Antimicrobial therapy and urinary tract infections: part 1-the other bad E. coli (Proceedings)


Antimicrobial therapy and urinary tract infections: part 1-the other bad E. coli (Proceedings)

"It is unwise to underestimate an adversary that has had a three billion year evolutionary head start" (Sayers, 2004). The advent of antimicrobial resistance is increasingly limiting therapeutic options in human and veterinary medicine. The ability of organisms to develop resistance to an antimicrobial varies with the species and strain. Among the most adaptable organisms is E. coli. Discovered in 1885 by a the ediatrician Theodore Escherich, it was originally discovered in neonatal fecal samples. Dr. Erich recognized E. coli was acquired at birth and remained with us till death, with strains coming and going. It is the most thorourghly understood microbe, and is critically important as a research tool. Through E. coli, we have come to understand such diverse activities as intermediary metabolism, DNA replication and RNA transcription, protein synthesis and genetic recombination. Indeed, recombinant products would not be possible without E. coli. Escherichia coli, a member of the family Enterobacteriaceae, is a lactose fermenter, causing a distinct color on diagnostic agar. It is the predominant facultative anaerobe (in the normal intestine of both humans and many warm-blooded animals), playing a major role as normal microflora.1-2 However, it also is ubiquitous in the environment, as is recognized by its appearance as contaminants in food stuffs. It has or acquires genes that encode for flagella, making it mobile. Its presence in the environment is used as a sentinel of environmental contamination. Referred to as the "cockroach" of microbes because of its adaptability, E. coli rapidly divides, potentially doubling its population every 20 minutes. Further, it is highly mutagenic, with spontaneous mutations occuring in of 1 per 100 thousand to 1 per billion new progeny (assume 1 gm of feces contains 100 million E coli) thus assuring opportunity for spontaneous mutation even in the absence of stimuli, such as drugs. E coli occurs in many hosts, and is present in multiple tissues, thus also being associated with diseases: the gastrointestinal tract, brain (humans: meningioencephalitis) and the urinary tract are major sites of pathology. Diarrhea, UTI, and sepsis are example sequelae. However, it is not appropriate to consider E. coli only as a pathogen. Indeed, E. coli enjoys a bit of a "Dr. Jeckell, Mr. Hyde" designation. A common research tool, K12 is a "wild type" isolate that expresses neither virulence or resistance and often serves as a control. In contrast, the most notorious E coli is O157:H7 (defined by antigens and genetic sequences that define it as a distinct strain); this isolate has been associated with contaminated food and is a cause of a hemolytic-uremic syndrome. The pathogenicity of these E. coli reflect its ability to acquire virulence factors.

Virulence and resistance are characteristics of concern for the patient infected with this organism. Virulence refers to the ability of an organism to cause disease whereas resistance refers to the ability of the organism to avoid harm, although clinically we tend to use the term in reference to avoidance of harm caused by antimicrobials. Resistance and virulence are often perceived to emerge simultaneously. Recently, however, studies suggest that resistance may be associated with a reduced potential for invasiveness and a decrease in the presence or the expression of some virulence factors in E. coli. Virulence implies the ability of an organism to cause harm to a patient and should not be confused with resistance; indeed, the two may be mutually exclusive. Although enteric E.coli are generally nonpathogenic, the presence of virulence factors in some strains allows classification of E. coli into 6 groups capable of causing enteric disease: Extraintestinal E coli (ExPEC) is a more recently classified pathotype; UPEC (uropathogenic) are included in this category. Although much attention has focused on the impact of enteropathogenic E. coli (e.g., OH157:H7) in human medicine, other E. coli, particularly ExPEC, also are associated with morbidity and mortality. These include sepsis associated (SEPEC) and neonatal meningitis associated (NEMEC) E. coli. The ExPEC appear to easily colonize the gastrointestinal tract, potentially displacing commensals, and eventually emerging as infectious organisms in other body tissues, particularly in the urinary tract. These factors are of concern not only to the small animal clinician, but increasingly are contributing to a potential public health concern. UPEC are ExPEC that acquire virulence factors necessary for survival of the organism outside of the gastrointestinal tract. In humans, E. coli is associated with 90% of UTI in otherwise healthy persons. It is also responsible for approximately 50% of nosocomial UTI. Emerging statistics indicate the same is true in dogs. The pathophysiology of human and canine UTI associated with E. coli is quite similar. Isolates causing UTI are from the gastrointestinal tract. Ascending infection up the urethra to the bladder may be further complicated by infection in the ureter and kidney if the isolate contains P fimbrae or the K antigen. Infection may also occur in the prostate. Once in the bladder, several virulence factors facilitate survival in the bladder. Initial release of cytotoxic materials destroy uroepithelial cells, facilitating penetration, but also providing nutrients for the microbes. Virulence factors facilitate scavenging of iron, a necessity in the bladder. However, among the host defenses is its own scavenging of iron, preventing the microbe from accessing the mineral. However, as a testament to the adaptability of E. coli is its ability to generate another virulence factor that inhibits the hosts ability to scavenge iron. Critical to successful infection is the ability of E. coli to adhere to the uroepithelium, thus protecting the microbe from bulk urine flow, among the most important defenses of the bladder. Adhesins involve mannose receptors which are recognized by the E. coli ; however, isolates with the K antigen do not detect mannose receptors. Once the E. coli has adhered to the uroepithelium, the production of biofilm will protect it from damage by host cells and antimicrobials. Biofilm communities are complex and sophisticated. Biofilm will potentially protect microbes such that they become senescent, and thus less susceptible to antimicrobial therapy. Such cells may remain under the uroepithelial cells until they are exfoliated, only to become active again such that infection continues. The genes that code for virulence are located on pathogenicity islands; generally,such organisms do not carry genes for resistance.

Studies have demonstrated transfer of resistant E. coli between animals and humans, a fact which was documented as early as 1975. Canine E. coli strains have been demonstrated to be phylogenetically similar to pathogenic strains infecting humans. Over 15% of environmental canine fecal deposits contain E. coli strains related to virulent human strains. Evidence that pets and owners share E. coli is increasing as has been demonstrated in studies within family members, including pets. However, what is not clear is if zoonoses or reverse zoonoses predominated, although it is more likely that owners are infecting or sharing isolates than the opposite. Nontheless, public health concerns mandate that antimicrobials be used judiciously; further, when considering options for treating or preventing UTI, attention must be given not only to the antimicrobial history of the veterinary patient, but also the household members-be they 4 legged or 2 legged.

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