Why didn't that antibiotic treatment work? Overview of bacterial skin diseases (Proceedings)

Bacterial skin infections represent a common condition affecting the canine and is often recurrent. The infective organism most frequently isolated is Staphylococcus intermedius although other species of staphylococcus may be involved. Most recently Staphyloccus schleiferi has been cultured from dogs with chronic recurrent pyoderma often demonstrating resistance to cephalexin and other cephalosporins.

Factors Related to Pyoderma

In general, canine pyodermas are secondary. Factors that are probably involved with the development or recurrence/perpetuation of the infection are multifactorial. They include the following: 1. The bacterial characteristics and pathogenic properties 2. underlying disease and its relationship towards decreasing the protective mechanisms of the skin and the permissive effects on host defense 3. The inflammatory response (or lack of) by the host.

The identification of the underlying/predisposing disease(s) become a predominant focus point in the treatment of the clinical case since this is an area of major concern in the evolvement of the disease but also it is one of the few areas we can do something about. Changing the bacterial characteristics is not possible and modifying the host response has proven to be of minimal value in eliminating the recurrent infection. Recognizing and treating the underlying disease(s) is of primary relevance although the problem may not always be easily determined and in some cases cannot be identified.

In the southeastern United States (and other geographic regions) allergic dermatitis is the most common predisposing factor. Atopy, flea allergy, food allergy and contact allergy. This is further complicated by the length of coat, amount of oiliness, scaliness or crusts (seborrhea) and the pets habits (environmental factors). Other disease considerations include ectoparasites (demodex, scabies, cheyletiella, fleas, etc.), and endocrinopathies (hypothyrodism, hyperglucocorticoidism or sex hormone disturbance), metabolic abnormalities (keratnization defects, idiopathic seborrheic dermatitis), hair follicle dysplasias and immunological incompetencies. A major predisposing factor of recurrent pyoderma in the dog is the administration of glucocorticoid compounds, particularly when given chronically or when long acting products are used. Therapeutic failures of pruritus to glucocorticoid therapy is most often a result of incomplete recognition and treatment of underlying factors, most common being infection. A chronic relapsing pyoderma is most likely secondary. The most common reason for therapeutic ineffectiveness or chronic/recurrent pyodermas is a failure to eliminate the active infection well into remission or control predisposing factors or the inability to identify other co-existing diseases (example of the atopic dog with coexisting flea allergy dermatitis, secondary bacterial pyoderma, yeast dermatitis and adult onset demodicosis).

Initial Troubleshooting the Relapsing Pyoderma

The following questions should represent a check list for evaluation of the dog with chronic recurrent pyoderma. Was the proper antibiotic selected? Was the drug dosed & administered properly? Was the animal reevaluated during treatment to determine the end point? Was the antibiotic used for sufficient duration? Were skin scrapings acquired? Was the animal pruritic and did the pruritus persist after the pyoderma had cleared? The approach to the clinical management of these cases include several objectives. The first is to acquire a detailed history and perform a com;ete clinical examination to lead toward the development of a differential diagnosis and diagnostic plan for the underlying disease as well as the symptoms of the pyoderma. The second is to formulate a plan to treat the underlying disease and also eliminate the current active infection. The final objective is to develop a plan that will reduce the recurrence of the pyoderma until the underlying/predisposing factors can be maximally controlled.

All cases with lesions suggestive of bacterial pyoderma should be skin scraped for evidence of ectoparasites (demodicosis). Lesions with suspicion of cutaneous malassezia should be should be evaluated by microscopic inspection of specimens obtained from the surface of the skin for the presence of yeast. Pustules should be evaluated by microscopic inspection of the pus carefully obtained from the lesion placed on a microscopic slide and stained. Bacterial cultures are not routinely performed on superficial pyoderma but may be indicated in the evaluation of deep pyoderma. Bacterial cultures should never be obtained without performing susceptability testing. Biopsies are often indicated for culture and susceptibility testing as well as histopathologic evaluation in refractory or recurrent cases. Therapy

Specific therapy should be directed at treating the underlying disease(s) in addition to systemic antibiotics. Antibiotics chosen for the management of canine pyodermas should have a known spectrum of activity against S. intermedius. Antibiotics that should never be used include penicillin, ampicillin, amoxicillin, tetracycline and sulfa drugs without potentiation. All antibiotics should be dosed on the basis of actual body weight determination. Antibiotics should be administered for a minimum of 21-30 consecutive days or 10 days beyond apparent remission. Deep pyodermas may require 8-12 weeks or even longer. Pyogranulomatous lesions (acral lick dermatitis) have taken as long as 4-6 months of continuous antibiotic treatment. It is not necessary to change antibiotics if they are still effective. One should watch for discrepancy between in vivo responsiveness and in vitro susceptability. Antibiotic responsiveness may change. Recognition of resistance patterns is essential. Proper dosing may make the difference between response and failure.

Problems Associated with Antibiotic Therapy:

The response is obviously predicated on the proper identification of a bacterial pyoderma realizing there are a number of non-bacterial and non-septic conditions that will mimic the clinical appearance of pyoderma. Co-existing or underlying diseases will affect the responsiveness to antibiotic therapy but are more likely to have the most dramatic influence on the relapse rate and remission interval. Recurrence of the pyoderma may be observed within several days of the cessation of antibiotic therapy. The effectiveness of an antibiotic is related to the previous use of that particular antibiotic and the chronicity of the problem and therapy. "First round" antibiotics such as used early in the treatment regimen (lincomycin, clindamycin, clavuanic acid potentiated amoxicillin, potentiated sulfas, etc.) may have limited or minimal effect on the chronic case but should always be considered in the early cases of bacterial infection. Ideally, cephalosporins should be used after the "first round" antibiotics. Fluoroquinilone antibiotics should be reserved for cases where there is identification of Gram negative organisms by culture or a multidrug resistance documented. Increased observations of refractoriness of the pyoderma to antibiotics previously considered the "second round" or drugs such as cephalosporins are being more commonly observed. While third generation cephalosporins(Cefpodoxime, Simplicef®& Cefovecin, Convenia®, Pfizer Animal Health) have enhanced the treatment process they are comparably vulnerable for methicillin resistance. Clinical observations of multi-drug resistant (MDR) Staphylococci are becoming more common. Reclassification of Staph. Spp. (S. schleiferi, S. pseudointermedius) has been associated with multidrug resistance. The possible zoonotic concern is a factor of human-pet interaction and there has been some concen for "reverse zoonosis" with an increased incidence of S. aureuscultured from wounds and abscesses. Tactics to reduce or avoid development of resistance needs prime consideration.

The mechanism of methicillin resistance involves the modification of penicillin binding proteins (PBP's), a pre requisite for cephalosporin antibacterial cell wall activity. All penicillins and cephalosporins (P-lactams) require binding to PBP in cell wall before drug is effective. Methicillin resistant staphylococci produce a low affinity PBP (PBP2a) due to expression of the mecA gene. The mecA gene located in a mobile area referred to as the staphylococcal chromosomal cassette (SCCmec). Enzymes necessary to excise the mecA gene from the cassette are also present allowing the gene to be excised and inserted into the staph's chromosomal structure resulting in production of PBP2a and subsequent resistance. Drugs are disabled because the binding affinity to PBP2a is very low and the activity hence suppressed. Another proposed method of methicillin resistance is the development of a thicker cell wall making antibiotic penetration more difficult. This results in the development of multiple antibiotic resistance, not just thep-lactams. Yet another mechanism other than mecA gene activation includes proteins involved with active removal of antibiotics. Membrane-bound pump activity limits antibacterial activity of many antibiotics whose mechanism involves internal cellular structures. The frequency of methicillin resistant Staph. has doubled in last two years with methicillin resistant Staph. Intermedius (MRSI) increased as much as ten fold since 2004. This is created by transfer of the mecA gene demonstrated in almost 50% of isolates tested from organisms collected from dogs. Fortunately only a small number of S. intermedius expressing mecA gene demonstrate methcillin resistance. Geographical variability is likely from antimicrobial pressure in areas where there is high use. The methodology of determining bacterial susceptability may change with the development of the "mutant prevention concentration". This varies from the conventional "minimum inhibitory concentration" as an antibiotic dosed at the top of the MIC results in first decline of organism concentration which corresponds to the MIC of "wild type" bacteria. The following plateau is caused by resistant mutant subpopulations that are not affected by the MIC of that drug. The second drop occurs when the MIC of the least susceptible organism is reached. This value is referred to as the mutant prevention concentration (MPC). Within the "mutant selection window", drugs exert selective pressure on microbial growth with organisms containing resistant genes having preferential growth. Seeking an alternative in these instances may be more difficult and predictably more expensive, The use of cephalosporins has conventionally been used in the event of failure recognized with more conservative antibiotics. Failure of cephalexin leaves few realistic choices. Methicillin resistant Staphylococcal bacteria will be resistant to ALL betalactam antibiotics and often will have resistance to fluoroquinolone antibiotics. Ideally, dogs with cephalosporin refractory pyoderma should be evaluated by sterile biopsy acquisition and submitted for culture and suscepatbility. The availability of minimum inhibitory concentrations (MIC's) may enhance the antibiotic choice and be helpful to the dosing of the selected antibiotic. Older, conventional drugs such as potentiated sulfas, clindamycin and chloramphenicol have been helpful in controlling infection caused by methicillin resistant staph. Multiple bacteria infections are observed in chronic, deep pyoderma in the dog, particularly when affecting the feet and face. Gram negative organisms may be found in addition to the Staphylococcal infection and usually represent opportunistic infection secondary to the staph.

Pseudomonas aeroginosa, Proteus mirabilis, Eschericia coli are more commonly identified. Fluoroquinolones are often required in these instances for systemic therapy. Chloramphenicol (33 mg/kg tid or 50 mg bid) in dogs with multi-drug resistance has a high rate of in vitro susceptibility but should be used with limited application to known cases with methicillin resistant organisms. Potentiated sulfonamides (Ormetoprim potentiated sulfadimethoxine (Primor®) preferred) has estimates of 55 % of methicillin resistant Staph. showing susceptabiltity. Clindamycin has been effective in less than 50 % but is aninexpensive alternative at 11 mg/kg qd or 5-8 mg/kg bid. Fluoroquinolones show less than 50% in vitro susceptability with marbofloxacin 5 mg/kg qd or enrofloxacin 5-10 mg/kg qd. While ciprofloxacin is commonly used because of its low cost, it may be one of the leading causes of multi-drug resistance and has controversial dosage and pharmacokinetics. It, like all the other fluroquinolones should not be used routinely. Aminoglycoside therapy has been used out of necessity. Amikacin and gentomycin have shown susceptability to methicillin resistant Staph., however parenteral administration and nephrotoxicity are major limiting factors. Linezolid, a member of the antibiotic family oxazolidinones is effective at a dose in dogs 20-30 mg/kg bid. It may be administered orally or parenterally. Since this drug is one of the antibiotics used in MRSA, its use in veterinary medicine remains highly controversial. It is very expensive but highly effective in multidrug-resistant Staphyloccus. Vancomycin demonstrates sensitivity to most resistant Staph. But it too is used in humans with MRSA and has the disadvantage pareneteral administration (intravenous treatment at 15 mg/kg IV q6h with fluids. It is recognized for being very nephrotoxic in dogs.

Other Antibiotic Choices

Macrolide antibiotics have been utilized in the treatment of bacterial pyoderma for many years (e.g. erythromycin). Other variations include azithromycin (Azithromax; Pfizer, NY, NY), and Clarithromycin (Biaxin; Abbott Laboratories, Abbott Park). They may demonstrate efficacy against Staphylococci sp. particularly early in the course of a recurrent pyoderma. Azithromycin dosage in dogs is 10 mg/kg administered every 24 hours. The feline dosage is 5 mg/kg every 24 hours. Azithromycin should be administered before feeding providing 2 hours for absorption before allowing the animal to eat. The dose of clarithromycin in dogs and cats is 2.5 mg-10 mg/kg administered orally every 12 hours. Side effects include gastrointestinal (diarrhea and vomiting) as in humans who also describe abdominal pain and headaches. Clarithromycin is contraindicated with concomitant use of terbinafine, cisapride or pimozide. Tylosin is also a macrolide commonly used in veterinary medicine. It has demonstrated good efficacy and negligible side effects when used to treat dogs with superficial bacterial pyoderma using a dosage of 20 mg/kg orally bid for 21-28 days. Lower dosages have been used. Beta-lactam antibiotics adopted for veterinary application include imipenem-cilastin (Primaxin; Merck). It is useful for pyoderma that is refractory to conventional antibiotics but very expensive and a parenteral drug. They are somewhat resistant to staphylococcal beta-lactamase. Imipenem-cilastin has broader spectrum of activity and may be considered in a combined staphylococcal and Pseudomonas infection. Primaxin is administered intravenously or intramuscularly at a dose of 3-10 mg/kg every 6-8 hrs for dogs only, and should be stored under refrigeration for 24 hour stability after reconstitution. Intravenous administration should be performed slowly to avoid nausea. A major limitation of imipenem-cilastin is the pain experienced upon intramuscular administration and local reaction (neurovascular damage) when the medication has been deposited outside the vein. Lidocaine has been reported to relieve discomfort when administered concurrently in intramuscular administration.

Once again, fluoroquinolone antibiotic therapy should be reserved for combined Gram negative infections or staphylococcal pyoderma that has become refractory to cephalosporin antibiotic therapy. They are commonly employed in the treatment of otitis media which typically includes Gram negative bacteria (Pseudomonas sp.). While there are some variations in susceptibility of bacteria and tissue drug levels, the mechanism of action is comparable among fluoroquinolones. Orbifloxacin has demonstrated lower skin penetration and higher minimal inhibitory concentrations than enrofloxacin and difloxacin. Enrofloxacin (Baytril, Bayer Corp) has flexible dosing (2.5-10 mg/kg once or twice daily) but is conventionally used at 5 mg/kg once daily where a lower dosage demonstrates decreased efficacy. Enrofloxacin has been shown to have higher tissue levels in inflamed skin in contrast to normal un-inflamed skin as a consequence of antibiotic concentration in white blood cells. Marbofloxacin has been useful for chronic otitis externa and otitis media and is an excellent choice for deep pyoderma with Gram negative organisms or cephalosporin resistant Staphylococcus spp. Cost factors may restrict the use in large dogs. Side effects of fluoroquinolones are relatively uncommon but should not be used in young dogs due to the concern for articular cartilage defects. Recommendations have been cited to exclude fluoroquinolones in dogs less than 1 year of age and less than 18 months in giant breed dogs. Higher dose enrofloxacin may (will?) cause retinopathy and lead to blindness in cats.

Failure of antibiotic therapy should be followed by more aggressive diagnostics and attempt to discover underlying or co-existing diseases. Macerated tissue cultures from biopsy specimens collected following a surgical scrub and submitted for bacteria isolation and susceptibility testing is important to include in the evaluation with the likelihood of antibiotic resistance developing. Treatment of the chronic relapsing case may result in the utilization of combined therapy or more aggressive treatment techniques. Among the options include chronic use of antibiotics, pulse therapy, sub-inhibitory antibiotic therapy, each with the liability of encouraging resistance. Persistent use of antibiotics is tolerated well by most dogs but may pose heavy financial burdens to the owner. Gastrointestinal disorders still remain the most common adversity.