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Antibiotic Resistance: Big Pharma’s Hand in the Disaster

The COVID-19 crisis has exposed the many failures of the neoliberal model

The global antibiotic crisis has increased the COVID-19 death toll. From the Second World War onwards, drug companies overproduced antibiotics and health professionals overprescribed. Bacteria grew resistant to the drugs. One major solution is for Big Pharma to conduct R&D into new antibiotics to keep one step ahead of bacterial mutations. But that’s not profitable. With few governments willing to intervene, the crisis will worsen.

Distinctions

COVID-19 is a virus, not bacteria. The World Health Organization, therefore, advises that antibiotics should not be used to prevent or treat the virus. But like the Flu Pandemic (1918-20), many COVID-19 victims do not die of the virus, but from bacteria-related secondary complications. It is important to note that the crisis of antibiotic resistance contributes to the deaths of many COVID-19 victims. In Italy, for instance, 8.5 percent of deaths from COVID-19 complications including bacterial superinfections, with many of the bacteria strains resistant to antibiotics. In March 2020, the World Health Organization said: “Dual infections with other respiratory viral and bacterial infections have been found in SARS, MERS and COVID-19 patients.” The American College of Cardiology states: “It is important for patients with CVD to remain current with vaccinations, including the pneumococcal vaccine given the increased risk of secondary bacterial infection with COVID-19.”

Worldwide, antibiotic-resistance to respiratory pathogens, including S. pneumoniae and M. tuberculosis has reached epidemic levels. Global antibiotic usage is expected to increase from 63,000 tons in 2010 to 105,000 tons by 2030: with nearly 100 percent increases in Brazil, China, India, Russia, and South Africa. The most frequently-used antibiotics are amoxicillin and clavulanic acid. These are regarded by the World Health Organization as first or second-line drugs. Others, including carbapenems, cephalosporins, and quinolones are recommended with caution due to their high levels of resistance. The second category accounts for around a fifth of all antibiotics used globally.

Antibiotic Crisis

Formal antibiotics and antimicrobials began with Paul Ehrlich’s discovery of a syphilis cure in 1909 and Sir Alexander Fleming’s discovery of penicillin in 1928.

From the 1940s to the 1980s, Big Pharma overproduced antibiotics and marketed them as a cure-all. One of the consequences was that bacteria mutated to survive. This led to widespread resistance to antibiotics. In 2013, Tom Fried, Director of the US Centers for Disease Control and Prevention, described humans as close to living in a “post-antibiotic era.” Antibiotic drugs were widely produced by foreign companies as generics. The increasing privatization of global healthcare markets, beginning roughly in the 1980s, meant that the production of niche drugs was more profitable for Big Pharma than the continued research into and development of new antibiotics. Dr. Joan Butterton, head of antibiotic research at Merck, notes that antibiotics are “made to be used as little as possible, so therefore companies aren’t making any return.” Giants do not profit from antibiotics and smaller companies haven’t the capital to wait to develop new products, ergo the giants are dumping their antibiotic arms onto smaller firms.

Most antibiotics work by inhibiting the ability of bacterial cells to synthesize their DNA and RNA proteins. After producing penicillin, the drug giant Eli Lilly produced the antibiotics vancomycin, erythromycin, Keflex, and Ceclor. From 1943 to 1960, penicillin, tetracycline, erythromycin, and methicillin were also developed. But, within the same period, the bacteria R. Staphylococcus, Shigella, Staphylococcus, and pneumococcus had each developed resistance. From 1967 to 1985, the drugs gentamicin, vancomycin, imipenem, and ceftazidime had been produced. But by 1988, Streptococcus, Enterococcus, Enterobacteriaceae, and Enterococcus had developed resistance. Lastly, between 1996 and 2010, the drugs levofloxacin, linezolid, daptomycin, and ceftaroline had been produced. But, by 2011, many of the aforementioned bacteria, as well as extensively drug-resistant (XDR) tuberculosis, pan-drug resistant (PDR) Acinetobacter, and N. gonorrhoeae, had also developed resistance.

Having created a crisis of resistance, Big Pharma is now abandoning the public. Fewer and fewer new antibiotics are coming onto the market. Kevin Outterson the head of CARB-X, a government-funded antibiotic resistance research project, said: “You’d never tell a cancer patient, ‘Why don’t you try a 1950s drug first and if doesn’t work, we’ll move on to one from the 1980s.’” Yet, that is what they are saying when it comes to the use of outdated genetics for treating bacteria. Per capita, rich countries are the biggest consumers of antibiotics, with the exception of a few poorer nations, including Turkey, Vietnam, and Saudi Arabia. Between 2000 and 2015, the consumption of antibiotics by low- and middle-income countries increased as followed: cephalosporins consumption by 339 percent), quinolones 125 percent, and macrolides 119 percent. Between 1999 and 2014, merely 12 new antibiotics went on sale across just 10 countries.

In June 2018, the French giant Sanofi sold its antibiotic branch to Germany’s Evotec. Another pharma giant, Novartis AG, sold biotech startups to Boston Pharmaceuticals. Bloomberg Businessweek provides an anecdotal example of the unprofitability of antibiotic R&D and sales for Big Pharma. The superbug Enterobacteriaceae is resistant to carbapenem (CRE). The US drug company Achaogen developed Zemdri, which kills CRE. Because the deadly CRE kills relatively few people, there is barely a market for Zemdri, hence the collapse of the company in 2019. Dr. Helen Boucher of Tufts Medical Center said: “We have a broken antibiotic market, and this is a stunning example of how broken it is.”

Factory Farms

At any one time on farms around the world there are 19 billion chickens, 1.5bn cows, 1bn sheep, and 1bn pigs. Each year 50bn chickens are slaughtered for food, as are 1.5bn pigs, and 500 million sheep. Worldwide, the amount of meat consumption by humans has tripled since 1970. Due to cruel factory-farming practices, animals are forced to live in their own filth. It is cheaper to cram animals into dirty pens and cages than to buy land and allow them to move. The latter would be more hygienic. It is also more efficient for farmers to use spare land for crop cultivation. To solve the paradox of raising animals in cheap but dirty conditions, farmers pump them full of bacteria-killing antibiotics. But doing so means that antibiotics enter the human food chain and contribute to the crisis of resistance. The market says the bigger the animal, the bigger the profit. Antibiotics are also used as growth promoters.

Factory farms have been expanding since the end of the Second World War. They resulted from mechanization and threatened the traditional factory farm. As family farmers either turned into factory farms or tried to compete with them, banks benefited from lending for technology purchases. Large amounts of animals were bred in confined spaces, risking the spread of disease. Antibiotics were used to kill animal disease. Industrial livestock breeding, rearing, and slaughter not only produced horrendous effects for animal welfare but also in the environment: dyes, methane, pesticides, and preservatives. Antibiotics entered the food chain in the 1940s, as farmers fed broiler poultry antibiotics as low-cost growth-promoters. Since the late-1970s, antibiotic animal feed was shown to have transferred to humans. Despite this, 80 percent of all antibiotics sold in the US are used in animals, the majority of which to promote growth and prevent infection. Up to 90 percent of bacteria are excreted by farm animals and widely dispersed via fertilizer, groundwater, and surface runoff.

A report by the US Agency for International Development (USAID), the World Food Programme, and the World Health Organization notes that in poor and rich countries alike, governments and publicly-employed veterinarians once treated animals. By the 1980s, however, fiscal constraints, notions of market efficiency, and suspicion of state-intervention led to privatized veterinary services. Both animal health and the supply of goods and services were affected, lessening the access of rural communities to vets, who favored more profitable urban markets. The report notes that “experiences with recent outbreaks of transboundary animal diseases such as HPAI H5N1 have emphasized the importance of public veterinary services.” It is worth considering the fact that USAID, an organization designed to push privatization under the cover of a foreign aid program, is highlighting the importance of the public sector. “Tasks such as surveillance, prevention, control, and eradication of highly contagious diseases with serious socioeconomic, trade, and public health consequences, quarantine and movement control, emergency responses, disease investigation and diagnosis, and vaccination and vector control require public intervention and are unlikely to be adequately provided by the private sector alone.” Yet, many of these vital public controls were missing when COVID-19 hit.

America’s China Market

China is the world’s largest producer and consumer of antibiotics, half of which are consumed by animals. Four fifths of Chinese chicken farmers use at least one prohibited antibiotic. The health of many Chinese people is already compromised by the quality of air, with nearly 100m people sick with chronic obstructive pulmonary disease. Such conditions make people more susceptible to bacterial infections. Antibiotic consumption increased by nearly 80 percent in China between 2000 and 2015, compared to the global average of 65 percent in the same period.

Big Pharma had to create a national market for antibiotics in China, as the nation was run by semi-autonomous provinces, much as it is today. Hospitals bought 85 percent of all pharmaceuticals: antibiotics being the single biggest product by the 1990s. Despite being limited to urban referral hospitals, the antibiotic cephalosporin remains popular. Cephalosporins appeared in China in 1982, when the US firm Bristol-Myers Squibb (BMS) began exporting. A couple of years later, BMS worked with the Sanwei Pharmaceutical in Shanghai to produce the antibiotic cefradine. Aventis and Glaxo (later GlaxoSmithKline) led the market. According to The Pharma Letter, by 1997, “most of the top-20 pharmaceutical companies’ joint ventures in China [we]re concentrated in Shanghai, Tianjin, Beijing, Wuxi and Suzhou.”

By the late-1990s under foreign direct investments (FDIs), 18 out of 20 top drug producers had established plants in China: Novartis, Glaxo Wellcome, Merck & Co, Hoechst Marion Roussel, Bristol-Myers Squibb, Johnson & Johnson, Pfizer, SmithKline Beecham, Hoffmann-La Roche, Bayer, Astra, Eli Lilly, Rhone-Poulenc, Schering-Plough, Pharmacia & Upjohn, Boehringer Ingelheim, Takeda Chemical, and Warner-Lambert. Eli Lilly sold its antibiotic production to China “to better focus our resources on the exciting new therapies that we are launching in our core therapeutic areas,” says expert, Amber Tong. US companies are “[c]apitalizing on the rich pipeline, faster and broader access in China.”

Like post-WWII US farmers, Chinese peasants have also increased their agricultural mechanization to the point where, by 2010, labor productivity had stagnated as agricultural productivity using machines continued to grow. Liu et al. note “the declining importance of agricultural land.” The government developed an industrial agriculture policy to meet the demands of accumulated capital. High yields resulted from the use chemical fertilizers and pesticides. Multiple cropping was extended to improve land usage. But it wasn’t particularly efficient. By 1978, the grain output increase of over 80 percent led to an annual sector growth rate of less than 3 percent. In the broader economy, labor productivity grew by 58 percent, but in agriculture, it fell annually by 0.2 percent. From 2000, the average annual migration from country to town totaled 15 million people. From 2004, the agricultural machinery industry enjoyed a 6 percent annual growth, thanks to government subsidies in the form of procurement.

Chinese industrial farm policy also wiped out the centuries-old effective culture of natural medicine, such as garlic and horseradish for use as antibiotics. In 2000, China produced 40 million tons of pork. Four years later, it was producing 56 million, as demand exceeded production. The number of large farms raising more than 3,000 pigs increased from 5 percent in 2003 to 14 percent in 2010. Simultaneously, and in keeping with the overall trend noted above, the number of farms producing fewer than 50 pigs declined from 71 percent to 36 percent.

In Xinjiang Province, pork production was 0.025 million tons in 1978. By 2010, it was 0.231. Pig manure samples show significant antibiotic levels (of tetracycline, sulfonamides, and quinolones), above the levels found in chicken and cow feces. Each year, Chinese farmers feed their animals over 8,000 tons of antibiotics: sulfonamides, tetracyclines, fluoroquinolones, macrolides, and β-lactams. Some areas are what the authors Yang et al. describe as antibiotic “hotspots”: Southwest China (Sichuan), Central China (Hunan), North China (Henan and Hebei), and the southeast coast (Fujian, Guangdong and Guangxi). To give some examples: In Hong Kong, over 80 percent of people tested positive for the aaaC2 gene, which resists the antibiotic, gentamicin. The acc(3)-IV gene confers resistance to the agricultural antibiotic, apramycin. Apramycin-resistant genes were found in swine-farm workers, where the antibiotic was used as a growth promoter. Certain cytoplasmic membranes contain proteinaceous transporters called the efflux pump. One such pump is called the OqxAB, after the genes that encode it. A study into E. coli in Chinese factory-farmed pigs found that the OqxAB gene was present in over 30 percent of E. coli.-infected human farmworkers. The fact that the farmworkers had never received antimicrobial or hospital treatment indicates the transmission of antibiotic-resistant OqxAB from swine to humans.

By 2015, nearly 60 percent of Chinese children had traces of antimicrobials in their urine, acquired it would seem from food and environmental pollution. Qu et al. outline likely candidates for why antimicrobial resistance is high in China: over-prescription during flu seasons, lack of public knowledge, “Financial incentives, such as mark-ups on drug price, is considered to be the main driver of over-prescribing in China.” The Chinese government has taken swift but inefficient action to ban certain antibiotics, replace them with organic acids, improve husbandry and welfare standards, and enforce and surveille. Furthermore, Chinese specialists have researched detection (including quorum sensing) and resistance, such as a new class of antibiotics (arylomycins).

Capitalist India

India is one of the largest consumers of antibiotics, given the product’s relative affordability, the size of the Indian population, and the potential market. Nearly 40 percent of India’s antibiotics are either substandard or counterfeited. Given that India has one of the lowest doctor-patient ratios in the world (0.8 per 1,000 people compared to 2.8 in the UK), people often self-prescribe and/or are given poor or inappropriate advice. Between 2000 and 2010, India’s retail antibiotic consumption increased by over 20 percent.

India is the world’s largest producer of fish and milk. Chicken consumption is expected to rise by 577 percent by 2030, relative to 2000 levels. In West Bengal, antimicrobial resistance to Gram-negative bacteria (which are dangerous because they camouflage themselves) were found in nearly 50 percent of cows’ milk. A fifth of samples were resistant to the drug vancomycin and a further fifth to methicillin. Among humans, “more than 70 percent isolates of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii and nearly half of all Pseudomonas aeruginosa were resistant to [the drugs] fluoroquinolones and third-generation cephalosporins.” Alarmingly, 100 percent of crabs, shellfish, and shrimp in Kerala are resistant to ampicillin, as are around 70 percent of those creatures to ceftazidime. Bacteria in water are also resistant to antibiotics. In surface waters, 17 percent of E. coli cultures were resistant to antibiotic cephalosporin. Likewise, in the major rivers of India, 17 percent of enzymes produced by bacteria, called Extended Spectrum Beta Lactamase, were resistant to drugs.

In Hyderabad (population nearly 7 million), waterborne E. coli is 100 percent resistant to antibiotics. Specialists Taneja and Sharma note: “India is still striving to combat old enemies such as tuberculosis, malaria and cholera pathogens, which are becoming more and more drug-resistant. Factors such as poverty, illiteracy, overcrowding and malnutrition further compound the situation.” In addition to animal products, the use of biocides, which kill “good” and “bad” bacteria, have been found to impair the natural bacteria-resisting vanA gene. India is also one of the biggest pharmaceutical water polluters, with over 28 mg/l of the antibiotic ciprofloxacin found in samples of effluent waters.

Unlike the US and China, India has not pursued an extensive policy of agricultural industrialization. By the mid-2000s, India had 140 million hectares of cultivated land directly worked by 225 million laborers. Despite the absence of centralized industrial policy, the laborers use 149 million pieces of farm machinery, 520 million hand tools, and 37 million animal-drawn implements. Work includes threshing, cutting, dusting, spraying, and crushing. There are 42 threshing accidents per 1,000 threshers. Around 22 per every 100,000 farmers are killed each year by their machines.

Over 700 million Indians depend on agriculture directly or indirectly for their livelihoods. Around 400 million Indians enjoy a strictly vegetarian and animal-milk diet. Indian Hindus tend not to eat cows and Indian Muslims tend not to eat pork. Indians eat 2 million tons of meat per annum. India has the second-largest goat population in the world after China, and 95 percent of goats are consumed locally. Chicken and fish are the preferred meats in rural areas. Urbanization has increased meat consumption. By 2014, India was the world’s second-largest beef exporter, after Brazil. Nearly 40 percent of agricultural output between 2005 and 2011 came from animal products. A third of incremental food inflation since 2009 has resulted from increased animal production. Indian farmers continue an epidemic of suicides: 300,000 in 20 years. Suicides are caused by rising equipment costs, debt, impossible competition against international market forces (e.g., WTO rules which prohibit the saving of seed), climate change and resultant unpredictable weather, over-regulation of small farmers and under-regulation of big agribusiness, and the monopolization of the once-lucrative cotton industry by biotech companies, particularly Monsanto (Bayer) which produced a self-destructive gene preventing cotton farmers from saving their seed. The Indian government banned the seed, but by 2012 it had already spread and was cultivated across 1.2 million hectares, compared to 6.2 million hectares of legal seed cultivation.

The Good Ol’ USA!

By the 1950s, resistance to penicillin was already apparent. Efforts to defeat bacteria with beta-lactam proved ineffective, with methicillin-resistant Staphylococcus aureus being identified within a decade: a disease that kills over 10,000 Americans a year. Ten, years later in the 1970s, the drug vancomycin was introduced to treat Staphylococcus aureus and staphylococci. Again, within ten years, the bacteria developed resistance. C. Lee Ventola writes that in addition to the overuse and misuse of antibiotics, “the lack of new drug development by the pharmaceutical industry due to reduced economic incentives” has been another factor. Ventola advocates for coordinated R&D. But funding cuts due to the financial crisis (2007-08), as well as mergers and acquisitions, have reduced the amount of research being conducted. For instance, between 1980 and 1984, US authorities approved 19 new antibacterial drug applications. Between 2010 and 2014, they approved just six.

In the US, 2.8m people are infected with antibiotic-resistant bacteria or fungi, which kill 35,000 Americans each year. Per annum 99,000 Americans die in hospital from contracting antibiotic-resistant pathogens and associated hospital-acquired infections: pneumonia and sepsis being the most common. Lost productivity due to antibiotic resistance in the US costs $35bn a year.

Over 60 percent of Americans with a bacterial infection are now resistant to antibiotics. The Infectious Diseases Society of America declared multi-drug antibiotic resistance a national security risk and a public health crisis. By 2010, the average American took 22 antibiotic pills a year. Incorrect prescriptions are a serious problem. In intensive care units, 30 percent of prescribed antibiotics are unnecessary, inappropriate, or suboptimal. Treatment indication, drug choice, and duration are wrong 30 percent of the time. Quality of healthcare is another serious problem. In the privatized, highly bureaucratic US, where under-diagnosing can save money for health providers, the pathogen of community-acquired pneumonia is correctly identified less than 8 percent of the time, compared to Sweden which has a near-90 percent identification rate. Resistance to nearly all antibiotics has development.

Profitability is a limiting factor. Big Pharma prefers to invest in medicines for chronic conditions. The net present value for a drug company producing an antibiotic is $50m compared to the production of a neuromuscular disease-treating drug, valued at $1bn. In addition, a course of antibiotics can cost $1,000 compared to cancer and chemotherapy drugs which cost tens of thousands. The fear of antibiotic resistance has led physicians to increasingly prescribe only for the worst cases, essentially lowering the value of the product and further disincentivizing Big Pharma R&D. In addition, because many antibiotics are non-patented generic drugs, consumers expect specialist antibiotics to be as cheap; another disincentive for corporations.

Wrap Up

The COVID-19 crisis has exposed the many failures of the neoliberal model, including the reliance on Big Pharma to keep the population heathy. Many coronavirus victims died of complications, including bacterial infections. For Big Pharma, other drugs are more profitable, so having created a resistance crisis, the companies now turn their backs. A humanistic response would be significant government funding for and intervention in the global antibiotic industry to develop new, effective drugs. The government would also be tightening prescription rules and promoting healthier farms that do not require massive antibiotic usage. But, if the financial crisis is an example of governmental responses to disaster, the burden of COVID-19 will again fall upon the poor.

T. J. Coles is director of the Plymouth Institute for Peace Research and the author of several books, including Voices for Peace (with Noam Chomsky and others) and  Fire and Fury: How the US Isolates North Korea, Encircles China and Risks Nuclear War in Asia (both Clairview Books).

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