Colonisation, contamination, carriage and infection
The terms colonisation, carriage and infection are often used interchangeably, which can be confusing. Infection refers to pathogenic invasion by the bacteria and associated inflammatory changes (e.g. pyoderma). Colonisation refers to persistent carriage of organisms without infection (e.g. as commensal bacteria). Colonisation sites for staphylococci include the nares and perineum, and, to a lesser extent, other skin and mucosal sites. Staphylococci can also be carried and disseminated by transient contamination without persistent colonisation. Transient contamination is most often associated with hand touch sites and poor hygiene. It is usually lost within 12-24 hours.
Meticillin-resistant staphylococci
Meticillin (previously known as methicillin) was one of the early penicillin drugs. Resistance to meticillin was used as a marker for widespread beta-lactam (i.e. penicillin and cephalosporin) resistance through presence of the mecA gene. mecA encodes an alternative penicillin binding protein (PBP), which does not bind beta-lactam drugs. This blocks their antimicrobial activity. Meticillin is no longer available (oxacillin is used instead), but the MRSA/MRSP terminology has stuck. mecA is carried on a part of the staphylococcal genome known as the staphylococcal chromosomal cassette (SCC). Several SCC types have been identified, which vary in length, structure and number of genes. MR staphylococci with different SCC types can therefore carry other genes encoding for resistance to other antimicrobial drugs.
Staphylococci can be broadly divided into coagulase-positive (CPS) and coagulase-negative (CNS) species. CPS are regarded as potential pathogens and are isolated from most staphylococci-associated infections. It is important to remember that most infections are secondary and healthy humans and animals can carry commensal CPS with little risk. CNS, in contrast, are rarely isolated from infections and are regarded as non-pathogenic commensal species. Meticillin-resistance has been identified in both CPS and CNS, and it is possible that CNS can act as reservoirs for transfer of resistance genes to the more pathogenic CPS.
MRSA
MRSA is probably the most well-known of the meticillin-resistant staphylococci, as it is the most common species associated with infections in both humans and animals. S. aureus is the most common CPS isolated from humans. Approximately a third of healthy humans are colonised with meticillin-sensitive S. aureus (MSSA), but less than 1% carry MRSA (although this can be higher in at-risk individuals such as healthcare workers). Working in veterinary practice is also a risk factor for MRSA carriage – studies have shown that 7-13% of vets and nurses were colonised with MRSA. They tended to carry specific MRSA isolates associated with their type of practice (i.e. small animal, equine or farm animal), suggesting that carriage was associated with exposure to animals and veterinary premises.
In the UK, the majority of human MRSA isolates are the hospital acquired (HA) epidemic (E) strains 15 and 16. MRSA-E15 is resistant to beta-lactams, fluoroquinolones and macrolides, whilst E16 can be resistant to further antimicrobials. Most MRSA colonisation and infection in dogs and cats is associated with MRSA E15. MRSA isolates from other species, in contrast, are more commonly associated with specific MRSA isolates that are uncommon in the human population. MRSA isolates from horses and farm animals, for example, are largely found in these species and are rare in the human population. They can, however, be isolated from in-contact humans such as vets, horse owners and farmers.
Studies have shown that less than 1% of healthy dogs, cats and horses in the UK are colonised with MRSA. The colonisation rates are, however, higher in vet-visiting populations and have reached 3-10% in surveys of patients going to secondary and tertiary referral hospitals.
Meticillin-resistant Staphylococcus pseudintermedius (MRSP)
Meticillin resistance has also been seen in other staphylococci more commonly associated with animals, particularly S. pseudintermedius (MRSP). S. pseudintermedius is thought to be involved in 95% of all canine pyoderma and is one of the most common organisms isolated from other infections in dogs and cats. The prevalence of MRSP is difficult to estimate – in some practices and locations it appears to be very high, but elsewhere it is rarely isolated. This may reflect its recent origin and rapid spread. Reports from referral practices suggest that the prevalence could be as high as 30% of infections in continental Europe and 70% in the US. Fortunately, the prevalence in the UK appears to be much lower at the moment (at The University of Liverpool we have only seen two clinical cases (a preavalence of ~0.002%) and we have not isolated MRSP from any dogs in our community surveys). Further vigilance and research is nevertheless needed.
MRSP is a particular concern as virtually all of the isolates from Europe and North America have been of a single clone (a group of highly related staphylococci). This clone appears to have spread rapidly around the world since it first originated. This MRSP clone, furthermore, is highly resistant to antimicrobials, exhibiting multi-drug resistance to five or more antimicrobial classes including penicillins, cephalosporins, fluoroquinolones, aminoglycosides, sulphonamides, macrolides, tetracyclines, fusidic acid and mupirocin. MRSP infections can therefore be difficult to manage.
Meticillin-resistant Staphylococcus schleiferi (MRSS)
Meticillin-resistant isolates of the CPS S. schleiferi subsp. coagulans (MRSS) have also been isolated from animals, especially dogs. MRSS seems to be common in North America, but rare in the UK. Some MRSS isolates may, however, have been misidentified as MRSP or MRSA and the prevalence of MRSS in the UK could have been underestimated. MRSS can also exhibit a greater range of antimicrobial resistance than MRSA, although they are generally more susceptible to antimicrobials than MRSP.
Meticillin resistance in coagulase negative staphylococci
Meticillin resistance is also seen in CNS. The prevalence of resistance in CNS from animals is often much higher than in CPS isolates, especially in horses. Fortunately, CNS such as S. schleiferi subsp. schleiferi, S. haemolyticus, S. vitulinus, S. sciuri, S. epidermidis and S. warneri are usually non-pathogenic, commensal species, as they lack many of the virulence factors associated with CPS. Some CNS, particularly S. schleiferi subsp. schleiferi, have nevertheless been isolated from pyoderma and wound infections in animals, although it can be difficult to determine their importance in mixed infections.
Infection with meticillin-resistant staphylococci
Infection with MRSA or MRSP is much less common than colonisation. Colonisation is of little risk to most healthy individuals, and infection is usually associated with specific risk factors. These include:
- Skin or mucosal barrier defects
- Compromised immune system
- Long term in-patients, especially stays in intensive care units
- Broad spectrum antibiotic therapy, especially multiple courses
- Surgery and/or the presence of implants including catheters
Diagnosis of MRSA or MRSP infections
It is not feasible in most first opinion practices to culture all animals with infections. Nevertheless, animals with the above risk factors should be cultured. In addition, any post-operative or nosocomial (e.g. healthcare acquired or associated) infection or any infection that does not respond to an empirical antibiotic (i.e. one selected on likely efficacy rather than culture) must also be cultured.
Any staphylococcal isolate with oxacillin or any unusual pattern of resistance (e.g. cephalosporin or fluoroquinolone resistance) should be viewed as potentially MRSA or MRSP. Confirmation, however, requires further biochemical and genetic tests (meticillin-resistant staphylococci can be both missed or over-diagnosed without the appropriate tests). Labs should also perform a D-test or PCR to identify inducible clindamycin resistance in all MRSA and MRSP isolates.
Treatment of MRSA and MRSP infections
Infections with meticillin-resistant staphylococci are challenging, but most infections in companion animals are treatable, especially if the underlying disease can be managed. In about half of the fatal cases, furthermore, death is attributable to the underlying condition not the infection. Infections with MRSP and MRSS, however, can be resistant to more antibiotics and difficult to treat.
The underlying condition must be diagnosed and managed for successful resolution. This may require referral to the appropriate specialist for further diagnosis and treatment. It is not enough to just treat the infection – this is usually ineffective and leads to the development of further resistance.
Antimicrobial therapy must be chosen on the basis of culture and sensitivity results, preferably using minimum inhibitory concentrations (MICs). MICs tell you how sensitive the organisms are, allowing you to select antibiotics that are likely to achieve effective concentrations at the site of infection. This may mean increasing the dose and/or frequency of treatment in some cases. Antibiotics reported as intermediate should not be used, as it is highly unlikely that they will achieve a therapeutic concentration at the site of infection.
Topical therapy
Topical therapy can be very useful. This is because topical treatment delivers the antimicrobial directly to the site of infection at a high concentration. This is typically in the mg/ml range instead of the μg/mg range achieved following systemic therapy. In vitro sensitivity tests are based on systemic therapy, and therefore underestimate the efficacy of topical therapy where the high antimicrobial concentration can overcome the resistance. Antimicrobials listed as intermediate or (in some cases) resistant can therefore be effective when used topically. Topical fusidic acid, for example, can be effective against MRSP isolates reported to be resistant to this drug in vitro.
Chlorhexidine is a highly effective topical antimicrobial. Recent studies have shown that it can be efficacious in MRSP-associated superficial pyoderma and that antimicrobial resistant bacteria are no less susceptible that sensitive isolates. Chlorhexidine shampoos and washes can therefore be very useful. Other antimicrobial shampoos, however, appear to be less useful against MRSA and MRSP.
Vets should use their imagination when it comes to devising other options for topical or local treatment – a number of topical antimicrobials are available as creams, gels, ointments or drops, antimicrobials can be added to creams and other solutions, and antimicrobial impregnated beads, gels and sponges can be used in wounds and joints etc. Many products are not licensed for animals, but their use can be clinically justified. Useful topical antimicrobials include gentamicin and other aminoglycosides, silver sulfadiazine, mupirocin and fusidic acid.
Systemic therapy
Systemic treatment options for MRSA can include clindamycin, but many isolates possess inducible resistance. These isolates appear to be sensitive in vitro, but in fact are resistant. Other systemic treatment options for MRSA include doxycycline or other tetracyclines, trimethoprim-sulphonamides, gentamicin and other aminoglycosides, chloramphenicol or florphenicol, and rifampicin. Systemic treatment options for MRSP are often limited by further antimicrobial resistance though. Most of these drugs are not licensed for systemic use animals and may have adverse effects.
Antimicrobials of critical importance in human health, such as vancomycin, linezolid and teicoplanin, should not be used in animals. These are last-line treatments for life-threatening antimicrobial resistant infections in humans and should be reserved for this use.
Decolonisation treatment
Most animals with MRSA or MRSP infections are also colonised at mucosal sites, although it is not always clear if this occurred before or after the infection. Swabs should be taken from the nares and perineum after clinical cure of the infection to determine whether the animal is colonised. Owners of animals colonised with MRSA or MRSP should be given advice about the risk factors for infection, but should also be reassured that these organisms pose little risk to healthy individuals. Owners should be advised on routine hygienic precautions, especially cleaning, hand washing, disinfection and avoiding mucosal contact.
Colonisation is usually lost in 1-6 months, once the animal is out of the veterinary environment, off antibiotics and back in the community. The MRSA and MRSP appear to be replaced by antimicrobial sensitive organisms. Simple hygienic precautions (especially hand washing and disinfection) and bathing, where appropriate, with chlorhexidine shampoos appear to be sufficient in most cases.
More active decolonisation may be necessary where there are risk factors that make in-contact humans more vulnerable to infection and/or the animal needs urgent surgery or other treatment. Active decolonisation usually involves daily chlorhexidine baths and topical therapy of the nares with fusidic acid or mupirocin. Decolonisation of animals may also be necessary in persistently colonised households, as colonised animals can be reservoirs for re-colonisation or infection of in-contact humans. Vets must work with medical teams in these circumstances to ensure that decolonisation of the whole household is successful.
Zoonotic colonisation and infection with meticillin resistant staphylococci
Staphylococci do not appear to be as species restricted as we once thought. Similar staphylococci can be isolated from both dogs and humans in 20-60% of households. One study of S. pseudintermedius associated deep pyoderma in dogs found that 75% of the owners were also colonised with S. pseudintermedius.
MRSA also appears to be readily shared between humans and animals. Most MRSA isolates from dogs and cats are identical to the most prevalent strains in the human population. Whilst MRSA isolates from other animals are rare in the general population they are frequently isolated from in-contact humans. Vets and owners caring for dogs and cats with MRSA infections are more likely to be colonised with MRSA than those caring for animals with other infections. Vets and nurses are more likely to be colonised with MRSA than the general public, and they are usually colonised with the same type of MRSA as the animals with which they come into contact. MRSP, in contrast, appears to be more species specific and is less commonly isolated from in-contact humans. The data on MRSP is, however, limited and further studies to determine its zoonotic potential are needed.
Fortunately, while zoonotic transfer and colonisation is fairly frequent, true zoonotic infections remain rare and sporadic. Colonisation seems to pose little risk to healthy individuals, and zoonotic infections are usually associated with specific risk factors.
It is very important to discuss the zoonotic potential of MRSA and MRSP with owners, so that risk factors can be identified and managed. Good hygiene will reduce zoonotic transmission. The most important measures are hand washing and disinfection, cleaning and disinfection of contaminated surfaces, and avoiding direct or indirect mucosal contact.
Where do the MRSA and MRSP infections come from?
It is often difficult to determine the source of infection for an individual animal, as the infection is not diagnosed until established and very few studies have differentiated nosocomial colonisation from animals colonised at admission. Nevertheless, evidence suggests that most infections are directly or indirectly acquired through veterinary premises. The carriage rate of MRSA and MRSP in healthy, non-vet visiting animals in the community is less than 1%, but the carriage rate in vet-visiting animals is higher, reaching 3-10% in secondary and tertiary referral cases. Other studies in referral centres showed that roughly half of the MRSA or MRSP cases were colonised or infected at admission and the other half became colonised or infected in the veterinary hospitals. Most of these animals had veterinary contact and antibiotic treatment prior to admission though. Risk factors for infection with MRSA and MRSP are, moreover, largely associated with veterinary treatment.
The responsibility and means for reducing the incidence of MRSA and MRSP infections in animals lies with the veterinary profession. Simple measures have greatly reduced the prevalence of MRSA in medical hospitals, and these are directly relevant to veterinary practice. They include high standards of clinical practice, good hygiene, effective infectious disease control programmes and responsible use of antibiotics. It is unlikely that infection with MRSA or MRSP would be regarded as evidence of negligence by itself in veterinary practice provided that these steps have been followed.
Infectious disease control programmes
All practices should have a written infectious disease control policy. All staff should be aware of the policy, and receive appropriate training. The policy must also be monitored and enforced. Outline infectious disease control programmes have been produced by a number of veterinary organisations including BSAVA and FECAVA. These can be readily adapted to the needs of an individual practice.
The most important measures include:
- Hand washing – hand-washing facilities must be available in all areas and instructions must be prominently displayed (ideally staff should be able to wash their hands after animal contact without having to touch anything else or leave the room)
- Cleaning – cleaning protocols must be clearly displayed in the appropriate areas, and cleaning should be divided into daily, weekly and monthly tasks based on risk (ideally a member of staff on their first day should be able to clean rooms and equipment correctly)
- Disinfection – appropriate disinfectants should be readily available and instructions for use should be prominently displayed (it is important to remember that disinfectants, including alcohol gels, are not effective if organic debris is present – visibly soiled surfaces and hands must be washed first).
- High standards of clinical practice should be maintained through training, provision of equipment and clearly displayed protocols – this includes handling of known or suspected MRSA/MRSP cases, clean techniques, aseptic surgery, isolation and barrier nursing
Rational and responsible use of antimicrobials
Veterinary practices should adopt guidelines for effective and responsible antimicrobial use. Some guidelines from pharmaceutical companies and veterinary organisations have been published, and more are in preparation. The most important points are:
- Ensuring that the patient has a bacterial infection, using specific clinical signs, cytology and, where necessary, bacterial culture and antibiotic sensitivity
- Speculative use of antibiotics to treat non-specific clinical signs should be avoided – they should not be routinely used to prevent infection except in high-risk situations where there is a proven benefit (e.g. certain surgical procedures)
- Ensuring that the infection warrants systemic antibacterial therapy - topical antimicrobial or antibiotic therapy should be considered in appropriate cases
- Selecting the most appropriate drug
- Using an efficacious dose for an adequate treatment period
- Maximising compliance
It is also important to use the lowest tier antibiotic that will treat the infection. First tier drugs include older antibacterials and/or narrow-spectrum drugs such as simple penicillins, tetracyclines, and sulfonamides. These are no less potent than 2nd or 3rd tier antibacterials in the appropriate circumstances. Second tier drugs include newer, broad-spectrum products that are more important for humans and animals and/or more prone to resistance (e.g. broad-spectrum beta-lactamase resistant penicillins, cephalosporins and macrolides). These should be used where culture or good empirical evidence indicates that 1st tier drugs will be ineffective. Third tier drugs are those very important to humans and animals (e.g. fluoroquinolones, anti-Pseudomonas penicillins, ceftazidime, imipenem etc.). They should only be used where culture indicates they are necessary. In one study, adoption of antibacterial use guidelines led to a significant fall in the use of 2nd and 3rd tier drugs with first line drugs accounting for approximately 90% of treatment.
Conclusion
The key points to managing the risks posed by antibiotic-resistant bacteria such as MRSA and MRSP are:
- Understand how and why antimicrobial resistance arises and spreads
- Don’t rely on antibiotics alone
- Use antibiotics appropriately
- Perform cultures and antibiotic sensitivity testing whenever possible
- Pay good attention to clinical practice, hygiene and infectious disease control
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