Why Colistin in Veterinary Medicine Was Positioned as a Second-Line Drug?

Post date:2019.02.25

On March 26, 2018, the Ministry of Agriculture, Forestry and Fisheries announced that Colistin products for livestock animals are second-line drugs. This time, we would like to explain the background of these measures.
Colistin was discovered by a Japanese pharmaceutical company in 1950 and its development was promoted in Japan. It is divided into peptide-based antibiotic and shows a sterilizing effect by binding to LPS. The effectiveness of colistin is proven, although it has strong side effects (e.g. renal dysfunction, neurotoxicity). The approval of colistin preparation for injection in human medicine was rescinded in 2004, due to such side effects, however, colistin was re-approved as an orphan drug in 2015 against a backdrop of an increase in multi-drug-resistant gram-negative bacterial infections. Indications for colistin are multi-drug-resistant gram-negative bacterial infections which show resistance to carbapenem, fluoroquinolone, and aminoglycoside antibiotics. These antibiotics are regarded as the most important antibiotics in human medicine.
Multi-drug-resistant gram-negative bacteria indicates multi-drug resistant Pseudomonas aeruginosa (MDRP), multi-drug-resistant Acinetobacter baumannii(MRAB), and Carbapenem-resistant enterobacteriaceae(CRE). These bacteria cause an opportunistic infection to immunocompromised patients and antimicrobial long-term users, and induce septicemia and various infections to the respiratory tract, urinary tract, skin, soft tissue, ears, and eyes. These infections are not rife in Japan now, however, no one can predict when they will increase hereafter like in other countries. Moreover, efficient antibiotics for these bacteria are extremely limited. Colistin is one of the few efficient drugs. Colistin is called an ‘antibiotic of last resort’ overseas, therefore, it is regarded as an important antibiotic in human medicine, and is used in limited amounts under strict management. On the other hand, colistin sulfate is used for animals as a veterinary medicine and in feed additives. The latest figures for amounts of sales shows, 10 tons used in swine for veterinary medicine, 18 tons used for swine, 5 tons for chicken, and 3 tons for cattle as feed additives; the total amount is 36 tons. This amount is too much.
Colistin is cationic and has hydrophobic, which shows antibacterial activity by binding to the gram-negative bacterial outer membrane and displacing magnesium and calcium in the membrane. Moreover, colistin has affinity to endotoxins of gram-negative bacteria (LPS), and binds to LPS and neutralizes the activity. That is why, colistin sulfate is frequently used for the treatment of swine edema disease caused by toxigenic Escherichia coli. Thus, not only Shiga toxins (STx2e) produced by pathogenic bacteria but also endotoxins are related to this disease, colistin shows both bactericidal effects and neutralizing activities of the LPS. On the other hand, mutation of the LPS had been considered important for bacteria to have resistance to colistin. Although colistin sulfate has been used for food-producing animals for a half century, resistant rate has not greatly varied and the appearance of resistant bacteria is limited.
However, the detection of the mobilized colistin resistance (mcr-1) gene which was reported in China in 2015 changed the situation drastically. After that, mcr-1-harbouring Escherichia coli which is regarded as a menace for humans, has been detected from food-producing animals, meat, and humans around the world. As introduced in this website, mcr-1-harbouring Escherichia coli was detected from healthy pigs at a low frequency in 2016, and also detected from pigs affected with edema and diarrhea at a high frequency. And more, it was also detected from domestic and imported pork and chicken, and humans. However, now there is no report to be detected from multidrug-resistant gram negative bacteria.

In response, the Food Safety Commission of Japan (FSCJ) notified the results of ‘Antimicrobial-resistant bacteria arising from the use of colistin sulfate in the livestock (Antimicrobial-resistant Bacteria)’ http://www.fsc.go.jp/english/evaluationreports/others_e1.data/kya03120816918_202.pdf

FSCJ conducted a risk assessment focusing on E. coli as a hazard, and the degree of possible selection of the hazard was evaluated as “medium”. In response, the Ministry of Agriculture, Forestry and Fisheries notified risk management measures of colistin sulfate, which prohibited the use of feed additives including colistin beginning in July 2018, and categorized colistin as second-line drug in veterinary medicine.
Veterinary medicines which are already categorized as second-line drugs are fluoroquinolones, third-generation cephalosporin, 15-membered macrolide, and colistin sulfate. If the isolation rate of colistin will increase or multidrug-resistant gram negative bacteria will be detected from humans, the regulation of colistin should be reinforced. Therefore, proper use is required to continue using colistin sulfate which is important in veterinary medicine.