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1 Sponsored by an educational grant from Pfizer Animal Health clinician s forum Expert Views from a Roundtable Insights from the Experts Current Thinking in Antimicrobial Resistance Antimicrobial resistance has become an issue for many types of infections in dogs and cats. One of the best examples is methicillin resistance in the canine pathogen Staphylococcus pseudintermedius. For many years, canine superficial pyoderma responded to most antibiotics that have activity against Staphylococcus spp. With methicillin-resistant skin infections, there are fewer antibiotic choices and treatment can be challenging. Although methicillin-resistant infections in dogs and cats are more commonly seen in dermatology referral practices, it is important for general practitioners to understand the risk factors and treatment options for these resistant infections. THE ROUNDTABLE DISCUSSION Dr. Gloyd: Let s start with a clinical question. John, please take us through the diagnostic plan for a patient with superficial pyoderma that you are seeing for the first time. Dr. Angus: The first thing to establish is whether it s a case of simple pyoderma, relapsing or recurring pyoderma, or a nonresponding infection. If it is a first infection, I need an antibiotic that will provide rapid, complete resolution. If it is a relapsing case that was initially managed successfully but keeps returning, I treat the current infection and diagnose the underlying disease otherwise the infection will relapse again. With a nonresponding infection, I establish why the antibiotic is not working so I can change the protocol. PARTICIPANTS Mark G. Papich, DVM, MS, DACVCP College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Valerie A. Fadok, DVM, PhD, DACVD Gulf Coast Veterinary Specialists Houston, Texas John C. Angus, DVM, DACVD Animal Dermatology Clinic Pasadena, California Kathy Gloyd, DVM, Moderator President, The Gloyd Group, Inc. Wilmington, Delaware clinician s forum 1

2 The drugs that are most commonly chosen for empirical therapy are the cephalosporins (which are historically very safe) and other beta-lactams, such as amoxicillin and clavulanic acid. Dr. Papich Culture vs Empirical Therapy Empirical therapy implies that you strongly believe your patient has a bacterial infection in the case of superficial pyoderma, with S. pseudintermedius. The antibiotic susceptibility of wild-type strains is known. So you do not need to test. Select a drug to which the organism is most likely to be susceptible. But be sure to pick a safe drug: You do not want to cause a new problem. The drugs that are most commonly chosen for empirical therapy are the cephalosporins (which are historically very safe) and other beta-lactams, such as amoxicillin and clavulanic acid. Clindamycin is also an acceptable first choice. Other drugs to which the organism is susceptible may not be your first choice because of side effects or other problems. For example, some veterinarians use trimethoprim sulfonamide, but it has some safety concerns and should probably be farther down the list. Dr. Papich Dr. Gloyd: What diagnostics guide your choice of therapy? Dr. Angus: On the initial visit for relapsing infections, which are probably the most common type, I perform cytology to confirm that it a bacterial infection. I also do a skin scraping to test for demodicosis, which is a great mimicker of bacterial infections. Dr. Gloyd: Val, what is your diagnostic approach to this same patient? Dr. Fadok: Cytology is wonderful for determining the cause of the infection. In our part of the country, the humid Southeast, many infections are mixed, with a combination of cocci and rods, cocci and yeast, or occasionally all three. Cytology helps guide empirical antimicrobial choices and the selection of appropriate topical therapy. In our area, many of the staphylococcal infections we see are methicillin-resistant, so if there is any hint in the history of poor response to antibiotics or immediate relapse after antibiotics have stopped, we perform culture and sensitivity testing. These results can take 7 days, so we start aggressive topical therapy during that time daily or every-other-day bathing with a chlorhexidine shampoo. Dr. Gloyd: When should a practitioner consider culture and sensitivity testing? Dr. Papich: If there is risk for resistance, susceptibility testing is important to assess the patient s response to the original therapy. If the patient has recently been exposed to antibiotics, resistance is likely and culture and susceptibility testing is recommended. Dr. Gloyd: Let s discuss that in greater detail later. John, because you have a referral practice, most of the animals have probably already been on an antibiotic of some type. Do you routinely culture those animals? Dr. Angus: It depends on the recent history. For example, if the infection resolves completely when the animal is on antibiotics but relapses after the antibiotics are stopped, I am not overly concerned about resistance and would proceed with empirical therapy. However, if the animal has cytologic evidence of an active bacterial infection, is currently or has recently been on antibiotics, or has a history of a slow or partial response, I culture on the first visit. Dr. Gloyd: Val, tell me about your protocol in light of what John and Mark have said. Dr. Fadok: We perform a culture in virtually all pyoderma cases because the patients are referred with a history of poor or incomplete response. The prevalence of methicillinresistant Staphylococcus in our practice is approximately 80%, and we rarely see firsttime cases of pyoderma. We start with cytol- 2 clinician s forum

3 I use a systemic antibiotic only for generalized pyoderma. If I can use topical therapy on more regionalized or local pyoderma, I do. Dr. Fadok ogy to confirm the presence of bacteria, then move on to culture and sensitivity testing. As I said before, we treat topically while we re waiting for the results. TREATING PYODERMA Dr. Gloyd: Val, how do you treat superficial pyoderma? Dr. Fadok: My philosophy has changed in the past 5 years. Before, we rarely had antibiotic failures and I may have been cavalier about prescribing antibiotics and I was lazier about advocating strongly for topical therapy. Now I use a systemic antibiotic only for generalized pyoderma. If I can use topical therapy on more regionalized or local pyoderma, I do. Fortunately, we have many choices of topical therapies these days. Superficial Pyoderma: Which Antibiotics? Dr. Gloyd: John, how do you decide what medications to use and prescribe in your clinic? Dr. Angus: In my practice I stock only veterinary-label drugs: I am a veterinarian, and evidence rather than guidelines dictates my use of these drugs. Veterinary drugs are the ones that have been studied and have established tissue concentrations and known pharmacodynamic characteristics. In addition, if a patient has an adverse reaction, I report that to the manufacturer. I only use nonveterinary drugs if no veterinary-label drug is available. Dr. Gloyd: Mark, what is the difference between various generations of cephalo - sporins? Do you consider third-generation cephalosporins such as Simplicef (cefpodoxime) and Convenia (cefovecin), which are veterinary-labeled, the big guns? Dr. Papich: I ve always disliked the term big guns because it implies that these drugs should be saved for rare instances or as a last resort. Rather than looking at them this way, I consider them the most highly active of the antibiotics available to veterinarians. The distinction between first-, second-, third-, and even fourth-generation cephalosporins is based on susceptibility against gram-negative bacteria. For treating Staphylococcus, there is no difference among first-, second-, and third-generation cephalosporins. However, a first-generation cephalosporin is rarely active against Escherichia coli (a gram-negative bacterium), but second-, third-, and especially fourth-generation cephalosporins are. Also, the classification is not really precise. For example, Convenia is classified as a thirdgeneration cephalosporin based largely on its structure, not its susceptibility pattern. Dr. Gloyd: Mark, how are Convenia and Simplicef different from other drugs in regard to pharmacokinetics? Dr. Papich: The choice of drugs is largely based on pharmacokinetics, not class. For example, Convenia has a long half-life (that is, a long time above the MIC [mean inhibitory concentration]) that makes it convenient. Simplicef also has favorable pharmacokinetics because it is relatively inactive when administered and causes less gastrointestinal upset and fewer intestinal reactions. After absorption, it actually has a longer halflife than some first-generation cephalo - sporins like cephalexin, which is why it can be given just once a day. Dr. Gloyd: John, how do you use these drugs in your practice? Dr. Angus: Like Mark, I am frustrated by the Time- or Concentration- Dependent Drugs As the name implies, for a time-dependent drug the length of time it remains above the minimum inhibitory concentration (MIC) determines effectiveness. For concentration-dependent drugs, what is important is how high the tissue level is above the MIC. If we are using a time-dependent drug, we need to make sure that the drug exceeds the MIC for as much of the dosing interval as possible, by either dosing often enough or using a long-acting drug. For concentration-dependent drugs, we need to give a large enough dose, even if the drug is only given once a day. Beta-lactams, which include cephalosporins and amoxicillin clavulanate, are examples of time-dependent drugs; fluoroquinolones are probably the best example of concentration-dependent drugs. Fortunately, the labeling of these drugs has, for the most part, taken these considerations into account. Dr. Papich clinician s forum 3

4 My goal is rapid and complete resolution of the infection. I usually use Convenia because of its optimal pharmacokinetics and ease of use. Using Cephalosporins The problem we have in Houston is the lack of efficacy of more narrow-spectrum drugs, such as erythromycin and clindamycin. Even amoxicillin potentiated by clavulanate is poorly effective in canine pyoderma, and all of these drugs are often in the history of dogs with methicillin-resistant infections. I prefer a cephalosporin, and the two that I prefer are Convenia and Simplicef. I was intrigued by a paper that came out a few years ago in which the author noted the phenomenon of MIC creep for cephalexin in the isolates of S. pseudintermedius at Louisiana State University. Older papers also suggest that if veterinarians use cephalexin, it should be used 3 to 4 times a day, as it is in humans. This is simply not practical. Furthermore, compliance with any oral drug can be poor, so I use Convenia whenever I can at least I know the antibiotic has gotten into the animal. Dr. Fadok concept of saving the big gun for when you really need it. My goal is rapid and complete resolution of the infection. I want to choose the best antibiotic for that infection. I usually use Convenia because of the points Mark made with regard to optimal pharmacokinetics and ease of use. Therapy for Recurrent Pyoderma Dr. Gloyd: If our patient had recurrent pyoderma, how would that change your answers? Dr. Angus: In cases of recurrent pyoderma, in which therapy is successful but the infection returns, then the patient is the source of its own infection. In other words, the dog has a complement of native, resident Staphylo - coccus that reinfects due to underlying disease. Antibiotics are more like pyoderma suppressants and won t completely eliminate the bacteria. We need to investigate environmental allergies (atopic dermatitis) and food allergies; verify that parasite prevention is adequate; and determine whether endocrine function is normal in particular, I investigate for hypothyroidism or Cushing s disease. Dr. Gloyd: What if resistant bacteria have emerged at this point? Dr. Papich: I agree with John that recurrence is more likely to result from underlying patient factors than resistance. However, with a resistant organism, the patient will not respond, and it is time to use culture and susceptibility testing to make sure you are targeting the right organism and also to aid in antimicrobial selection. It is hard to predict susceptibility because it varies greatly. Dr. Gloyd: Is there confusion about which bacteria species are resistant? Dr. Papich: Yes. The species of Staphy lo coccus we see most often in both dogs and cats is S. pseudintermedius, formerly S. intermedius. People are most likely to be infected with S. aureus. Many practitioners have probably heard the term MRSA, meaning methicillinresistant S. aureus. These bacteria are rare in companion animals because their skin does not support growth. If veterinarians encounter S. aureus, especially MRSA, it probably came from a person, and they need to talk to the owner about the patient s history and home environment. Dr. Gloyd: Is it true that the first cases of resistance resulted from MRSA? Dr. Angus: Yes. I first became aware of methicillin resistance in dogs that were infected by the human MRSA. MRSA incidence in my practice has not changed, but methicillinresistant S. pseudintermedius has increased dramatically over the past 10 years. It is important to determine whether you have resistant S. aureus or pseudintermedius. If it is S. aureus, it is nearly guaranteed that a person in the household is a carrier or is clinically infected. 4 clinician s forum

5 Antibiotics are not meant to be used long-term they should be used only for short periods. Dr. Fadok Dr. Gloyd: Val, can you estimate how many S. pseudintermedius resistant cases you see in a month or a year? Dr. Fadok: I see about 10 to 15 cases per week (and that does not include cases seen by my two colleagues). Dr. Gloyd: John, do you see any correlation between, for example, injectable cephalo - sporins and resistance? Dr. Angus: No. How resistance develops tends to be misunderstood. Cephalosporinspecific resistance is rare, and we have been using these drugs in dogs for 30 to 40 years. Whenever I encounter a cephalosporinresistant bacterium, it is almost always methicillin-resistant Staphylococcus. And we did not create that situation if the Staphylo - coccus carried the meca gene, which codes for methicillin resistance, it would be resistant to all beta-lactams. CAUSES & IMPLICATIONS OF RESISTANCE Dr. Gloyd: Val, one of your specialties is immunology, and you have monitored resistance for a number of years. What do you think is the cause? Dr. Fadok: The problem seems to have more to do with the bacteria than the host immune system. Pyoderma has been recurrent and frustrating in dogs for my entire career, but infections that do not respond to antibiotic therapy were very rare. Now, they just keep coming back. We know from studies of atopic dermatitis in humans and to some extent in dogs that mounting a T-helper-2 response to bacteria causes plenty of inflammation but does not kill the bacteria. In fact, Staphylococcus is known to promote the shift Do we know what is causing the increase in Staphylococcus-resistant pyoderma? Unfortunately not. If we did, we could stop it. Even physicians have not determined the exact cause in human cases. Perhaps the cases of methicillin-resistant S. pseudintermedius that we see have genetic elements that originated from S. aureus. At some point, these species probably arose as independent clones from different regions of the world and of the country. However, there is a possibility of shared genetic elements from S. aureus. Antibiotic pressure results in emergence of resistant organisms. Until the late 1990s and early 2000s, it was rare to see methicillin-resistant S. pseudintermedius, but now it is quite common. With regard to when it started, there seems to have been a gradual increase around 2003 and 2004, followed by a rather sharp increase. There has been no leveling off in veterinary medicine, but there has been some leveling off of S. aureus in human medicine. Dr. Papich to the T-helper-2 response, essentially making the dog allergic to its own bacteria. In the past, many of these dogs simply lived on antibiotics daily or as pulse therapy. Antibiotics are not meant to be used long-term they should be used only for short periods. Antibiotics at therapeutic doses (based on MIC testing) have selected for the most resistant bacteria we see today. Dr. Gloyd: Here is the key question of our discussion: Is there evidence that any of our veterinary-approved and labeled drugs select for, rather than cause, resistance? Dr. Papich: Antibiotics do not cause bacterial resistance they select for resistant strains among the susceptible strains. Which antibiotics are more likely to produce this selection in our patients? There certainly is no smoking gun, if you want to put it that way. We discussed earlier about how the increase in resistant bacteria occurred in the early 2000s, but Simplicef was approved around 2004 and Convenia in In other words, increased resistance occurred before these approvals, so the evidence does not support the assumption that these drugs have contributed to resistance. clinician s forum 5

6 You want to use your antibiotics to resolve that infection, not necessarily to prevent the next one. Have the current prescribing habits of veterinarians caused the increase in Staphylococcus-resistant pyoderma? We do not create de novo methicillin resistance in our patients; they acquire it from contact, often while on antibiotics. For example, a patient that seems to have methicillin-susceptible Staphylococcus can receive beta-lactams. However, if methicillin-resistant Staphylococcus is present, the drugs may still select for these resistant strains as some bacteria will fail to respond and survive the treatment. The reason for the increase in cases is not because we have had dramatic changes in antibiotic use but because once the Staphylococcus has the meca gene, it is going to have a better chance of surviving than other Staphylococcus in an antibiotic world. We did not create this situation it was probably established in human hospitals. However, now that it is established in our canine population, it is our problem to address. Is there evidence that cephalosporins or other beta-lactam antibiotics select for resistant E. coli in the gastrointestinal tract, and are there public health risks? There is no question that every oral antibiotic changes the bacterial flora. What is questionable is whether this causes a risk. For example, if we create resistant bacteria in the gastrointestinal tract (that persists for some time, although the length of time varies among the antibiotics) in a dog or cat, is that a public health risk? There is no strong evidence that it is. I know of no association between drug-resistant bacteria, such as E. coli, originating from companion animals and causing resistant infections in people. In food animals, use of antibiotics is a different story because we eat them, but because we are not in the habit of eating dogs and cats, the risk from that population is different. Dr. Papich Dr. Gloyd: John, how should we evaluate owner lifestyles and environments in the context of resistance? Are any patterns starting to evolve? Dr. Angus: There is no evidence of a pattern, but we do need to be cognizant of whether another animal in the household has had, for example, a methicillin-resistant Staph y lo cocc u s infection and then another one 3 years later. Is that a long-term, persistent, resident genetic element in the native Staphylococcus for that dog, or do different infections occur when antibiotics have been stopped for a certain length of time? We don t know. Dr. Gloyd: John, are you concerned about resistance from a clinical point of view? Dr. Angus: Yes. Our goal in treating an infection is to help restore the animal to a normal state of being. We use antibiotics as a tool against the bacteria that are causing the infection. You want to use your antibiotics to resolve that infection, not necessarily to prevent the next one. Once it is resolved, you should discontinue the systemic antibiotic but continue to use the topical antiseptic. Stopping the antibacterial shampoo prematurely is common. Dr. Gloyd: John, what antibiotic are you most likely to use to treat an animal with a resistant infection? Dr. Angus: That would be based on culture and sensitivity testing. Dr. Gloyd: And Mark was saying that culture and sensitivity vary greatly. Dr. Angus: It is because resistant bacteria are less predictable. Now, if I have methicillin-resistant Staphylococcus, the best readily available systemic antibiotic is chloramphenicol, which we use almost exclusively for that purpose. I think one of the reasons we can still use chloramphenicol is the nature of the genetic elements developed in the antibiotic-intensive environment of human hospitals: they do not use chloramphenicol. So 95% of the methicillin-resistant Staphylo - coccus cases in my practice are still susceptible. Almost 100% are still susceptible to amikacin, but it needs to be injected and can cause kidney injury, so it is not my first choice. Resistance to clindamycin, doxycycline, and trimethoprim sulfonamide antibiotics is less predictable. However, if a sulfa antibiotic is likely to work and beta-lactams are not an option, then of course you have to use it, but you must monitor the patient appropriately. 6 clinician s forum

7 If the laboratory reports that a strain is resistant, we need to contemplate what could be considered second-tier antibiotics, almost every one of which has some kind of a problem. Dr. Papich Nosocomial Concerns Susceptible and resistant strains differ in antibiotic susceptibility, not pathogenicity, so the most important step is to minimize exposure of susceptible dogs to resistant Staphylococcus while on antibiotics. In my hospital, dogs that have known resistant Staphylococcus are taken into the room sooner. We institute very strict hand hygiene between patients we wash hands before and after seeing the patient, regardless of whether we are wearing gloves, and gloves are essential if you are going to touch pus. We also use hand sanitizers between patients, and I think that has been helpful. But even if you are sanitary, the next thing that you touch probably is not. You will notice I am not wearing a tie today. That is because ties are rarely laundered, and they provide no benefit to patient care. If I wash and sanitize my hands and then straighten my tie to meet the next client, I have recontaminated myself. You have to be conscious of all objects: floors, tables, hands, the things you hang around your neck like a stethoscope, the otoscope cones, and the otoscope handle. Many of us clean otoscope cones between patients, but when was the last time you cleaned the otoscope handle? THE ROLE OF TOPICAL THERAPY Dr. Gloyd: John, do you advocate topical therapy? Dr. Angus: Absolutely. If you are treating a kidney infection, you cannot take the kidney out, wash it in chlorhexidine, and put it back in. But because the skin is on the outside, we can take advantage of a second approach to resolving infection and preventing resistance. If you use a systemic antibiotic and apply your topical antiseptic of choice, it should eliminate any surviving bacteria, reducing the chances for resistance. Dr. Gloyd: Mark, I assume you agree from a pharmacology standpoint? Dr. Papich: Yes. As John points out, you are treating the outside of the patient. Resistant bacteria other than Staphylococcus for example, E. coli and some of what we call extended-spectrum beta-lactamase, which is highly resistant E. coli occur in the gut, and there are other bacteria that also become resistant because of oral medications. Relying more on topical therapy and less on oral therapy has natural benefits. Dr. Gloyd: Val, what are your first drugs of choice for treating recurrent pyoderma? Dr. Fadok: About 4 years ago, we preferred potentiated sulfas, but now sensitivity dictates three choices: chloramphenicol, amikacin, and rifampin. Many dogs are sensitive only to rifampin or amikacin alone, so we, unfortunately, are using much more rifampin as monotherapy these days. Dr. Gloyd: Mark, are these the kinds of antibiotics to which resistant bacteria are sensitive? Dr. Papich: Yes. Fortunately, we do have data from published studies as well as surveys from individual hospitals on the antibiotics to which some resistant strains are more likely to be susceptible. In our discussion of empirical choices, we talked about the selection of a beta-lactam a cephalosporin because it is safe. We do not want to cause a new problem. However, if the laboratory reports that a strain is resist- Efficacy of Topical Therapy We did a study to determine whether shampooing alone could resolve superficial pyoderma caused by methicillin-resistant S. pseudintermedius. (Our isolates are particularly resistant most of the time they are sensitive only to amikacin and rifampin.) Ten dogs were bathed daily with 3% or 4% chlorhexidine shampoo. All dogs had at least a 50% reduction in pyoderma scores after 2 weeks, with 100% resolution in 30 days. It was labor-intensive, but it worked. It has the added advantage of precluding the need for more toxic antibiotics, and it removes antibiotic pressure from the bacteria. The hope is that they will return to being sensitive to methicillin. Dr. Fadok clinician s forum 7

8 Whatever disinfectant you use, be sure to apply it to every surface with which the animal comes in contact. ant, we need to contemplate what could be considered second-tier antibiotics, almost every one of which has some kind of a problem. Chlor am phenicol is more likely to make an animal sick, and there are some human health risks associated with exposure. It also has to be given more frequently at high doses, which sometimes cause stomach upset. We occasionally use rifampin, but that also has risks. As John mentioned, aminoglycosides are good drugs, but again, they are not risk-free. We see more adverse reactions to sulfonamides than some of the other classes. These problems are why we reserve the second-tier antibiotics for the more resistant strains. Dr. Angus: When we evaluate susceptibility profiles, I have noticed that many methicillin-resistant Staphylococcus infections are also resistant to fluoroquinolones, so these drugs are not good second-tier antibiotics for these infections. However, for wild-type Staphylococcus, we have many effective betalactams, so fluoroquinolones do not have to be our first choice unless other factors preclude use of a beta-lactam or clindamycin. Dr. Gloyd: With chloramphenicol, how many working owners can give a drug 4 times a day? Dr. Angus: Very few, despite their best intentions. The harder you make any therapeutic plan for owners, the less likely they will be to follow it. My goal is to do as much in the clinic as possible. For example, I ll give an injection of Convenia if the patient has a susceptible strain. But if I am forced to prescribe chloramphenicol because of resistant Staph - ylococcus, I will need to communicate often with the owner. In addition, we are seeing hindlimb weakness in conjunction with high doses of chloramphenicol given for extended periods. This is not discussed in the literature. 8 clinician s forum PREVENTING MRSP SPREAD Dr. Gloyd: Val and John, what protocols do you follow for environmental cleaning? Dr. Fadok: In our clinic, we clean frequently with bleach throughout the day. If we see a patient with MRSP (methicillin-resistant S. pseudintermedius) or suspected MRSP, we and the technicians change our lab coats afterward. We have hand sanitizer in each room, and, of course, we wash our hands between patients. We also try to remember to sanitize doorknobs, drawer pulls, computer keyboards, and phones. Dr. Angus: The cleaning products should have efficacy against Staphylococcus, and you need to follow the instructions with regard to killing those bacteria. Lately we have been using accelerated hydrogen peroxide; it is considered one of the most effective products against Staphylococcus. It is also safe for the environment and easy to use. Whatever product you use, be sure to apply it to every surface with which the animal comes in contact. Important Safety Information SIMPLICEF should not be used in dogs that are hypersensitive to penicillin or cephalosporin. Safety in pregnant and lactating animals or breeding male dogs has not been established. See full prescribing information on page 63. Important Safety Information CONVENIA is not for use in dogs or cats with a history of allergic reactions to penicillins or cephalosporins. Similar to the other cephalosporins, side effects for both dogs and cats include vomiting, diarrhea, decreased appetite/anorexia and lethargy. The safety of CONVENIA has not been determined in lactating or breeding animals. See brief summary of prescribing information on page 64. AIF

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