Antibiotic resistance outstripping new medicines

June 3, 2014 by Timothy Beardson

Global resistance to antibiotics is rapidly becoming a major problem, with the emergence of a growing number of antibiotic resistance genes. As the world’s largest producer of pork, the second largest producer of poultry, the largest feed importer and the fourth largest dairy producer, these problems are already seriously affecting China, where research suggests that the way in which antibiotics are used is exacerbating what is already a serious crisis.

The extent of the potential problem is highlighted by European data that shows that patient survival rates of infections from antibiotic-resistant strains of diseases are only half those of patients with infections that remain sensitive to drugs.

A recent report from the World Health Organisation (WHO) on Antimicrobial Resistance says that “resistance to common bacteria has reached alarming levels in many parts of the world indicating that many of the available treatment options for common infections in some settings are becoming ineffective”.

The costs are frightening; The US Centers for Disease Control and Prevention (CDC) estimates that antibiotic resistance is responsible for $29bn in healthcare costs and $35bn in lost productivity in the United States alone.

The reasons for antibiotic resistance vary. However, antibiotic over-usage is well known to create a natural resistance amongst infections. Nor is this simply as issue of human consumption of medicine – although over-prescription is certainly a problem: the main problem is the heavy use of antibiotics as growth promoters for livestock.

Antibiotics – both for humans and for livestock – is a huge business. Worldwide, the antibiotic industry manufactures 20 tons hourly, but China is both the world’s largest producer and largest consumer. A 2007 survey found that the estimated annual antibiotics production in China was 210m kg, of which 46.1% was used in livestock industries – at least four times the amount used in the US livestock industry in 1999. The US is now almost entirely reliant on China for the manufacture of the crucial ingredients for nearly all antibiotics, steroids and many other live-saving drugs.

The use of antibiotics for livestock in most cases is not to cure infection but for “marketability”. In the US, where 23,000 people die each year due to antibiotic resistance, 80% is non-medical, according to the FDA. One recent report by the Natural Resources Defense Council noted that the FDA itself allowed 30 potentially harmful antibiotics – 18 rated as ‘high risk’ – to remain on the market as additives to livestock feed and water.

In China it is even worse, particularly in the pig industry, where it is not unusual to use eight times the amount of antibiotics that are used on American farms.  .

The problem is that the antibiotics are not absorbed by the animals, but quickly enters human food chain, as much of the animal waste (an annual total of more than 600m tonnes in China) is recycled as manure for crops. Research in China indicates “evidence from the past 35 years establishes that farm antibiotic use correlates repeatedly with the rise and spread of associated resistance genes in human pathogens, as well as the direct transfer of antibiotic-resistant bacteria from animals to humans”. The Chinese industry is “unmonitored”, meaning it is uncontrolled, even though research has shown that the manure can concentrate antibiotics by a factor of tens of thousands.

Work is going on in some places to reduce the massive use of antibiotics in farm-reared animals. The US has worked to eliminate antibiotics from domestically-reared farm salmon and is now addressing livestock antibiotics. And the World Organisation for Animal Health, the US FDA and the WHO are all involved in initiatives to improve the regulation of veterinary antibiotics in more than 100 developing countries. Unfortunately, China’s policy is a long way behind.

Human antibiotic use is equally controversial. And there are specific circumstances that lead to the massive over-prescription of antibiotics in China. Doctors there are generally in the lowest graduate income segment and hospitals often incentivise doctors through payments to recommend expensive treatments and drugs, leading to excess consumption of antibiotics. Antibiotic sales alone are estimated to generate a quarter of hospital revenues. It is estimated that two-thirds of hospitalised patients in China receive antibiotics compared with less than a third worldwide. There is a similar disparity for outpatients in China compared to the rest of the world.

Furthermore, China does not control antibiotic sales and many would-be patients elect for self-prescription because it is cheaper than seeing a doctor. China is the eighth highest non-prescription antibiotic user. The result is excessive antibiotic use and the widespread resistance of many well-known infections to treatment. The average person in China consumes ten times as many antibiotics as the average American, with a result that drug-resistant TB in China is now 3.5 times the level of the developed world. This also explains why China’s general resistance is more than twice that of the US and growing much faster.

Weak controls on drug sales and rising income have meant an explosion in antibiotic use in many developing – and even developed – countries. According to a paper in Nature, from 2005 to 2010, Egypt increased antibiotic use by 300% and India by 500%.

In the United States, there are two principal problems. As the nature of an infection is initially often obscure and yet fast-developing, doctors are strongly tempted to prescribe multiple antibiotic solutions. Second, as the bacteria are mutating so rapidly, prescribing the correct antibiotics is difficult. The CDC estimates that “about half the antibiotics prescriptions written in the United States are inappropriate”.

The twin scourges of excessive human antibiotic use and widespread and unnecessary use in livestock are exacerbated by a third factor – failure to bring new antibiotics to the market.

There have been no new classes of antibiotics for 25 years and every class of existing antibiotic is compromised by resistance, as are many antivirals, antiparasitic and antifungal drugs. According to Nature: “Between 1983 and 1992, 30 new antibiotics were approved by the US Food and Drug Administration. From 2003 to 2012, the number was just seven. Why? Because there are too few incentives and too many regulatory barriers for the commercial sector to invest what is needed for the development of new antimicrobials.”
“Twenty years ago, we still had hope,” says Dr Nancy Khardori, professor of internal medicine at the Eastern Virginia Medical School. “We still had something in our pocket for when we would get down the line, and we would be able to overcome those bacteria that have become resistant. Now, in many respects, we’re at the end of the line. There is not much in the pipeline (developing new drugs). That is the major difference between then and now.”

And, of course, new drugs will themselves in turn fall prey to resistance, thus having a finite effective life.

Facing this challenge, policymakers have disappointed. The WHO has engaged slowly with antibiotic resistance. The FDA in America has only reluctantly addressed non-therapeutic antibiotic use in livestock. China is now trying to control antibiotic usage in medicine. The WHO, perhaps belatedly, describes the problem as “so serious that it threatens the achievements of modern medicine. A post-antibiotic era—in which common infections and minor injuries can kill—far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century”.

China’s State Food and Drug Administration is also trying to change habits, but with little success. A survey of 8,000 people in China in 2012 found that roughly 23% take antibiotics as soon as they suspect they have the common cold, while 9% will do the same when they have diaorrhoea.

We need lower antibiotic prescription, more focussed on where it counts, and a tough reining in of non-therapeutic antibiotic use in the livestock industry in both China and the US. The price for delay is continuing rises in global antibiotic resistance and potential pandemics.

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