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Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM)

1) Overview

The Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) is a nationwide monitoring of antimicrobial-resistant bacteria in the animal area, conducted by the Ministry of Agriculture, Forestry and Fisheries since 1999 through its network with livestock hygiene service centers across Japan. JVARM provides globally important information, and is cited as one of the examples of monitring systems in “Antimicrobial resistance: global report on surveillance 2014,” published by WHO.

Figure 1. Overview of veterinary antimicrobial resistance monitoring

Figure 1. Overview of veterinary antimicrobial resistance monitoring

Figure 2. Antimicrobial resistance monitoring in food-producing animals in farms

Figure 2. Antimicrobial resistance monitoring in food-producing animals in farms

Figure 3. Antimicrobial resistance monitoring in food producing animals in slaughterhouses

Figure 3. Antimicrobial resistance monitoring in food producing animals in slaughterhouses

Under JVARM, three monitorings are conducted: (1) monitoring of the volumes of use of antimicrobials (estimated from the volumes of sales); (2) monitoring of antimicrobial resistance among indicator bacteria derived from healthy animals, and among pathogenic bacteria mediated by food; and (3) monitoring of antimicrobial resistance among pathogenic bacteria (clinical isolates) derived from diseased animals. While verifying the efficacy of veterinary antimicrobials, JVARM also provides basic data for risk assessment and risk management concerning antimicrobial resistance, taking into account influence on human healthcare (Figures 1, 2 and 3). The results of JVARM are published on the website of the National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries.[28] In FY2016, reviews were performed concerning how to strengthen antimicrobial resistance surveillance on aquatic animals, and how to conduct antimicrobial resistance surveillance on companion animals, in response to the strategies of the National Action Plan on Antimicrobial Resistance (AMR).

2) Monitoring details on the volumes of sales of antimicrobials

An annual monitoring is conducted on the volumes of sales of veterinary antimicrobials, based on the reported quantities of veterinary drugs handled by marketing authorization holders, pursuant to Article 71-2 of the Veterinary Drug Control Regulations (MAFF Ordinance No. 107 of 2004). Starting 2000, the scope of monitoring has included the volume of sales by active pharmaceutical ingredient and by the route of administration, and the estimated volume of sales by animal type, in addition to the volumes of sales by antimicrobial type and by dosage form. As is stated in Chapter 6.8 of the OIE Terrestrial Animal Health Code concerning the monitoring of antimicrobial agents used,[29] data are required regarding the volumes of use of active ingredients by animal type, in order to identify and compare the volumes of use in individual countries. Therefore, reports have been issued based on the relevant survey results.

3) Monitoring details on antimicrobial resistance

For the monitoring of clinical isolates, bacterial strains are isolated and identified from materials for pathological appraisal by prefectural livestock hygiene service centers, and the MIC values for these strains are measured by the National Veterinary Assay Laboratory using a broth microdilution method based on the CLSI Criteria. For the monitoring of pathogenic bacteria mediated by food and indicator bacteria, antimicrobial susceptibility tests have been conducted by livestock hygiene service centers since 1999, isolating Salmonella and Campylobacter as pathogenic bacteria mediated by food, and Escherichia coli and Enterococcus as indicator bacteria, via feces from beef-cattle, pigs, and broilers and layers in farms. Annual continued education are conducted at the National Veterinary Assay Laboratory in order to standardize the isolation and identification of bacterial strains and antimicrobial susceptibility testing. National Veterinary Assay Laboratory also conducts monitoring regarding source farms of samples, dates of sampling, the status of use of therapeutic antimicrobials and antibiotic feed additives, and so on. As described in the later in the section, sampling locations for the survey of pathogenic bacteria mediated by food and indicator bacteria were switched from farms to animal and poultry slaughterhouses in FY2016.

As of 2016, the scope of monitoring broadly includes active ingredients that are considered important in antimicrobials for animals, for both animals and human health, and antimicrobial feed additives: ampicillin, cefazolin, cefotaxime, streptomycin, dihydrostreptomycin, gentamicin, kanamycin, erythromycin, tylosin, lincomycin, tetracycline, oxytetracycline, chloramphenicol, colistin, bacitracin, virginiamycin, salinomycin, nalidixic acid, ciprofloxacin, enrofloxacin, and trimethoprim. Antimicrobial agents subject to monitoring are selected for each bacterial species, according to the past monitoring results and Chapter 6.7 of the OIE Terrestrial Animal Health Code.[30]

4) System for the antimicrobial resistance monitoring

Currently, there are 170 prefectural livestock hygiene service centers across Japan, which have cooperated in establishing the nationwide JVARM network. For the monitoring of clinical isolates, bacterial strains are isolated and identified from diseased animals by livestock hygiene service centers, and the MIC values for these strains are measured by the National Veterinary Assay Laboratory (Figure 2). From 2000 to 2016, pathogenic bacteria mediated by food and indicator bacteria derived from healthy animals were isolated and identified from the feces of specified animals, and subsequently the relevant MIC values were measured, by livestock hygiene service centers. The submitted data were aggregated and analyzed by the National Veterinary Assay Laboratory, and were published as JVARM data.

In contrast, animal and poultry slaughterhouses have been selected as sampling locations for antimicrobial resistance monitoring in Europe and the U.S., since they are proximal to food and are capable of more integrated collection of feces. Therefore, sampling of feces from healthy animals in animal and poultry slaughterhouses started in FY2012 (Figure 3), and sampling of feces in farms was discontinued in FY2016. Accordingly, sampling locations for the monitoring of pathogenic bacteria mediated by food and indicator bacteria from healthy animals were switched to animal and poultry slaughterhouses.

Isolated strains collected under JVARM are examined and stocked by the National Veterinary Assay Laboratory, which also performs the analysis of genetic properties and the clarification of antimicrobial resistance mechanism, in order for the molecular epidemiological survey of antimicrobial-resistant strains. Antibiotic feed additives are analyzed by the Food and Agricultural Materials Inspection Center (FAMIC). Data collected through JVARM are published on the website of the National Veterinary Assay Laboratory every year. The data are also utilized for risk assessment by the Food Safety Commission as well as for science-based risk management measures.

5) Monitoring on the sales volumes of antimicrobials

Each marketing authorization holder of veterinary drugs annualy submit, to the National Veterinary Assay Laboratory, the sales volume of antimicrobials from January 1 to December 31, using a designated reporting form. The data are aggregated and published on the website of the National Veterinary Assay Laboratory as “Annual Report of Sales Amount and Sales Volume of Veterinary drugs, Quasi-drugs and Medical Devices.”

Figure 4.

Figure 4.

6) Collaboration with JANIS

Since FY2012, collaboration has been promoted between JVARM and JANIS (Japan Nosocomial Infections Surveillance). The data of Escherichia coli derived from healthy animals collected under JVARM are converted into a format comparable with JANIS data, and the results are published as antibiograms on the website of the National Veterinary Assay Laboratory.[31] These data enable the comparison of trends in antimicrobial-resistant bacteria between humans and animals.

Figure 5. Comparison of the proportion of third-generation cephalosporin-resistant Escherichia coli derived from humans and those derived from food-producing animal

Figure 5. Comparison of the proportion of third-generation cephalosporin-resistant Escherichia coli derived from humans and those derived from food-producing animal

The proportion of third-generation cephalosporin-resistant strains derived from humans and those derived from broilers had an increase trend until 2011. The proportion, however, has rapidly decreased in broilers since 2012. This is probably due to the withdrawal of the off-label use of the third-generation cephalosporin after the explanation of the JVARM data to related associations. [32] On the other hand, the proportion still continues to rise in humans, indicating different trends between humans and broilers.

Figure 6. Comparison of the proportion of fluoroquinolone-resistant Escherichia coli derived from humans and those derived from food-producing animal

Figure 6. Comparison of the proportion of fluoroquinolone-resistant Escherichia coli derived from humans and those derived from food-producing animal

While a consistent increase was observed in fluoroquinolone-resistant strains derived from humans from 2003 to 2013, the proportion of fluoroquinolone-resistant strains derived from food-producing animal remained low, indicating different trends between humans and food-producing animal.

7) Prospect

The key issues in JVARM are that 1) only limited fish species are included in the scope of monitoring of aquaculture; 2) no monitoring is implemented concerning companion animals; 3) only limited monitoring and analysis are conducted regarding antimicrobial-resistant genes; and 4) no monitroing is implemented regarding the volume of use of human antimicrobials on companion animals. The existing monitoring in food-producing animal will be continued under JVARM. Several steps will be taken to address the issues from 2017, which include 1) increasing fish species included in the scope of monitoring of aquaculture; 2) implementing monitoring of companion animals; 3) performing analysis on antimicrobial-resistant genes, including whole genome analysis using next-generation sequencers; and 4) implementing monitoring on the volume of use of human antimicrobials on companion animals. To further promote one health monitoring, further collaboration with JANIS will be pursued by comparing antimicoribal-resistant bacterias at a genetic level through whole genome analysis data. Those data accumulated will lay the ground for risk assessment and risk management, by clarifying the transmission process of antimicrobial-resistant bacteria, through linkage with other areas.