How I Treat Methicillin-Resistant Staphylococcal Pyoderma
World Small Animal Veterinary Association World Congress Proceedings, 2014
Valerie A. Fadok, DVM, PhD, DACVD
North Houston Veterinary Specialists, Spring, TX, USA

Staphylococcal infections in dogs are not as simple to treat since the emergence of methicillin resistance. Most infections in dogs are caused by methicillin resistant Staphylococcus pseudintermedius (MRSP). We can also see methicillin resistant S. schleiferi (MRSS) and less commonly, S. aureus (MRSA), the human pathogen. In most dogs with methicillin resistance, a history of repetitive courses of antibiotics for treatment of pyoderma is obtained.

Methicillin resistance in the staphylococcal bacterium is mediated by the acquisition of a mobile gene cassette (staphylococcal chromosome cassette/SCCmec) containing the mec gene, most often mecA, which encodes for an abnormal penicillin binding protein, PBP2a gene. This protein's conformation is different, and it cannot bind beta-lactam antibiotics. Higher doses of antibiotics cannot overcome this mutation, thus beta-lactams are no longer effective. The SSCmec can also carry other genes that mediate resistance to additional classes of antibiotics, and therefore many MRSP are multidrug resistant as well.

The first step in treating methicillin resistant staphylococcal pyoderma is to recognize its presence. Indications that methicillin resistant infections could be present include a failure to respond to antibiotics previously used successfully, and a failure to response to all beta-lactam antibiotics. If a dog fails to respond to an injection of cefovecin then either the infection is methicillin resistant, or the lesions are not caused by staphylococci. Failure to respond to cephalexin given twice daily is suspicious but not diagnostic for MRS, as at least in some parts of the world, cephalexin used twice daily is not always successful. Failure to respond to other classes of antibiotic implies that the organism could also be multidrug resistant. It is very important not to try to pick antibiotics empirically when we suspect MRS. We need to collect samples for culture and sensitivity and we need to be sure that our laboratories tell us what species of Staphylococcus is involved, so we can advise our clients about any potential zoonotic hazards.

Topical therapy is a critical part of treatment. Published evidence suggests that the most effective shampoos are those containing 2–4% chlorhexidine. As we wait for culture and sensitivity, owners can bathe daily with this shampoo, or at least 3 times that week, using sprays or rinses in between. Bathing is a powerful tool. It removes the crusts laden with the staph, it soothes the skin, and it makes the dogs look, feel, and smell better more quickly. In fact, should culture and sensitivity reveal a multidrug resistant bug, daily bathing can be used to resolve the infection without antibiotics. Even if antibiotics can be used, bathing frequently will shorten the course of therapy. For example, we have had excellent results using rifampin for 2 weeks, with 3 x weekly bathing with chlorhexidine. Accelerated hydrogen peroxide offers substantial antistaphylococcal activity and it can be used for the environment as well as on animals. Bleach has been recommended; it is not clear what concentration is optimal. Dilutions range from 1:64 to 1:250, with no evidence yet for which is most efficacious.

With the loss of beta-lactams, we can consider choosing other classes if they are reported as sensitive.

Here are some tips for using these antibiotics successfully:

 Macrolides: Most dermatologists advocate for the use of clindamycin. If clindamycin is considered, it is important to look at the sensitivity to erythromycin and other macrolides/lincosamides. Staphylococci can contain a resistance gene called the clindamycin inducible resistance factor. The presence of this factor is suggested when erythromycin is reported as resistant and clindamycin as sensitive. Under these circumstances erythromycin should not be used as it will likely result in a treatment failure.

 Tetracyclines: While most S. pseudintermedius are resistant to tetracyclines, they can be used if indicated by sensitivity testing. It is important to note that the breakpoints used to predict sensitivity to doxycycline are not correct, and result in some resistant bacteria being called sensitive. Until these breakpoints are revised, if doxycycline is reported as sensitive, have a look at the MIC. If it is greater than 0.5 microgram/ml, we can predict a therapeutic value.

 Potentiated sulfas: Potentiated sulfas can be extremely helpful for pyoderma. Ormetoprim-sulfadimethoxine (Primor, Zoetis) can be used once daily. Sulfa antibiotics have the potential to cause side effects, including arthropathy in Doberman pinschers, exacerbation of keratoconjunctivitis sicca, a lowering of thyroid hormone levels and drug eruptions including urticarial. The incidence of side effects is low but owners should be counseled to look out for them.

 Fluoroquinolones: There is some concern about using fluoroquinolones for methicillin resistant staphylococcal infections, because it is possible that resistance might develop during treatment. This seems particularly true when older fluoroquinolones (enrofloxacin, ciprofloxacin) are used at doses that will achieve less than the mutant prevention concentration in tissue. Ciprofloxacin is not recommended because 20% of dogs don't absorb it well, and because it may not be possible to achieve a mutant prevention concentration in the tissue. This author has used marbofloxacin successfully at 5.5 mg/kg/day, which appears to be the mutant prevention concentration.

 Chloramphenicol: Chloramphenicol can be used successfully in some cases. It must be given every 8 hours and side effects of nausea, loss of appetite, and vomiting are common. In addition, some dogs have developed a rear limb paresis, the pathogenesis of which is not known. It resolves when treatment is stopped. Chloramphenicol can cause aplastic anemia in humans; while it has never been shown that handling the capsules results in this side effect, we recommend that clients wear gloves when handling this drug.

 Amikacin: Amikacin is less likely to cause renal problems than gentamicin, and so it is preferred for treating pyoderma when an aminoglycoside is needed. It seems to work better for deep pyodermas than superficial pyodermas, in my experience. It can be dosed at 15 mg/kg subcutaneously every 24 h. Because of the potential for renal toxicity, monitoring is recommended. For an otherwise healthy dog, a urinalysis once weekly can be used to check for casts, proteinuria, and changes in specific gravity. Urinalysis is more sensitive than assessment of BUN or creatinine levels. Some clinicians advocate for the use of subcutaneous fluids when using amikacin. We have no evidence that this will reduce renal toxicity, and I am not comfortable with putting large volumes of fluids in the subcutaneous space of a dog with a resistant skin infection.

 Rifampin: Rifampin is an older antibiotic often used in combination with other antimicrobials in the treatment of human tuberculosis. Contrary to what we have been taught, rifampin can be and has been used as monotherapy for methicillin resistant staphylococcal infections in dogs. Because it has the potential to cause hepatotoxicity, liver enzyme levels should be monitored before treatment, and every 10–14 days during treatment. By keeping the total daily dose at 10 mg/kg, we seem to get very good response with minimal toxicity. Owners should be cautioned to watch for appetite loss and vomiting. I have found that by combining bathing 3 x weekly with rifampin orally, we can resolve most superficial pyodermas within 2 weeks.

Table of antibiotic doses for canine pyoderma

Cefovecin (Convenia)*

8 mg/kg subQ; repeat in 2 weeks if necessary

Cefpodoxime (SIMPLICEF)*

5–10 mg/kg QD (higher doses best)

Cephalexin*

22–30 mg/kg TID

Lincomycin (Lincocin)

20 mg/kg BID

Clindamycin

11 mg/kg QD to BID

Amoxicillin-clavulanate (Clavamox)*

20 mg/kg BID to TID

Ormetoprim-sulfadimethoxine (Primor)

27.5–30 mg/kg QD

TMP-sulfa

20–30 mg/kg BID

Doxycycline (if sensitive)

10 mg/kg BID

Minocycline (if sensitive)

5–10 mg/kg BID

Marbofloxacin (Zeniquin)

5.5 mg/kg QD

Enrofloxacin (Baytril)

20 mg/kg QD

Ciprofloxacin (not recommended)

30 mg/kg QD***

Chloramphenicol

50 mg/kg TID

Amikacin

15 mg/kg subQ QD

Rifampin

5–10 mg/kg QD****

* Not for use in methicillin resistant infections
*** Ciprofloxacin, while inexpensive, is a second generation fluoroquinolone with less activity against gram-positive bacteria than we would like. It has been shown in 2 different studies to be very inconsistent in absorption. If used, use at the high dose. It may be helpful to crush the tablets to help promote absorption but we really don't know as much about this antibiotic in dogs as we would like. (This from
data provided by Dr. Mark Papich, NCSU.)
****Keep dose at a max of 10 mg/kg/day to reduce risk of hepatic damage, including necrosis and death.

Most dogs with recurrent pyoderma have an unresolved underlying cause. Once methicillin resistant staphylococcal infections are diagnosed, there is a 50% chance that subsequent infections will be MRS as well. Culture and sensitivity may need to be performed with each subsequent infection. The goal is to prevent relapse.

Long term maintenance for dogs will include management of the underlying cause, regular bathing, skin barrier repair, and in some cases, the use of Staphage Lysate (SPL). I have found that many atopic dogs with recurrent pyoderma are allergic to staphylococcal proteins, as indicated by intradermal testing and/or serum testing for IgE against Staphage Lysate. Thus it is possible that the SPL is acting as allergen specific immunotherapy for these dogs. It can be used as a sole agent, or mixed into injection or sublingual immunotherapy vaccines.

References

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2.  Godbeer SM, Gold RM, Lawhon SD. Prevalence of mupirocin resistance in Staphylococcus pseudintermedius. J Clin Microbiol. 2014;52(4):1250–1252.

3.  Kloos I, Straubinger RK, Werckenthin C, Mueller RS. Residual antibacterial activity of dog hairs after therapy with antimicrobial shampoos. Vet Dermatol. 2013;24(2):250–e54.

4.  Lloyd D. Recognising and controlling risk factors for antimicrobial resistance. Schweiz Arch Tierheilkd. 2010;152(3):131–134.

5.  Loeffler A, Cobb MA, Bond R. Comparison of a chlorhexidine and a benzoyl peroxide shampoo as sole treatment in canine superficial pyoderma. Vet Rec. 2011;169(10):249.

6.  Moodley A, Damborg P, Nielsen SS. Antimicrobial resistance in methicillin susceptible and methicillin resistant Staphylococcus pseudintermedius of canine origin: literature review from 1980 to 2013. Vet Microbiol. 2014;171(3–4):337–341.

7.  Murayama N, Nagata M, Terada Y, Shibata S, Fukata T. Efficacy of a surgical scrub including 2% chlorhexidine acetate for canine superficial pyoderma. Vet Dermatol. 2010;21(6):586–592.

8.  Murayama N, Terada Y, Okuaki M, Nagata M. Dose assessment of 2% chlorhexidine acetate for canine superficial pyoderma. Vet Dermatol. 2011;22(5):449–453.

9.  Murayama N, Nagata M, Terada Y, Okuaki M, Takemura N, Nakaminami H, Noguchi N. In vitro antiseptic susceptibilities for Staphylococcus pseudintermedius isolated from canine superficial pyoderma in Japan. Vet Dermatol. 2013;24(1):126–129, e29.

10. Papich MG. Selection of antibiotics for meticillin-resistant Staphylococcus pseudintermedius: time to revisit some old drugs? Vet Dermatol. 2012;23(4):352–360, e64.

11. Papich MG. Antibiotic treatment of resistant infections in small animals. Vet Clin North Am Small Anim Pract. 2013;43(5):1091–1107.

12. Perreten V, Kadlec K, Schwarz S, Grönlund Andersson U, Finn M, Greko C, et al. Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study. J Antimicrob Chemother. 2010;65(6):1145–1154.

13. Rota A, Milani C, CorrÁ M, Drigo I, Börjesson S. Misuse of antimicrobials and selection of methicillin-resistant Staphylococcus pseudintermedius strains in breeding kennels: genetic characterization of bacteria after a two-year interval. Reprod Domest Anim. 2013;48(1):1–6.

14. Valentine BK, Dew W, Yu A, Weese JS. In vitro evaluation of topical biocide and antimicrobial susceptibility of Staphylococcus pseudintermedius from dogs. Vet Dermatol. 2012;23(6):493–e95.

15. van Duijkeren E, Catry B, Greko C, Moreno MA, Pomba MC, Pyörälä S, et al. Review on methicillin-resistant Staphylococcus pseudintermedius. J Antimicrob Chemother. 2011;66(12):2705–2714.

16. Young R, Buckley L, McEwan N, Nuttall T. Comparative in vitro efficacy of antimicrobial shampoos: a pilot study. Vet Dermatol. 2012;23(1):36–40, e8.

  

Speaker Information
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Valerie A. Fadok, DVM, PhD, DACVD
North Houston Veterinary Specialists
Spring, TX, USA


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