A new study by Chinese scientists suggests the country's formal ban on the use of the last-resort antibiotic colistin for growth promotion in livestock has had a significant short-term impact on colistin resistance in China.
The study, published last week in The Lancet Infectious Diseases, found that the April 2017 ban led to a substantial decline in the use of colistin as a feed additive in Chinese agriculture and was associated with a decline in colistin resistance in both animals and humans in China, as well as a drop in human carriage of the MCR-1 mobile colistin-resistance gene.
Colistin is considered a crucial antibiotic for human health because it's one of the last options for treating multidrug-resistant infections. But it's also long been used to promote food-animal growth in many parts of the world. The Chinese government's ban came in the wake of the discovery of MCR-1 in 2015 and its subsequent global spread.
The emergence of the gene, which was first discovered in Escherichia coli bacteria from Chinese pigs and Chinese hospital patients, is suspected to be the result of widespread use of the drug as a growth promoter in Chinese livestock. Chinese hospitals didn't start using colistin until 2017.
Since the discovery of MCR-1, the gene, and several variants, have been identified in humans, animals, and meat products in more than 50 countries across six continents. The rapid spread of MCR-1 has become a global public health concern because bacteria carrying it can cause human infections that are nearly impossible to treat with existing antibiotics. In addition, the mobile pieces of DNA that carry MCR-1, known as plasmids, are easily shared between different species of bacteria and frequently carry other resistance genes.
Evaluating the ban's impact
To evaluate the effects of the April 2017 ban, which prohibited the use of colistin sulfate premix as an animal feed additive in mainland China (but did not ban prescription use of the drug for treating sick animals or disease control in herds), the researchers examined sales of colistin in agriculture across mainland China. They also assessed patterns of colistin resistance, colistin residues, and MCR-1 abundance in E coli from animals and humans, from 2015 and 2019.
To do so, they used data from the China Veterinary Drug Association, the China Surveillance on Antimicrobial Resistance of Animal Origin database, and the China Antimicrobial Surveillance Network (CHINET). They also collected and analyzed fecal samples and rectal swabs from farms and hospitals in different regions of the country.
The results showed that production of colistin sulfate premix declined from 27,170 tons in 2015 to 2,497 tons in 2018, with the most significant drop occurring from 2016 through 2017. Sales of colistin sulfate premix fell from US $71.5 million in 2015 to US $8.0 million in 2018.
Analysis of colistin residue concentrations and relative abundance of MCR-1 in animal fecal samples found that, across 118 farms in four provinces, the mean colistin residue concentration fell from 191.1 micrograms per kilogram (μg/kg) in 2017 to 7.5 μg/kg in 2018 (P < 0.0001), and the median relative abundance of MCR-1 declined from 0.0009 (Interquartile range [IQR], 0.0001 to 0.0059) in 2017 to 0.0002 (0.0000 to 0.0020) in 2018 (P = 0.0001).
Across 23 provinces and municipalities, colistin-resistant E coli (CREC) was identified in 34% of pig feces samples (1,153 of 3,396) in 2015-16 vs 5.1% (142 of 2,781) in 2017-18 (P < 0.0001). In chickens, CREC was identified in 18.1% of samples (474 of 2,614) in 2015-16 versus 5% of sample (143 of 2,887) in 2017-18 (P < 0.0001).
Meanwhile, the assessment of fecal samples and rectal swabs from patients in hospitals across 24 provincial capital cities and municipalities found that human carriage of MCR-positive E coli (MCRPEC) was identified in 14.3% of samples (644 of 4,498) in 2016 compared with 6.3% of samples (357 of 5,657) in 2019 (P < 0.0001). CHINET data showed that clinical CREC infections in 26 provinces and municipalities constituted 1.7% of E coli infections (1,059 of 62,737) in 2015-16 versus 1.3% (794 of 59,385) in 2018-19 (P < 0.0001).
"Our data provide evidence that the withdrawal of colistin as an animal growth promoter in China has had a significant and positive impact on reducing colistin residues and CREC in animals, and MCRPEC carriage and CREC infections in humans," the authors of the study wrote. "Therefore, the withdrawal of colistin as a growth promoter is a crucial step in preserving this essential antibiotic for human medicine."
Decreases not universal
But the study did not find declines in colistin resistance everywhere. Five provinces saw no decline in CREC in chicken fecal samples after the colistin ban, while 12 provinces saw an increase in CREC prevalence in people, and five saw a rise in MCRPEC prevalence in people. The authors said this could be linked to continued therapeutic use of colistin in animals, along with increasing hospital use.
The authors also noted that the ban on colistin for growth promotion may not be the only explanation for the decline in colistin-resistance and MCR-1 carriage. Another reason could be that carrying the MCR-1 gene has a significant fitness cost for bacteria and hampers their ability to spread. However, they cautioned that certain MCR variants, such as MCR-3.1 and MCR-3.5, don't pose such a high fitness cost and could replace MCR-1.
Since China's ban on the use of colistin as a feed additive for growth promotion in livestock, other countries have followed suit, including Japan and India. But with the population and demand for meat growing in many parts of the developing world, the authors said an urgent global discussion is needed on how to preserve colistin, and other medically important antibiotics, for the future.
"Such a discussion should address how to implement definitive and enforced policies that separate classes of drugs to be used in humans and those to be used in animals," they wrote.