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MRSA: What it means for both large and small animal practitioners

Article

Staphylococcus aureus is an important human pathogen and is a significant cause of hospital acquired (nosocomial) infection of surgical wounds and infections associated with indwelling medical devices. Staphylococcus aureus can colonize the skin and nares of humans which facilitate its transmission, particularly in the healthcare setting.

What is MRSA?

Staphylococcus aureus is an important human pathogen and is a significant cause of hospital acquired (nosocomial) infection of surgical wounds and infections associated with indwelling medical devices. Staphylococcus aureus can colonize the skin and nares of humans which facilitate its transmission, particularly in the healthcare setting.

Staphylococcus species are ubiquitous non-motile, non-spore-forming Gram positive cocci bacteria that produce catalase which grow primarily as facultative anaerobes. Taxonomically, the Staphylococcus genus falls under the phylum Firmicutes, class Bacilli, Bacillales order, and Staphylococcaceae family. Members of this genus are characterized by being round, typically 1µm in diameter and can be found as single cells, pairs, or tetrads though they are prone to clumping into bunches, giving rise to the cocci designation, a name derived from the Greek kókkus which means grain, seed, or berry. Phenotypically, the staphylococci are usually further classified according to the presence of the active coagulase enzymes which induces rabbit plasma to clot.

Staphylococci are found on the skin and on the mucous membranes of humans and animals; many strains are host specific and may or may not cause disease in the host. Commensal bacteria colonize the skin, filling an environmental niche and helping to protect the host from colonization by pathogenic bacteria by competing for nutrients and preventing the adherence of pathogenic bacteria. They can also directly deter pathogenic bacteria by excreting toxic metabolites which make the local environment untenable to other bacteria. In humans, commensal staphylococci are generally coagulase-negative species with S. epidermidis and S. hominis being the most commonly identified.

Methicillin-Resistant Staphylococcus aureus (MRSA) emerged in 1961 after the introduction of methicillin in 1959 for treatment of penicillin-resistant staphylococci. Since its emergence, MRSA has become an important problem in human medicine and presents a challenge to treatment due to its tendency to be multiply drug resistant.

Medical advances in therapeutics have continuously sought to overcome the bacteria's incursions. Prior to the development of antibiotics, little could be done against this and other bacteria. But the addition of penicillin to the clinical formulary in 1948 revolutionized medical management of infectious bacterial diseases. Penicillin and members of the beta-lactam antibiotic class are bacteriocidal as they target the bacterial enzymes involved in cell wall biosynthesis, known as the penicillin binding proteins (PBP), thereby preventing cross-linking of the peptidoglycans in the bacterial cell wall and inhibiting cell growth ). S. aureus soon adapted to the new environmental pressure with some strains developing resistance to the beta-lactam antibiotic within a year. These resistant strains produced penicillinases (also known as beta-lactamases) that attacked the penicillin's four-membered beta-lactam ring structure by disrupting the amide bond of the ring and inactivating the antibiotic. These plasmid-encoded penicillin-resistant strains soon became widespread and comprise the first wave of antibiotic resistance in the hospital setting, necessitating a new therapeutic option.

A new line of antibiotics, fortified against the beta-lactamases produced by the bacterium were developed to target these newly resistant strains. Methicillin, a beta-lactamase-resistant antibiotic was first used in 1959 and demonstrated efficacy in inhibiting cell wall synthesis by bacteria despite the presence of beta-lactamases. However reports of resistance to methicillin and members of its class surfaced by 1961, denoting the start of the second wave of antibiotic resistance. Though methicillin is no longer clinically utilized, S. aureus strains that exhibit resistance to the beta-lactamase antibiotic class are known as methicillin-resistant S. aureus (MRSA). In order to meet this classification, a MRSA strain must demonstrate a minimum inhibitory concentration (MIC) of oxacillin (a laboratory standard for the beta-lactamase class) ≥4µg/mL. Alternatively, a zone of inhibition ≤10mm around an oxacillin-impregnated disk would be considered resistant when performing a disk diffusion test. Staphylococcus aureus are further typed by the genes they actually carry. Several genetic epidemiological methods such as pulsed-field gel electrophoresis (PFGE) are utilized to study the differences between strains.

It stands to reason, therefore, that the presence of antibiotic resistance limits the clinician's ability to prescribe pharmacological agents that will curb the spread of the bacteria. Combine this with the presence of other virulence factors identified in S. aureus and it is evident that the bacterium poses a threat to the wellbeing of people and animals.

Defining MRSA Infections in Humans

Following the first reports of resistance in 1961, MRSA has been a constant hindrance and potential threat to the hospitalized patient. The bacterium has a predilection for catheter sites, in-dwelling devices, and surgical incisions; hospital-acquired MRSA (HA-MRSA) has historically been a nosocomial infection of concern but the risk has increased in recent years. A study by Panlilio et al. found that nosocomial MRSA infections increased from 2.4% in 1975 to 29% in 1991. The number of beds a facility had impacted the rate of infection, with larger institutions demonstrating a faster climb in the number of resistant cases. In 2003, >60% of all isolates obtained from all adult patients in intensive care units were MRSA, which translates into a 3.1% annual increase from 1992 to 2003. A retrospective survey of the National Hospital Discharge Survey looking at S. aureus-related hospitalizations and deaths between 1999-2005 found that though annual admissions increased ~8% during those years, the number of S. aureus related hospitalizations increased 62% over the same time period, from 294,570 (95% CI 257,304-331,836) to 477,927 (95% CI 421,665-534,189). Strikingly, the estimated number of MRSA-related hospitalizations more than doubled in the same time period, from 127,036 (95% CI 112,356-141,716) to 278,203 (95% CI 252,788-303,619). The resulting overall rate of S. aureus-related diagnoses per 1,000 hospitalizations increased 50% from 9.17 to 13.79 while MRSA-related discharges per 1,000 hospitalizations more than doubled, from 3.95 to 8.02. In their study, the authors estimated that S. aureus-related deaths averaged ~10,800 (range 7,440-13,676) per year but that MRSA-related deaths averaged ~5,500 per year (range 3,8909-7,372). These hospital-acquired strains developed a characteristic pattern of multi-drug resistance since methicillin-resistance imparts resistance against the entire beta-lactam class, including the cephalosporins. Resistance to erythromycin, levofloxacin, and constitutive clindamycin resistance is also commonly found in these strains. Nosocomial transfer occurs among hospitalized patients, likely by means of fomite transfer via colonized staff or equipment. Over the past 20 years, newer strains have been noted with increasing frequency. Initially labeled community-associated because patients diagnosed with these MRSA strains lacked traditional risk factors, these strains were thought to be escaped hospital strains that had become feral while circulating in the general population. Without antibiotic pressure, these strains had retained their resistance against penicillins but tended not to be multi-drug resistant. Community-associated MRSA patients tended to present to emergency rooms with skin and soft tissue complaints, commonly complaining of a spider bite. The characteristics that define these community-associated MRSA (CA-MRSA) and separate them from the traditional HA-MRSA are listed in Table 1.

The emergence of MRSA in a population not previously considered at risk was and continues to be concerning. Though reports of isolations from indigenous populations in Australia cropped up in the early 1990s, the CA-MRSA strains first came to the forefront in the USA when the University of Chicago Children's Hospital reported on the increased prevalence of MRSA in patients with no previous predisposing risk factors. In their retrospective study, the authors looked at S. aureus isolates obtained from hospitalized children in 1988-1990 and then compared these to isolates from 1993-1995 and found that the number of hospitalizations from CA-MRSA rose and that the prevalence increased from 10 per 100,000 admissions to 259 per 100,000 admissions. However, concern was heightened when the CDC reported the death of four previously healthy children in the Midwest due to respiratory failure or secondary to multi-organ dysfunction caused by MRSA infection; none of the children had any risk factors for the development of traditional HA-MRSA.

Following the initial reports, CA-MRSA strains were reported in inmates, military recruits, athletes, minority populations, men who have sex with men, and in poor urban adults. In a short amount of time, the frequency of outbreaks involving CA-MRSA increased dramatically. CA-MRSAs have become so prevalent, that though 59% of all skin and soft tissue infections presenting to 11 emergency departments nationwide were MRSA, 99% of these were community-associated strain. Given this rate of spread, it was not long before reports of CA-MRSA in the hospital setting followed making the original definition for CA-MRSA strains debatable; in some cases the traditional HA-MRSA strains have been displaced by CA-MRSA as the predominant nosocomial infection, making the naming nomenclature outdated.

Why Should Veterinarians Care?

Initial epidemiological studies into the presence of MRSA in pets have identified fairly low rates of infection or colonization. This is most likely due to the fact that S. aureus is a human-adapted strain so it would have to overcome species' specific immune responses every time the bacterium jumps host species. Notwithstanding, S. aureus does commonly cause pyodermas and other clinical diseases in animals. The earliest report of veterinary MRSA isolation was in a mastitic dairy cow in 1972. Since then, dogs, cats, horses, pigs, and poultry have been identified with the bacterium. MRSA has been more recently found in companion animals, with the first reports of a colonized dog arising in 1994 and thereafter by the detection of MRSA in cats in 1998. Following an outbreak, sampling at a Canadian university's veterinary teaching hospital large animal clinic was instituted and found that 4% of horses in 2000 and 8% of horses in 2002 were colonized with MRSA. In a broader study surveying S. aureus isolates submitted by diagnostic laboratories at seven veterinary teaching hospitals in the USA, 14% (n=9) of the isolates were found to be MRSA though none of the PFGE patterns matched each other; they were not compared to existing human strains.

Recent attention has revolved around the high prevalence of colonization of MRSA in pigs and pig farmers which has primarily been evaluated in the Netherlands. An initial study found that 23% (n=6) of pig farmers sampled were colonized, representing a >760x higher risk of colonization by swine farmers as compared to the rest of the Dutch population. The authors were also able to demonstrate transmission between species and found that spa-type t108 was the most prevalent MRSA, though all the recovered strains were nontypeable using PFGE. In a larger subsequent colonization study, de Neeling et al. identified 39% (n=209) of the swine sampled were colonized with MRSA at the time of slaughter and that all the samples belonged to ST398. In order to evaluate the potential for widespread colonization of pig farmers on the North American continent, pigs and pig farmers in Ontario, Canada were swabbed and 20% (n=5) and 24.9% (n=71), respectively, were found to be colonized with MRSA, though the predominant strain was a HA-MRSA.

As the human-animal bond tightens and pets play increasingly integral roles in the home, the potential for cross-colonization and infection has raised concerns in both the human and veterinary medical fields. Weese et al. report several case studies of companion animal MRSA isolations that were identical to strains obtained from either attending veterinary technician staff or their owners (85). In the equine study noted above, 14% (n=17) of the staff at the veterinary hospital were found to be colonized with MRSA which, combined with case histories and repeat sampling, lead the authors to conclude that 63% (n=17) of the equine cases were nosocomial transmissions. A subset of these isolates were typed and all demonstrated SCCmecIV but lacked PVL genes.

With this possible host-range expansion, the epidemiology of the disease could be further complicated if reservoiring occurs in pets as has been suggested by one group (86). An example of this complication was described by van Duikjeren et al. when they reported a recurring outbreak in a nursing home which was only resolved once the affected nurse was treated, in addition to her affected infant and colonized dog (87). Cases such as this underscore how detrimental it may be to both people and animals if MRSA gains a solid foothold in non-human species and develops an additional host predilection.

A convenience sampling was performed at 3 secondary and tertiary care veterinary facilities in Florida to determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in the canine, feline, and equine pet populations. Nasal swabs were collected and processed following standard microbiological techniques. Full antibiograms were performed to confirm antibiotic resistance and pulsed-field gel electrophoretic (PFGE) characterization was used to determine the strain. Each MRSA isolate was matched to 2 methicillin-sensitive S. aureus (MSSA) and PCR was performed to identify virulence factors. Positive isolates were submitted for sequencing and the sequences were aligned. The overall prevalence was low as only 6 isolates were determined to be MRSA of 966 patients sampled; 4 of these were the community-acquired USA300 strain based on PFGE. The recovered MRSA isolates demonstrated multi-drug resistance. The 5 genes tested were present in all 4 USA300 and in 1 MSSA. Another MSSA had 4 of 5 genes. The nontypeable MRSA and the remaining MSSA only had 2 genes present. Though of low prevalence, 4 of the MRSA isolates obtained were USA300 clones and carried similar virulence factors to the strains circulating in the human population.

Recommendations if a methicillin resistant S. aureus is isolated from a pet?

If a pet demonstrates colonization, submit that isolate to your local health department for typing. There are clearly defined high risk subtypes of bacteria that are primarily found in humans. Indicate to the owner that the animal may be colonized with a potential human pathogen. Indicate to the owner that the owner, if worried, can go to the local health department for a culture of the nasal swab. If both are colonized and there is a significant health risk to the owner, then institute antibiotic treatment only based on culture and sensitivity. Alternatively, have the owner wear gloves and a surgical mask when handling the dog and re-culture in 30 days to confirm long term colonization. There is no evidence that euthanasia of these animals is required and that doing so would limit infection in their owners.

When the isolation of Staphylococcus aureus that demonstrates resistance to methicillin occurs:

1. Consideration of the context of isolation: Is the animal sick? Is the animal on antibiotics? What type of site was this cultured from?

2. Institute normal precautionary measures for those in contact with the animal. The most important depends on the status of the animal, people, and continued risk. Gloves are essential!

3. Confirm microbiologically that a MRSA is present and type the MRSA at the local public health department.

4. Institute management efforts that allow clearance of the agent if confirmed. Whenever possible, TAKE OFF antibiotics.

5. Institute resampling protocol to confirm clearance. More than likely once the antibiotic pressure is minimal, the animal will clear.

From our recent studies and from the literature, several important points should be understood:

1. Not all MRSA's are the same. Human MRSA types are different in general from animal types.

2. Human type MRSAs appear to arise from earlier versions of antibiotic resistant organisms and are still associated with health care whether hospital acquired or community acquired.

3. Companion animals and horses may not become "reservoirs" for human type MRSAs. The colonization may depend on the clinical state of the animal, the presence of antibiotics, and the status of the humans in contact with the animal.

4. Colonization of humans with animal origin MRSA-types has this far appeared to be OCCUPATIONAL.

5. Common precautions and judicious management of these animals is warranted if a resistant S. aureus is isolated.

6. Euthanasia of animals because a resistant S. aureus is isolation is unwarranted on the basis of risk to humans.

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