Definition of Asymptomatic Bacteriuria and Infectious Diseases Society of America Recommendations

ASB is defined as the presence of bacteria in a noncontaminated urine specimen obtained from a patient without signs and symptoms of UTI. In asymptomatic women, the diagnosis of ASB requires the isolation of the same organism in 2 consecutive voided urine specimens isolated in quantitative count greater than or equal to 100,000 colony-forming units (CFUs). In asymptomatic men, a single voided urine specimen with 1 bacterial species isolated in quantitative count greater than or equal to 100,000 CFUs/mL or a single catheterized specimen with 1 bacterial species isolated in quantitative count greater than or equal to 100 CFUs/mL in asymptomatic male or female patients constitutes the diagnosis of ASB ( Box 1 ). The significance of ASB and the effects of antimicrobial treatment on this condition are well established in some populations but remain unproved or uncertain in others. In 2005, the IDSA published clear, evidence-based guidelines on the diagnosis and treatment of ASB in adults. The only populations the IDSA recommended for screening and treatment included pregnant patients to reduce the incidence of pyelonephritis and premature delivery and patients undergoing invasive genitourinary surgery to reduce the incidence of bacteremia and sepsis. The IDSA strongly recommended against screening for ASB in premenopausal nonpregnant women, women with diabetes mellitus, hospitalized patients without UTI symptoms, ambulatory elderly adults, elderly institutionalized residents in long-term care facilities, patients with spinal cord injuries, or individuals with indwelling urethral catheters. Despite these available clear guidelines from the IDSA, clinicians continue to misdiagnose and inappropriately manage ASB. This article reviews the following:

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  A review of the epidemiology and risk factors for ASB

  
  
• •
  

  A review of the literature encompassing the management of ASB in patients with diabetes mellitus

  
  
• •
  

  The basic science of ASB

  
  
• •
  

  A discussion of translational barriers to the application of the IDSA recommendations and approaches to reducing these barriers

Definition of Asymptomatic Bacteriuria and Infectious Diseases Society of America Recommendations

ASB is defined as the presence of bacteria in a noncontaminated urine specimen obtained from a patient without signs and symptoms of UTI. In asymptomatic women, the diagnosis of ASB requires the isolation of the same organism in 2 consecutive voided urine specimens isolated in quantitative count greater than or equal to 100,000 colony-forming units (CFUs). In asymptomatic men, a single voided urine specimen with 1 bacterial species isolated in quantitative count greater than or equal to 100,000 CFUs/mL or a single catheterized specimen with 1 bacterial species isolated in quantitative count greater than or equal to 100 CFUs/mL in asymptomatic male or female patients constitutes the diagnosis of ASB ( Box 1 ). The significance of ASB and the effects of antimicrobial treatment on this condition are well established in some populations but remain unproved or uncertain in others. In 2005, the IDSA published clear, evidence-based guidelines on the diagnosis and treatment of ASB in adults. The only populations the IDSA recommended for screening and treatment included pregnant patients to reduce the incidence of pyelonephritis and premature delivery and patients undergoing invasive genitourinary surgery to reduce the incidence of bacteremia and sepsis. The IDSA strongly recommended against screening for ASB in premenopausal nonpregnant women, women with diabetes mellitus, hospitalized patients without UTI symptoms, ambulatory elderly adults, elderly institutionalized residents in long-term care facilities, patients with spinal cord injuries, or individuals with indwelling urethral catheters. Despite these available clear guidelines from the IDSA, clinicians continue to misdiagnose and inappropriately manage ASB. This article reviews the following:

• •
  

  A review of the epidemiology and risk factors for ASB

  
  
• •
  

  A review of the literature encompassing the management of ASB in patients with diabetes mellitus

  
  
• •
  

  The basic science of ASB

  
  
• •
  

  A discussion of translational barriers to the application of the IDSA recommendations and approaches to reducing these barriers

Fimbriae

Perhaps the most studied factor in differentiating uropathogenic bacteria from ASB is the presence of specific fimbriae on the bacterial surface. Fimbriae are complex structures that mediate adherence to host epithelium through protein receptors. Uropathogenic E coli has been found to express a markedly different fimbriae profile than ASB, including type 1, P, F1C, Dr, Auf, S, and M fimbriae. Of all of these, P fimbriae expression has shown the strongest correlation to acute disease severity, found on the surface of more than 90% of E coli -causing pyelonephritis but on less than 20% of ASB strains.

P fimbriae bind to Galα1-4Galβ epitopes of glycolipids on the urothelium, leading to the activation of the innate immune system promoting the release of cytokines and recruitment of neutrophils. The expression of type 1 fimbriae, which bind to the mannosylated epitopes of bladder urolotheial integrin molecules, is also intimately involved in bacterial adherence and immune activation. Although type 1 fimbriae are expressed by more than 90% of ASB strains, a cluster deletion has been identified in its coding gene, fimH , which may negate its ability to facilitate adherence and immune activation. A recent study confirmed 26% of fimH -positive ASB strains were unable to express functional type 1 fimbriae. This supports the hypothesis that many ASB strains may carry virulence genes but fail to express the associated phenotype for functional virulence. Recently, the detection of 2 previously uncharacterized fimbriae, Yad and Ygi, were found more than twice as prevalent in uropathogenic E coli than ASB strains and associated with virulence-related activities including motility, biofilm formation, and cell adherence. Although the expression of other fimbriae, such as F1C and Dr, have also been studied, their contribution to virulence is much less clear but likely contributable to the overall pathogenetic profile.

Lipopolysaccharides

LPS is an endotoxin of gram-negative bacteria, containing the lipid type A anchored in the outer membrane, which activates Toll-like receptor (TLR) 4 on the urothelium and induces immune system activation. This mechanism has proved responsible for significant fever and acute systemic illness associated with septicemia and is undoubtedly a contributor to the virulence of uropathogenic bacteria. Capsular polysaccharides surround bacteria and protect the organism from host defenses in blood and tissues. Mutant bacteria with genetically altered capsular polysaccharide expression have shown significantly reduced virulence in experimental UTI animal models. LPS from ASB E coli has biotherapeutic activity.

Toxins

Two major toxins produced by uropathogenic E coli are hemolysin and cytotoxic necrotizing factor 1 (CNF1). Hemolysin is a secreted protein found more commonly in uropathogenic strains than fecal strains, which inserts into host cell membranes leading to epithelial damage and hemorrhage. Hemolysin activity has been shown to correlate to the severity of clinical infection, found in only 14% of ASB strains and in 47% and 31% of E coli -causing cystitis and pyelonephritis, respectively. Although the actual expression of the hly A gene encoding for hemolysin was found in 58% of ASB, only 14% were functionally hemolytic compared with 100% functional hemolysis when found in E coli causing pyelonephritis. Thus, genetic mutation leading to dysfunction of the toxin itself may significantly contribute to the benign nature of ASB strains. CNF1 is a cytokine released by uropathogenic E coli that leads to activation of the Rho family of GTP-binding proteins on the host urothelium and has been implicated in inducing bladder cell apoptosis. CNF1-positive E coli strains have been shown to cause more inflammation than strains lacking production of this toxin.

Host Factors

Fimbriae-mediated adhesion to the host urothelium activates TLR4 signaling, which triggers cytokine production and neutrophil recruitment for bacterial destruction and also determines the severity of signs and symptoms related to acute infection. The loss of functional TLR4 signaling and activation promotes long-term bacterial colonization and can lead to ASB. Mutations in the TLR4 promotor, which significantly reduce the efficiency of TLR4 expression, have been shown in children with ASB compared with age-matched controls and those with acute pyelonephritis. Thus, these mutations may be protective against recurrent acute UTIs and disease severity.

Growth Factors

The ASB strain E coli 83,972, initially isolated from a young Swedish girl who carried it asymptomatically for 3 years, is the most widely studied strain of nonvirulent E coli . Despite the loss of functional fimbriae and inability to activate host innate immune response, this nonvirulent strain grows well in human urine and can outcompete uropathogenic E coli strains. This property has led to its instillation as a prophylactic treatment method in patients with recurrent UTIs, refractory to traditional medical therapy. The survival fitness of E coli 83,972 compared with uropathogenic bacteria was initially assumed related to unique biosynthetic pathways, enabling the nonvirulent strain to more efficiently utilize metabolic compounds, such as iron and amino acids for more rapid growth. Genetic sequencing studies, however, have shown surprisingly little divergence of ASB strains from uropathogenic E coli in gene expression concerning metabolic pathways. It is, therefore, speculated that the superior growth of E coli 83,972 may be due to overall energy conservation, because the production of virulent-factors, such as fimbriae, are costly to produce, but the exact fitness advantage mechanisms remain largely unknown.

Use as Biotherapeutics

The ability of ASB strains to outcompete uropathogenic E coli has led to the clinical study of its use a live biotherapeutic in patients with recurrent, symptomatic UTIs. Sundén and colleagues in 2010 randomized 20 patients with incomplete bladder emptying and history of recurrent UTIs to intravesical inoculation with E coli 83,972 or saline. Patients who showed elimination of the bacterial strain by sterile urine culture underwent repeat inoculations. They showed a significantly longer time to first infection (11.3 vs 5.7 months) and fewer total numbers of symptomatic infections (13 vs 35 episodes) in patients who received ASB inoculation versus saline controls. Thus, a model for deliberate ASB as a protective mechanism for patients at high risk of recurrent UTI was established. Darouiche and colleagues in 2011 performed a similar study on spinal cord injury patients with a history of recurrent UTIs, inoculating 17 patients with the ASB strain E coli HU2117 and comparing results to 10 patients receiving saline placebo. They showed a significant decrease in the average number of UTIs over 1-year follow-up (0.50 episodes in the treatment group vs 1.68 in the placebo group). In a murine model, Rudick and colleagues in 2014 compared the use of ASB inoculation with E coli 83,972 to ciprofloxacin to treat acute UTI. Although both treatments showed equal clearance of uropathogenic bacteria, the ASB strain provided superior reduction in pain than ciprofloxacin, comparable to that of intravesical lidocaine. In addition to its analgesic benefit, ASB inoculation was also proved effective at clearance of a wide variety of bacterial pathogens, including Proteus mirabilis, Enterococcus faecalis , and Klebsiella pneumonia . Although promising, the complexity of administration and monitoring as well as the associated expense of ASB strain inoculation may continue to limit its clinical application.