Epidemiology of Methicillin-Resistant Staphylococci
Definitions of methicillin and multidrug resistance
The antibacterial drug methicillin was first introduced in 1959, and at the time it was hoped that it would be the end of staphylococcal resistance to the penicillin drugs. However, the first methicillin-resistant Staphylococcus aureus (MRSA) strain emerged within only 2 years. Even though methicillin is no longer used in clinical practice and the drugs oxacillin or cefoxitin are used as the surrogate for antimicrobial susceptibility testing in most microbiology laboratories, the term “methicillin-resistant” (MR) has persisted in the medical lexicon. Since the discovery of cephalosporins in the 1970s, the term MR has served to label staphylococcal strains that are resistant to all β-lactam drugs (including penicillins, cephalosporins, and carbapenems). The only exception is the newest generation of cephalosporins that were specifically developed for the treatment of MRSA infections (eg, ceftaroline); to the best knowledge of the authors, these drugs have not yet been used to treat animal patients. Strains of MR Staphylococcus (MRS) may express coresistance to any combination of other drug classes, including aminoglycosides, fluoroquinolones, lincosamides, macrolides, tetracyclines, potentiated sulfonamides, chloramphenicol, and rifampicin. When a MRS strain expresses coresistance to at least 2 additional antimicrobial classes, it may be referred to as multidrug-resistant (MDR), and if the strain is nonsusceptible to all but 2 or fewer antimicrobial classes, the term “extensively drug-resistant” (XDR) may be applied. Although XDR presents a major therapeutic challenge to veterinarians, antimicrobial resistance alone is not a true virulence factor; thus, a resistant strain is not necessarily more invasive, destructive, or proinflammatory than a susceptible one.1 In fact, the acquisition of certain antimicrobial resistance genes may come at a fitness cost to the bacterium. For example, MR in some strains of MRSA is associated with reduced production of biofilm and cytolytic toxins.2
Evolution of methicillin resistance
β-Lactam antimicrobials inhibit bacterial cell wall synthesis by targeting the activity of bacterial transpeptidases known as penicillin-binding proteins (PBPs). Staphylococcal MR arose due to mutations in the mecA and mecC genes, which encode for the PBP2a enzyme that has a low affinity for β-lactam antimicrobials. Therefore, PBP2a continues to build bacterial cell walls even in the presence of β lactam drugs, which leads to the resistant phenotype.3 For mecA encoded oxacillin resistance the activity of PBP2a is dependent on the presence of a functional native PBP2 to provide the transglycosylation activity in addition to its own transpeptidase activity. The PBP2a produced by the mecC gene appears to be unique from that produced by the mecA gene because it does not require a functional native PBP2 to produce high-level oxacillin resistance.4 The mec genes are carried on Staphylococcus chromosomal cassettes known as SCCmec, and these cassettes may be easily transferred between staphylococcal species and different strains within a species. This includes coagulase-negative staphylococci, which predominantly serve as colonizing commensal microflora but may serve as reservoirs of antimicrobial resistance genes.5 Other mobile genetic elements that encode for virulence genes have also been shown to be highly mobile between cocolonizing strains of S aureus in vivo.6 Epidemiologically successful strains (clones) of pathogenic staphylococci may then proliferate and coamplify the impact of mobile drug resistance and virulence factors within human and animal populations.
It has long been assumed that MR first arose due to selective pressure applied to staphylococci during the therapeutic use of methicillin in human patients. However, a recent report7 has shown that a mecC gene arose in strains of S aureus linked to European hedgehogs prior to the development of antimicrobial drugs, likely as a consequence of coevolutionary adaptation of S aureus in hedgehogs infected by the dermatophyte species Trichophyton erinacei. Production of 2 naturally occurring β-lactam antibiotics by T erinacei appears to have applied this selective pressure.
Evolution of methicillin resistance in Staphylococcus aureus
Initially, MRSA infections were predominantly limited to human healthcare facilities (so called hospital-acquired [HA]-MRSA), but in the mid-1990s, new clones arose that caused infections in people with no history of exposure to healthcare systems. Termed community-acquired (CA)-MRSA, these strains were initially transferred most commonly within sports teams, gyms, spas, military facilities, and prisons. Over time, niche drift occurred, with the archetypal hospital strains “escaping” into community circulation (where they were then referred to as healthcare-associated [HCA]-MRSA), while CA-MRSA strains became resident in some hospitals where they have caused nosocomial infections.8 Even though MRSA infections are relatively uncommon in dogs and cats, it has been the HCA strains (such as MRSA strain USA 100) that have caused the majority of canine and feline MRSA infections in North America (reviewed by Morris et al).1
In North American horses, MRSA stain USA 500 has long dominated as a cause of colonization and infection. USA 500 had been a major agent of human CA-MRSA infections beginning in the mid-1990s but was largely supplanted in people by the newly emergent USA 300 strain (reviewed by Akridge et al).9 As USA 500 was “pushed” out of people by the more epidemiologically successful strain, it became “stranded” in horses where it continues to cause infection of horses and occasionally in the people who work with them. It was assumed for some time that USA 500 infections had become scarce in people, but a more recent study10 of the genetic phylogeny of this clade has shown that the ancestral strains originally designated as USA 500 are still active in North America, representing the third most common cause of human MRSA infections as of 2013.
Also emerging worldwide in a very short period of time have been large animal associated-MRSA strains (LA-MRSA). Although human-source MRSA strains had been identified from animal infections beginning in 1972, it was not until the identification of MRSA strain type 398 (ST398) in 2005, isolated from European livestock,11 that strong epidemiological evidence of de novo emergence within animals (and subsequent zoonosis to people) was documented. In some early cases, human outbreaks in countries with a low prevalence of MRSA infections were tied to livestock exposures only through robust epidemiological investigations. In 2011, a novel mec gene, designated mecC, was identified in a LA-MRSA strain isolated from cattle in Europe.12 Since that time, other LA-MRSA strains have been identified, solidifying the importance of production animals in the spread of new MRSA strains with public health implications. Currently, MRSA ST398 has disseminated globally and across many host species, while becoming a more common cause of human infections. Most recently, a study13 of the S aureus genetic lineage clonal complex (CC) 398, to which MRSA ST398 belongs, suggests that the genetic adaptation of this CC in livestock began prior to 1970, long before it acquired the mecC gene. The acquisition of antimicrobial resistance factors was likely hastened by antimicrobial use in animal production systems.
Evolution of methicillin resistance in Staphylococcus pseudintermedius and S schleiferi
During the continuing evolution of the MRSA pandemic, it was perhaps not surprising to also see the rapid world-wide emergence of MR S pseudintermedius (MRSP) between 2004 and 2010 in companion animals. Studies of the population genetic structure of S pseudintermedius infection isolates obtained from animals in North America and Europe subsequently proved them to be highly clonal. At the time of this initial report (2010), 2 major clonal lineages had disseminated throughout Europe (sequence type [ST] 71) and North America (ST 68).14 Emergence and replacement by other clonal lineages have since been reported by multiple investigators, including a recent report15 that documented the dissemination of new clones across the continental United States.
Sequencing of the mecA gene from S pseudintermedius has revealed a high degree of homology (95 to 100%) with the mecA gene of S aureus, suggesting horizontal transfer of the gene or acquisition from a common ancestral source (eg, CoNS).16 The structure of the MRSP phylogenetic tree suggested that the mecA gene had been acquired by S pseudintermedius on multiple occasions and several different continents by 2007,16 a phenomenon that has undoubtedly continued since that time.
Like MRSA and MRSP, methicillin-resistant S schleiferi (MRSS) has evolved within a clonal population structure but has predominantly been documented in North America.17 A limited number of MRSS strain types (n = 15), as defined by pulsed-field gel electrophoresis, were identified in a collection of 161 clinical isolates that were submitted to a clinical microbiology laboratory in the USA between 2003 and 2007.17 In a follow-up report18 from the same laboratory, it was noted that the population had undergone further periodic selection (reduction of dominant strain types) to 3 major clonal groups, during the period of 2008 to 2013. To the best knowledge of the authors, an international survey and comparison of S schleiferi strain types have not been reported.
S schleiferi is a coagulase-variable species and has traditionally been subspeciated based on coagulase status: S scheliferi susbsp Schleiferi (coagulase negative) and S scheiferi subsp Coagulans (coagulase positive). However, molecular epidemiological studies17 have shown that clonal clusters of S schleiferi are heterogenous for both coagulase types. This fact has led to a paradigm shift in the way veterinary microbiology laboratories must report culture and susceptibility results for CoNS (reviewed by Morris et al1). There is currently some debate within the peer-reviewed literature over recently suggested nomenclature changes for coagulase-positive and coagulase-negative S schleiferi, but more work is needed to resolve these differences. S schleiferi is the second most common cause of bacterial pyoderma and otitis externa in dogs (following S pseudintermedius) in North America but is much less frequently isolated from cats and horses.1 Strains of MRSS often express MDR or XDR and are most commonly isolated from canine pyoderma and otitis cases following prior antimicrobial exposures.17 This suggests that antimicrobial therapy has eliminated (or at least severely reduced) the dog’s colonizing strain of S pseudintermedius, providing an opportunity for the drug-resistant S schleiferi to gain dominance.
Transmission Dynamics of MRS
It is clear based solely on the extensive clonal distribution of MRSA, MRSP, and MRSS that contact transmission via living and inanimate mechanical vectors occurs commonly (Figure 1). A large evidence base has accrued regarding the role of the household environment as a reservoir for MRSA (reviewed by Davis et al),19 and a study20 of homes in which human MRSA patients reside showed that environmental surfaces, pets, and pet bedding were contaminated with the patient’s MRSA strain. Contamination of retail meats (pork, beef, and poultry products) by MRSA has also been demonstrated, where the majority of strains involved are human associated (rather than livestock associated).21
The one-health paradigm as it applies to cutaneous pathogens such as multidrug-resistant Staphylococcus spp and Pseudomonas aeruginosa. Known and suspected risk factors for animal acquisition and cross-species sharing are listed. MRSA = Methicillin-resistant (MR) Staphylococcus aureus. MRSP = MR S pseudintermedius. MRSS = MR S schleiferi. Figure 1 was created with BioRender.com.
Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0557
The evidence base for interspecies transmission of MRSP and MRSS is less extensive but still convincing. There is no other reasonable explanation for how pandemic strains of MRSP could have become so globally dispersed without assistance from the human carriage and contamination of mechanical vectors. Numerous studies have documented human carriage and environmental contamination with MRSP in households, veterinary hospitals, and grooming facilities (reviewed by Morris et al1; Figure 1). Interspecies microbial sharing appears to occur even in the context of brief interactions between hospitalized children and the dogs used for interactive therapy sessions, where shifts in the relative abundance and diversity of the nasal microbiomes of both participants can be documented.22 It therefore seems likely that the owners and animal care personnel who handle pets with MRS pyoderma could be involved in the cross-transmission of colonizing MRS to other animals.
Nosocomial transmission of both MRSA and MRSP (which can be detected by screening methods) is well documented within human and veterinary hospitals, but fortunately, the “attack rate” (development of clinical infection) is low in healthy individuals. The challenge when dealing with commensal bacteria as ubiquitous as the staphylococci, which may colonize transiently and have a low infection attack rate, is the development of strategies for controlling further dissemination of pathogenic strains. This is a seemingly impossible task under the constraints of current technologies, so current recommendations stress hygienic practices and temporary isolation of pets with confirmed infections. For more information, the reader is encouraged to review the consensus statements published by a working group of the World Association of Veterinary Dermatology,1 which is freely available at https://wavd.org/continuing-education/consensus-guidelines/
Mechanisms of colonization and infection by staphylococci
An important concept to understand when considering the dynamics of staphylococcal transmission is that all animals are normally colonized by staphylococci, including the species that are most commonly implicated as pathogens. Cutaneous infections occur when permissive host conditions, such as immune dysregulation, skin inflammation (produced by primary skin disorders such as atopic dermatitis), or physical trauma disrupt the skin’s normal barrier functions. Because bacterial pyoderma and otitis are secondary processes, the incidence of staphylococcal infections will reflect the distributions of predisposing diseases within an animal population. Prior antimicrobial therapy is a well-documented risk factor for the acquisition of MRS colonization and subsequent infection.1
Multiple colonizing strains can occupy an individual’s carriage sites23 and can be replaced over time, especially in response to antimicrobial therapies that suppress a susceptible population.24 Bacterial pyoderma is usually caused by a dog’s dominant colonizing strain of Staphylococcus.25 This phenomenon explains why atopic dogs often acquire broadly resistant MRSP or MRSS strains after successful treatment of a staphylococcal pyoderma (Figure 2). In this scenario, a dog’s colonizing strain of susceptible Staphylococcus is eliminated, along with the pyoderma, by antimicrobial treatment. This allows a staphylococcal strain that is resistant to the drug to recolonize the pet.24 Therefore, if the primary disease condition is not addressed, the next episode of pyoderma that the dog experiences will often be resistant to this drug class and often many others in the case of MDR and XDR strains.
Hypothesized mechanism by which dogs acquire multidrug-resistant (MDR) staphylococci and subsequent MDR bacterial pyoderma.
Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0557
It is not possible to estimate the global prevalence of MRS colonization of domestic animals, which is expected to vary by animal species, geographic region, and antimicrobial use patterns within that region. Colonization surveys (from dogs, cats, and horses) have been reported from individual institutions, but these represent cross-sectional snapshots specific to a given time, place, and defined population (often collected within dermatology referral practices). The prevalence of MRS isolated from veterinary clinical specimens can best be estimated locally by microbiology laboratories, and some may provide composite antibiograms upon request. Composite antibiograms are antimicrobial susceptibility patterns compiled for a specific bacterial species over a specified period of time.
On a more global level, large-scale surveillance efforts may serve to inform policy decisions regarding the regulation of antimicrobial drugs on a national level and therapeutic guidelines for practitioners. The largest surveillance program for skin pathogens (as known to the authors) is the pan-European ComPath surveillance program, which uses a standardized sampling protocol and a centralized laboratory to collect skin, soft tissue, and ear canal culture specimens from dogs and cats, submitted by general veterinary practices in 12 European countries.26 The most recent data from this program, published in 2020 for the sampling period of 2013 to 2014, reported the prevalence rates of MRSP and MRSA to be 10.6% (69 of 651 isolates) and 31.4% (32 of 102 isolates), respectively. This can be compared to their prior report27 (published in 2016 for the sampling period of 2008 to 2010) of 6.3% and 5.4% prevalence for MRSP and MRSA, respectively, which demonstrates a clear and rapid rise in methicillin resistance within these staphylococcal species. For specific recommendations on antimicrobial therapy of these pathogens, the reader is referred to current guidelines documents.1,28
Epidemiology of Pseudomonas Aeruginosa
P aeruginosa is a common cause of treatment-resistant otitis externa and otitis media in dogs, which may result in significant morbidity for pets and costly medical expenditures for their owners. Clinical observations support an opportunistic role for P aeruginosa in otic infections, where overgrowth within diseased ear canals occurs when commensal bacterial flora is inhibited by antimicrobial drugs. Culture-based and microbiome studies have shown that P aeruginosa is rarely present in the healthy canine ear canal (reviewed by Bradley et al).29 Dogs with otic infections likely acquire the organism through transmission from environmental reservoirs. For example, an epidemiological study30 of dogs with otitis showed swimming or visiting a dog park to be factors associated with a 64% increase in risk to develop Pseudomonas otitis compared to control dogs (those with otitis associated with other types of bacteria) in a multivariable model.
P aeruginosa is intrinsically resistant to many antimicrobials including aminopenicillins, most cephalosporins (except ceftazidime), chloramphenicol, TMS, and tetracyclines. Acquired resistance is also found in isolates including against aminoglycosides, carbapenems, and fluoroquinolones. Currently, Clinical and Laboratory Standards Institute (CLSI) breakpoints have been established for amikacin, ceftazidime, gentamicin, levofloxacin, and piperacillin/tazobactam for skin and soft tissue infections in dogs and only enrofloxacin for cats. It has been suggested by the CLSI supporting Vet09 document that for most of these drugs it may be appropriate to extrapolate interpretations for cats using the breakpoints for dogs. Some laboratories may also use human breakpoints to test other drugs including carbapenems.31 P aeruginosa can easily develop resistance to antimicrobials during therapy, and it has been suggested that reculture and antimicrobial susceptibility testing may be warranted after 3 to 4 days.32
P aeruginosa is a genetically diverse organism. Genetic analysis of field strains derived from human, animal, and environmental sources has shown that the organism has formed a largely nonclonal population structure globally and that genetic recombination occurs frequently.33 However, the extensive overlap of core strain genomes has been demonstrated through analysis of environmental and human-sourced isolates, and wild-type environmental isolates express an extensive set of virulence genes that may promote pathogenicity in animals.33 These findings support the clinical observations that human and animal infections may originate from environmental sources (Figure 1). The constitutive expression of virulence genes by an environmental saprophyte makes P aeruginosa a particularly agile opportunistic pathogen.
One of the most common habitats for P aeruginosa is water, where it may reside in a wide variety of aquatic environments (eg, rivers, sea water, bottled drinking water, and tap water).34 The organism has also been identified in human and veterinary skin and hair care products and may contaminate the otoscope cones and ear bulb syringes used in veterinary practices. In people, bacterial folliculitis causing painful papules and nodules on the hands and feet may be acquired from exposure to contaminated swimming pools, hot tubs, saunas, and whirlpool baths (referred to as “hot hand-foot syndrome”) and is generally associated with ubiquitous gram-negative bacteria such as P aeruginosa (reviewed by Cain and Mauldin).35 A similar condition is documented in dogs, where water immersion or exposure to grooming products may result in a painful, dorsally distributed bacterial furunculosis. This syndrome, commonly referred to as “postgrooming furunculosis” (PGF), includes characteristic clinical and histological skin lesions from which P aeruginosa is commonly isolated by bacterial culture.35 Owners of dogs with PGF will often report the use of grooming products (shampoos and conditioners) that have been diluted with tap water and stored for future use, but these diluted products are rarely available for culture sampling. Therefore, a study36 was designed to investigate the prevalence of and risk factors for contamination of nonmedicated dog grooming products used in private homes or professional pet grooming salons. In this study, 14 of 117 samples (11.97%) were contaminated by P aeruginosa, and a highly significant risk factor associated with the isolation of the organism (odds ratio = 15.5) was the dilution of the product with water. Although this circumstantial evidence (“guilt by association”) strongly supports a role for contaminated grooming products in the pathogenesis of PGF, there have been no large-scale studies to link contaminated products directly to clinical cases. However, a well-documented single case of PGF in which genetically concordant P aeruginosa isolates were obtained from both the dog’s skin lesions and the shampoo used prior to lesion onset provides a clear example of putative causation.37 It is therefore recommended that if grooming products are diluted for ease of application, they should be used immediately and any diluted product remaining should be discarded rather than stored for future use.
Transmission Dynamics of P Aeruginosa
Nosocomial transmission of P aeruginosa is well documented in human healthcare settings, especially related to tap water and hand cleansing materials (reviewed by Kerr and Snelling).38 Hospital-acquired infections most commonly develop in immunocompromised patients and burn victims, and predominantly involve bacteremia, postoperative infections, urosepsis, or pneumonia.38 As would be expected in a hospital setting, nosocomial infections are usually caused by a single endemic clone that is resident within the facility. “Community-acquired” P aeruginosa infections are mainly related to the recreational use of hot tubs and therefore caused by sporadically occurring (nonclonal) environmental strains. However, a city-wide outbreak with a “wild type” P aeruginosa clone (wild type defined as susceptible to all anti-pseudomonal drugs) was documented in Cape Town, South Africa. The widespread occurrence of this virulent strain suggests that dissemination may have occurred through the municipal water supply.39
Cross-species dissemination of P aeruginosa has been documented. In a microbiological survey of healthy captive snakes, clonal strains were isolated from snake feces, their prey and water sources, and other animals in the environment and from the mouths of their human handlers.40 Of particular concerns are reports41,42 of carbapenemase-producing carbapenem-resistant P aeruginosa (CP-CRPA) from companion animals, including a report of suspected transmission from a dog to a person. In this latter report,42 a high-risk hospital-acquired P aeruginosa clone expressing MDR was isolated from the dog’s ear canal, several locations within the home environment, and from the owner who had recently been discharged from hospitalization in an ICU. These reports demonstrate the value of a one-health approach to the investigation of high-impact bacterial pathogens identified from animal samples.
In domestic animals, studies of P aeruginosa infection isolates have varied in whether the clonal expansion was detected within a local population. Geographically clustered ruminant mastitis isolates in Israel were heterogenous43 as were animal-source isolates in France (although the limited expansion of several clones was noted).44 In direct contrast to these reports, evidence for the expansion of highly drug-resistant clones was reported from samples submitted by 152 primary-care animal hospitals to a central laboratory in Japan.45 In addition, a prospective study30 of canine Pseudomonas otitis cases identified the clonal expansion of several P aeruginosa strains across dogs living in a major U.S. metropolitan area, even though the study subjects had no clear epidemiological links to one another. The results reported by these 2 studies30,45 suggest that successful strain types may be proliferating across the large catchment areas represented and raises the question of whether MDR strains may be arising within the community of dogs and their owners. In the canine otitis study,30 identical strain types were cultured from water sources (bowls and taps) and oral samples of the dogs’ human companions, providing clear evidence of dog-person-environmental sharing. However, due to the cross-sectional design of the study, the point source from which these P aeruginosa strains originated could not be determined.
Conclusion
An understanding of the evolution, dissemination, and spread of clinically relevant MRS and P aeruginosa can be helpful to a veterinarian because it informs the preventative and therapeutic approaches to infections caused by these pathogens. Staphylococci are normal inhabitants of the skin, so prevention of infection should be geared toward the management of underlying conditions and enhancing the defenses of the susceptible individual. It also highlights the need to prevent the spread of antimicrobial-resistant strains within veterinary facilities by the implementation of adequate infection prevention strategies such as proper hand hygiene and interruption of fomite transmission.1 P aeruginosa, on the other hand, is an environmental organism where environmental hygiene and limitation of animal behaviors (ie, swimming, bathing with contaminated products) that could lead to exposure may be important mitigative steps in addition to the treatment of underlying conditions.
The emergence of MDR and XDR strains of cutaneous pathogens will likely continue at a rapid pace in veterinary practice. Broadly, there is a need to promote the use of culture and susceptibility testing to guide antimicrobial therapy, develop rapid laboratory tests for resistance, and build antimicrobial stewardship programs within the profession. For the individual practitioner, the rapid identification of clinical cases of infection and the development of a therapeutic approach with a high likelihood of success are important steps to maximize positive outcomes for individual patients. Tools for success include the use of currently available clinical guidelines for the diagnosis and treatment of pyoderma.1,43 Guidelines for the diagnosis and treatment of otitis externa and otitis media are expected from the World Association of Veterinary Dermatology in 2023. In addition, empirical therapy should be based on regional susceptibility patterns for staphylococci, which may be available from local microbiology laboratories. MRS and P aeruginosa are among the most difficult pathogens faced by veterinary practitioners, but with continued research and application of an ever-expanding knowledge base, there is still the opportunity to slow and mitigate their impacts across the one-health spectrum.
Aknowledgments
No third-party funding or support was received in connection with the writing or publication of this manuscript. The authors report no conflicts of interest.
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