Monitoring AMR in 𝘾𝙖𝙢𝙥𝙮𝙡𝙤𝙗𝙖𝙘𝙩𝙚𝙧

Campylobacter

Campylobacter species are among the most prevalent  zoonotic  bacteria and are the leading cause of human gastroenteritis worldwide. Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli) are the most clinically relevant Campylobacter  species  and are jointly responsible for the majority of Campylobacter-associated diarrheal disease in humans.

Campylobacter are small, curved bacteria with one or two polar flagella that allow them to move around. They are widely distributed in the environment and are often present as a  commensal  bacterium in the intestines of most warm-blooded animals. While C. jejuni is more commonly found in poultry, C. coli is more prevalent in pigs. Both species can also be harboured by cattle, sheep, pets, wild birds and mammals, and can be present in water contaminated by faeces of colonised animals.

The most common transmission routes of Campylobacter species, including the resistant ones, are the consumption of undercooked poultry meat, unpasteurized milk and fresh dairy products, and ready-to-eat food products. Environment can also play an important role in the transmission. Drinking untreated water, swimming in natural waters, or having direct contact with animals are also risk factors associated with campylobacteriosis.

EFSA has published a dedicated story map on  Campylobacter , where more detailed information on the  organism , the  disease , the  distribution  and the different  transmission routes  can be found. The EFSA’s story map on Campylobacter also includes information on the  monitoring of Campylobacter in the EU  and the  prevention  of Campylobacter infection.

The most recent findings on the occurrence of C.jejuni and C.coli in humans, animals and food in the EU can be found in the  EFSA-ECDC EU One Health Zoonoses report  and are also summarised in a dedicated  section  of the Campylobacter story map.

The infographic presented in the right panel visualises how people and animals may get infected with Campylobacter. The information presented also applies to the transmission of resistant Campylobacter. Source: EFSA story map on Campylobacter, section  'How people and animals get infected with Campylobacter' , available online.

AMR in Campylobacter

 Antimicrobial resistance  is a global challenge and the over-use and misuse of antimicrobials for treating animal and human's infections contribute to this problem.

Resistant bacteria, including resistant Campylobacter, can be:

  • Transmitted between animals, humans and the environment.
  • Transmitted via food, including food derived from animals, such as meat, milk, eggs, etc.

Due to its ubiquitous nature in food-producing animals, Campylobacter is often exposed to antimicrobials used at farm level to ensure animal health. This exposure creates a selection pressure that can lead to the development of resistance to several classes of antimicrobials. This has become a serious public health concern as Campylobacter infections in humans show increasing resistance to treatment. Indeed, most antibiotic-resistant human infections are caused by zoonotic isolates ( Whitehouse et al., 2018 ).

Analysing and comparing AMR trends and resistance patterns in Campylobacter originating from both food-producing animals and from humans can help determine if resistant cases of campylobacteriosis in humans are caused by the zoonotic transmission of resistant Campylobacter or if they are primarily a result of human antimicrobial usage.

Mechanisms of resistance

All C. jejuni and C. coli are  intrinsically resistant  to a few antibiotics, bacitracin and ceftiofur ( Whitehouse et al., 2018 ), and have acquired  multiple resistance mechanisms  against other antibiotics that are commonly used in veterinary and human medicine to treat infections.   

Different mechanisms of antimicrobial resistance can be observed in Campylobacter. Both C. jejuni and C. coli can acquire  mutations  in genes that make them less susceptible to important antimicrobials such as fluoroquinolones and macrolides ( Whitehouse et al., 2017 ).

The most important resistance mechanisms in C. jejuni and C. coli are associated either with modifications of the different biological systems allowing the production of proteins, or with effects on bacterial cell membranes ( Iovine 2013 ,  Wieczorek and Osek 2013 ). In particular, the following mechanisms of resistance were observed:

  • Several point mutations have been identified on the 23S ribosome rRNA encoding gene, which constitutes one of the main biological systems of protein synthesis and is a preferred target for antibiotics. Macrolides indeed inhibit bacterial growth by binding to ribosomes and interfering with protein synthesis. These mutations thus prevent the identification of the bacteria by the antibiotics and have been recognized as the most common mechanism of macrolide (i.e. erythromycin) resistance in C. jejuni and C. coli.  
  • Similarly, the resistance to ciprofloxacin is mainly mediated by point mutations in a specific gene called DNA gyrase A (gyrA), in a target genetic region associated with the quinolone resistance-determining region (QRDR).
  • Campylobacter can also modify the molecular target sites recognized by antibiotic molecules to identify the bacteria: this is the case for the target sites of macrolides macrolides antibiotics (i.e., erythromycin), fluoroquinolones (i.e., ciprofloxacin) and tetracycline actions.
  • Campylobacter can also acquire antimicrobial resistance by decreasing its membrane permeability so that antimicrobials cannot enter in the cell or at least their intracellular concentration is decreased and the bacteria may become resistant.
  • Campylobacter can additionally actively expel fluoroquinolones (i.e., ciprofloxacin), tetracycline and macrolides (i.e., erythromycin) thanks to an enhanced activity of the efflux pump system encoded notably by the cmeA gene.

For further general information on AMR, please consult the dedicated EFSA story map on monitoring AMR (available  online 

Spread of resistance

The occurrence of resistance in Campylobacter may depend on several factors. The selective pressure caused by the antimicrobial use in food-producing animal populations, the  clonal spread  of resistant organisms, the dissemination of genetic elements, such as resistance plasmids, and the effects of co-selection in bacteria exhibiting  multidrug-resistance  are important factors to consider.

Combined Resistance

Ciprofloxacin and erythromycin belong to the fluoroquinolones and macrolides antimicrobial classes, respectively. These two substances are considered critically important for the effective treatment of human campylobacteriosis ( WHO, 2024 ).

Consequently, the emergence of combined resistance to ciprofloxacin and erythromycin in Campylobacter originating from food-producing animals carries significant public health implications, since it could compromise the successful treatment of human campylobacteriosis.

Complete susceptibility and multidrug resistance

Some Campylobacter  strains  can be resistant to multiple antimicrobials. When this happens, these Campylobacter strains are called  multidrug-resistant  (MDR). The occurrence of MDR Campylobacter is a severe public health problem because they can cause infections that are challenging to treat due to the limited or even no remaining therapeutic options.

However, other Campylobacter strains can be completely susceptible (CS) to antimicrobial agents. This means that they are not resistant to the tested antimicrobial substances, and therefore infections caused by these bacteria are easier to treat.

The interactive infographic shows the main mechanisms of resistance in Campylobacter coli and Campylobacter jejuni: each mechanism is displayed and detailed in different boxes that can be opened by clicking on the plus (+) buttons.

EU monitoring and EFSA's role

Humans

The EU monitoring of AMR in Campylobacter isolates from humans is managed by  ECDC  and follows an EU protocol ( ECDC ,  EU protocol in 2016 ,  updated in 2021 ).

Every year, each EU MS reports results of  antimicrobial susceptibility testing  (AST) for Campylobacter spp. isolates from clinical cases of campylobacteriosis with a panel of four antimicrobials: gentamicin, ciprofloxacin, erythromycin, and tetracycline. Additionally, some MSs report results for resistance to the optional combination of amoxicillin and clavulanic acid.

Food and animals

The AMR monitoring in C. jejuni and C. coli from caecal samples collected at the slaughterhouse from broilers, fattening turkeys, cattle under one year of age and fattening pigs is mandatory in the EU in accordance with  Decision (EU) 2020/1729 . Sampling of fattening turkeys and bovine animals under one year of age is voluntary for MSs where the national production of corresponding meat is less than 10 000 tons per year.

To ensure that a representative and randomised number of C. jejuni and C. coli isolates is collected from each sampled animal species, each EU MS is requested to apply the legislative requirements for sampling design and AMR testing laid down in the Decision (EU) 2020/1729. The data collected according to the harmonised monitoring requirements are therefore comparable across the EU. Each MS is requested to collect, at a biannual basis, at least 170 isolates of the nationally most common Campylobacter species (among C. coli and C. jejuni) obtained from broilers and turkeys (in even years), and from calves and fattening pigs (in odd years). For MSs with small productions of broiler meat or pig meat (i.e. less than 100 000 tons per year), a minimum of 85 isolates should be tested.

After collecting samples through the AMR monitoring program, the isolates undergo antimicrobial susceptibility testing (more details available in the  AMR story map ). All stages of testing, isolation and interpretation of results are harmonized to contribute to the representativeness and reliability of AMR data: 

  • Harmonized isolation and identification methods
  • Harmonized antimicrobial susceptibility testing (AST), by broth microdilution
  • Harmonized panel of antimicrobials by using a predetermined list of substances that includes antimicrobials of public health relevance, wide use in animals or of epidemiological importance. As stated in Decision (EU) 2020/1729, the harmonised panel includes the following antimicrobials: ciprofloxacin, erythromycin, ertapenem, chloramphenicol, tetracycline, and gentamicin.
  • Harmonized criteria for interpreting resistance by fixing  epidemiological thresholds (ECOFF)  (see the  ‘Monitoring antimicrobial resistance’  story map for more details).

Further details on the sampling framework and analysis related to the harmonised monitoring of AMR in Campylobacter (C. jejuni and C. coli) are described in  Decision (EU) 2020/1729  - Part A of the Annex.

The interactive infographic summarises the main aspects of the EU monitoring of C.jejuni and C.coli in animals according with Decision (EU) 2020/1729. When clicking on the plus (+) button, further details of the corresponding topics are displayed.

Occurrence of AMR in 2022-2023 

The most recent findings on the occurrence of C. jejuni and C. coli in humans, animals and food in the EU can be found in the  EFSA EU zoonoses report . The key findings are presented in this section.

  • For 2023, 24 MSs and two non-MS (Iceland and Norway) reported data on antimicrobial resistance (AMR) in Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli) from humans. In the same year, data on AMR in C. jejuni and C. coli from cattle under 1 year of age were reported by 11 MSs and one non-MS, whereas data on AMR in C. coli from fattening pigs were reported by 27 MSs and three non-MSs. In 2022, data on AMR in C. jejuni from broilers and from fattening turkeys were reported by 26 MSs, the United Kingdom (Northern Ireland) and three non-MSs, and by 10 MSs, respectively, whereas data on AMR in C. coli from broilers and from fattening turkeys were reported by 24 MSs, the United Kingdom (Northern Ireland) and three non-MSs, and by 11 MSs, respectively.
  • Resistance rates differed greatly between reporting countries, between antimicrobials and between the two Campylobacter species, with overall higher values in C. coli than in C. jejuni.
  • Levels of resistance to ciprofloxacin ranged from high and very high to extremely high, respectively, in C. jejuni and C. coli isolates, recovered from humans and food-producing animals in the EU. In 2023, levels of resistance to ciprofloxacin in human C. jejuni isolates ranged from 27.6% to 97.5% among the MSs while for C. coli isolates, 16 out of 18 countries reporting at least 10 C. coli isolates found levels of ciprofloxacin resistance higher than 70%. In food-producing animals, the highest levels of resistance to ciprofloxacin were observed in C. coli isolates, ranging from 54.3% in fattening pigs to 84.1% in fattening turkeys. An extremely high level of resistance to ciprofloxacin was also observed in C. coli isolates from cattle under 1 year of age (80.4%) in 2023, as well as in C. jejuni isolates from poultry (78.1% in fattening turkeys and 70.9% in broilers) in 2022.
  • Resistance to erythromycin was very low to low in C. jejuni from humans and food-producing animals but was higher in C. coli, ranging from overall 6.7% in humans to 31.6% in cattle under 1 year of age.
  • The whole genome sequencing results reported for erythromycin-resistant C. jejuni and C. coli isolates from food-producing animals in 2022–2023, mostly those highly resistant (MIC ≥ 512 mg/L), showed detection of the mutation A2075G in the 23SrRNA gene and no detection of the transferable erm(B) gene in most isolates. A single isolate of C. coli from cattle under 1 year of age was reported positive to the presence of erm(B), and two isolates presented a mutated rplV gene (one C. coli isolate from fattening pigs and from cattle under 1 year of age). Among countries reporting WGS data for Campylobacter isolates from humans, no erythromycin resistance mechanisms were detected.
  • The combined resistance to both ciprofloxacin and erythromycin, two critically important antimicrobials for treating campylobacteriosis, was generally rare to low in C. jejuni from humans and food-producing animals. The combined resistance was higher in C. coli isolates, with low levels observed in humans (6.8%) and broilers (8.2%), moderate levels in fattening pigs (10.6%) and fattening turkeys (17.4%), and high levels in cattle under 1 year of age (30.3%). This finding may be a cause for public health concern.
  • The moderate and high observed levels of resistance to gentamicin and ertapenem in C. coli isolated from cattle under 1 year of age in 2023 (10.5% and 35.5%, respectively), and the moderate to very high levels of resistance to ertapenem in C. jejuni and C. coli isolated from poultry in 2022 might be a cause for public health concern as those are recommended antimicrobials for treatment in severe invasive Campylobacter infections in humans. Gentamicin resistance in C. coli from humans was observed at low levels except in one MS, while ertapenem is not yet included in the priority panel for Campylobacter monitoring of human isolates at EU level.
  • Although findings on ertapenem resistance should be interpreted with caution due to the lack of a validated EUCAST epidemiological cut-off for ertapenem, the results show a shift toward higher MIC values for Campylobacter isolates from cattle under 1 year of age and from fattening pigs between 2021 and 2023.
  • The prevalence of resistance to selected antimicrobials in C. jejuni and C. coli from cattle under 1 year of age and fattening pigs in 2023 has been estimated at country-level. Between-country variability, from rare, low or moderate to extremely high levels, was observed in the prevalence of ciprofloxacin-resistant and tetracycline-resistant C. jejuni and C. coli isolates. Notably, a more limited between-country variability and lower levels of prevalence of resistance were found for erythromycin-resistant Campylobacter.
  • Overall, complete susceptibility (CS), defined in this report as susceptibility to ciprofloxacin, erythromycin, tetracycline and gentamicin, was higher in C. jejuni than in C. coli isolates. The overall CS observed in C. jejuni isolates was 25.5% in humans in 2023, and among C. jejuni from food-producing animals, it was lowest in fattening turkeys (16.5%) and highest in fattening pigs (51.1%). Regarding overall CS among C. coli isolates, it was moderate in humans (11.0%), broilers (13.1%) and fattening pigs (19.7%), and low in fattening turkeys (4.4%) and cattle under 1 year of age (4.5%).
  • Multidrug resistance (MDR), defined in this report as resistance to at least three antimicrobials among ciprofloxacin, erythromycin, tetracycline and gentamicin, was generally very low for C. jejuni isolated from humans (0.6%) and ranged from very low to low (1.0% to 4.3%) in the animal species considered. Compared to C. jejuni, MDR was markedly higher in C. coli, specifically occurring in 8.6% of the isolates from humans, 34.8% of isolates from cattle under 1 year of age, 16.9% of isolates from fattening turkeys, 10.7% of isolates from fattening pigs, and 8.3% of isolates from broilers. These results agree with the higher levels of resistance to selected antimicrobials seen in C. coli isolates.
  • Over the period 2014–2023, resistance to ciprofloxacin in C. jejuni from humans increased in 11 MSs and decreased in three reporting countries (two MSs and one non-MS). In the same period, resistance to ciprofloxacin in C. jejuni increased in six MSs and in one MS from broilers and fattening turkeys, respectively, while it decreased in three MSs and in one MS from the same animal populations. Resistance to ciprofloxacin in C. coli from humans increased in two MSs and decreased in two MSs in the period 2014–2023. Similarly, in the same period, resistance to ciprofloxacin in C. coli from fattening pigs increased in two MSs and decreased in two non-MSs, while it increased in one MS in C. coli from broilers.
  • In the same period, erythromycin resistance decreased in C. jejuni from humans in ten countries (nine MSs and one non-MSs), from broilers in six MSs, and from fattening turkeys in two MSs. Erythromycin resistance also decreased in C. coli from humans in nine MSs, and from fattening pigs in four MSs. An increasing trend in erythromycin resistance was observed in C. jejuni from humans in two MSs and from broilers in one MS, and in one MS in C. coli from humans.

The two bar plots display the comparison of occurrence of resistance between humans and animals for C. jejuni and C. coli. The resistance occurrence is displayed for the substances: erythromycin, ciprofloxacin, gentamicin, tetracycline and erythromycin/ciprofloxacin. In the graph on the right panel, XI is the abbreviation for Northern Ireland (United Kingdom). Source:  2021/2022 AMR EUSR 

 Note:  In accordance with the Agreement on the withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community, and in particular Article 5(4) of the Windsor Framework (see Joint Declaration No 1/2023 of the Union and the United Kingdom in the Joint Committee established by the Agreement on the withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community of 24 March 2023,  OJ L 102, 17.4.2023, p.87 ) in conjunction with section 24 of Annex 2 to that Framework, for the purposes of this Regulation, references to Member States include the United Kingdom in respect of Northern Ireland. 

References

How to prevent AMR in Campylobacter?

Important actions have been implemented to prevent and control the spread of AMR in humans. These strategies aims to prevent the overuse and misuse of antibiotics and to provide information on the responsible use and prescription of antibiotics. An awareness campaign against AMR has been developed, addressed particularly to medical doctors but also to the general public.

Since Campylobacter is a foodborne zoonotic agent, reducing the prevalence of Campylobacter in food-producing animals and the use of antimicrobials in animal husbandry can also impact in decreasing the burden for public health. Unfortunately, there is currently no control programs in place in the EU to set official targets to reduce the prevalence of Campylobacter species in food-producing animals.

Nevertheless, concrete measures to reduce the needs of antimicrobial agents in animal husbandry and lower the resulting impacts on food safety in the European Union have been reviewed by EFSA and the European Medicines Agency (EMA) ( EMA and EFSA, 2017 ). A wide range of control strategies have been implemented in several EU MSs with the aim to fight AMR through reducing antimicrobial use in animal husbandry. Successful strategies follow an integrated, multifaceted approach which considers the local livestock production system and involves all relevant stakeholders — from governments to farmers. EFSA and EMA concluded that it is reasonable to assume that reducing antimicrobial use in food-producing animals would result in a general decrease in antimicrobial resistance of bacteria they carry and subsequently in the food products derived from these animals.

Reducing the use of antimicrobials in food-producing animals, replacing them where possible and re-thinking the livestock production system is essential for the future of animal and public health ( EMA and EFSA dynamic infographic ).

  • REDUCE THE USE OF MICROBIALS
    • Set targets for reducing the use of critically important antimicrobials that are crucial for the treatment of serious human diseases, including campylobacteriosis.
    • Increasing responsibility of veterinarians regarding their prescribing decisions, which should be based on regular farm visits, clinical examination of animals and laboratory tests.
    • Use antimicrobials only if when needed. In particular, antimicrobials should not be used to prevent diseases in healthy animals.
  • REPLACE ANTIMICROBIALS WITH ALTERNATIVE TREATMENTS
    • Consider alternatives to antimicrobials that have been shown to improve animal health and that could reduce the need for antimicrobials (i.e.  probiotics ,  prebiotics ,  bacteriophages , or  organic acids ).
    • Research new alternatives to antimicrobials or to reduce their need.
    • Develop a EU Structure a legal framework to promote the development and possible authorisation of products that can be used as alternatives to antimicrobials.
  • RETHINK THE LIVESTOCK PRODUCTION SYSTEM
    • Improve prevention and control of zoonotic diseases in animals.
    • Explore alternative farming systems leading to a reduced use of antimicrobials
    • Invest on education and awareness of  antimicrobial resistance at all levels of society and especially for veterinarians and farmers.

EFSA and the European Medicines Agency coordinate these actions in an integrated strategy, and monitor the antimicrobial resistance in the EU, but governments, industries, health care providers, scientist, and consumers also have a role to play.

Further reading

References: