Antimicrobial resistance: are we there yet? (Proceedings)


Antimicrobial resistance: are we there yet? (Proceedings)

Nov 01, 2010

The ability of organisms to develop resistance to an antimicrobial varies with the species and strain. Many organisms remain predictably susceptible to selected drugs (eg, Brucella, Chlamydia); whereas others are becoming problematic (Pasteurella multocida). Others have proven be a therapeutic challenge because of resistance that rapidly impairs efficacy of even new antimicrobials (E coli, Klebsiella pneumoniae, Salmonella, Staphyloccoccus aureus, Streptococcus pneumonia). In general, these organisms have developed multidrug resistance (MDR). Emergence of extended spectrum extended spectrum beta-lactamases (ESBL) is an example of the relentless adaptive nature of microbes toward designer drugs intended to preclude the advent of resistance. The ESBLs are encoded by large plasmids that can confer the information between strains as well as different species of organisms. The gene mutation confers resistance to newer cephalosporins includeing cefotaxime, ceftazidime and ceftriaxone, as well as cefpodoxime, or 4th generation including cefepime (no longer marketed in the USA); cefipime has been cited as possibly being effective against ESBL.The impact on clavulanic acid and sulbactam is not clear, although their use in place of cephalosporins appears to reduce the emergence of ESBL and may reduce the emergence of other resistant pathogens such as Clostridium difficile and vancomycin-resistant enterococci.. The ESBL are most commonly found in Klebsiella spp, E. coli or Proteus mirabilis (3.1-9.5%), but they also have been detected in other members of the Enterobacteriaceae and in Pseudomonas aeruginosa. Nosocomial organisms are another example of a source of resistant microbes. They are opportunists, probably most commonly from the environment, that cause infections as a result of medical treatment, usually in a hospital or clinic setting. Nosocomial infections are formally defined as infections arising after 48 hr of hospital admission. Because bacterial colonization by nosocomial isolates hospital occurs in the upper respiratory tract, gastrointestinal tract, urogenital tract, and skin of many patients within a few days of hospitalization, nosocomial infections not surprisingly most commonly occur in the respiratory or urinary tract or skin. Infection frequently is associated with invasive procedures. Isolates causing nosocomial infections generally are In some human intensive care units, selected isolates are characterized by resistance prevalence of 86%; resistance results in increased morbidity, mortality, and increased costs. Because nosocomial organisms are characterized by complex resistant patterns, their effective therapy often requires more expensive and potentially toxic drugs and selection clearly should be based on C&S . Nosocomial infections in veterinary critical care patients has been reviewed. The organisms associated with noscomial infections in dogs and cats have been many and diverse, varying with the report. Included (but not exclusively) are Serratia spp, Staphylococcus spp, Streptococcus spp, Klebsiella spp, Enterococcus spp, and E. coli. As in humans, predisposing factors have included catheters and previous antimicrobial therapy.

Methicillin resistance (MRSA; S. aureus; MRSP; S. intermedius [pseudintermedius] 38

Multidrug resistance is now considered the normal response to antibiotics for Gram positive cocci pneumococci, enterococcis and staphylococci. Methicillin resistance (MRSA; S. aureus; MRSP; S. intermedius [pseudintermedius]38 is indicated by the presence of the mecA gene, which encodes a mutation in PBP2a, thus reducing its affinity for the beta-lactam ring, rendering the organism resistant to all beta-lactams. The mecA gene is carried on the staphylococcal chromosomal cassette (SCC); currently 5 SCCmec have been described.39 Protectors such as clavulanic acid are ineffective.21 Detection of MRSA or MRSP on C&S generally is based on resistance to oxacillin, which is more stable than methicillin in disks used for testing. However, variability in testing methods can profoundly alter results; as such, cefoxitin might be a more appropriate indicator of multidrug resistance in these organisms.40 Alternative procedures, such as polymerase chain reaction, or latex agglutination have been used to detect the gene responsible for the formation of penicillin-binding protein 2a (mecA) of MRSA and other techniques such as pulse-field gel electrophoresis (PFGE) or multilocus sequence typing (MLST) that identify the specific strain of MRSA (eg. USA 100 or USA 300), It is likely that this area of diagnostics will be refined in the next decade. Antibiotics are associated with induction, selection, and propogation of MRSA. The wide use of cephalosporins, in particular, may have contributed significantly to the advent of MRSA. MRSA in human patients has evolved from a hospital-acquired (HA-MRSA; nosocomial), in which occurs most commonly in patients immunocompromised by disease, drugs, procedures and duration of hospitalization, to a community acquired infection (CA-MRSA), in which otherwise healthy persons are infected, usually in the skin or soft tissue. Crowded conditions, shared items and poor hygiene increase the risk of community acquired infection. Although it is community acquired MRSA strain USA300 that appears to be most commonly associated with increased colonization in dogs and cats, it is USA100, most commonly associated with hospital acquired-MRSA infections in humans, that most commonly is associated with infections in dogs and cats animals 302 According to the Center for Disease Control, the incidence of MRSA doubled in human medicine in the 7 year period between 1999 and 2006. The impact of MRSA in veterinary medicine is increasingly problematic, not only because of its impact on the patient, but the public health considerations. The mec gene has been detected in methicillin-resistant Staphylococcus aureus organisms infecting dogs40-42 and MRSA has been associated with infection in dogs.43 However, MRSA also has been found in up to 4% of healthy dogs, with identification complicated by the need for multiple sampling sites (nasal and rectal or perineal). Risk factors for the presence of MRSA in pets or working dogs (ie, detection or aid dogs), include contact with human hospitals (particularly if patients were licked or patients fed the dogs treats) and children.42 Infections have been isolated in family members and pets in the same household, but this is likely to reflect transmission from humans to the pet.40-42,44 It is likely that colonization is transient in animals. However, healthy pets have been demonstrated to be potential reservoirs for transmission of MRSA to healthy handlers and a potential health risk to immunocompromised patients (human and presumably other animals in the household). According to the AVMA, colonization by MRSA is suggested to be an occupational risk for veterinarians, although the frequency of infection associated with MRSA in veterinarians compared to other professions has not been documented. Methicillin resistant Staphyloccoccus intermedius (pseudointermedius) 45 has a prevalence of 0.58% to 2% in healthy dogs and up to 4% healthy cats42,46 with the mec gene present in each canine MRSP isolate in one study.47 Human colonization with MRSP is unusual.42 However, MRSP has been reported as a cause of infection in human patients 42 and transmission from pets with pyoderma has been confirmed.48,49 Although the true public health significance of MRSA and MRSP (or other MDR ognaisms) in pets is not clear, the fear of infection may be as important as true risk, necessitating proper hygiene and other proactive measures such that human or animal health (including unnecessary euthanasia) are not risked. The American Association of Veterinary Medicine offers a website that includes a discussion of MRSA zoonoses, including sources of guidelines that might decrease the risk presented to susceptible humans (; accessed January 01, 2010). Among the more important actions that can be taken is establishment of infection control policies and guidelines in each veterinary practice. In general, commen sense approaches should prevail (eg, minimizing intimate contact, personal and environmental hygiene, etc). This includes cleansing of hands of handlers, and the paws (or body?) of animals that might be exposed to MRS, including those visiting human health care facilities. The risk of colonization is increased 6 fold in aid animals (those providing assisted interventions for humans). It is the very immunocompromised patient that is at risk for MRS infection acquired from an animal. In such cases, the carrier or infected animal should be removed from the environment until successfully treated for methicillin-resistant Staphylococcus. For dogs with skin infections, cultures are indicated to detect MRS, particularly in animals for which infection does not resolved. Successful resolution of colonized or infected animals may require both topical (for skin infections) and systemic therapy may be indicated. Evidence of successful treatment might be based on skin swabs of the ear, nose and perianal region. Care must be taken to assure that the laboratory providing culture procedures is well-versed in the diagnosis of MRS, including speciation of coagulase positive organisms. The multidrug resistance associated with MRSA is now evolving toward other (non-beta lactam) antibiotics. This reflects in part, other resistance genes in the gene cassette carrying the mec gene.42 Drugs that are impacted include fluorinated quinolones and aminoglycosides. Although newer fluorinated quionlones (e.g., levfloxacin) appear to be more effective than older drugs in vito, particularly to Staphylococcus, it is not clear if this translates to better clinical efficacy.21 Glycopeptides such as vancomycin are the initial drugs used to treat MRSA in humans, although increasingly vancomycin resistant staph infections (VRSA) have emerged. Multidrug resistant Enterococcus also is an emerging issue; its emergence also appears to be correlated to use of cephalosporins. Enterococcus faecalis more so than Enterococcus faeclis is likely to develop resistance and speciating Enterococcus on susceptibility testing might be prudent. Resistance reflects a change in PB-V and the risk is increased when drugs effective against Enterococcus are used. Detection of MRSA on C&S generally is based on resistance to oxacillin, which is more stable in disks used for testing. Over the 30 to 40 years since the methicillin resistant classification was coined, the infections associated with the organisms have lead to increasing mortality and morbidity. Susceptibility to a number of alternative antimicrobials, including fluorinated quinolones, aminoglycosides, and glycopeptides (vancomycin) is now decreasing.