In 1894, Escherich cultured “bacillus coli” in the urine of children with urinary tract infections and described pyelitis as the disease of childhood. He gave his name to the bacteria, which caused 85% of acute urinary tract infections. Escherichia coli (E. coli), are facultative anaerobes from the bowel flora. They ascend via the short urethra. Women who have proven E. coli urinary tract infections can be shown to have colonization of the vaginal introitus with E. coli bacteria of the same serotype. A small percentage of community-acquired infections are from other Gram-negative bacteria: Klebsiella and Proteus. Staphylococcus saprophyticus is the most important of the Gram-positive pathogens. Fungi and viruses are rare causes of acute cystitis in the community, but these play a more important part in hospital-acquired infections, or in people who are immunosuppressed. Genital herpes may be a cause of frequency, dysuria, and even acute retention.

Bacteria can gain access to the bladder by three possible routes: ascending the very short female urethra, or by lymphatic or haematogenous spread. The overwhelming number of bacterial infections are due to local ascending infection. Infection is determined by the size of the inoculum, the host resistance or defence factors, and the virulence of the pathogen. For example, if the host defences are compromised, only a small inoculum of bacteria is required to produce an infection. In the normal woman with no abnormalities of anatomy or function, a large inoculum of virulent bacteria is required to produce a symptomatic urinary infection. Indeed, the frequent flushing of the bladder by urine is thought to defend a woman from frequent small inocula of bacteria that never proceed to actual infection. The urine itself inhibits bacteria due to its high osmolarity, high urea concentrations and low pH. Tamm – Horsfall proteins competitively inhibit the attachment of E. coli to the mucosal surface of the bladder and aggregate bacteria in the urine.

Much research has gone into the virulence factors that might change E. coli from a harmless commensal in the bowel flora to a virulent uropathogen. In order to facilitate the ascent of bacteria from vaginal introitus and the periurethral skin into the urethra and bladder, the E. coli needs to stick to the uroepithelial cells. There are various bacterial surface structures called adhesins and complimentary components, the host receptors, which allow binding to the epithelial surface. In normal women the bacteria have to be virulent in order to cause an infection, whereas if there is a gross underlying structural abnormality, the patient falls prey to a variety of normal bowel flora. The bacterial adhesins take the form of fimbriae; these are peptide subunits that can probe the epithelial surface for receptors. These adhesins act as virulence factors. At a cellular level expression of pili, or fimbriae, is much commoner in isolates from patients with cystitis. Type I fimbriae are present in all E. coli, and are believed to promote initial colonization. There is little difference between virulence of E. coli in women with recurrent or sporadic urinary tract infections, but it seems to be the receptor repertoire for organisms on host urogenital cells that influences susceptibility. Women with recurrent infection have longer durations of vaginal colonization with uropathogenic E. coli, and threefold more E. coli adhering to the vagina, and voided uroepithelial cells.

There are genetically determined differences in urogenital cell-receptor availability and binding characteristics, which may influence a woman’s susceptibility to recurrent urinary tract infections. Women with recurrent urinary tract infections are three to four times more likely to be non-secretors of ABH blood-group antigens, than controls. The secretor gene encodes one of many glycosyltransferases that determine the carbohydrate composition of cell-surface glycoproteins and glycosphingolipids. Some of these serve as binding sites for uropathogenic E. coli. In the vaginal epithelium of non-secretors, there are two extended-chain glycosphingolipids that bind uropathogenic E. coli more avidly than do other glycosphingolipids. Research is now looking at developing soluble carbohydrate inhibitors to prevent adhesion of pathogenic bacteria to the vaginal mucosa.

Certain features of the host response to bacterial attachment have also been examined. The uroepithelium produces interleukin 6 and 8 in response to a urinary tract infection. In women with acute cystitis the systemic immune response is very weak, and local antibody responses are short lived. Urogenital tissues contain antimicrobial peptides, but their role in urinary tract infections is unknown. Much greater understanding of the host immune response is needed before a vaccine is possible. However, a group are looking at a vaccine based on E. coli type I fimbrial components.

The normal microbial ecology of the vagina has also caused interest. Factors that disrupt the normal flora, promote the uropathogen predominance that promotes recurrent urinary tract infections. The most important factors are recent use of ОІ-lactam antimicrobials, the more alkaline postmenopausal state (before treatment with exogenous oestrogen), or spermicides for contraception.

Normal vaginal bacterial commensals, lactobacilli, interfere with E. coli adherence to uroepithelial cells and probably have a protective effect in normal women. Lactobacillus suppositories, designed to promote the normal state of vaginal flora, are being investigated. There is a thin mucopolysaccharide coating of the transitional epithelial cells of the bladder mucosa, which also inhibits E. coli fimbrial attachment. It has also been suggested that antibiotic prophylaxis may work at subtherapeutic doses because the antibiotics inhibit fimbrial production, thus reducing the virulence of E. coli, allowing the normal host defence mechanisms of phagocytosis and mechanical flushing to prevent the bacteria colonizing the bladder.

Trimethoprim

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