Antibiotic resistance in staphylococci associated with cats and dogs

Dogs and cats have become an integral part of modern society in the developed world and as such attention is given to their care and welfare. At some stage of their lives many cats and dogs suffer from skin and other superficial staphylococcal infections such as pyoderma and otitis externa and are therefore treated with antibiotics. This practice has led to the emergence of resistant staphylococci in these animals. Antimicrobial susceptibility studies in companion animals have revealed that staphylococci isolated from cats and dogs exhibit similar resistance patterns to human staphylococci and that resistance development is influenced by the frequency of use of certain antibiotics. This review examines the antibiotic resistance patterns of the most frequently isolated staphylococci from cats and dogs and the mechanisms underlying resistance. The possible transfer of methicillin-resistant staphylococci from cats and dogs to humans has been identified as a potential public health issue. Typing tools used for epidemiological differentiation of pathogenic and nonpathogenic staphylococci and for species identification studies may help to elucidate the importance or otherwise of this problem. Staphylococci are Gram-positive cocci, which are nonmotile, nonspore forming and facultative anaerobes that are commonly found on the skin of mammals. Thirty-seven species have been identified (Euzeby 1997) and all species are part of the normal microflora of the skin and mucosal surfaces of the upper respiratory tract of man and animals. In dogs Staphylococcus intermedius causes infections such as pyoderma and otitis externa, however, Staphylococcus aureus and Staphylococcus schleiferi are emerging as common pathogenic species in small animals (Igimi et al. 1990; Bes et al. 2002a; Frank et al. 2003; Yamashita et al. 2005). Staphylococci do not generally appear to cause any major specific diseases in cats (Igimi et al. 1994) but cases of superficial dermatitis, bacterial folliculitis and superficial pyoderma caused by Staph. intermedius have been reported (Austin 1978; Scott 1980). Intimate association between potential hosts can enhance staphylococcal dispersal as they are easily spread by skin-to-skin contact, aerosols from sneezing and coughing and also through saliva. Upon gaining entry into deeper tissues of the body, staphylococci especially Staph. aureus can cause a wide variety of diseases in man (exfoliative skin diseases, toxic shock syndrome and food poisoning) and animals (mastitis, pyoderma and otitis externa). A wide range of antibiotics has been used to treat infections in dogs and cats caused by staphylococci and have led to the emergence of resistant strains. Antibiotics frequently used in cat and dog therapy are: penicillins, cephalosporins, macrolides, lincosamides, fusidic acid, tetracyclines, chloramphenicol, potentiated sulphonamides, aminoglycosides and fluoroquinolones (Watson and Rosin 2000). Kunkle (1987) and Reedy et al. (1997) concluded that dogs, which had not received prior antibiotic therapy were much more likely to have staphylococci isolates that were susceptible to a wide spectrum of drugs compared with those that had received prior antimicrobial drugs. Cats and dogs could also acquire resistance determinants from their surroundings via food and contaminated bedding and faeces (Patel et al. 1999). Resistance to antibiotics seen in staphylococci of animal origin shows both similarities and differences to that in human strains. On one hand, use of specific antibiotic compounds in both humans and animals is followed by an increase of the prevalence of resistant strains to that antibiotic. On the other hand, the most common resistance seen in cat and dog isolates is to the penicillins, tetracyclines and erythromycin (Noble 1996; Prescott et al. 2002) whereas there is often much more extensive resistance seen in many human isolates (Jones et al. 2004). The pattern of antibiotic resistance observed in cats and dogs correlate with the amount and frequency of use of certain antibiotics. Studies conducted in late 1950s when antibiotics had just been introduced into clinical use in cats shows that most of the Staph. aureus isolated from the nostrils were susceptible to penicillin (Mann 1959). Various studies in recent years have shown that staphylococci isolated from cats have become resistant to at least one class of antibiotics (Love et al. 1981). Medleau and Blue (1988) observed that Staph. aureus, Staph. intermedius and Staphylococcus epidermidis isolated from cats were frequently resistant to penicillin G, ampicillin and tetracyclines. Studies conducted in Brazil found that isolates from healthy cats were frequently resistant to penicillin G, oxacillin, tetracyclines and enrofloxacin and that coagulase-positive staphylococci from cats were much more resistant when compared to coagulase-negative species (Lilenbaum et al. 1998,1999). This is probably due to the fact that, the major pathogenic staphylococci Staph. aureus and Staph. intermedius are not indigenous to cats and rarely cause disease in them (Igimi et al. 1994). An increase in resistance in coagulase-negative staphylococci to cotrimoxazole, lincomycin, enrofloxacin or oxytetracycline has been reported in England (Patel et al. 1999). It is apparent therefore that it is not only coagulase-positive species from cats that have developed resistance mechanisms to various antibiotics but coagulase-negative species which constitute the normal bacteria flora in cats can also acquire resistance to at least one antibiotic. In contrast, other studies have found that staphylococci from both healthy and diseased cats are susceptible to gentamicin, clavulanic acid-amoxycillin, chloramphenicol, cephalexin and bacitracin (Medleau and Blue 1988; Lilenbaum et al. 1998,1999; Patel et al. 1999). Studies of antimicrobial sensitivity of dog isolates of staphylococci were first reported in the 1960s (Shimizu and Shibata 1967). Rohrich et al. (1983) reported Staph. aureus and Staph. intermedius isolated from urinary tract infections in dogs in the US were highly susceptible to ampicillin, chloramphenicol, trimethoprim–sulfamethoxazole, nitrofurantoin, cephalexin, kanamycin and gentamicin. Moderate resistance was observed for nalidixic acid and oxytetracycline. Further studies by Cox et al. (1984) and Medleau et al. (1986) in the US on dogs with clinical infections including urinary tract infection and dogs suffering from pyoderma respectively have shown that Staph. intermedius was more resistant to ampicillin, penicillin and tetracycline. Several other studies in recent years on different infections in dogs have shown that resistance in Staph. intermedius is most common to ampicillin, penicillin and tetracycline (Greene and Lammler 1993; Pedersen and Wegener 1995; Pellerin et al. 1998) in agreement with earlier studies. Hoekstra and Paulton (2002) in a Canadian study observed that resistance to antibiotics in dog isolates is dependent on the species, site of isolation, sex and age of the animal. That is, Staph. aureus were significantly more resistant to cloxacillin and erythromycin compared with Staph. intermedius and that ear isolates, irrespective of species were more resistant to cephalothin compared with isolates from other body sites. Data collected over a 15-year period on Staph. aureus and Staph. intermedius of canine origin in another Canadian study depicts a picture of increased resistance to some antimicrobials but decreased resistance to others, reflecting the patterns of use of specific antibiotics in veterinary hospitals (Prescott et al. 2002). Penicillin and ampicillin resistance was observed in this study but there was a slight decrease in resistance to trimethoprim–sulfonamides. Erythromycin and clindamycin resistance however remained constant as a result of on-going use of these antibiotics and there was an increase in resistance to cephalothin, enrofloxacin and gentamicin. Antibiotic susceptibility studies in isolates from dogs have largely concentrated on Staph. aureus and Staph. intermedius with very little investigation of coagulase-negative species. Recently a study of canine ear isolates from Japan found resistance to a range of antibiotics in a small number of coagulase-negative isolates (Yamashita et al. 2005). Resistance reported included penicillin, ampicillin, fluoroquinolones, kanamycin and erythromycin. More studies are therefore needed on coagulase-negative species from dogs, which form the bulk of resident staphylococci on dogs to assess the potential to transfer of resistance genes to the coagulase-positive species. Since the commercial introduction of antibiotics into clinical use staphylococci have shown rapid acquisition of resistance to almost all the major classes of antibiotics, particularly in those strains associated with nosocomial infections in humans. Very little is known about the development and spread of antimicrobial resistance in staphylococci in cats and dogs. However, plasmids are likely to play a very important role in the spread of antimicrobial resistance in these organisms. Plasmids can act directly as carriers of resistance genes or as vectors for transposon-borne resistance genes. Horizontal gene transfer has been reported to occur between Staph. aureus and Staph. intermedius and Staph. aureus and coagulase-negative staphylococci (Schwarz and Noble 1999). Staphylococci share an ecological habitat with a wide range of Gram-positive and negative species on the skin, mucosal surfaces and respiratory tract of mammals and therefore are exposed to a wide gene pool. Resistance genes are easily acquired in such a polymicrobial environment. Their habitat on mammals makes staphylococci very amenable to spread from one animal to another and in some situations to humans by cat and dog bites (Talan et al. 1989). Staphylococci are largely species specific and most of the times strains from one species do not cause infections in another species and there are few reports in the literature of spread of staphylococci between species. However, human Staph. aureus and possibly Staph. epidermidis strains can cause infection in other animals such as cattle and cats (Hummel and Meene 1979; Cox et al. 1985). Mechanisms of resistance of the various classes of antibiotics used in cats and dogs therapy are discussed below. 3.2.1 Penicillins. Penicillins are one of the earliest classes of antimicrobial agents to be used in human medicine and also used to treat large and small animals for a variety of disease conditions (Harvey and Hunter 1999). Penicillin is use to treat pyoderma in dogs and cats. Intrinsic resistant to penicillins caused by the production of β-lactamases is very wide spread among canine staphylococci (Medleau et al. 1986; Kruse et al. 1996). In human medicine, there is increasing prevalence of methicillin or oxacillin-resistant staphylococci especially in Staph. aureus and of late, there have been reported cases of isolation of methicillin-resistant staphylococci (MRS) in cats and dogs (Lilenbaum et al. 1998,1999; Gortel et al. 1999; Pak et al. 1999; Tomlin et al. 1999; van Duijkeren et al. 2003; Kania et al. 2004). The isolation rate from animals is very low (Gortel et al. 1999) when compared to the isolation rate from humans, but this methicillin-resistant Staph. aureus and Staph. intermedius strains have the potential to cause zoonotic infections in humans (Tanner et al. 2000; Manian 2003). Coagulase-negative MRS such as Staph. epidermidis, Staphylococcus hominis, Staphylococcus haemolyticus, Staphylococcus xylosus, Staphylococcus felis and Staphylococcus simulans have also been isolated from cats and dogs (Lilenbaum et al. 1998; Gortel et al. 1999) and there are recent reports of detection of the mecA gene in Staph. schleiferi and Staphylococcus warneri isolated from the ear canals and skin pyodermas of dogs (Kania et al. 2004; Yamashita et al. 2005). Methicillin resistance is related to the production of a modified penicillin-binding protein, referred to as PBP2A or PBP2 (Georgopapadakou et al. 1982; Hartman and Tomasz 1984). PBP2A is a low-affinity binding protein encoded by mecA gene. Resistance is associated with the acquisition of a large DNA element that ranges from 20 to more than 100 kb termed the staphylococcal cassette chromosome mec (SSCmec) (Katayama et al. 2000), which is integrated into the chromosome of Staph. aureus. In human medicine, MRSA infections are very difficult to treat but the clinical significance in cats and dogs has not been investigated. 3.2.2 Tetracyclines. Tetracyclines have been used widely for therapy and prevention of bacterial infections in humans, animals and plants (Roberts 1996). Four different tetracycline resistance (tet) genes assigned to classes K, L, M and O have been detected in staphylococci of animal origin (Schwarz et al. 1998b; Kim et al. 2005). These genes encode resistance mechanisms such as active efflux and ribosome protection (Roberts 1996). Tetracycline influx proteins K and L consist of 14 transmembrane regions (Paulsen et al. 1996; Roberts 1996) and the corresponding genes, tetK and tetL, are most often plasmid borne (Schwarz and Noble 1999). tetM and tetO that code for ribosome protective proteins have been identified in staphylococci and they appear to be inducible by tetracycline. The tetM gene is part of conjugative transposons and exhibits a broad host range (Roberts 1996; Taylor and Chau 1996). 3.2.3 Macrolides. Macrolides are widely used in veterinary medicine for the treatment of infections caused by Staph. intermedius resistant to penicillins (Prescott et al. 2000) and resistance to spiramycin in Staph. intermedius has been reported (Pedersen and Wegener 1995; Pellerin et al. 1998). Staphylococcal resistance to macrolides is mainly due to erythromycin-resistance methylases, which cause target-site modification. Active efflux and enzymatic inactivation has also been reported (Schwarz and Noble 1999). Target modification is the most common mechanism and it involves the demethylation of adenine residues in the 23S rRNA (Werckenthin et al. 2001). Four rRNA methylase (erm) genes namely, erm(A), erm(B), erm(C) and erm(F) have been identified in staphylococci of animal origin (Schwarz and Blobel 1990; Schwarz et al. 1990,1998a; Eady et al. 1993; Lodder et al. 1996,1997; Werckenthin et al. 1996,1999; Chung et al. 1999; Jensen et al. 1999; Werckenthin and Schwarz 2000). The distribution of these genes among staphylococci of animal origin is highly specific, with ermB being the most dominate genes in canine Staph. intermedius isolates (Eady et al. 1993; Boerlin et al. 2001). 3.2.4 Mupirocin. Mupirocin shows activity mainly against Gram-positive bacteria such as staphylococci and streptococci. It is occasionally used in veterinary medicine to treat canine pyoderma caused by multi-resistant Staph. intermedius (Werckenthin et al. 2001). It acts by competitively inhibiting isoleucyl tRNA synthase, thereby preventing incorporation of the amino acid isoleucine into growing polypeptide chains during polypeptide synthesis (Hughes and Mellows 1978a,b,1980) and finally results in breakdown of protein biosynthesis. Mupirocin resistance could be high or moderate depending on whether the resistance gene is plasmid or chromosomally located. Resistant staphylococci harbour plasmids that carry the mupA gene (Needham et al. 1994). 3.2.5 Fluoroquinolones. Fluoroquinolones are a group of antibiotics with a wide spectrum of activity amongst Gram-positive and negative bacteria where they act by inhibiting the DNA gyrase, an enzyme responsible for packaging DNA within the cell (Lloyd et al. 1999). Enrofloxacin and marbofloxacin have been used extensively in the treatment of pyoderma caused by Staph. intermedius in dogs (Paradis et al. 1990; Ihrke 1996; Koch and Peters 1996; Ihrke et al. 1999). Resistance to fluoroquinolones may be due to the result of stepwise mutations in DNA gyrase. Although fluoroquinolone resistance has been well studied in human medicine there has been little investigation in animal isolates especially those from companion animals. Lloyd et al. (1999) reported a prevalence level of 0.9% fluoroquinolone resistance amongst 858 Staph. intermedius isolates from dogs examined between 1996 and 1998. A much higher rate (8–12%) in Staph. intermedius isolated from dogs in Sweden has been reported (SVARM 2002). 3.2.6 Sulfonamides and trimethoprim. These have a broad spectrum of activity and are very effective in treating pyoderma. Resistance to sulfonamide is believed to emanate from the overproduction of p-amino benzoic acid probably due to chromosomal DNA mutation (Werckenthin et al. 2001). Trimethoprim resistance is due to dihydrofolate reductases that have a low affinity for trimethoprim. The mechanisms of resistance of sulfonamides and trimethoprim have not been specifically investigated in cats and dogs but in humans, genes encoding for dihydrofolate reductase (dfr) A and B have been identified (Rouch et al. 1987). 3.2.7 Chloramphenicol. Chloramphenicol is occasionally used in dogs and cats. Resistance to chloramphenicol is thought to be due to enzymatic inactivation (Schwarz and Noble 1999) by plasmid-borne chloramphenicol acetyltransferases encoded by cat genes. Expression of cat genes found in staphylococci is inducible by chloramphenicol via translational attenuation (Lovett 1990). Schwarz et al. (1995) investigated chloramphenicol resistance in seven canine Staph. intermedius. Four of the isolates had cat genes that were located on a plasmid and the remaining three isolates had cat genes that were located in the chromosomal DNA. 3.2.8 Aminoglycosides. Aminoglycosides have wide veterinary applications and resistance to streptomycin, neomycin and kanamycin is a common phenomenon in animal pathogens (Prescott et al. 2000). A large variety of genes encoding for aminoglycosides resistance by acetyltransferases, nucleotidyltransferases and phosphotransferases have been described in staphylococci (Shaw et al. 1993). Aminoglycosides resistance genes aaDE, sat4 and aphA-3 have been identified in canine Staph. intermedius (Boerlin et al. 2001). These genes mediate resistance to streptomycin, streptothricin and neomycin. The first report of the isolation of MRSA from animals appeared in 1975 when it was reported that MRSA had been isolated from the milk of mastitic cows (Devriese and Hommez 1975). At that time the MRSA isolates were suspected of being transferred from the dairymen to the cows on the basis of phenotypic characteristics and because at that time occurrence of MRSA in animals was considered a rare event. Recent studies have reported the isolation of MRSA from several species of animals (Hartman et al. 1997; Shimizu et al. 1997; van Duijkeren et al. 2004a) and methicillin-resistant coagulase-negative staphylococci have even been isolated from chickens and horses (Kawano et al. 1996; Yasuda et al. 2000). Although MRSA and methicillin-resistant coagulase-negative staphylococci are not clinically important in cats and dogs, a few reports in the past have suggested the transfer of Staph. intermedius from dogs to humans (Harvey et al. 1994; Tanner et al. 2000) and there is somewhat anecdotal evidence that MRSA has been transferred indirectly from a dog to a patient in an intensive care unit (Cefai et al. 1994) and a patient and his wife in a household setting (Manian 2003). Studies based on pulse-field gel electrophoresis and SCCmec typing of Staph. aureus strains isolated from a dog and its owner show possible transmission of MRSA between a human and a dog (van Duijkeren et al. 2004b). On circumstantial grounds a cat has been implicated in the passive transfer of MRSA among hospital patients in a ward (Scott et al. 1988). Several reports in the past have indicated that antimicrobial resistant staphylococci isolated from cats were acquired from their owners and in those studies Staph. aureus were the predominant species (Hearst 1967; Krogh and Kristensen 1976; Devriese et al. 1984). The determination of epidemiological relationships of staphylococci isolated from cats and dogs is of particular importance for the differentiation between clonal spread and the horizontal spread of resistance genes. Typing methods used in studying staphylococci of cats and dogs origin can be grouped into broad phenotypic and methods are based on of a gene for differentiation and they such as antimicrobial susceptibility typing and et al. methods on the other hand, are those based on the of an and they and gel electrophoresis et al. of these methods in of their to canine and staphylococci Antibiotic susceptibility Antibiotic susceptibility patterns have been used extensively and to be used to staphylococci of canine and origin because of their low of for and of However, it can be a time and when large of isolates the introduction of high such as and antibiotic susceptibility with large of is more and 1994; et al. 2003). The to the use of antibiotic susceptibility patterns is their because antimicrobial resistance is constant from used of antimicrobial agents and 1996) and it is often associated with such as transposons and plasmid 1994). typing of Staph. aureus of human origin was by the about years et al. and has been used to staphylococci of human and animal of are used for typing isolates from animal species. Various are of typing of canine isolates (Greene and Lammler 1993). The human and are of typing than of canine staphylococci typing has been to possible transmission of staphylococci from cats and dogs to human and the results indicated that the dog strains were with human but of the cat strains had similar to some human (Mann et al. The most recent report of typing of canine staphylococci to be the by et al. isolated in this study appeared to be highly specific for Staph. intermedius but patterns were observed it was difficult to between isolates from healthy and animals. typing may be a in related strains of Staph. intermedius and Staph. aureus of canine and The of typing it isolates on the basis of a phenotypic that has it not all isolates and it of a large number of and which its use to small number of et al. In recent from of chromosomal DNA to the have been used for epidemiological studies of canine gene and 1986; et al. is a based on the detection of differences in the within or the and 23S genes. This has that is epidemiological studies et al. 1996) and the identification of species et al. 2000). Pedersen and Wegener (1995) observed differences in patterns between isolates from otitis externa, pyoderma cases and healthy dogs but and Schwarz (1995) not any differences between Staph. intermedius from canine pyoderma or from healthy carriers the fact that both studies used the This has found little recent in canine Staph. intermedius and there are reported studies of it is difficult to on its in epidemiological and identification studies but in human medicine, it is frequently used because of its et al. 1993). gel electrophoresis involves the of a bacteria with a enzyme that has a few and may from to kb et al. It has been extensively to different strains of Staph. aureus of human origin including methicillin-resistant Staph. aureus and 1993; et al. 1995; Manian 2003). Shimizu et al. reported a typing of canine strains of Staph. intermedius by applications of in canine staphylococci typing of MRS et al. 1999; Yamashita et al. 2005). The of is very high and has been shown to be to and et al. 1994; et al. from are more and very has been as a for MRSA typing et al. The of the to results with the of the and the of the is a that the of an 1993). et al. (1997) this to Staph. intermedius of canine and human concluded that, man and dogs carry the strains of Staph. intermedius and that dogs probably act as a The of as an epidemiological typing has been in a wide variety of pathogenic bacteria et al. et al. et al. In all these as a to typing methods such as and plasmid The and low could that may be a for the epidemiological typing of and canine However, it to and the enzyme electrophoresis The first reported of of to Staph. intermedius of canine origin from et al. The of Staph. intermedius from normal skin and variety of disease conditions in dogs was The observed between isolates of Staph. intermedius from healthy and diseased dogs, compared to results and Schwarz has been to many bacterial species including Staph. aureus et al. but the to a large on the number of used et al. 1994). This is a of of specific of DNA. This has the to of of a particular DNA with high within have many applications such as detection of resistance genes and for epidemiological studies. In the study of has been used to the mecA gene in Staph. aureus, Staph. Staph. epidermidis, Staph. hominis, Staph. and Staph. xylosus, Staph. Staph. warneri of canine origin (Gortel et al. 1999; Pak et al. Kania et al. 2004; Yamashita et al. 2005). Typing can be into or DNA and 1996). is the most frequently used and it has had some in the zoonotic transmission of canine Staph. intermedius (Tanner et al. 2000), identification of Staph. schleiferi (Yamashita et al. and studies et al. In human medicine, typing with methods has been for caused by a wide range of bacterial pathogens such as and and 1998; et al. 2000; et al. 2000; et al. 2000; et al. 2000). However, there has been little of typing to staphylococci of canine and In this review have staphylococcal susceptibility and resistance to various classes of antibiotics used for cat and dog mechanisms of resistance and typing commonly used in differentiation of and canine Antibiotic resistance in staphylococci is not well studied or staphylococci have received some attention but the used in epidemiological studies have not been to between disease staphylococci and nonpathogenic Methicillin resistant staphylococci especially MRSA a public health but there have only been studies of methicillin resistance in and canine of the reported cases of methicillin resistance in or canine staphylococci on antibiotic susceptibility patterns which can be influenced by conditions such as and in the and of the basis of resistance. there are of human Staph. aureus strains resistant to methicillin in which the mecA gene but which have been shown to β-lactamases or to carry of the normal penicillin-binding proteins and 1986; Tomasz et al. et al. 2002). At this stage it is not these mechanisms also play a part in methicillin resistance in animal strains. The rapid emergence and spread of resistant staphylococci in cats and dogs is a Resistant staphylococci in cats and dogs are similar to human staphylococci that is, highly resistant to penicillin, ampicillin and tetracycline. typing tools such as gel typing and the introduced DNA be to antibiotic resistance in and canine studies have investigated the of resistant staphylococci of dogs and there are reports on cats. studies are to treatment of animals and also to any role cats and dogs play in the of antimicrobial resistance in human The that dogs and cats could as a for MRSA infections in human may on to their However, it is important to that Staph. aureus is rarely from cats and very few cases of methicillin-resistant Staph. intermedius have been reported it may be that are at of MRSA from their owners than the other

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