Urinary Tract Infections

Overview of UTI 7 million office visits yearly 1 million hospitalizations About 2/3rds of patients are women; 40% to 50% of women have UTI at some point during their lives Important complications of pregnancy, diabetes mellitus, polycystic disease, renal transplantation, conditions that impede urine flow (structural and neurologic)

Overview of UTI by age and sex

Terms Urinary tract infection Significant bacteriuria Asymptomatic bacteriuria Acute pyelonephritis Chronic pyelonephritis “Upper” versus “lower” UTI Urethral syndrome

Terms (2) UTI: the finding of microorganisms in bladder urine with or without clinical symptoms and with or without renal disease Significant bacteriuria: the finding of > 105 cfu/ml of urine (but lower counts can be significant)

Terms (3) Asymptomatic bacteriuria: Significant bacteriuria without clinical symptoms or other abnormal findings. Acute bacterial pyelonephritis: a clinical syndrome of fever, flank pain, and tenderness, often with constitutional symptoms, leukocyte casts in the urine, and bacteriuria; or histologic findings thereof

Terms (4) Chronic bacterial pyelonephritis: Long-standing infection associated with active bacterial growth in the kidney; or the residuum of lesions caused by such infection in the past Chronic interstitial nephritis: renal disease with histologic findings resembling chronic bacterial pyelonephritis but without evidence of infection

Terms (5) “Upper UTI”: infection above the level of the bladder “Lower UTI”: infection at or below the level of the bladder “Urethral syndrome”: clinical manifestations of lower UTI (dysuria, frequency, urgency) without significant bacteriuria

Terms (6) Pyuria: the presence of pus (WBC’s [leukocytes] in urine, which may or may not be caused by UTI. The preferred method for quantitation is enumeration in unspun urine using a counting chamber. The leukocyte esterase nitrite test has a sensitivity of between 70% and 90% for symptomatic UTI

Asymptomatic bacteriuria In patients with asymptomatic bacteriuria without infection, a colony count of > 105 cfu/ml defines infection Screening has little apparent value in adults except during pregnancy and prior to urologic surgery Up to 40% of elderly men and women have asymptomatic bacteriuria

Frequency of significant bacteriuria After one bladder catheterization: 2% Medical outpatients: 5% Pregnancy at term: 10% Hypertensive patients: 14% Diabetes mellitus: 20% Women with cystocoele: 23%

Frequency of significant bacteriuria (2) Congenital urologic disease: 57% Hydronephrosis; nephrolithiasis: 85% Indwelling catheter, open drainage > 48 hours: 98% (reference: Jackson et al, Arch Intern Med 1962; 110: 663)

Screening for significant bacteriuria Screening for asymptomatic bacteriuria in adults has little value except for two situations: pregnancy (because of the high risk of acute pyelonephritis with its accompanying risk of fetal complications) and prior to urologic surgery (because of the risk of postoperative sepsis).

Urinary tract bacteriology At room temperature, the doubling time of common aerobic bacteria is about 20 minutes Some contaminants in voided urine: Lactobacilli, Cornyebacterium species, Gardnerella, alpha-hemolytic streptococci, anaerobes Any bacterial growth is significant if the specimen is collected from a normally-sterile site (e.g., direct bladder puncture)

Urinary tract bacteriology (2) In pyelonephritis, the “>105 cfu/ml” rule breaks down; fewer colonies can be significant. Up to 20% of young women with acute uncomplicated pyelonephritis have between 103 and 104 cfu/ml. In catheterized patients in whom specimens are obtained directly from the catheter, between 102 and 104 cfu/ml should may be significant.

Urinary tract bacteriology (3) Patients with uncomplicated infection almost invariably have a single organism; this is not necessarily the case with complicated infections Unspun midstream urine: One bacterium/high-powered field (hpf) correlates with > 105/ml (thus, high positive predictive value)

Urinary tract bacteriology (4) Gram’s stain of spun urine: absence of visible bacteria makes > 105 cfu/ml highly unlikely (that is, high negative predictive value) 20% of patients with urinary tract infection do not have pyuria

Etiology of community-acquired UTI Aerobic gram-negative rods most often E. coli accounts for about 90% Staphylococcus saprophyticus has been increasingly appreciated in recent years (with seasonality, tending to occur in the summer) Rare: anaerobes; pyogenic cocci; viruses

Etiology of nosocomial UTI E. coli is the most common pathogen However, also common are other Enterobacteriacae (Proteus, Klebsiella, Enterobacter, Serratia, Providencia species) and Pseudomonadaceae (notably, Pseudomonas aeruginosa) Enterococci: often in obstructive uropathy Yeasts: Candida albicans, others

Urease-producing microorganisms Urease splits urea into ammonia, which has a direct toxic effect on the kidney; inactivates C4, and alkalinizes the urine with production of struvite crystals (MgNH4P04.6H20) crystals Proteus mirabilis most often; also Providencia, Morganella, S. saprophyticus, Klebsiella, Corynebacterium D2; mycoplasma Eradicate if at all possible

UTI in children Newborns: overall rate is about 1% (higher in males than in females) Preschool children: UTI is 10 to 20 times more common in girls School-aged children: about 1.2% of schoolgirls have bacteriuria on any given day

UTI in adults Women: bacteriuria increases with age and sexual activity Men: bacteriuria is rare before age 50 (and as a corollary, calls for more aggressive evaluation than in women). Subsequently, bacteriuria increases with onset of prostatism

Role of bacterial virulence in UTI Bacterial adherence to uroepithelial cells involves specific binding of bacterial surface receptors (adhesins) to complementary components on the epithelial cells (receptors). The ability of E. coli to adhere to uroepithelial cells is associated with the presence of pili or fimbriae.

The role of bacterial virulence (2) Specificity has been associated with the Gal-alpha-->4-Gal specific adhesion localized at the fimbrial polymer. However, virulence of E. coli strains does not seem to depend upon a single virulence factor. There may well be an additive effect among multiple virulence factors (including adhesins, hemolysin, capsular polysaccharide, aerobactin)

Host defenses: antibacterial properties of urine Osmolality (extremes of high or low osmolalities inhibit bacterial growth) High urea concentration High organic acid concentration pH

Host defenses: anti-adherence mechanisms Bacterial interference (naturally endogenous bacteria in the urethra, vagina, and periurethral region) Urinary oligosaccharides (have the potential to detach epithelial-bound E. coli Tamm-Horsfall protein (uromucoid): coating of E. coli by this protein might prevent attachment

Host defenses: miscellaneous Mucopolysaccharide lining of the bladder Urinary immunoglobulins Spontaneous exfoliation of uroepithelial cells with bacterial detachment Mechanical flushing of micturition

Routes of urinary tract infection Ascending infection is thought to be the common route of nearly all forms of urinary tract infection (bacteria initially colonize periurethral tissues) Descending (hematogenous) infection can be important for a few organisms such as S. aureus and Candida albicans, but in general the kidney resists “metastatic infection.”

Mechanisms of lower UTI Experimentally, 99.9% of a bladder inoculum of bacteria is promptly excreted by voiding. Possible biologic explanations for the frequency of UTI in some women include: deficient antibodies in vaginal secretions; and biochemical differences in receptors on uroepithelial cells.

Mechanisms of upper UTI Ascent of bacteria from the bladder to the kidneys is promoted by obstruction and by reflux. In addition, motile bacteria can ascend against the flow of a column of urine. Gram-negative bacteria (or endotoxin derived from them) can inhibit ureteral peristalsis.

Mechanisms of upper UTI (2) The renal medulla is an “immunologic desert.” Its low pH (< 5. 5) and high osmolality (which may reach 1300 mOsm/LK with a sodium of 425 mM and urea of 850 mM) drastically interfere not only with all aspects of leukocyte function but also with antibody and complement function.

Localization of upper versus lower UTI Indirect: pattern of recurrence (i.e., same organism?); maximum urinary concentration; water loading test; serum antibodies; cellular excretion; urinary proteins Direct: renal biopsy; ureteral catheterization; Fairley’s bladder washout test; antibody-coated bacteria test

Localization of upper versus lower UTI (2): in practice Frequency, dysuria, and urgency (lower UTI symptoms) can occur with upper UTI as well. Fever and flank pain indicate acute upper urinary tract infection. Scarring of the kidney by imaging procedures suggests chronic UTI. The distinction is sometimes difficult.

Acute uncomplicated cystitis in young women Acute dysuria in young women usually indicates: acute bacterial cystitis; the urethral syndrome; or vaginitis Acute bacterial cystitis is usually characterized by sudden onset, multiple urinary symptoms, pyuria, and sometimes hematuria

Acute uncomplicated cystitis in young women (2) Although most patients have lower urinary symptoms only, 30% to 50% may have subclinical renal involvement Causes: E. coli (80%), S. saprophyticus (10% to 15%), and occasionally Klebsiella, Proteus mirabilis, and other microorganisms

Acute uncomplicated cystitis in young women (3) A short course of antibiotics (e.g., three days) usually suffices Abbreviated work-ups (e.g., leukocyte-esterase nitrite test) without culture or routine follow-up is now acceptable for typical encounters.

Acute uncomplicated pyelonephritis in young women Largely a clinical diagnosis Pyuria is usually present; about 20% have positive blood cultures; causative organisms the same as with cystitis Predisposing factors: structural abnormalities; strains of E. coli with unique markers; genetically-determined carbohydrate receptors on uroepithelial cells

White blood cell casts Highly significant! Presence suggests pyelonephritis

Recurrent UTIs in women Between 20% and 25% of young women with acute uncomplicated cystitis have 2 or more infections per year, usually due to reinfection with a different E. coli strain Predisposing factors: genetically-determined receptors on uroepithelial cells; diaphragm-spermicide use

Complicated UTIs Definition: UTI in patients with predisposing anatomic, functional, or metabolic abnormalities Spectrum of organisms is skewed toward difficult-to-treat pathogens (e.g., Pseudomonas sp., yeasts, enterococci, Enterobacteriaceae other than E. coli)

Catheter-associated UTI Over 1 million catheter-associated UTIs occur in the United States each year Risk factors: female sex; duration of catheterization; disconnecting the junction between the catheter and the collecting tube

Long-term bladder catheterization Incidence of significant bacteriuria in patients who are not receiving antibiotics is 8% to 10% per day More than 85% of patients have at least two strains of bacteria and 10% have more than five strains Some species (notably, enterococci, Pseudomonas, and Proteus) notoriously tend to persist

Prostatitis Relapsing acute urinary tract infection in men caused by the same bacterial species often suggests chronic prostatitis with periodic spill-over into the bladder Symptoms: pelvic “heaviness,” rectal or perineal pain, urinary hesitancy, dribbling, and burning A risk of catheterization