Who Is Responsible For Antibiotic Resistance?

We commonly blame physicians for overprescribing antibiotics, patients for demanding them and, increasingly, agribusiness for squandering antibiotics as growth promoters. All of those are major problems. One less-often mentioned factor is a side effect of the manufacturing process itself, where pharmaceutical companies dump huge quantities of antibiotics into wastewater—which then goes into rivers, or is used in irrigation.

Antibiotic production

Given that 40% of the world’s population lives in Bangladesh, China, India and Pakistan, and that manufacturing costs are lower, many major pharmaceutical companies have placed production facilities there. Reportedly, Indian companies supply 20% of the world’s generic drugs, and China exports more than 60% of the total active pharmaceutical ingredients for the global pharmaceutical industry.

Many drugs are made in India, so this has been the focus of considerable research; Patancheru, near Hyderabad, India, has a treatment plant that receives wastewater from 90 pharmaceutical companies which discharge 400,000 gallons daily. This effluent from manufacturing is combined with domestic wastewater. In India, only 24 % of domestic waste undergoes treatment.

Pharmaceutical companies near Hyderabad--note Dr. Reddy's and Novartis

Researchers from Sweden have studied the area around Hyderabad for a number of years, publishing a series of reports since 2007. They found a number of drugs contaminating the water, some in concentrations higher in the water than in patients’ blood. The worst was pollutant was ciprofloxacin, with concentrations up to 31 mg/L and in only one day totaling “44 kg, which is equivalent to Sweden’s entire consumption over 5 days, or, expressed in another manner, sufficient to treat everyone in a city with 44 000 inhabitants.” These researchers also found that the effluent was toxic to many organisms, and that it promoted resistance genes. Almost 2% of DNA samples from downstream sites sampled had resistance genes.

High levels of ciprofloxacin were found in river sediments downstream from the Indian treatment plant

But it’s not just India. For example, oseltamivir (Tamiflu) has been found in the Rhine River, and tetracycline and penicillin products in China. Denmark and Croatia had sulfonamides, Norway had bacitracin, and Pakistan had several types of antibiotics.

While not focusing on pharmaceutical manufacturing waste, in the US, a New Mexico study found hospital effluent containing sulfamethoxazole, trimethoprim, ciprofloxacin, ofloxacin, lincomycin, and penicillin. Interestingly (but not surprising), ofloxacin was found in effluent from assisted living and retirement facilities, but not in wastewater from student dormitories.

What happens with this antibiotic impregnated wastewater? 

In addition to direct consumption of treated water, which still contains significant amounts of drugs, wastewater byproducts (sludge) are used to irrigate and fertilize crops, especially in impoverished areas overseas, at the same time dispersing resistance genes throughout the environment. (Sludge, aka "Biosolids" are also used in the US as fertilizers, around Washington, D.C., for example). Wastewater may also be used to water plants in parks, aerosolizing and spreading resistant organisms at the same time as water is sprayed, and further dispersing resistance genes throughout the soil.

As one group describes, “This complex domestic wastewater becomes a genetic reactor where microbes undergo gene transfer and turn into multidrug resistant microbial strains.

The spread of resistance genes isn’t localized to areas adjacent to the manufacturers. For example, drug resistant bacteria were isolated from the water and sediment in Puri, India, a popular tourist destination with more than 4 million visitors per year. Wastewater is untreated, spreading resistant organisms back home with the returning tourists. (The same pattern is a huge concern with the upcoming Olympics in Brazil. There, although Rio de Janeiro has a population of 12 million, 70 percent of Rio’s sewage goes untreated into the bay, the site of the 2016 water sport competitions. Multi-drug resistant organisms carrying carbapenem-resistant Klebsiella pneumoniae enzyme (CRE), aka KPC, have been found in the water there).

Given the poor domestic sanitation, a fairly mobile population, and the poor wastewater treatment practices that spur antibiotic resistance, it is no surprise to see the recent reports of newborns dying from antibiotic resistant infections in India—58,000 of them, just last year in India.

Multi-drug resistant E. coli has been found in the Arctic, spread by migrating birds. So resistance genes can be found even in remote regions, not directly related to local selection pressure for the development of resistance.

How might we manage the spread of multi-drug resistant bacteria?

Clearly, this will require a multi-pronged approach. Besides the need to control agricultural misuse, a major area that requires urgent attention is the need for improved sanitation globally--according to the World Health Organization, an estimated 2.6 billion people lack access to even basic sanitation.

We also need better regulation of industrial waste and strengthening and enforcement of whatever environmental protections are available. Amy Pruden, Joikim Larsson, et. al. have an excellent overview of management options, ranging from wastewater and biosolid treatment, to limiting agricultural and aquacultural use, and the use of alternatives to antibiotics.

One thing individuals can do is to educate about safe drug disposal. The Drug Enforcement Agency had a program for nine years: Got Drugs? - National Prescription Drug Take-Back Day; they collected 309 tons of drugs last year alone. Unfortunately, they have discontinued that program. Drugs should be thrown out it the trash, not flushed down the drain.

Tackling antibiotic resistance will require attention to multiple aspects that contribute to the problem. While pharmaceutical waste has been a relatively overlooked piece of the puzzle, Dr. Larsson believes "the most important driver is the use, overuse and misuse of antibiotic in humans and animals, together with insufficient hygiene and travel."

The antibiotic pipeline is only a trickle. We have to preserve the resources we have, or we may, indeed, go back to the pre-antibiotic era and the dire predictions I shared from the recent Wellcome/UK antibiotic resistance report.



Cipro figure courtesy Kristiansson E, Fick J, Janzon A, Grabic R, Rutgersson C, et al. (2011) Pyrosequencing of Antibiotic-Contaminated River Sediments Reveals High Levels of Resistance and Gene Transfer Elements. PLoS ONE 6(2): e17038. doi:10.1371/journal.pone.0017038
