especially in subtherapeutic amounts, was associated with the development of resistant bacteria, and that treated animals might serve as a reservoir of antimicrobial-resistant pathogens that could produce human disease.
[i]n 1977, FDA proposed to withdraw the new animal drug approvals for subtherapeutic uses of penicillin and tetracyclines in animal feed on the ground that evidence showed that these drugs, when used for such purposes in animal feed, had not been shown to be safe. These two drugs were chosen because of their importance in human medicine.
[t]he proposal was criticized because, at that time, there was not adequate epidemiological evidence (or only just-emerging evidence) to show that drug-resistant bacteria of animal origin were commonly transmitted to humans and caused serious illness. Subsequently, Congress directed FDA to conduct further studies related to the use of antimicrobials in animal feed and to hold in abeyance the implementation of the proposed antimicrobial withdrawal actions pending the outcome of these studies.
It might be interesting to know who in congress, or outside of congress, was responsible for this foot-dragging.

Then in 1980 The National Academy of Sciences, at FDA's request, gave this report
...that a very limited amount of epidemiological research had been completed on either the subtherapeutic or therapeutic use of antimicrobials in animal feed. According to the study report, much of the information available on the subject involved “poorly controlled studies of small numbers of subjects for brief periods”. Based on a consideration of available evidence, the report concluded that existing data could neither prove nor disprove the postulated hazards to human health from subtherapeutic antimicrobial use in animal feed. However, the report cautioned that “The lack of data linking human illness with subtherapeutic levels of antimicrobials must not be equated with proof that the proposed hazards do not exist. The research necessary to establish and measure a definitive risk has not been conducted and, indeed, may not be possible.”
Apparently, they didn't want to offend anyone. Then, FDA asked the Seattle-King County Health Department to perform a study:
In 1984, the Seattle-King County Health Department prepared a report summarizing the results of the study. The 1984 study report found that C. jejuni was a more common cause of enteritis than Salmonella. Also, it concluded that C. jejuni "does appear to flow from chickens to man via consumption of poultry products". The report stated, "isolates from human cases and those from retail poultry had similar antibiotic susceptibility patterns, including prevalence of 29.7% and 32.8%, respectively, for tetracycline resistance, which was found to be plasmid-mediated".
A 1988 Institute of Medicine report, requested by the FDA, concerning Salmonella infections that resulted in death
...was unable to find a substantial body of direct evidence demonstrating that the subtherapeutic use of penicillin or tetracycline in animal feed posed a human health hazard. Nonetheless, the Committee’s 1988 report found a considerable body of indirect evidence implicating both subtherapeutic and therapeutic use of antimicrobials as a potential human health hazard. The Committee also strongly recommended further study of the issue.
Even the World Health Organization could put 2 and 2 together correctly on the issue. In 1997, after studying the matter, it arrived at
the conclusion that all uses of antimicrobials lead to the selection of resistant forms of bacteria. Furthermore, the report stated that “low-level, long-term exposure to antimicrobials may have greater selective potential than short-term, full-dose therapeutic use". The report found that the selection of resistant bacteria has adverse consequences for preventing and treating disease in humans, animals, and plants.
A 1999 Government Accountability Office report recommended that
the departments of Agriculture and Health and Human Services work together to develop and implement a plan with specific goals, time frames and resources needed for determining the safe use of antibiotics in agriculture.
Also in 1999 the European Commission reported that
actions should be taken promptly to reduce the overall use of antimicrobials. Four primary recommendations were forwarded: (1) antimicrobial drugs should be used prudently; (2) infections should be prevented and resistant organisms contained; (3) research for new modalities of prevention and treatment of infections should be undertaken; and (4) the effects of such interventions should be monitored and evaluated.
A 2000 World Health Organization "Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food" report by expert consultation read, in part:
The Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE) participated in the June 2000 WHO expert consultation, the purpose of which was to develop global principles for minimizing the negative public health impact associated with the use of antimicrobial agents in food-producing animals while providing for their safe and effective use in veterinary medicine.

The principles were part of a comprehensive WHO global strategy for the containment of antimicrobial resistance and provided a framework of recommendations to reduce the overuse and misuse of antimicrobials in food-producing animals for the protection of human health. The principles strengthened and endorsed earlier WHO recommendations such as the need to terminate the use of antimicrobial growth promoters pending comprehensive human health safety evaluations, the need to ensure that all antimicrobials for animal use are only supplied through authorized outlets (e.g., by veterinary prescription), and the need to establish surveillance systems on antimicrobial drug consumption.
And then
In December 2003, the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and the World Health Organization (WHO) convened a workshop to “perform a scientific assessment of the antimicrobial resistance risks arising from non-human usage of antimicrobials and to formulate recommendations and options for future risk management actions to be considered by the Codex Alimentarius Commission (Codex) and OIE”.

The expert panel’s findings from the workshop were documented in a report which contained a number of conclusions, including: 1) “there is clear evidence of adverse human health consequences due to resistant organisms resulting from non-human usage of antimicrobials;” 2) “the amount and pattern of non-human usage of antimicrobials impact the occurrence of resistant bacteria in animals and on food commodities and thereby human exposure to these resistant bacteria;” 3) “the foodborne route is the major transmission pathway for resistant bacteria and resistance genes from food animals to humans, but other routes of transmission exist;” and 4) the “consequences of antimicrobial resistance are particularly severe when pathogens are resistant to antimicrobials critically important in humans”.
In the following year this group established some guidelines, saying, among other things, that
...good agricultural practices can reduce the necessity for antimicrobials...

In 2003 the Institute Of Medicine issued a report, "Microbial Threats to Health: Emergence, Detection and Response" that included recommendations
to “more finely target the use of antimicrobials” including expanding efforts to decrease the inappropriate use of antimicrobials in human medicine. In addition, the committee recommended that “FDA ban the use of antimicrobials for growth promotion in animals if those classes of antimicrobials are also used in humans”.
That was fairly explicit.

In 2004 in response to a request from Congress (apparently out to lunch with lobbyists for 35 years), the Government Accountability Office studied the issue again and reported
that antibiotic-resistant bacteria have been transferred from animals to humans. GAO also stated that many of the studies reviewed as part of GAO’s research found that this transference from animals to humans poses significant risks for human health. According to GAO’s findings, studies have shown two types of evidence related to the transfer of antibiotic-resistant bacteria from animals to humans. First, some studies have provided evidence of associations between changes in antibiotic use in animals and resistance to antibiotics in human bacteria. Second, GAO concluded that studies that have examined the genetic makeup of the bacteria have provided stronger scientific evidence that antibiotic-resistant Campylobacter and Salmonella bacteria are transferred from animals to humans. In those studies, strains of antibiotic-resistant bacteria infecting humans were indistinguishable from those found in animals, leading researchers to conclude that the animals were the source of human infection.
Why did it take so long to arrive at the same conclusions at which the UK's Swann Report study arrived in 1969?

U.S. Department of Health and Human Services read the GAO report and issued the following comments:
“The draft report presents or refers to significant and growing evidence demonstrating the human health consequences of drug resistant infections related to antibiotic use in agriculture.” “These [11 additional] studies, along with those cited in the GAO report, all demonstrate a relationship between the use of antimicrobials in food-producing animals, antibiotic resistance in humans, and adverse human health consequences as a result. We believe that there is a preponderance of evidence that the use of antimicrobials in food-producing animals has adverse human consequences.” “There is little evidence to the contrary.”
The FDA finally agrees in 2010 saying that it
...has reviewed the recommendations provided by the various published reports and, based on this review, believes the overall weight of evidence available to date supports the conclusion that using medically important antimicrobial drugs for production purposes is not in the interest of protecting and promoting the public health.
And it proposes the following 2 Principles:
1. The use of medically important antimicrobial drugs in food-producing animals should be limited to those uses that are considered necessary for assuring animal health.

2. The use of medically important antimicrobial drugs in food-producing animals should be limited to those uses that include veterinary oversight or consultation.
It took Heracles one day. After 41 years, the FDA is still working on it.

July 2, 2010.