Multidrug-resistant staphylococcal skin infections

 

Introduction

Infections with multidrug-resistant staphylococci (MDRS) are commonly encountered in both human and veterinary medicine, and such infections are challenging on both an individual case basis and a community level. The prevention of colonization and infection with MDRS is important in maintaining the health of patients, veterinary staff and the public, and there have been numerous publications concerning the risk factors for development of, testing for, and treatment of MDRS in recent years. This article provides a practical overview of MDRS infection in dogs, including how and when to test, the implications for the home and veterinary practice environments, and management strategies to both resolve infection and prevent re-infection.

What’s the background of Staphylococcus species? 

Staphylococcus is a genus of Gram-positive, coccoid bacteria that can be classified into several groups. In the veterinary field the most significant groups are coagulase-positive S. intermedius (S. pseudintermedius, S. delphini and S. intermedius) and S. aureus1. 

S. pseudintermedius is the most common bacteria isolated from healthy dogs, with the highest carriage rates (in descending order) on the oral mucosa, perianal skin, nasal mucosa and groin 1, and it has been shown that dogs with atopic dermatitis have a higher colonization rate compared to their healthy counterparts 2. S. aureus is a commensal of the skin and nasopharynx of healthy humans and, as with S. pseudintermedius, can also be an opportunistic pathogen 3.

Colonization and subsequent infection by staphylococci occur via bacterial adhesion to corneocytes, but this is variable. It is known that S. pseudintermedius adheres with greater affinity to canine over human corneocytes 1, whereas S. aureus has a lower affinity for canine compared to human corneocytes, and canine nasal carriage of methicillin-resistant S. aureus (MRSA) is thought to resolve rapidly without treatment 4. Transmission of S. pseudintermedius from dogs to humans is possible but uncommon. Following adhesion to corneocytes, indirect transmission of both susceptible and MDRS species may occur via shedding of desquamated cells into the environment, and it is therefore important to implement infection control whether there is active infection or simply colonization with MDRS.

How is multidrug resistance defined? 

Multidrug resistance (MDR) is not a term exclusive to staphylococci, as it defines any bacteria showing resistance to one or more antibiotics in at least three different classes; for example, S. pseudintermedius showing resistance to cephalexin, clindamycin and doxycycline, or Pseudomonas aeruginosa showing resistance to marbofloxacin (or enrofloxacin), gentamicin and polymyxin B 5. Methicillin-resistant staphylococci (MRS) defines a genetically distinct group of staphylococci with resistance to β-lactam antibiotics. The resistance is due to acquisition of the mecA gene that encodes for penicillin-binding protein (PBP2a), a transpeptidase involved in bacterial cell wall synthesis. PBP2a has a lower affinity for β-lactam antibiotics than other transpeptidases 6, and the mecA gene confers resistance to most β-lactam antibiotics including methicillin, penicillin and the majority of cephalosporins. With MRSA, progression to multidrug resistance occurs with the accumulation of multiple resistance genes around the mecA gene inside the bacterial “cassette” (the SCCmec) 7.

In humans there are two main routes of infection by MRSA: hospital associated, and community acquired. The hospital infections are nosocomial (i.e., acquired whilst the patient is hospitalized or undergoes a medical procedure) whilst the latter occur in patients with no healthcare contact, and have distinct pheno- and genotypes distinguishing them from hospital-acquired MRSA 8. In dogs, cutaneous infections with MRSA are much less common than infections with methicillin-resistant S. pseudintermedius (MRSP) 9.

How is MDR identified and treated?

Whenever a MDR infection is suspected, certain steps must be taken to protect the health and welfare of the patient, clients, staff and other animals that may directly or indirectly contact the bacterium. Once the presence of infection is confirmed via cytology, MDR is determined via culture and susceptibility testing (CST). Where the MDR infection is a Staphylococcus species the carriage status, via sampling of staphylococcal carriage sites, should be established. Effective infection control measures are then implemented in order to reduce shedding of MDRS into the home and veterinary practice environments, and to reduce the risk of transfer to other animals and humans. Finally, appropriate treatment that is effective in resolving the infection but avoids further selection for antimicrobial resistance must be chosen.

How is infection confirmed? 

The first step in the investigation of any suspected cutaneous bacterial infection is the identification of consistent lesions on physical examination (Figure 1), followed by skin sampling and cytology. It is important to note that staphylococci cultured from a non-sterile site (such as the skin or ear canal) does not confirm the presence of infection, only the presence of the bacterium at the test site. Bacterial infection is confirmed via cytology which demonstrates the phagocytosis of bacteria by neutrophils and/or macrophages following appropriate sampling of a skin lesion (Figures 2 and 3).

How is testing for MDRS performed?

Once bacterial infection is confirmed by cytology, CST can be performed to determine the species of bacteria involved and establish susceptibility to systemic antimicrobial drugs. Note that routine susceptibility panels do not provide information on susceptibility to topical antimicrobials. CST should be performed in all cases where systemic antimicrobials are deemed necessary for treatment. The morphology of the phagocytosed bacteria observed on cytology should match that of the cultured bacterium to verify that the bacteria causing the infection is the same as the one cultured. 

As with conventional bacterial infections, MDRS may be identified by aseptic sampling using a sterile bacteriology swab. The sample is submitted in transport media suitable for aerobic bacteria (e.g., Amies Bacterial Transport Medium) with or without charcoal for routine CST. PCR testing for mecA is the gold standard for identification of methicillin resistance 10, but this is not always available at commercial laboratories, and so diagnosis is usually based on selective culture. CST can be used to confirm the presence of MDRS in one of two situations; either at the site of infection and/or at staphylococcal carriage sites (i.e., assessment for carriage status).

1. For any suspected case of MDRS, CST should be performed at the site of infection. In bacterial infections where topical antimicrobial treatment is likely to be adequate (i.e., the majority of bacterial skin and ear infections), culture determines the presence of MDRS to inform appropriate infection control. Recognizing the risk factors for the development of MDRS/MRS can prompt the clinician to perform testing (Table 1). One of the main risk factors for MRSP colonization is prior exposure to antibiotics, so CST should be considered for any patient presenting with a bacterial infection that has recently received a course of antibiotics for any reason. Numerous classes of antibiotics have been shown to select for MRS, and MRSP may be isolated from carriage sites even after MRS pyoderma has resolved 11. Empirical use of antimicrobials should therefore be avoided unless there is a risk to life, or if delaying treatment will result in significant morbidity.

 

2. In animals with confirmed MDRS infection, it is prudent to assess for colonization of carriage sites by MDRS. Colonization in itself does not dictate the need for decontamination, but knowledge of its presence is important for infection control; a colonized dog has the potential to shed and transmit the bacterium from sites other than the site of infection. For this type of MDRS testing, cytology is not required, as only the presence of MDRS is needed to confirm colonization. Three bacteriology swabs from the nasal mucosa, gingival mucosa and perianal skin may be submitted as a pooled sample for culture. Positive results indicate MDRS to be present at one or more of the carriage sites. As active decolonization is not necessary in the majority of cases, susceptibility testing of carriage sites is not required, although where susceptibility testing of carriage sites is performed, around 80% of Staphylococcus spp. isolated are the same as in pustules from remote body locations 14. Some dogs, particularly those living in environments where strict hygiene protocols are not followed, can carry MRSP for more than 12 months 15.

 

What about carrier animals?

Carrier animals are individuals whose staphylococcal carriage sites (nasal and oral mucosa, perianal skin) are colonized with MDRS in the absence of active infection elsewhere on the body. Dogs may be long-term carriers of MRSP, but only temporarily (days to weeks) carry and shed MRSA. In humans, testing to identify asymptomatic MRSA carriers is not done, but those at risk of infection (e.g., individuals preparing to undergo surgery) are tested and decolonized as appropriate. Decolonization also takes place if there are high-risk people in the same household or recurrent infections in a household member 16. In the veterinary field a proactive testing system for patients at risk of MDRS infection should be adopted, and, as with the human situation, those scheduled for complicated procedures (particularly surgery for permanent implants) should be tested and decolonized as necessary.

Routine testing for carrier status in patients that have recovered from MDRS infection is sometimes advocated, and as noted above, dogs may shed MRSP for up to a year following resolution of infection. In countries where the prevalence of MRSP is low, use of environmental control measures and antimicrobial treatment of carriage sites until two consecutive negative carriage site screens (a reasonable time between tests is 3 weeks) are obtained, is a sensible method to reduce shedding of MRSP 16.

Infection control in the clinic

A number of studies have identified veterinary staff to be at higher risk for carriage of both MRSA and MRSP compared to the general population 17. It is therefore essential that practice protocols are in place to prevent transfer of and infection with MDRS in staff and patients. Simple measures may be employed to reduce both direct transmission of MDRS between patients and staff and indirectly via fomites. Personnel can actively reduce the spread of bacteria by washing their hands in an approved manner with soap and water, or where hand washing is not possible, use of an alcohol-based hand sanitizer 16. 

Cleaning and disinfection are required to reduce environmental contamination with MDRS. Amongst the disinfectants commonly used in veterinary practice, those containing quaternary ammonium and hydrogen peroxide have been shown to kill Staphylococcus spp. 16. It is important to remove all organic matter from surfaces by routine cleaning prior to use of disinfectants, as they cannot percolate through organic debris and biofilms, and MDRS may be able to survive in these microenvironments. 

The following protocol may be used to reduce the risk of direct transmission and environmental contamination of MDRS when dealing with outpatients with active infection and/or MDRS carriage:

• The patient should be seen at the end of the day, and should wait outside the practice until the consultation. 
• Infected wounds should be covered prior to entry into the practice.
• The patient should be taken straight into the consultation room, avoiding the waiting area if at all possible. 
• Trolleys should be used to transport patients if possible (to reduce the potential for contamination of the floor before it can be cleaned and disinfected).
• The consult room should be clean and contain only equipment necessary for the patient being seen.
• The room and trolley (if used) should be cleaned and disinfected immediately following the consultation.

Appropriate personal protective equipment (PPE) should be used by all staff in direct contact with the patient. This consists of gloves, apron/gown/overalls, sleeve protectors (if a bare-below-the-elbow policy is not already in place) and shoe covers. A change of clothes following contact with MDRS patients is required unless the staff member is completely covered by PPE. Clothing should be placed in a bag during transport and washed at 60C for 10 minutes and tumble dried if possible 18. Masks are not necessary to prevent respiratory infection, as the bacteria are not airborne, but they may be useful in preventing staff from touching their faces, and therefore reducing the risk of colonization with MDRS 16.

For MDRS patients requiring hospitalization, the following steps may be taken to minimize the risk of transmission of MDRS to staff and other patients and contamination of the environment:

• The patient’s MDRS infection site(s) should be covered with an impermeable dressing.
• Patients should be housed in an isolation ward. 
• The number of staff interacting with the patient should be kept to a minimum and PPE should be worn (as above).
• If the patient needs to be moved, this should be done via a trolley to avoid contamination of floors.
• Gloves should be changed following removal of dressings from infected wounds, prior to application of clean dressings.

Infection control in the home

Home management of MDRS patients poses several challenges, as both the pet and the environment are potential reservoirs of infection for in-contact people and other animals. The home is also generally less amenable to the cleaning and disinfection protocols used in a medical environment. However, management of MDRS infection and natural decolonization is possible in the home and is generally preferable to hospitalization, as it reduces the risk of transfer to a larger number of people and potentially high-risk patients.

The risk of infection with MRSP in healthy people is low, but immunosuppressed individuals and those with open or surgical wounds are at greater danger of infection; they should be provided with specific advice on how to reduce the risk and advised to consult with their doctor for further support. Contact between the patient, its environment and any high-risk individuals should be prevented wherever possible. Where this is not practical, prevention of direct contact should be attempted by housing the animal and high-risk person in different areas of the home. Steps that may be taken to minimize transmission in the home include: 

• Wash bedding and toys daily – such items have been associated with infection and carriage of MDRS in pets 16.
• Apply alcohol hand gel and/or wash hands following contact with the pet. 
• Prevent the pet from licking people. 
• If exercising other dogs in the household, keep them on leads and avoid areas where other animals are likely to be encountered, such as parks.
• Prompt disposal of feces followed by hand washing.
• Gloves (and other PPE) should be used when handling the infection site.
• Frequent cleaning and disinfection of the pet’s environment – consider isolating the pet to an area of the house that is easy to clean. 
• Prevent the pet from sleeping in the owner’s bed.

 

Treatment options for MDRS infection

Management of infection can be challenging due to the reduced number of antimicrobial treatment options and the need for strict infection control protocols. Despite this, the prognosis for recovery from MDRS against wild type infection is the same, provided any underlying condition predisposing to infection (e.g., atopic dermatitis) is treatable 16. The choice of antimicrobial agent depends on the infection severity (surface, superficial or deep) and extent (localized or widespread) (Table 2). Topical antimicrobial therapy should be considered for all cutaneous bacterial infections due to the higher local concentrations achieved compared with systemic antimicrobials.

 

Topical therapy

As with any superficial bacterial skin or ear infection, first-line therapy for MDRS infection is topical antimicrobials – for example, 2-4% chlorhexidine, which is effective against MDRS in vivo 19. One study demonstrated marked improvement of clinical signs in seven out of ten dogs with superficial pyoderma following 2-3 times weekly bathing in a 3% chlorohexidine-based shampoo for 10 minutes over 21 days 20. This regime would be appropriate for superficial pyoderma involving MDRS. Topical chlorhexidine is also commercially available in wipe, foam/mousse and spray formulations; daily use of such products can be an adjunct to bathing and may help speed resolution of infection, and some owners also find them easier to use. 

Another topical antiseptic shown to be effective against MDRS is sodium hypochlorite (NaOCl), the active ingredient in bleach. A 6.15% solution of sodium hypochlorite has been shown in vitro to have bactericidal activity against MRSP at dilutions between 1:32 and 1:265 21. Non-perfumed dilute household bleach may be used as a rinse following routine shampooing once to twice weekly, for example 5 mL of 5% bleach in 2 liters of waters to make the rinse. NaOCl is the sodium salt of hypochlorous acid (HOCl), an oxidizing agent widely used as a disinfectant and commercially available as a spray and hydrogel for treatment of skin infections in animals. HOCl has been shown to be effective against MRSP, extended spectrum β-lactamase-producing Escherichia coli and MDR P. aeruginosa in an in vitro pilot study 22.

Serious adverse effects from topical therapy are uncommon and limited to acute hypersensitivity reactions and contact dermatitis. However, regular use of chlorhexidine shampoo and/or NaOCl rinses may cause excessive drying of the skin, necessitating use of a moisturizing shampoo or conditioning spray.

Systemic therapy

For deep bacterial pyoderma or infections that are unlikely to respond to topical therapy alone (e.g., widespread superficial bacterial pyoderma in an immunosuppressed animal), systemic antimicrobials are usually indicated. Such therapy applies selection pressure on both the infection-causing bacteria and the skin and gut microbiota. For this reason, selection of the narrowest spectrum antimicrobial, used for the minimum time period to resolve the bacterial infection, is recommended in order to reduce the risk of development and shedding of further MDR organisms. Where systemic antimicrobials are deemed necessary, drug choice should always be guided by susceptibility testing, with topical antimicrobials used adjunctively to speed resolution of infection and reduce the need for systemic drugs. If appropriate, topical antimicrobials may still be considered for first line therapy and should be instituted whilst susceptibility results are pending. In addition to antimicrobials, anti-inflammatory drugs may be helpful in some cases in resolving cutaneous infections, particularly those affecting the ear canal. In cases where infection has resulted from cutaneous inflammation and/or there is severe inflammation present because of chronic disease, short-term anti-inflammatory doses of systemic and/or topical corticosteroids can be of benefit in immunocompetent animals.

The evidence for the length of treatment required for MDRS infections is currently limited. Repeat CST can be performed at the carriage sites at the end of a treatment course to monitor response, and this should be performed no sooner than at seven-day intervals. The current guidelines for duration of treatment for superficial pyoderma is three weeks, or one week beyond clinical resolution, and four to six weeks, or two weeks beyond clinical resolution, for deep pyoderma 16.

 

What about biofilm management?

One of the many defense mechanisms of staphylococci is the ability to produce biofilm. This can severely hinder treatment of MDRS infections, especially those involving skin folds, the ear canals and surgical implants. Biofilms are a community of staphylococci producing and growing within a protective extra-cellular matrix, which serves as a physical barrier between the bacteria and both systemic and topical antimicrobial agents. In the human field there have been a number of initiatives to try to combat biofilms, including removal of implants and infected foreign bodies, and high dose topical and systemic antimicrobials. Physical removal of the biofilm by washing, wiping or flushing is a crucial step in resolving the infection. There are also several novel treatments currently undergoing investigation, including metal chelators such as ethylenediaminetetraacetate (EDTA), enzymes, phytochemicals and bacteriophages, but further studies are required 23. Topical N-acetylcysteine (NAC) is used to disrupt biofilm in both veterinary and human medicine; available as a solution in combination with tris-EDTA, it may be used to flush the skin and ears to break down biofilm prior to use of antimicrobial agents. Both NAC and tris-EDTA have been shown to be effective anti-S. pseudintermedius and P. aeruginosa biofilm agents in vitro 24.

Conclusion

Long-term management and prevention of MDRS infection requires identification and management of any primary disease process predisposing to bacterial infection. Evidence-based guidance on the use of antimicrobial agents for the prevention of MDRS infection is lacking, but systemic antimicrobials can encourage the development of MDRS infection and should be avoided unless absolutely necessary. Whilst resistance to topical antimicrobial agents is also possible, regular use of such treatments may be useful in prevention of bacterial overgrowth and infection in susceptible animals. Long-term treatment success is inextricably linked with the underlying cause of the infection, and if it can be identified and successfully managed the prognosis is generally good. Failure to address any underlying disease makes relapse of MDRS infection more likely.