Monday, April 11, 2016

Nature Pushes Back Against A Miracle

"It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them."  Alexander Fleming, discoverer of penicillin, Nobel Prize in Physiology or Medicine; from his 1945 Nobel Lecture.

The overuse, misuse, and abuse of antibiotics in human health care and animal husbandry, and the consequent emergence of antibiotic-resistant bacteria, reveal the ineptness and corruption of the conventional medical establishment in America. Doctors, pharmaceutical-biotech companies, industrial farming operations, and the FDA share responsibility. "There is no longer time for silence and complacency." ("Society's failure to protect a precious resource: antibiotics"; doi: 10.1016/S0140-6736(11)60401-7).

A March 25, 2016 New York Times article titled "How To Stop Overprescribing Antibiotics" gets one's attention: do you mean that prescribing doctors continue to over-prescribe antibiotics? Apparently the answer is "Yes". The article promotes the authors' research and suggests that doctors are just as irrational as the rest of us. (Don't let that information get out.) They say their research demonstrates that some very simple measures could be used to reduce the amount of unnecessary prescriptions written by doctors.

The article notes a couple of strategies that haven't worked. Educating doctors and patients about antibiotic use and abuse "has had only a modest effect". Alerts to doctors via electronic health records didn't work because doctors ignored the messages. "And offering doctors financial incentives" to not prescribe antibiotics doesn't work so well either "because the payments are modest relative to a doctor's salary." This last strategy is the most preposterous of all: paying doctors a bonus to do what they're getting paid to do in the first place.

The article mentions a study published in JAMA Internal Medicine that explored the effect of something called "decision fatigue" on the rate of prescribing unnecessary antibiotics. It found that "decision fatigue progressively impairs clinicians' ability to resist ordering inappropriate treatments." In other words, the later in the day you go to the doctor the greater your chance of getting a 'scrip for antibiotics.

The antibiotic penicillin is called the first "miracle drug" for its ability to stop bacterial infections. Its first important use was in World War II to treat soldiers' infected wounds. But it took only 20 or 30 years for the miracle to fade. By 2013 a CDC official had announced the end of the age of antibiotics and the beginning of a nightmare. "Miracle" may have been an overstatement.

A CDC Report, "Antibiotic Resistance Threats In The United States, 2013" estimates that "...more than two million people are sickened every year with antibiotic resistant infections, with at least 23,000 dying as a result". It calls these "minimum estimates". It also lists Candida, a yeast normally found in small amounts in the gastrointestinal tract and whose population increases with the use of antibiotics, as a serious threat due to its growing resistance to the anti-fungal drug fluconazole.

The 2013 CDC Report says that antibiotic-resistant infections "require prolonged and/or costly treatments, extended hospital stays..." and so on, adding "considerable and avoidable costs to the already overburdened U.S. healthcare system." Estimates of cost to the U.S. economy from antibiotic resistance, though hard to calculate, range from "$20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year (2008 dollars)".

The CDC Report says "up to 50% of all the antibiotics prescribed for people are not needed or are not optimally effective as prescribed." Of the subtherapeutic use in food animals to promote growth, the Report says " is not necessary, and the practice should be phased out."

Antibiotics pose another problem, however. The proper use of antibiotics has many side effects. A 2012 Time article says that 140,000 people, many of them children, go to a hospital emergency room each year with a bad reaction to appropriately prescribed antibiotics, and 9,000 of these have to be hospitalized. The CDC Report says that 1 out of 5 emergency room visits for adverse drug reactions are for antibiotics and that antibiotics are the most common cause of emergency room visits for children 18 years old and younger. Candida overgrowth, noted above, which represents a change in the human microbiome, is a potentially dangerous side-effect of proper antibiotic use.

The history of the antibiotic resistance debacle, in spite of Fleming's 1945 warning, begins on the farm. In the early 1950's the FDA approved the use of penicillin and a couple other antibiotics in sub-therapeutic doses as "feed additives" after it was discovered that the antibiotics fattened food animals such as chickens, pigs, and cattle. But in 1969 the U.K. "Swann Report on the Use of Antibiotics in Animal Husbandry" said that the rising rate of antibiotic resistant bacteria was due to the subtherapeutic use of antibiotics in animal feed. The FDA wasn't sure, so it put together its own fact finding group, which found that subtherapeutic antibiotics in animal feed was causing the emergence of antibiotic-resistant bacteria. It took FDA until 1973 to threaten to dis-approve the 1950's decision to use antibiotics in food-animal feed - unless "industry" could prove the safety of these feed additives. In 1978, after an abundance of convincing research in the U.S. and elsewhere showing that the subtherapeutic dose of antibiotics in animal feed causes the emergence of antibiotic-resistant bacteria, FDA decided to have a hearing on the issue. However, the U.S House of Representatives Committee on Appropriations ordered FDA to put a hold on its hearings and to do more research. FDA then asked the National Academy of Sciences to do the research. In 1980 the National Academy of Sciences said, in a kind of backward wink-wink statement, that it could not prove that the subtherapeutic use of antibiotics is safe. No worries, in 1980 the House Committee ordered more research. In 1981 the Senate Committee on Appropriations asked for more research so FDA asked a health department in Seattle to do this research. The Seattle researchers found DNA proof of resistance that was transmitted to other bacteria. Enter the pharmaceutical industry, which tried to pressure the FDA into dropping its intention to hold hearings on the issue. FDA resisted. In 1988 the Institutes of Medicine warned that the farming practice potentially was a hazard to human health. Thirteen years pass. In 2001, the American Medical Association comes out against antibiotics in animal feed. Two years later the Institutes of Medicine issues a second, more direct warning. In 2004, FDA considers telling feed manufacturers that subtherapeutic dosing of antibiotics is "high risk". In 2010 FDA prepares a document recommending that industry voluntarily limit the use of antibiotics in animal feed. In 2011, however, FDA withdrew its efforts and did not issue its recommendations. (Partly based on Maryn McKenna's chronology.)

Subtherapeutic doses of antibiotics in animal feed has been used as a "growth promoter" since the 1950's when farmers, and then scientists, discovered that feeding chickens a by-product of antibiotic production made them grow faster, live longer, and lay more eggs. Suddenly the survival of the human race was no longer in question- at least in terms of the world's "dwindling resources". In this way, antibiotics made possible intensive, industrial farming. More farm animals could be crowded into the same space and develop less disease even as they brought higher profits in the marketplace with small doses of antibiotics in their feed.

All of this was going on while doctors were handing out prescriptions for antibiotics to their patients for viral infections, which do not respond to antibiotics. Prescribing antibiotics for acute bronchitis, a viral infection for which antibiotics are useless, has remained at 73% for 30 years in the U.S. according to an October 2013 CNN online article.

In 2009, nine FDA employees wrote a letter to President Obama saying that FDA was "fundamentally broken". In addition, the agency had been accused by three Congressmen of "being too close to industry". Today FDA's home page says "Protecting and Promoting Your Health". They must be looking in the mirror. The FDA website page Consumer Updates features an article titled "Phasing Out Certain Antibiotic Use in Farm Animals". It says that it is "implementing a voluntary plan with industry to phase out the use of certain antibiotics for enhanced food production." Anticipating the question, "Why Voluntary?" the answer provided is that "it's the fastest, most efficient way to make changes." Really? Finally, the page gives an assurance: "Based on our outreach, we have every reason to believe that animal pharmaceutical companies will support us in this effort," says Michael R. Taylor, FDA's Deputy Commissioner for foods and veterinary medicine. This last statement appears to have been dated Dec. 11, 2013.

"We estimate that between 2010 and 2030, the global consumption of antimicrobials will increase by 67%..." according to"Global trends in antimicrobial use in food animals," in PNAS February 2015; doi: 10.1073/pnas.1503141112.

A 2015 FDA report "Antimicrobials sold or distributed for use in food producing animals" says  that the domestic sale and distribution  of approved antimicrobials for food producing animals increased by 17% from 2009 to 2013. Microbiologist and congresswoman Louise Slaughter, in discussing Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues by Dr. Martin Blaser, says that as of April 2015 "80% of antibiotics sold in the U.S. are used on mostly healthy animals on factory farms." She says, "Blaser's work is a stunning dose of reality in an environment flooded with corporate-agenda-fulfilling pseudoscience."

Michael R. Taylor was appointed to the newly created Commissioner position in FDA by the Obama administration. But Taylor has been through the industry-government revolving door so many times his head must be spinning. Taylor is a previous Vice President for Public Policy at Monsanto and a lobbiest for the company. Taylor also worked at the Department of Agriculture.

The obvious question is "Why is a lawyer who was a Monsanto V.P. and lobbiest, the FDA's Deputy Commissioner for foods and veterinary medicine?

According to Wikipedia, in 1991 Taylor left a law practice to accept a "newly created post of 'Deputy Commissioner for Policy'" at FDA where he promoted the positions that (1) milk from cows treated with Monsanto's rBGH should not have to be labeled, and (2) the FDA policy statement regarding the acceptance and promotion of genetically engineered foods. Under Taylor's tenure, FDA decided that genetically modified foods are exempt from testing because they're food additives, which are generally recognized as safe (GRAS). However, this was not the consensus among scientists at FDA.

That is, in recent history, two positions have been created at FDA for Michael Taylor.

In the early 1990's another former Monsanto employee, Margaret Miller, was appointed as Deputy Director of New Animal Drugs at FDA. Miller approved a report from Monsanto that attested to the safety of Monsanto's recombinant bovine growth hormone (rBGH). rBGH is given to milk cows to increase production but it also increases the incidence of mastitis, cancer, and other health problems in the cows. No worries. Miller approved an increase by 100 times the legal limit the amount of antibiotics that could be given to the cows. Oh, and the rBGH report she approved while at FDA was written by - herself, Margaret Miller, while she worked in research at Monsanto. ("Question Is Raised on Hormone Maker's Ties to FDA Aides," New York Times, April 1994.)

(While antibiotic resistance was exploding as a public health hazard around the country, at FDA claims were made of the safety and importance of genetically engineered food without their having been tested and against the opinions of agency scientists.)

Antibiotic over-prescribing to humans and subtherapeutic dosing to farm animals have been identified as causal in the emergence of antibiotic-resistant bacteria. However, research has demonstrated that for some antibiotics "extremely low concentrations, similar to concentrations found in natural environments, can select for resistant bacteria." This finding suggests that "antibiotic release into the environment might be a significant contributor to the emergence and maintenance of resistance...." Antibiotic concentrations several hundred times lower than previously determined for bacterial susceptibility will select for and enrich resistant bacteria, according to this research. ("Selection of Resistant Bacteria at Very Low Antibiotic Concentrations", doi: 10.1371/journal.ppat.1002158). In other words, any amount of antibiotics in any environment will tend to induce resistance in the bacteria it is designed to kill, and the emergent, resistant bacteria may be more lethal than the predecessor. Moreover, bacteria with the antibiotic-resistance gene-material have been found in agriculture sectors other than that of food animals. For example, resistant E. coli in spinach may have emerged in cattle eating feed containing a subtherapeutic dose of antibiotics.

A "miracle drug" that has saved many lives also has caused suffering and death. And many who have taken antibiotics prescribed appropriately have developed health issues that until recently have been invisible or mysterious to those who prescribe.

"Antibiotic use is the most common and significant cause of major alterations in normal GIT [gastrointestinal tract] microflora." These alterations "are now believed to be contributing factors to many chronic and degenerative diseases." "...infrequent antibiotic use has much longer lasting effects on the microflora and its metabolic activities than was previously believed." Alteration in gut microflora after antibiotic use increases the risk of infection by pathogens. Recent research has shown that one course of antibiotics alters gut microflora metabolism for 16 months. ("The Causes of Intestinal Dysbiosis: A Review", by Hawrelak and Myers in Alternative Medicine Review, 2004.)

"Dysbiosis" is an intestinal microbial imbalance in which the "good" bacteria no longer control the "bad" bacteria and there is an increase in the yeast population. Antibiotic use is a primary cause of intestinal dysbiosis.

"The human gut contains an immense number of microorganisms, collectively known as the microbiota... The microbiota can be viewed as a metabolic 'organ' exquisitely tuned to our physiology that performs functions that we have not had to evolve on our own... Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host... Adult humans are composed of an estimated 10 times more resident microbial than human cells.... We speculate that changes in microbial ecology prompted by Western diets, and/or differences in microbial ecology between individuals living in these societies, may function as an 'environmental' factor that affects predisposition toward energy storage and obesity." ("The gut microbiota as an environmental factor that regulates fat storage," November 2004; doi: 10.1073/pnas.0407076101).

Obesity, Type 2 Diabetes, and other health problems have been increasing since the 1980's. By 2014 38% of American adults were obese ("Obesity Rises Despite All Efforts", November 2015, New York Times). Despite a decrease in caloric intake and a general improvement in diet, Americans mysteriously get fatter. Antibiotics are used to fatten chickens, pigs, and cows - it should come as no surprise that they will fatten humans, too.

A 2015 Danish study ("Use of Antibiotics and Risk of Type 2 Diabetes: A Population-Based Case-Control Study", doi: concluded that results "could support the possibility that antibiotics exposure increases type 2 diabetes risk. However, the findings may also represent an increased demand for antibiotics from increased risk of infections in patients with yet-undiagnosed diabetes." A review of this research suggests that children who have had antibiotics experience a change in metabolism due to a change in the composition of their microbiome and consequently develop type 1 diabetes.

A 2015 article in International Journal of Obesity (doi: 10.1038/ijo.2015.218) concluded "...antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies."

In "Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice" (doi: 10.4161/19490976.22014.990790) researchers reported that "A 2-week antibiotics treatment induced a colonic dysbiosis..." and "changes in the innate intestinal immune system..." and "...short- and long-term antibiotic treatments seem to generate different states of dysbiosis...."

"Altering the Intestinal Microbiota During a Critical Developmental Window Has Lasting Metabolic Consequences", Cell, August 2014, (doi: 10.1016/j.cell2014.05.052). This study was performed on mice. However, there are implications for humans: "In humans, early-life microbiota disruption, either due to delivery by Caesarian section or antibiotics, is associated with increased risk of overweight status later in childhood...." The researchers, using a mouse model, showed that "subtherapeutic antibiotic treatment delivered at weaning increased adiposity."

"Antibiotic use in early life was associated with the development of childhood asthma, a risk that may be reduced  by avoiding the use of BS [broad-spectrum] cephalosporins." "Increased Risk of Childhood Asthma From Antibiotic Use in Early Life," (Chest, June 2007; doi: 10.1378/chest.06-3008).

"From 1980 through 1992, increasing prescribing... was found for the more expensive, broad-spectrum antimicrobial drugs, such as cephalosporins... The increased use of broader spectrum and more expensive antimicrobial drugs have implications for all patients because of the impact on health care costs and the potential for the emergence of antimicrobial resistance." ("Trends in Antimicrobial Drug Prescribing among office-based physicians in the United States," JAMA, 1995 Feb 11;279(6):434.)

"Exposure to at least one course of antibiotics in the first year of life appears to be a risk factor for the development of childhood asthma." Additional studies are needed to confirm this conclusion, the article says. ("Does Antibiotic Exposure During Infancy Lead to Development of Asthma?" Chest, March 2006; doi: 10.1378/chest.129.3.610).

Subtherapeutic antibiotic treatment "alterations of the microbiome may affect pluripotent cells that can become osteoblasts, adipocytes, or myocytes," ("Antibiotics in early life alter the murine colonic microbiome and adiposity; doi: 10.1038/nature11400).

The abstract of "Dysbiosis of the Gut Microbiota in Disease" (Microbial Ecology in Health and Disease 2015, 26: 26191 - http// begins "There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome, and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity."

Results  from "Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders" ( "support a gut-microbiome-brain connection in a mouse model of ASD [autism spectrum disorder] and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders."

Reviewing the hundreds of articles detailing the unwanted side-effects of antibiotic use and abuse, one occasionally, unbelievably, comes across the phrase "...but more research is needed...."

In January 2016 at the World Economic Forum in Switzerland 80 pharmaceutical and biotechnology companies complained that they've phased out their antibiotics research efforts because there wasn't any money in it. In a "Declaration" presented at the Forum these companies acknowledge that combating antibiotic resistance "is a top priority for global policy and public health." But because the value to society is not reflected in the costs for developing the drugs, the companies "call on governments to commit to allocating the funds needed to create a sustainable and predictable market for these technologies...." In other words, the wealthiest and most ethically challenged companies in the world want governments to subsidize their research and development of new antibiotic drugs and to "mitigate financial risk". Before following this recommendation, governments first might calculate in monetary terms the responsibility that these companies share in the overuse of antibiotics and the emergence of resistant bacteria. Where was their social consciousness in the 1980's when they tried to pressure FDA into dropping proposed hearings on the safety of antibiotics in animal feed and later when its sales reps pushed doctors to prescribe the expensive broad spectrum cephalosporins?

It's the end of the "miracle" and the "antibiotic age", and it's the end of "The War On Bugs" and the perception that permits such metaphors. The "bugs" have won because their natural adaptive response is more powerful than the human intellect.