Antimicrobial resistance and its potential transmission from animals to man has become a major issue, both politically and scientifically and is leading to greater controls, both in North America and Europe, on how we use antibiotics in agriculture and veterinary medicine. There is deep and sincere concern expressed by the medical profession about the worsening antimicrobial resistance situation in man and the potential that agricultural/veterinary use of antimicrobials is adding to their problem – to a large extent – the ‘myth’? Hence there is a call for a ‘One Health’ approach between human and animal use of antibiotics to try to combat the problem. However, much of the proposed legislation and controls on veterinary medicine is not based on factual assessments but assumptions, and the contribution that agricultural use is making on human antimicrobial resistance problems has not been quantified – the ‘reality’?
This paper attempts to quantify the significance of the use of antimicrobials in pigs on human antimicrobial resistance or enables it to be determined on a national basis.
Overview of resistance development and spread
The use of antibiotics, especially when given by mouth, either in feed or in drinking water or tablets etc. may have a direct effect on the bacteria in the gut; i.e. kills them off if they are susceptible. They may be good bacteria or the bad pathogenic bacteria that you are trying to treat like Escherichia coli or Brachyspira hyodysenteriae. This exposure may select for organisms that are either inherently resistant, so they don’t die, then they multiply because of reduced competition or selects for resistant bacteria that have already acquired resistance. Bacteria can acquire resistance either by mutations of their DNA (remember they are often growing and multiplying at a very fast rate) and if this mutation is on chromosomes this leads to clonal spread as the bacteria multiply e.g. Campylobacter coli and fluoroquinolone resistance. Sometimes they acquire resistance via plasmids, which are passed from one cell to another by conjugation (almost sexually) and some bacteria like E. coli can spread plasmids very readily and these carry potentially resistant genes so are spread horizontally to possibly susceptible bacteria or potentially other bacterial species. Less common routes of transmission are by transformation; they pick up DNA left by other bacteria or by transduction where bacteriophages (viruses) inject the DNA. After treatment, the gut flora stabilises over time and often returns to what it was before. Some bacteria that have resistant genes or plasmids do not always survive or compete very well and naturally die off. Hopefully, the pig has developed immunity or is resistant to further infections.
Generally, in pig medicine we use a lot of oral antimicrobials via feed or drinking water; hence many of the bacteria we find in the gut carry a higher level of resistance. Resistance is often higher in young or weaned pigs where they have been treated but by the time they go for slaughter the resistance is less (Table 1). This is important to reduce potential indirect transmission of resistance via meat contamination.
We also use oral antibiotics to treat respiratory diseases such as Mycoplasma hyopneumoniae (enzootic pneumonia), Actinobacillus pleuropneumoniae, or systemic diseases like Streptococcus suis (strep meningitis) of Haemophilus parasuis (Glässer’s disease). Generally, resistance is lower against these infections but the gut flora is exposed at the same time, hence tetracycline resistance is very high in E. coli (around 80%) but relatively low in A. pleuropneumoniae (24%).
Table 1. Comparison of antimicrobial resistance (%) in E. coli by age group in the UK (VMD, 2015).
Key: * not available UK
We also use oral antibiotics to treat respiratory diseases such as Mycoplasma hyopneumoniae (enzootic pneumonia), Actinobacillus pleuropneumoniae, or systemic diseases like Streptococcus suis (strep meningitis) or Haemophilus parasuis (Glässer’s disease). Generally, resistance is lower against these infections but the gut flora is exposed at the same time, hence tetracycline resistance is very high in E. coli (around 80%) but relatively low in A. pleuropneumoniae (24%, Table 2).
Table 2. Antimicrobial resistance (%) in the EU to A. pleuropneumoniae, S. suis and H. parasuis (El Garch et al, 2015).
Key: e = estimate.
If low preventive levels or growth promotion levels are used this also increases the exposure of the gut flora, which may lead to greater resistance. So saying however, some bacteria acquire resistance quicker than others e.g. E. coli and some antibiotics develop resistance more slowly e.g. aminoglycosides such as neomycin and apramycin.
Some antibiotics given by injection are excreted primarily by the kidney (amoxycillin, ceftiofur) and thereby do not have such an impact on gut flora. Others, like enrofloxacin and tiamulin are metabolised and excreted mainly by the liver and bile duct directly into the gut and again can expose the gut flora to the drug. The former kidney excretors are good for kidney infections caused by E. coli and the liver excretors are often good for treating gut infections, like enrofloxacin and E. coli and tiamulin and B. hyodysenteriae (swine dysentery).
There is concern about multiple resistance development to pig pathogens by veterinarians and farmers e.g. we have multiple resistant B. hyodysenteriae in the EU, resistant to all licensed antimicrobials, which has made it necessary to depopulate herds. However, the main public concern about resistance in pigs in particular, is the potential transference of resistance, whether via zoonotic bacteria, which cause disease in man such as Salmonella or Campylobacter spp and make them more difficult to treat, or by commensal bacteria, such as E. coli and Enterococcus spp, which may transmit resistance via plasmids and genes to the human gut flora but may not cause disease directly in man. Staphylococcus aureus has become a recent concern, as it can colonise a pig’s nose and may spread to man. In many countries in the EU and also N. America, many pig farms carry the methicillin resistant form (MRSA) in particular CC398. The bacterium can colonise the pig’s nose and live there quite happily and may not cause disease, however it can colonise a human nose also but usually for a short time; it can cause disease in man but hospitals that screen patients are very worried about it coming into the wards and being spread to other patients or contaminating wounds of the carriers post surgery.
Methicillin-resistant Staphylococcus aureus (MRSA)
The direct spread of MRSA from pigs to man has been a major issue. Ninety percent of MRSA CC398 human carriers and infected patients in Denmark (DANMAP, 2011) were associated with pig farming, either workers/farmers or veterinarians and their families. In Germany, colonisation was reported at 83% in pig farmers and 4.3% of their families (Cuny et al, 2009). Additionally, 36% of pig veterinarians and 14% of slaughterhouse workers (Blaha et al, 2009) had nasal colonisation. The spread beyond to the general population was very limited. The methicillin-susceptible form (MSSA) has been around for a long time in humans but somehow got into pigs and it is postulated that the widespread use of 3rd generation cephalosporins in the 2000’s probably selected for MRSA in piggeries. Methicillin or related compounds are not used in pig medicine but once it has the mecA gene it is resistant to all beta-lactam (penicillin-based) antibiotics. The pig associated MRSA is usually tetracycline resistant and has been found to have a chromium/zinc resistance cra gene associated with the mecA gene. Both tetracyclines and zinc oxide are widely used in many pig-producing countries but these are not primary selectors of methicillin resistance but may be co-selectors if they have the resistance genes as well as they may kill off susceptible bacteria, enhancing the survival of the resistant bacteria.
In Denmark, there is great concern about the spread of MRSA from pigs to man. The Danes (DVFA, 2014) identified that in 2013, 68% of finisher herds were MRSA positive and colonisation with MRSA CC398 in man was increasing rapidly to 643 cases (30.7%) of overall MRSA colonised patients and infection and clinical disease associated with CC398 was 156 cases (16.8%) and of these, bacteraemias were 1.8% and actual deaths were lower at approximately 0.8% (Table 3). All mortalities had a number of serious underlying diseases.
Table 3. Epidemiology of direct contact infections from pigs to stockmen – MRSA Denmark.
The potential direct spread of the pig MRSA to stockmen can be very high and therefore methicillin resistance spread to stockmen is also high. By comparison, the spread amongst the general Danish population is incredibly low and potential infection rate is 0.0028% in comparison with 1.1% in stockmen.
Barlow et al (2003) in the UK reported that 21% of pig stockmen were seropositive to S. suis type 2; there were approximately two clinical cases/year over a 20 year period and approximately 12.5% of cases died from the infection. One death was in a case who was asplenic (immunocompromised). Approximately, 20-30% of UK pig farms are affected by S. suis infections. Interestingly, almost all of the isolates in the UK cases were penicillin susceptible, the main antibiotic used for treatment, so penicillin resistance transfer per se was not the issue and could be considered as effectively zero.
Direct transmission of S. suis to pig farm workers can be considered high at 21% causing seroconversion but infection transmission amongst the general public is low at 0.0032% and penicillin resistance transfer is zero (Table 4).
In contrast, Nijsten et al. (1996) in the Netherlands found that the antibiotic resistance of E. coli in faecal samples of pig farmers was significantly lower than samples obtained from pigs. The resistance patterns of only 4% of farmer E. coli were the same as pigs from the same farm. DeBeen et al. (2014) did show that direct transmission of E. coli carrying plasmids and extended-spectrum beta lactamase (ESBL) resistance genes could be transmitted from pigs to farmers.
Direct spread of bacteria from pigs tofarmers can be considered high and as a consequence, the potential risk of the direct spread of antimicrobial resistance can also be considered high.
Table 4. Epidemiology of direct contact infections from pigs to stockmen – S. suis UK.
Campylobacter spp are currently the most frequently transmitted enteric infections transmitted from animals to man, mainly by contaminated food and the environment (EFSA/ECDC, 2014a). Campylobacter jejuni infections are the most common in man accounting for approximately 94.4% and C. coli for approximately 5.6% (Mughini Gras et al., 2012) in a Dutch case control study. Chickens have a similar proportion of Campylobacter species to humans and cattle are predominantly C. jejuni too. Pigs however, carry predominantly C. coli and Burch (2002) concluded that using macrolide (erythromycin) resistance as a marker, pig C. coli were unlikely to contribute significantly to human C. coli infections. Carcass contamination of pork with Campylobacter spp is also very low at 0.6% but chicken carcasses are high at 31% (EFSA, 2011). Mughini Gras et al. (2012) looked at a combined case control and genetic source attribution analysis for both C. jejuni and C. coli in the Netherlands, using multi-locus sequence typing (MLST). Overall, they attributed cases, 66.2% to chicken, cattle 20.7%, sheep 2.5%, pigs only 0.3% and environment 10.1%.
The susceptibility of C. jejuni to the fluoroquinolone, ciprofloxacin, is relatively low but the susceptibility to macrolides (erythromycin) is comparatively high (EFSA/ECDC, 2014b, Table 5). In contrast the susceptibility of ciprofloxacin to porcine C. coli is higher but erythromycin lower.
Therefore, based on the Mughini Gras et al (2012) attribution, a likely EU assessment (EFSA/ECDC, 2014b) of resistance attribution to humans of the 214,268 reported cases from Campylobacter spp infections can be made for pigs and poultry for macrolides (Table 6).
Table 5. Resistance* (%) of Campylobacter spp to antimicrobials in the EU.
(EFSA/ECDC, 2014b) *Human data used clinical breakpoints, whereas animal data used epidemiological cut-off breakpoints, so not directly comparable. MS = Member States
Table 6. Comparison of Campylobacter spp transmission by pigs and chickens to humans and macrolide resistance in the EU.
Key: Macro = Macrolide *Reported cases of campylobacter in man; Cc = C. coli; Cj = C. jejuni; ND = No data.
Macrolide resistance is transmitted by pigs to man at a very low rate of 0.00003% or 0.03 people /100,000 population and the incidence or potential macrolide resistance transfer from chickens is also low 0.0005% or 0.5 people/100,000 population. This is in accord with the European Medicines Agency’s categorisation of macrolides (EMA, 2014) as a lower risk family of antimicrobials in their Category 1, in contrast to the World Health Organisation’s (WHO, 2011) assessment of being a Highly Critically Important Antibiotic (HCIA).
The incidence of reported salmonella cases has been steadily falling in the EU since 2004 when it was 195,947 cases (EFSA/ECDC, 2010) until 2012 when it was 91,034 cases (EFSA/ECDC, 2014a), a 54% fall, following the introduction of vaccine and hygiene measures in poultry flocks. The main effect has been a reduction of the incidence of S. enterica Enteritidis, which contaminated meat and eggs but S. Typhimurium cases, the main pig isolate, have stayed much the same (Table 7).
In the EU, in contrast, the main human salmonella serovars were 41.3% S. Enteritidis and 29.3% S. Typhimurium and monophasics (EFSA/ECDC, 2014a). Pigs are commonly associated with S. Typhimurium but phage typing of GB isolates tells a different story that possibly only one third (9.8%) are pig associated(AHVLA, 2014) and therefore 51.1% are chicken associated (both S. Enteritidis and S. Typhimurium).
The antimicrobial resistance patterns for S. Typhimurium have been reported in EFSA/ECDC (2014b, Table 8).
Table 7. Isolation of the most common salmonella serovars in humans and animals (%) in GB (AHVLA, 2014).
Table 8. A comparison of antimicrobial resistance (%) to human and animal S. Typhimurium isolates (EFSA/ECDC, 2014b).
Key: MS = Member States; 3G = 3rd generation cephalosporin; *Clinical breakpoint; **Epidemiological cutoff value.
The estimation of transfer of cefotaxime (3G) (ESBL) resistance from pigs and chickens to man via Salmonella spp infections is summarised in Table 9.
Table 9. Comparison of Salmonella spp transmission by pigs and chickens to humans and cefotaxime 3G (ESBL) resistance.
Key: ND = No data; *Reported cases of salmonella in man (EFSA/ECDC, 2014a).
The estimated transmission rate of cefotaxime (3G) resistance via Salmonella spp from pigs to man is 0.00004% or 0.04people/100,000 population. For chickens the transmission rate is higher at 0.00037% or 0.37people/100,000 population. On this basis ESBL resistance transmission can be considered very small even for chickens.
There have been a number of reports in the EU looking genetically at ESBL resistance genes found in urinary tract infections and blood-borne infections in man and comparing them from ESBLs found in animals and food (Wu et al, 2013, SVARM, 2015; DANMAP, 2015; Burch, 2015).
These results demonstrated that 2/747 (0.27%) ESBL resistant genes were identical to genes found in animals and food and that 745/747 (99.73%) were attributable to human use of 3rd and 4th generation cephalosporins in man (Table 10). Surprisingly, the Danes concluded in their report that “consumption of meat may currently be considered an insignificant source for the human infections” (DANMAP, 2015). Using the SVARM (2015) data the attribution rate of ESBLs from animals to human infections was 1/379 (0.26%), which represents on a transmission rate basis that the number of clinical cases potentially caused by ESBL containing E. coli from food/farm animals = 21.2/8,161 cases or an infection rate of 0.00022%/year on a 9.5 million population basis. This represents 0.22 people/100,000 population out of 85people/100,000 population which would normally get infected, i.e. an extremely low infection rate.
Table 10. Combined results ESBL resistance gene attribution from animals and food and those in clinical infections in man (Wu et al, 2013, SWARM, 2015; DANMAP, 2015).
Risk Assessment Summary
A comparison of risk assessments for transfer of infectious agents and antibiotic resistance transfer from pigs to man are summarised in Table 11.
Table 11. Comparison of risk assessments for transfer of infectious agents and antibiotic resistance transfer directly from pigs to farmers or indirectly from meat to man.
In comparison, direct transmission from pig to farmer is potentially very high, depending on the organism and the infection on the farm. Indirect transmission from meat to man is apparently very low.
The direct transmission of infectious agents from pigs to man, working and caring for the animals, is unfortunately very high. It also depends on which bacteria are present on the farm. The transmission of MRSA to farmers and veterinarians appears to be very high. Fortunately, colonisation in man is not long lived and there is a low incidence of infection and disease with it. Similarly, for S. suis, the transmission probably in the air and dust is also very high and the colonisation and seroconversion is also high but the incidence of disease is low. Escherichia coli probably can be easily transmitted by faecal and dust contact to the farmer and may be ingested. Fortunately, colonisation is comparatively low and infections are low but the spread of plasmids and resistance genes does occur.
Indirect transmission via pig meat and its products would appear to be very low. Only 0.3% of human Campylobacter spp infections are attributed to pigs. Macrolide resistance may be a little higher than say in poultry but overall the infection rate and resistance transmission rate is very low. Salmonella in man is changing in the EU with an over 50% reduction, mainly of the chicken infection S. Enteritidis. Sero-typing of S. Typhimurium, the main pig strain, shows that both poultry and cattle contribute also and it is not just pigs that carry it. ESBL resistance is not high so actually the transmission rate of this important resistance is low. Recent data regarding ESBL resistance transmission by E. coli also demonstrates a very low transmission rate from food to man and causing infections in man. There is a different epidemiology of resistance transmission spreading in man because of the high usage of cephalosporins in man and the transmission of infectious agents and their resistance genes particularly in hospitals (Overdevest, et al, 2011).
Antibiotics must be used responsibly in pigs and the future legislation is likely to reduce their use by banning growth promotion and moving them under veterinary prescription. In the EU we are going further by banning prophylactic use and restricting in-feed medication. The ‘myth’ that antibiotic use in pigs causes a huge amount of resistance in man does not stand up to close scrutiny and hopefully the ‘reality’ will be taken on board by legislators to prevent over-restriction of the use of antibiotics in veterinary medicine and endangering the health, welfare and productivity of pig production.
Presented at the 16th London Swine Conference: "A Platform For Success" London, Ontario, April 5-6, 2016.
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