Case 2

Question 1

ANATOMIC AND HISTOLOGIC FEATURES OF THE URINARY BLADDER

Answer 1

● The urinary bladder is a muscular organ which, when full, can extend up well above the level of the pubic symphysis holding as much as a liter of urine (it can distend still further in pathologic conditions).

● The urinary bladder lies wholly outside the peritoneum although a layer of peritoneum is in contact with the superior surface of the bladder.

● The urinary bladder is a urine reservoir whose shape varies with its degree of fullness. It has a narrow neck, which descends to the urogenital diaphragm, where it unites with the urethra.

● In the male, the neck lies just superior to the prostate, and in the female it lies just anterior to the middle third of the vagina.

● Superior to the neck is the body of the bladder, which is roughly in the shape of an inverted triangle.

● The superior surface of the bladder faces upward and is covered by peritoneum. The apex of the bladder is its most anterior point on the superior surface, where the bladder was attached to the urachus in fetal life.

● In the adult state, this is represented by the median umbilical ligament, which is seen as an unpaired midline ridge of tissue on the interior surface of the anterior abdominal wall, connecting the bladder apex to the umbilicus.

● The anterolateral surfaces of the bladder are “cradled” in a space “supported” on each side by the two superior and inferior pubic rami. The posteroinferior surface of the bladder is called the base.

● The base of the bladder is nearly vertical, faces posteriorly, and resembles an inverted triangle in shape.

● The two ureters enter the bladder wall at positions corresponding to two of the “corners” of the base of this triangle.

● The third point of the triangle is positioned inferiorly, where the bladder outlet joins the urethra.

● In the female, the base of the bladder is in contact with the anterior surface of the vagina and in the male, with the seminal vesicle and ejaculatory ducts.

● Although other parts of the bladder change position and/or shape in correspondence to bladder fullness, the base remains in a similar orientation regardless of bladder fullness.

● When empty, the bladder has a narrow, elongated shape. aligned along a superoinferior axis parallel to the anterior body wall.

● The midline anterior surface of the empty bladder rests against the pubic symphysis and the internal surface of the urogenital diaphragm When full, the bladder expands to a nearly spherical shape and appear to “tip” forward, its superior surface now facing anterior and resting on the levator ani, pudendal cleft (space between the labia), and pubic symphysis.

● The wall of the bladder is made up of thick smooth muscle running in several planes. The muscle is called the detrusor.

● The presence of this muscle in the bladder wall creates a series of irregular thickened ridges on the interior wall of the bladder; these are known collectively as the bladder trabeculae.

● While most of the interior of the bladder is trabeculated, at the trigone the mucosal lining is smooth.

● The trigone is the triangular smooth mucosal region outlined by imaginary lines linking the orifices of the two ureters and the urethra.

● Along the upper side of the trigone, the mucosa is raised, forming a roughly horizontal line connecting the two ureteral orifices. This is known as the interureteric crest.

● Just deep to the trigonal mucosa is a specialized layer of trigonal smooth muscle.

● The trigonal musculature contracts differently than the detrusor muscle.

● While the detrusor muscle lies within the body of the entire bladder and is innervated by parasympathetic nerves, the trigonal smooth muscle is located only in the trigonal area and is innervated instead by sympathetic nerves.

● Smooth musculature downward from the trigone to encircle the bladder neck and urethra (in part).

● This extension of bladder smooth muscle is called the vesical sphincter.

● It extends inferiorly, in the male, to a point slightly above the orifices of the ejaculatory ducts in the prostatic urethra.

● In the female it is rudimentary and probably has little or no role in continence.

● Muscular control of urinary continence is still a controversial issue in clinical anatomy.

● The ureters enter the bladder at the corners of the trigone.

● The ureters penetrate the external wall of the bladder wall and actually “tunnel” some distance before emerging into the bladder interior at the ureteric orifices.

● This arrangement allows for the ureters to be compressed during distension and active contraction of the detrusor, preventing reflux of urine backward into the ureter.

● The neck of the male bladder penetrates the prostate gland and continues as the prostatic urethra.

● As the urethra passes through the urogenital diaphragm, a thickened and circular sphincter urethrae (sometimes called the external urethral sphincter) forms a collar around the urethra.

● This sphincter represents a specialization of the deep transverse perineal muscle.

● This striated muscle sphincter is under voluntary control and probably represents the best and most important mechanism to maintain urinary continence, in both sexes.

Question 2

Encompasses a variety of clinical etiologies including asymptomatic bacteriuria (ABU), cystitis, prostatitis and pyelonephritis. It may be asymptomatic (subclinical infection) or symptomatic (disease).

Answer 2

URINARY TRACT INFECTION

UTI may be asymptomatic (subclinical infection) or symptomatic (disease). Thus, the term urinary tract infection encompasses a variety of clinical entities, including asymptomatic bacteriuria (ASB), cystitis, prostatitis, and pyelonephritis. The distinction between symptomatic UTI and ASB has major clinical implications. Both UTI and ASB connote the presence of bacteria in the urinary tract, usually accompanied by white blood cells and inflammatory cytokines in the urine.

Question 3

Occurs in the absence of symptoms attributable to bacteria in the urinary tract and does not usually require treatment.

Answer 3

ASYMPTOMATIC BACTERIURIA

However, ASB occurs in the absence of symptoms attributable to the bacteria in
the urinary tract and usually does not require treatment, while UTI has more typically been assumed to imply symptomatic disease that
warrants antimicrobial therapy.

Question 4

Terms

Answer 4

urinary tract infection
denotes symptomatic disease;

cystitis, symptomatic infection of the bladder; and

pyelonephritis, symptomatic infection of the kidneys.

Question 5

Refers to acute cystitis or pyelonephritis in nonpregnant outpatient women without anatomic abnormalities or instrumentation of the urinary tract.

or refers to an infection confined to the bladder, or acute cystitis. (21st ed)

Answer 5

UNCOMPLICATED UTI

Question 6

Is a catch-all term that encompasses all other types of UTI. Both UTI and ABU connote the presence of bacteria in the urinary tract, usually accompanied by white blood cells and inflammatory cytokines in the urine. (Harrison’s 18th edition)

What is accompanied by symptoms that suggest the infection extends beyond the bladder, such as a fever or signs or symptoms of systemic illness? (21st ed)

Answer 6

COMPLICATED UTI

Question 7

What occurs when the infection involves the renal parenchyma?

Answer 7

Pyelonephritis

Question 8

What is not necessarily complicated; individual episodes can be uncomplicated and treated as such?

Answer 8

Recurrent urinary tract infection

Question 9

What can be either symptomatic (CAUTI) or symptomatic?

Answer 9

Catheter-associated bacteriuria

Question 10

TWO GENERAL ANATOMIC CATEGORIES OF UTI

Answer 10

● Acute infections of the urinary tract can be subdivided into two general:
○ anatomic categories:
■ Lower tract infection (urethritis and cystitis)
■ Upper tract infection (acute pyelonephritis,
prostatitis, intrarenal and perinephric abscess.

● In most instances, growth of more than 100,000 organisms per milliliter from a properly collected midstream “clean catch’ urine sample indicates infection.

Question 11

EPIDEMIOLOGY AND RISK FACTORS OF UTI

Answer 11

Except among infants and older adults, UTI occurs far more commonly
in females than in males.

During the neonatal period, the incidence of UTI is slightly higher among males than among females because male
infants more commonly have congenital urinary tract anomalies.

After 50 years of age, obstruction from prostatic hypertrophy becomes common in men, and the incidence of UTI is almost as high among
men as among women.

Between 1 year and ~50 years of age, UTI and recurrent UTI are predominantly diseases of females. The prevalence of ASB is ~5% among women between ages 20 and 40 and may be as
high as 40–50% among elderly women and men.

As many as 50–80% of women in the general population acquire at
least one UTI during their lifetime—uncomplicated cystitis in most
cases.

Recent use of a diaphragm with spermicide, frequent sexual
intercourse, and a history of UTI are independent risk factors for acute
cystitis.

Cystitis is temporally related to recent sexual intercourse in a
dose–response manner, with an increased relative risk ranging from 1.4 with one episode of intercourse in the preceding week to 4.8 with five episodes. In healthy postmenopausal women, sexual activity, diabetes mellitus, and incontinence are risk factors for UTI.

Many factors predisposing women to cystitis also increase the risk of pyelonephritis. Factors independently associated with pyelonephritis
in young healthy women include frequent sexual intercourse, a new sexual partner, a UTI in the previous 12 months, a maternal history of UTI, diabetes, and incontinence.

The shared risk factors for cystitis and
pyelonephritis are not surprising given that pyelonephritis typically arises through the ascent of bacteria from the bladder to the upper urinary tract. However, pyelonephritis can occur without symptomatic antecedent cystitis.

About 20–30% of women who have had one episode of UTI will have recurrent episodes. Early recurrence (within 2 weeks) is usually regarded as relapse rather than reinfection and may indicate the need
to evaluate the patient for a sequestered focus. Intracellular bacterial
communities of infecting organisms within the bladder epithelium have been demonstrated in animal models of UTI and in exfoliated human urothelial cells, but the clinical impact of this phenomenon in
humans is not yet clear.

The rate of recurrence ranges from 0.3 to 7.6 infections per patient per year, with an average of 2.6 infections per year. It is not uncommon for multiple recurrences to follow an initial infection, resulting in clustering of episodes. Clustering may be related temporally to the presence of a new risk factor, to the sloughing of the
protective outer bladder epithelial layer in response to bacterial attachment during acute cystitis, or possibly to antibiotic-related alteration of the normal flora.

The likelihood of a recurrence decreases with increasing time since the last infection. A case–control study of predominantly
white premenopausal women with recurrent UTI identified frequent
sexual intercourse, use of spermicide, a new sexual partner, a first UTI
before 15 years of age, and a maternal history of UTI as independent
risk factors for recurrent UTI.

The only consistently documented
behavioral risk factors for recurrent UTI include frequent sexual intercourse and spermicide use.

In postmenopausal women, major risk factors for recurrent UTI include a history of premenopausal UTI and anatomic factors affecting bladder emptying, such as cystoceles, urinary incontinence, and residual urine.

In pregnant women, ASB has clinical consequences, and both
screening for and treatment of this condition are indicated. Specifically,
ASB during pregnancy is associated with maternal pyelonephritis, which in turn is associated with preterm delivery. Antibiotic treatment of ASB in pregnant women can reduce the risk of pyelonephritis, preterm delivery, and low-birth-weight babies.
The majority of men with UTI have a functional or anatomic abnormality of the urinary tract, most commonly urinary obstructionsecondary to prostatic hypertrophy. That said, not all men with UTI
have detectable urinary abnormalities; this point is particularly relevant for men ≤45 years of age.

Lack of circumcision is associated with
an increased risk of UTI because Escherichia coli is more likely to colonize the glans and prepuce and subsequently migrate into the urinary tract of uncircumcised men.

Women with diabetes have a two- to threefold higher rate of ASB and UTI than women without diabetes; there is insufficient evidence on which to base a corresponding statement about men. Increased duration of diabetes and the use of insulin rather than oral medication are associated with an elevated risk of UTI among women with diabetes. Poor bladder function, obstruction in urinary flow, and
incomplete voiding are additional factors commonly found in patients with diabetes that increase the risk of UTI. Impaired cytokine secretion may contribute to ASB in diabetic women. The sodium–glucose cotransporter 2 (SGLT2) inhibitors used for treatment of diabetes result in glycosuria. Initial concerns that these drugs as a class increased the risk of UTI are not supported by data.

Question 12

ETIOLOGY OF ACUTE CYSTITIS

Answer 12

The uropathogens causing UTI vary by clinical syndrome but are usually enteric gram-negative rods that have migrated to the urinary tract.

The susceptibility patterns of these organisms vary by clinical syndrome and by geography. In acute uncomplicated cystitis in the United States, the etiologic agents are highly predictable: E. coli accounts for 75–90% of isolates; Staphylococcus saprophyticus for 5–15% (with particularly frequent isolation from younger women); and Klebsiella,
Proteus, Enterococcus, and Citrobacter species, along with other organisms, for 5–10%. Similar etiologic agents are found in Canada, South America, and Europe. The spectrum of agents causing uncomplicated
pyelonephritis is similar, with E. coli predominating. In complicated
UTI (e.g., CAUTI), E. coli remains the predominant organism, but other aerobic gram-negative rods, such as Pseudomonas aeruginosa and Klebsiella, Proteus, Citrobacter, Acinetobacter, and Morganella species, also are frequently isolated. Gram-positive bacteria (e.g., enterococci and Staphylococcus aureus) and yeasts also are important pathogens in complicated UTI. Data on etiology and resistance are generally obtained from laboratory surveys and should be understood in the
context that organisms are identified only in cases in which urine is sent for culture—typically, when complicated UTI or pyelonephritis is suspected. Genetic sequencing of the bladder microbiome or of all the bacteria that can be identified in the bladder has consistently demonstrated that more bacterial species are present than can be identified by routine culture methods, in both symptomatic and asymptomatic states. The clinical significance of these non-cultivatable organisms is unknown but has challenged the assumption that the bladder is normally a sterile site.

The available data demonstrate a worldwide increase in the resistance of E. coli to specific antibiotics commonly used to treat UTI.

North American, South American, and European surveys from women
with acute cystitis have documented resistance rates of >20% to trimethoprim-sulfamethoxazole (TMP-SMX) in many regions and >10% to ciprofloxacin in some regions. In community-acquired infections, the increased prevalence of multidrug-resistant uropathogens has left few oral options for therapy in some cases. Since resistance rates vary by local geographic region, with individual patient characteristics, and over time, it is important to use current and local data when choosing a treatment regimen.

Question 13

PATHOGENESIS

Answer 13

■ PATHOGENESIS
The urinary tract can be viewed as an anatomic unit linked by a
continuous column of urine extending from the urethra to the kidneys.

In the majority of UTIs, bacteria establish infection by ascending from the urethra to the bladder. Continuing ascent up the ureter to the kidney is the pathway for most renal parenchymal infections.

However, introduction of bacteria into the bladder does not inevitably lead to sustained and symptomatic infection. The interplay of host, pathogen, and environmental factors determines whether tissue invasion and symptomatic infection will ensue (Fig. 135-1).

For example, bacteria often enter the bladder after sexual intercourse, but normal voiding and innate host defense mechanisms in the bladder eliminate these organisms. Any foreign body in the urinary tract, such as a urinary catheter or stone, provides an inert surface for bacterial colonization.

Abnormal micturition and/or significant residual urine volume promotes infection. In the simplest of terms, anything that increases the likelihood of bacteria entering the bladder and staying there increases the risk of UTI.

Bacteria can gain access to the urinary tract through the bloodstream. However, hematogenous spread accounts for <2% of documented UTIs and usually results from bacteremia caused by relatively virulent organisms, such as Salmonella and S. aureus.

Indeed, the isolation of either of these pathogens from a patient without a catheter or other instrumentation warrants a search for a bloodstream source.

Hematogenous infections may produce focal abscesses or areas of pyelonephritis within a kidney and result in positive urine cultures. The pathogenesis of candiduria is distinct in that the hematogenous route is
common. The presence of Candida in the urine of a non-instrumented immunocompetent patient implies either genital contamination or potentially widespread visceral dissemination.

Environmental Factors 

VAGINAL ECOLOGY
Vaginal ecology is an important environmental factor affecting the risk of UTI in women. Colonization of the vaginal introitus and periurethral area
with organisms from the intestinal flora (usually E. coli) is the critical initial step in the pathogenesis of UTI. Sexual intercourse is associated with an increased risk of vaginal colonization with E. coli and thereby increases the risk of UTI.

Nonoxynol-9 in spermicide is toxic to the normal vaginal lactobacilli and thus is likewise associated with an increased risk of E. coli vaginal colonization and bacteriuria. In postmenopausal women, the previously predominant vaginal lactobacilli are replaced with colonizing gram-negative bacteria. The use of topical
estrogens to prevent UTI in postmenopausal women is controversial; given the side effects of systemic hormone replacement, oral estrogens should not be used to prevent UTI.

ANATOMIC AND FUNCTIONAL ABNORMALITIES
Any condition that permits urinary stasis or obstruction predisposes the individual to UTI. Foreign bodies such as stones or urinary catheters provide an inert surface for bacterial colonization and formation of a persistent biofilm. Thus, vesicoureteral reflux, ureteral obstruction secondary
to prostatic hypertrophy, neurogenic bladder, and urinary diversion surgery create an environment favorable to UTI. In persons with such conditions, E. coli strains lacking typical urinary virulence factors
are often the cause of infection. Inhibition of ureteral peristalsis and decreased ureteral tone leading to vesicoureteral reflux are important in the pathogenesis of pyelonephritis in pregnant women. Anatomic factors—specifically, the distance of the urethra from the anus—are considered to be the primary reason why UTI is predominantly an illness of young women rather than of young men.

Question 14

Host Factors

Answer 14

The genetic background of the host influences the individual’s susceptibility to recurrent UTI, at least among women. A familial disposition to UTI and to pyelonephritis is well documented. Women with recurrent UTI are more likely to have had their first UTI before the age of 15 years and to have a maternal history of UTI. A component of the underlying pathogenesis of this familial predisposition to recurrent UTI may be persistent vaginal colonization with E. coli, even during asymptomatic periods. Vaginal and periurethral mucosal cells from women with recurrent UTI bind threefold more uropathogenic bacteria than do mucosal cells from women without recurrent infection. Epithelial cells from women who are nonsecretors of certain blood group antigens may possess specific types of
receptors to which E. coli can bind, thereby facilitating colonization and invasion. Mutations in host innate immune response genes (e.g., those coding for Toll-like receptors and the interleukin 8 receptor) also have been linked to recurrent UTI and pyelonephritis. The genetic
patterns that predispose to cystitis and pyelonephritis appear to be distinct.

Question 15

Microbial Factors

Answer 15

An anatomically normal urinary tract presents a stronger barrier to infection than a compromised urinary tract. Thus, strains of E. coli that cause invasive symptomatic infection of the urinary tract in otherwise normal hosts often possess and express genetic virulence factors, including surface adhesins that mediate binding to specific receptors on the surface of uroepithelial cells. The best-studied adhesins are the P fimbriae, hair-like protein structures that interact with a specific receptor on renal epithelial cells. (The letter P denotes the ability of these fimbriae to bind to blood group antigen P, which contains a d-galactose-d-galactose residue.) P fimbriae are important in the pathogenesis of pyelonephritis and subsequent bloodstream invasion from the kidney.

Another adhesin is the type 1 pilus (fimbria), which all E. coli strains possess but not all E. coli strains express. Type 1 pili are thought to play a key role in initiating E. coli bladder infection; they mediate binding to mannose on the luminal surface of bladder uroepithelial cells. Toxins, metal (iron) acquisition systems, biofilm formation, and capsules
also can contribute to the ability of pathogenic E. coli to thrive in the bladder.

Question 16

APPROACH TO THE PATIENT

Clinical Syndromes

The most important issue to be addressed when a UTI is suspected is the characterization of the clinical syndrome as ASB, uncomplicated cystitis, pyelonephritis, prostatitis, or complicated UTI. This
information will shape the diagnostic and therapeutic approach:

Answer 16

ASYMPTOMATIC BACTERIURIA
A diagnosis of ASB can be considered only when the patient does not have local or systemic symptoms referable to the urinary tract.
The clinical presentation is usually bacteriuria detected incidentally when a patient undergoes a screening urine culture for a reason unrelated to the genitourinary tract. Systemic signs or symptoms such as fever, altered mental status, and leukocytosis in the setting of a positive urine culture are nonspecific and do not merit a diagnosis of symptomatic UTI unless other potential etiologies have
been considered.

CYSTITIS
The typical symptoms of cystitis are dysuria, urinary frequency, and urgency. Nocturia, hesitancy, suprapubic discomfort, and gross hematuria are often noted as well. Unilateral back or flank pain suggest that the upper urinary tract is involved, and are thus inconsistent with uncomplicated cystitis. Fever likewise suggests invasive infection beyond the bladder, involving kidney, prostate, or bloodstream.

PYELONEPHRITIS
Mild pyelonephritis can present as low-grade fever with or without lower-back or costovertebral-angle pain, whereas severe pyelonephritis can manifest as high fever, rigors, nausea, vomiting, and flank and/or loin pain. Symptoms are generally acute in onset, and symptoms of cystitis may not be present. Fever is the main feature
distinguishing cystitis from pyelonephritis. The fever of pyelonephritis typically exhibits a high spiking “picket-fence” pattern and resolves over 72 h of therapy. Bacteremia develops in 20–30% of cases of pyelonephritis. Patients with diabetes may present with obstructive uropathy associated with acute papillary necrosis when the sloughed papillae obstruct the ureter. Papillary necrosis may also be evident in some cases of pyelonephritis complicated by obstruction, sickle cell disease, analgesic nephropathy, or combinations of these conditions. In the rare cases of bilateral papillary
necrosis, a rapid rise in the serum creatinine level may be the first indication of the condition. Emphysematous pyelonephritis is a particularly severe form of the disease that is associated with the production of gas in renal and perinephric tissues and occurs almost exclusively in diabetic patients (Fig. 135-2). Xanthogranulomatous pyelonephritis occurs when chronic urinary obstruction
(often by staghorn calculi), together with chronic infection, leads to suppurative destruction of renal tissue (Fig. 135-3). On pathologic examination, the residual renal tissue frequently has a yellow coloration, with infiltration by lipid-laden macrophages. Pyelonephritis can also be complicated by intraparenchymal abscess formation; this development should be suspected when a patient has continued fever and/or bacteremia despite antibacterial therapy.

PROSTATITIS
Prostatitis includes both infectious and noninfectious abnormalities of the prostate gland. Infections can be acute or chronic, are almost always bacterial in nature, and are far less common than the noninfectious entity chronic pelvic pain syndrome (formerly known as chronic prostatitis). Acute bacterial prostatitis presents as dysuria, frequency, and pain in the prostatic pelvic or perineal area. Fever and chills are usually present, and symptoms of bladder outlet obstruction are common. Chronic bacterial prostatitis presents more insidiously as recurrent episodes of cystitis, sometimes with associated pelvic and perineal pain. Men who present with recurrent cystitis should be evaluated for a prostatic focus as well as urinary retention.

COMPLICATED UTI
Complicated UTI presents as a systematic illness with an infectious focus in the urinary tract and frequently occurs in patients with an anatomic predisposition to infection, such as a foreign body in the urinary tract, or with factors predisposing to a delayed response to therapy.

Question 17

From TG:

CELLULAR AND COLONIAL MORPHOLOGICAL CHARACTERISTICS OF E. coli

Answer 17

● Escherichia coli is a gram negative, rod shaped bacterium. Its colonies have a metallic green sheen when grown in Eosin Methylene Blue (EMB) agar.

● It has a pink — purple coloration when grown in MacConkey agar due to its ability to ferment lactose. It is also indole positive and Beta hemolytic.

● Escherichia coli normally reside in the colon without causing disease. However, there is an amazing amount of DNA being swapped about among the enterics by conjugation with plasmid exchange, lysogenic conversion by temperate bacteriophages and direct transposon mediated DNA insertion.

● When E.coli acquires virulence in this manner, it can cause disease.

● The virulence factors that are present in E. coli are the following:
○ 1. Mucosal interaction — Mucosal adherence with pili and ability to invade intestinal epithelial cells.
○ 2. Exotoxin production — Heat labile, and stable toxin, Shiga-like toxin.
○ 3. Endotoxin — Lipid A portion of lipopolysaccharide
○ 4. Iron binding siderophore: obtains iron from human transferrin and lactoferrin.

● The acquisition of pili virulence factor allows E.coli to travel up to the urethra and infect the bladder (cystitis) and sometimes further up to the kidneys (pyelonephritis).

Question 18

From TG:

PATHOGENESIS OF ACUTE CYSTITIS

MORPHOLOGY - Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the bladder. In gross appearance, there is hyperemia of the mucosa, sometimes associated with exudate.

Answer 18

HEMORRHAGIC CYSTITIS
● This is designated when there is a hemorrhagic component found in the gross specimen. This form of cystitis sometimes follows radiation injury or antitumor chemotherapy and is often accompanied by epithelial atypia. Adenovirus may also cause hemorrhagic cystitis.

SUPPURATIVE CYSTITIS
● It is characterized by the accumulation of large amounts of suppurative exudate. When there is ulceration of large areas of the mucosa or sometimes the entire bladder mucosa, this is now known as ulcerative cystitis.

CHRONIC CYSTITIS
● Persistence of the infection leads to this type of cystitis, differs only from the acute form only in the character of the inflammatory infiltrate.
● There is more extreme heaping up of the epithelium with the formation of a red, friable, granular, and sometimes ulcerated surface.
● Chronicity of the infection gives rise to fibrous thickening in the muscularis propria and consequent thickening and inelasticity of the bladder wall.

FOLLICULAR CYSTITIS
● Is characterized by the aggregation of lymphocytes into lymphoid follicles within the bladder mucosa and underlying wall.

EOSINOPHILIC CYSTITIS
● Manifested by infiltration with submucosal eosinophils together with fibrosis and occasional giant cells. Most cases of eosinophilic cystitis represent nonspecific subacute inflammation, although, rarely these lesions are manifestations of a systemic allergic disorder.

Question 19

MORPHOLOGIC CHARACTERISTICS OF ACUTE PYELONEPHRITIS

Answer 19

● The hallmarks of acute pyelonephritis are patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis.

● The suppuration may occur as discrete focal abscesses involving one or both kidneys, which can extend to large wedge-shaped areas of suppuration.

● The distribution of these lesions is unpredictable, but in pyelonephritis associated with reflux damage occurs most commonly in the lower and upper poles.

● In the early stages, the neutrophilic infiltration is limited to the interstitial tissue. Soon, however, the reaction involves tubules and produces a characteristic abscess with the destruction of the engulfed tubules.

● Characteristically, the glomeruli appear to be resistant to infection. Large areas of severe necrosis however, eventually destroy the glomeruli, and fungal pyelonephritis often affects the glomeruli.

● Three complications of acute pyelonephritis are encountered in special circumstances.
○ Papillary necrosis — is mainly seen in diabetics and in those with urinary tract obstruction. It is usually bilateral but may be unilateral. One or all of the pyramids of the affected kidney may be involved. The tips or distal 2/3 of the pyramids have areas of gray-white to yellow necrosis. On microscopic examination, the necrotic tissue shows characteristic coagulative necrosis, with preservation of outlines of the tubules.
○ Pyonephrosis — is seen when there is total or almost complete obstruction, particularly when it is high in the urinary tract. The suppurative exudate is unable to drain and thus fills the renal pelvis, calyces and ureter.
○ Perinephric abscess — implies extension of suppurative inflammation through the renal capsule into the perinephric tissue.

● After the acute phase of pyelonephritis healing occurs. The neutrophilic infiltrate is replaced by one that is predominantly mononuclear, with macrophages, plasma cells and later lymphocytes. The inflammatory foci are eventually replaced by scars that can be seen on the cortical surface as fibrous depression.

● Such scars are characterized microscopically by atrophy of tubules, interstitial fibrosis and lymphocytic infiltrate.

● However, the pyelonephritic scar is almost always associated with inflammation, fibrosis, and deformation of the underlying calyx and pelvis, reflecting the role of ascending infection and vesicoureteral reflux in the pathogenesis of the disease. (Robbins and Cotran 7th ed.)

Question 20

PATHOPHYSIOLOGY OF ACUTE CYSTITIS

Answer 20

● In the vast majority of UTIs, bacteria gain access to the bladder via the urethra. Ascent of bacteria from the bladder may follow and is probably the pathway for most renal parenchymal infections.

● The vaginal introitus and distal urethra are normally colonized by diphtheroids, streptococcal species, lactobacilli, and staphylococcal species but not by the enteric gram-negative bacilli that commonly cause UTIs.

● In females prone to the development of cystitis, however, enteric gram-negative organisms residing in the bowel colonize the introitus, the periurethral skin, and the distal urethra before and during episodes of bacteriuria.

● The factors that predispose to periurethral colonization with gram-negative bacilli remain poorly understood, but alteration of the normal vaginal flora by antibiotics, other genital infections, or contraceptives (especially spermicide) appears to play an important role.

● Loss of normally dominant H202-producing lactobacilli in the vaginal flora appears to facilitate colonization by E. coli. Urethral massage during intercourse may also facilitate the entry of periurethral bacteria to the bladder.

● Under normal circumstances, bacteria placed in the bladder are rapidly cleared, partly through the flushing and dilutional effects of voiding but also as a result of the antibacterial properties of urine and the bladder mucosa. Owing mostly to a high urea concentration and high osmolarity, the bladder urine of many normal persons inhibits or kills bacteria.

Question 21

FACTORS CONTRIBUTING TO PATHOGENESIS OF ACUTE CYSTITIS

• GENDER AND SEXUAL ACTIVITY
• PREGNANCY
• OBSTRUCTION
• GENETIC FACTORS
• NEUROGENIC BLADDER DYSFUNCTION
• VESICOURETERAL REFLUX
• BACTERIAL VIRULENCE FACTORS

Answer 21

GENDER AND SEXUAL ACTIVITY
● The female urethra appears to be particularly prone to colonization with colonic gram-negative bacilli because of its proximity to the anus, its short length (about 4cm), and its termination beneath the labia. Sexual intercourse causes the introduction of bacteria into the bladder and is temporarily associated with the onset of cystitis. Voiding after intercourse reduces the risk of cystitis, probably because it promotes the clearance of bacteria introduced during intercourse.
● The use of spermicidal compounds with a diaphragm or cervical cap or of spermicide-coated condoms dramatically alters the normal introital bacterial flora and has been associated with marked increases in vaginal colonization with E. coli in the risk of UTI.
● In males who are <50 years old and who have no history of heterosexual or homosexual rectal intercourse, UTI is exceedingly uncommon, and this diagnosis should be questioned in the absence of clear documentation.
● An important factor predisposing to bacteriuria in men is urethral obstruction due to prostatic hypertrophy. Homosexuality is also associated with an increased risk of cystitis in men, probably related to rectal intercourse. Lack of circumcision has been identified as a risk factor for UTI in both neonates and young men.
● Men and women who are infected with HIV and who have CD4+ T cell counts <200/uI are at increased risk of both bacteriuria and symptomatic UTI.

PREGNANCY🤰
● UTIs are detected in 2 to 8% of pregnant women. Symptomatic upper tract infections, in particular, are unusually common during pregnancy; fully 20-30% of pregnant women with asymptomatic bacteriuria subsequently develop pyelonephritis.
● This predisposition to upper tract infection during pregnancy results from decreased ureteral tone, decreased ureteral peristalsis, and temporary incompetence of the vesicoureteral valves. Bladder catheterization during and after delivery causes additional infections.
● Increased incidences of low-birth-weight infants, premature delivery, and newborn mortality result from UTIs during pregnancy, particularly those infections involving the upper tract.

OBSTRUCTION
● Any impediment to the free flow of urine-tumor, stricture, stone, or prostatic hypertrophy, results in hydronephrosis and a greatly increased frequency of UTI. Infection superimposed on urinary tract obstruction may lead to rapid destruction of renal tissue.
● It is of utmost importance, therefore, when infection is present, to identify and repair obstructive lesions. On the other hand, when an obstruction is minor and is not progressive or associated with infection, great caution should be exercised in attempting surgical correction.

GENETIC FACTORS
● Increasing evidence suggests that host genetic factors influence susceptibility to UTI. A maternal history of UTI is more often found among women who have experienced recurrent UTIs than among controls. It has been demonstrated that nonsecretors of blood group antigens are at increased risk of recurrent UTI; this predisposition may relate to a different profile of determined

NEUROGENIC BLADDER DYSFUNCTION
● Interference with the nerve supply to the bladder, as in spinal cord injury, tabes dorsalis, multiple sclerosis, diabetes, and other diseases, may be associated with UTI. The infection may be initiated by the use of catheters for bladder drainage and is favored by the prolonged stasis of urine in the bladder.
● An additional factor often operative in these cases is bone demineralization due to immobilization, which causes hypercalciuria, calculus formation, and obstructive uropathy.

VESICOURETERAL REFLUX
● Defined as reflux of urine from the bladder cavity up into the ureters and sometimes into the renal pelvis, vesicoureteral reflux occurs during voiding or with elevation of pressure in the bladder. This condition is demonstrated by finding retrograde movement of radiopaque or radioactive material during a voiding cystourethrogram.
● Vesicoureteral reflux is common among children with anatomic abnormalities of the urinary tract as well as among children with anatomically normal but infected urinary tracts In the latter group, reflux disappears with advancing age and is probably attributable to factors other than UTI. Long term follow up of children with UTI who have reflux has established that renal damage correlates with marked reflux, not with infection.

BACTERIAL VIRULENCE FACTORS
● BVF markedly influences the likelihood that a given strain, once introduced into the bladder will cause UTI. Most E. coli strains that cause symptomatic UTIs in non-catheterized patients belong to a small number of specific O, K and H serogroups. These Uropathogenic clones have accumulated a number of virulence genes that are often closely linked on the bacteria; chromosome in “virulence islands”.
● Nearly all E. coli strains causing acute pyelonephritis and most of those causing acute cystitis are uropathogenic. In contrast, infections in patients with structural or functional abnormalities of the urinary tract are generally caused by bacterial strains that lack these uropathogenic properties; the implication is that these properties are not needed for infection of the compromised urinary tract.

Question 22

CLINICAL MANIFESTATIONS OF ACUTE CYSTITIS

Answer 22

● The typical symptoms of cystitis are dysuria, urinary frequency and urgency. Nocturia, hesitancy, suprapubic discomfort and gross hematuria are noted as well. (Harrison’s 18th ed.) Physical examination generally reveals only tenderness of the urethra or suprapubic area.

● If a genital lesion or a vaginal discharge is
evident,especially in conjunction with fewer than105 bacteria per milliliter on urine culture, then pathogens that may cause urethritis, vaginitis, or cervicitis, such as C. trachomatis, N. gonorrhoeae, Trichomonas, Candida and Herpes simplex virus should be considered.

Question 23

CLINICAL MANIFESTATION OF ACUTE PYELONEPHRITIS

Answer 23

● Mild pyelonephritis can present as low-grade fever with or without lower-back or costovertebral angle pain and tenderness whereas, severe pyelonephritis can manifest as high fever, rigors, nausea, vomiting, and flank and/or joint pain. Symptoms are generally acute in onset and symptoms of cystitis may not be present.

● Fever is the main feature distinguishing cystitis from pyelonephritis. The fever of pyelonephritis typically exhibits a high, spiking “picket-fence” pattern and resolves over 72 hr. of therapy. Bacteremia develops in 20-30% of cases of pyelonephritis. (Harrison’s 18’ ed.)

Question 24

TG:

DIAGNOSTIC MODALITIES USED TO DIAGNOSE ACUTE CYSTITIS

Answer 24

HISTORY
● The diagnosis of any UTI syndrome or ABU begins with a detailed history. The history given by the patient has a high predictive value in uncomplicated cystitis.

URINE DIPSTICK TEST
● Understanding the parameters of the dipstick test is important in interpreting its results. Only members of the family Enterobacteriaceae convert nitrate to nitrite and enough nitrite must accumulate in the urine to reach the threshold of detection. If a woman with acute cystitis is forcing fluids and is voiding frequently the dipstick test for nitrite is less likely to be positive even when there is E.coli present.
● The leukocyte esterase test detects this enzyme in the host’s polymorphonuclear leukocytes in the urine, whether the cells are intact or lysed. Either nitrite or leukocyte esterase positivity can be interpreted as a positive result. Blood in the urine may also suggest the diagnosis of UTI.
● Urine dipstick tests can confirm the diagnosis of uncomplicated cystitis in a patient With a reasonably high pretest probability of the disease. A negative dipstick test is not sufficiently sensitive to rule out bacteriuria in pregnant women in whom it is important to detect all episodes of bacteriuria.

URINE MICROSCOPY
● Reveals pyuria in nearly all cases of cystitis and hematuria in —30% of cases. Patient’s symptoms and presentation should outweigh an incongruent result on automated urinalysis.

URINE CULTURE
● It is the gold standard for UTI; unfortunately, however, culture results do not become available until 24 hours after the patient’s presentation. Identifying specific organisms requires another 24hr.
● Studies of women with symptoms of cystitis have found that a colony count threshold of **>10^2 bacteria/mL is more sensitive (95%) and specific (85%) than a threshold of >10^5 bacteria/mL for the diagnosis of acute cystitis in
women.
● In men, the minimal level indicating infection appears to be 10^3 bacteria/mL. In most cases, a culture that yields mixed bacterial species is contaminated except in settings of long-term catheterization, chronic urinary retention, or the presence of a fistula between the urinary tract and the gastrointestinal or genital tract. (Harrison’s 18’ ed.)

Question 25

DIAGNOSTIC TOOLS

Answer 25

History
The diagnosis of any of the UTI syndromes or ASB begins with a detailed history (Fig. 135-4). The history given by the patient
has a high predictive value in uncomplicated cystitis. A meta-analysis evaluating the probability of acute UTI on the basis of history and physical findings concluded that, in women presenting with at least one symptom of UTI (dysuria, frequency, hematuria, or back pain)
and without complicating factors, the probability of acute cystitis or pyelonephritis is 50%. The even higher rates of accuracy of selfdiagnosis among women with recurrent UTI probably account for the success of patient-initiated treatment of recurrent cystitis. If vaginal
discharge and complicating factors are absent and risk factors for UTI are present, then the probability of UTI is close to 90%, and no laboratory evaluation is needed. A combination of dysuria and urinary
frequency in the absence of vaginal discharge increases the probability
of UTI to 96%. Further laboratory evaluation with dipstick testing or urine culture is not necessary in such patients before the initiation of definitive therapy, unless concern for resistant pathogens suggests a need for urine culture.
In applying the patient’s history as a diagnostic tool, the physician
must remember that the studies included in the meta-analysis cited above
did not enroll children, adolescents, pregnant women, men, or patients
with complicated UTI. One significant concern is that sexually transmitted disease—that caused by Chlamydia trachomatis in particular—may be inappropriately treated as UTI. This concern is particularly relevant for female patients under the age of 25. The differential diagnosis to be considered when women present with dysuria includes cervicitis (C. trachomatis, Neisseria gonorrhoeae), vaginitis (Candida albicans,
Trichomonas vaginalis), herpetic urethritis, interstitial cystitis, and noninfectious vaginal or vulvar irritation. Women with more than one sexual partner and inconsistent use of condoms are at high risk for both UTI and sexually transmitted disease, and symptoms alone do not
always distinguish between these conditions.

Urine Dipstick Test, Urinalysis, and Urine Culture Useful
diagnostic tools include the urine dipstick test and urinalysis, both of which provide point-of-care information, and the urine culture, which can retrospectively confirm a prior diagnosis and provide organism
susceptibility data for the patient’s next UTI. Understanding the parameters of the dipstick test is important in interpreting its results. Only members of the family Enterobacteriaceae convert nitrate to
nitrite, and enough nitrite must accumulate in the urine to reach the threshold of detection. If a woman with acute cystitis is forcing fluids and voiding frequently, the dipstick test for nitrite is less likely to be
positive, even when E. coli is present. The leukocyte esterase test detects this enzyme in polymorphonuclear leukocytes in the host’s urine, whether the cells are intact or lysed. Many reviews have attempted to
describe the diagnostic accuracy of dipstick testing. The bottom line for clinicians is that a urine dipstick test can confirm the diagnosis of uncomplicated cystitis in a patient with a reasonably high pretest
probability of this disease; either nitrite or leukocyte esterase positivity can be interpreted as a positive result. Blood in the urine also may suggest a diagnosis of UTI. A dipstick test negative for both nitrite and leukocyte esterase in this type of patient should prompt consideration
of other explanations for the patient’s symptoms and collection of urine
for culture. A negative dipstick test is not sufficiently sensitive to rule out bacteriuria in pregnant women, in whom it is important to detect all episodes of bacteriuria.
Urine microscopy reveals pyuria in nearly all cases of cystitis and hematuria in ~30% of cases. In current practice, most hospital laboratories use an automated system rather than manual examination for
urine microscopy. A machine aspirates a sample of the urine and then classifies the particles in the urine by size, shape, contrast, light scatter, volume, and other properties. These automated systems can be overwhelmed by high numbers of dysmorphic red blood cells, white blood
cells, or crystals; in general, counts of bacteria are less accurate than are
counts of red and white blood cells. The authors’ clinical recommendation is that the patient’s symptoms and presentation should outweigh an incongruent result on automated urinalysis. The detection of bacteria in a urine culture from a patient with symptoms of cystitis can confirm the diagnosis of UTI; unfortunately, however, culture results do not become available until 24 h after the patient’s presentation. Furthermore, the presence of bacteriuria
does not mean the patient has urinary symptoms, so a positive urine culture is consistent with both cystitis and ASB. Identifying specific organism(s) can require an additional 24 h. Studies of women with
symptoms of cystitis have found that a colony count threshold of ≥102 bacteria/mL is more sensitive (95%) and specific (85%) than a threshold of 105
/mL for the diagnosis of acute cystitis in women. In men, the minimal level indicating infection appears to be 103/mL.
Urine specimens frequently become contaminated with the normal microbial flora of the distal urethra, vagina, or skin. These contaminants can grow to high numbers if the collected urine is allowed to
stand at room temperature. In most instances, a culture that yields mixed bacterial species is contaminated except in settings of long-term catheterization, chronic urinary retention, or the presence of a fistula between the urinary tract and the gastrointestinal or genital tract.

Question 26

■ DIAGNOSTIC APPROACH
The approach to diagnosis is influenced by which of the clinical UTI syndromes is suspected and presence of risk factors for resistance (Fig. 135-4).

Answer 26

Uncomplicated Cystitis in Women Uncomplicated cystitis in women can be treated on the basis of history alone. However, if the symptoms are not specific or if a reliable history cannot be obtained,
then a urine dipstick test should be performed. A positive nitrite or leukocyte esterase result in a woman with one symptom of UTI increases the probability of UTI from 50% to ~80%, and empirical treatment can be considered without further testing. In this setting, a negative dipstick result does not rule out UTI, and a urine culture, close clinical follow-up, and possibly a pelvic examination are recommended. In women with pregnancy, suspected bacterial resistance, or recurrent UTI, a urine culture is warranted to guide appropriate therapy.

Cystitis in Men
The signs and symptoms of cystitis in men are similar to those in women, but this disease differs in several important ways in the male population. Collection of urine for culture is strongly recommended when a man has symptoms of UTI, as the documentation of bacteriuria can differentiate the less common syndromes of acute and chronic bacterial prostatitis from the very common entity of chronic pelvic pain syndrome, which is not associated with bacteriuria and thus is not usually responsive to antibacterial therapy. Men with febrile UTI often have an elevated serum level of prostate-specific antigen as well as an enlarged prostate and enlarged seminal vesicles on ultrasound—findings indicative of prostate involvement. In a study of 85 men with febrile UTI, symptoms of urinary retention, early recurrence of UTI, hematuria at follow-up, and voiding difficulties were predictive of surgically correctable disorders. Men with none of these symptoms had normal upper and lower urinary tracts on urologic workup. In general, men with a first febrile UTI should have imaging performed (CT or ultrasound); if the diagnosis is unclear or if UTI is recurrent, referral for urologic consultation is appropriate.

Asymptomatic Bacteriuria
The diagnosis of ASB involves
both microbiologic and clinical criteria. The microbiologic criterion (including in urinary catheter–associated asymptomatic bacteriuria) is ≥105 bacterial CFU/mL of urine. The clinical criterion is an absence of signs or symptoms referable to UTI.

Question 27

TG

METHODS OF DETECTION OF BACTERIURIA

Answer 27

● Determination of the number and type of bacteria in the urine is an extremely important diagnostic procedure. In symptomatic patients, bacteria are usually present in the urine in large numbers (>10S/ml).

● In asymptomatic patients, two consecutive urine specimens should be examined bacteriologically before therapy is instituted, and >105 bacteria of a single species per milliliter should be demonstrable in both specimens.

● Antiseptic solutions should not be used in washing the periurethral area before collection of the urine specimen. Water diuresis or recent voiding also reduces bacterial counts in urine.

● Rapid methods of detection of bacteriuria have been developed as alternatives to standard culture methods. These methods detect bacterial growth by photometry, bioluminescence, or other means and provide results rapidly, usually in 1 to 2 hrs.

● Microscopy of urine from symptomatic patients can be of great diagnostic value.

● Microscopic bacteriuria, which is best assessed with Gram-stained uncentrifuged urine, is found in more than 90% of specimens from patients whose infections are associated with colony counts of at least IOS/ml and this finding is very specific.

● The detection of bacteria by urinary microscopy thus constitutes firm evidence of infection, but the absence of microscopically detectable bacteria does not exclude the diagnosis.

● Although many authorities have recommended that urine culture and antimicrobial susceptibility testing be performed for any patient with a suspected UTI, it may be more practical and cost-effective to manage women who have symptoms characteristic of acute uncomplicated cystitis without an initial urine culture. Two approaches to presumptive therapy have generally been used.

● In the first, treatment is initiated solely on the basis of a typical history and/or typical findings on physical exam.

● In the second, women with symptoms and signs of acute cystitis and without complicating factors are managed with urinary microscopy.

● A positive result for pyuria and/or bacteriuria provides enough evidence of infection to indicate that urine culture and susceptibility testing can be omitted and the patient treated empirically. Urine should be cultured, however, when a woman’s symptoms and urine examination findings leave the diagnosis of cystitis in question

Question 28

TG

PREVENTION OF RECURRENT UTI

Answer 28

● Recurrence of uncomplicated cystitis in reproductive-age women is common, and a preventive strategy is indicated if recurrent UTIs are interfering with a patient’s lifestyle. Three prophylactic stages are available: continuous, post-coital, or patient-initiated therapy.

● Continuous prophylaxis and postcoital prophylaxis usually entail low doses of TMP-SMX, a fluoroquinolone, or nitrofurantoin. Typically a prophylactic regimen is prescribed for 6 months and then discontinued at which point the rate of recurrent UTI often returns to baseline.

● Patient initiated therapy involves supplying the patient with materials for urine culture and self-medication with a course of antibiotics at the first symptoms of infection.

Question 29

TREATMENT
Urinary Tract Infections

Answer 29

Treatment of UTI accounts for a major proportion of antimicrobial use in ambulatory care, inpatient care, and long-term-care settings.

Responsible use of antibiotics for this common infection has broad implications for preserving antibiotic effectiveness into the future.

Nevertheless, antimicrobial therapy is warranted for any UTI that is truly symptomatic. The choice of antimicrobial agent, the dose, and the duration of therapy depend on the site of infection and the presence or absence of complicating conditions. Each category of UTI warrants a different approach based on the particular clinical syndrome.

Antimicrobial resistance among uropathogens varies from
region to region and impacts the approach to empirical treatment of UTI. E. coli ST131 is the predominant multilocus sequence type found worldwide as the cause of multidrug-resistant UTI.

Recommendations for treatment must be considered in the context of local resistance patterns and national differences in some agents’ availability. For example, fosfomycin and pivmecillinam are not available in all countries but are considered first-line options where they are available because they retain activity against a majority of uropathogens that produce extended-spectrum β-lactamases.

Thus, therapeutic choices should depend on local resistance, drug availability, and individual patient factors such as recent travel and antimicrobial use.

UNCOMPLICATED CYSTITIS IN WOMEN
Since the species and antimicrobial susceptibilities of the bacteria that cause acute uncomplicated cystitis are highly predictable, many episodes of uncomplicated cystitis can be managed over the telephone (Fig. 135-4). Most patients with other UTI syndromes require further diagnostic evaluation. Although the risk of serious complications with telephone management appears to be low, studies of telephone management algorithms generally have involved otherwise healthy women who are at low risk of complications of UTI.

In 1999, TMP-SMX was recommended as the first-line agent for treatment of uncomplicated UTI in the published guidelines of the Infectious Diseases Society of America. Since then, antibiotic
resistance among uropathogens causing uncomplicated cystitis has increased, appreciation of the importance of collateral damage (as defined below) has increased, and newer agents have been studied. Unfortunately, there is no longer a single best agent for acute uncomplicated cystitis.
Collateral damage refers to the adverse ecologic effects of antimicrobial therapy, including killing of the normal flora and selection of drug-resistant organisms. The implication of collateral damage for UTI management is that a drug that is highly efficacious for the treatment of UTI is not necessarily the optimal first-line agent
if it also has pronounced secondary effects on the normal flora or is likely to adversely affect resistance patterns. Drugs used for UTI that have a minimal effect on fecal flora include pivmecillinam, fosfomycin, and nitrofurantoin. In contrast, trimethoprim, TMP-SMX, quinolones, and ampicillin affect the fecal flora more significantly; these drugs are notably the agents for which rising resistance levels have been documented.

Choosing judiciously whether to initiate antibiotic therapy and then selecting the most urinary-focused agent for the shortest appropriate duration are important factors in global efforts to
stem the rise of antimicrobial-resistant organisms. Several effective therapeutic regimens are available for acute uncomplicated cystitis in women (Table 135-1). Well-studied first-line agents
include TMP-SMX and nitrofurantoin. Second-line agents include β-lactams. There is increasing experience with the use of fosfomycin for UTIs (including complicated infections), particularly
for infections caused by multidrug-resistant E. coli.

According to an advisory from the U.S. Food and Drug Administration (FDA),
fluoroquinolones should not be used for uncomplicated cystitis unless no alternatives are available. Pivmecillinam is not currently available in the United States or Canada but is a popular agent in
some European countries. The pros and cons of specific agents are discussed briefly below.

Traditionally, TMP-SMX has been recommended as first-line treatment for acute cystitis, and it remains appropriate to consider the use of this drug in regions with resistance rates not exceeding
20%. In women with recurrent UTI, prior cultures can be used as a guide to TMP-SMX susceptibility, although interim acquisition of resistant bacteria can occur. TMP-SMX resistance has clinical significance: in TMP-SMX-treated patients with resistant isolates, the time to symptom resolution is longer and rates of both clinical and microbiologic failure are higher. Individual host factors associated
with an elevated risk of UTI caused by a strain of E. coli resistant to TMP-SMX include recent use of TMP-SMX or another antimicrobial agent and recent travel to an area with high rates of TMP-SMX resistance. Prior urine cultures with an organism resistant to TMPSMX also are a strong indication of risk of resistance in the current infection. The optimal setting for empirical use of TMP-SMX is uncomplicated UTI in a female patient who has an established relationship with the practitioner and who can thus seek further care if her symptoms do not respond promptly.

Resistance to nitrofurantoin remains low despite >60 years of use, as several mutational steps are required for the development of bacterial resistance to this drug. Nitrofurantoin remains highly active
against E. coli and most non–E. coli isolates. Proteus, Pseudomonas, Serratia, Enterobacter, and yeasts are all intrinsically resistant to this drug. Although nitrofurantoin has traditionally been prescribed as a 7-day regimen, guidelines now recommend a 5-day course, which
is as effective as a 3-day course of TMP-SMX for treatment of acute cystitis; 3-day courses of nitrofurantoin are not recommended for acute cystitis. Nitrofurantoin does not reach significant levels in tissue and cannot be used to treat pyelonephritis.

Guidelines also recommend fosfomycin as a first-line agent to treat acute, uncomplicated cystitis in women. Oral fosfomycin is given as a single 3-g dose sachet (powder) that is dissolved in a glass
of water and swallowed. Fosfomycin interferes with cell wall formation and is bactericidal. While fosfomycin susceptibility remains very high among E. coli, Pseudomonas is intrinsically resistant to
fosfomycin, and its activity against Klebsiella species is unreliable.

Fosfomycin susceptibility does not appear on standard, automated microbiological susceptibility reports.

Most fluoroquinolones are highly effective as short-course therapy for cystitis when the causative organism is susceptible to them; the exception is moxifloxacin, which may not reach adequate urinary levels. The fluoroquinolones commonly used for UTI include ciprofloxacin and levofloxacin. The two main concerns about fluoroquinolone use for acute cystitis are the propagation of fluoroquinolone resistance, not only among uropathogens but also among other organisms causing more serious and difficult-to-treat infections at other sites, and their rare but potentially serious adverse effects. For example, quinolone use in certain populations, including adults >60 years of age, has been associated with an increased
risk of Achilles tendon rupture. Other potential side effects include irreversible neuropathy. An association with aortic dissection has been noted by both the FDA and the European Medicines Agency.
In light of these detrimental effects, the FDA issued an advisory against using fluoroquinolones to treat acute cystitis in patients who have other therapeutic options.

β-Lactam agents generally have not performed as well as TMPSMX or fluoroquinolones in acute cystitis. Rates of pathogen eradication are lower and relapse rates are higher with β-lactam drugs.

The generally accepted explanation is that β-lactams fail to eradicate uropathogens from the vaginal reservoir. Many strains of E. coli that are resistant to TMP-SMX are also resistant to amoxicillin and cephalexin; thus, these drugs should be used only for patients infected with susceptible strains. However, given rising resistance to
TMP-SMX and the goal of avoiding fluoroquinolones, oral cephalosporins (such as cefpodoxime and cefixime) are increasingly appearing in UTI treatment algorithms.

Urinary analgesics are appropriate in certain situations to speed resolution of bladder discomfort. The urinary tract analgesic phenazopyridine is widely used but can cause significant nausea. Combination analgesics containing urinary antiseptics (methenamine, methylene blue), a urine-acidifying agent (sodium phosphate), and an antispasmodic agent (hyoscyamine) also are available. Interest in the responsible use of antibiotics has led to exploration of antibiotic-sparing approaches to the treatment of acute uncomplicated cystitis. Both placebo and analgesics alone have proved inferior to antibiotics for resolution of symptoms and
prevention of pyelonephritis. Delayed therapy, in which a woman receives a prescription for antibiotics but fills it only if symptoms fail to resolve in a day or two, has the potential advantage of avoiding antibiotic use in those who either do not have cystitis to begin with or have a mild case that resolves spontaneously. The downside is that women who really do have cystitis endure discomfort for
a longer period and may meanwhile progress to pyelonephritis.

However, one certain measure for more responsible use of antibiotics in cystitis is to treat for the correct duration; in practice, many episodes of acute cystitis are treated longer than is recommended by evidence-based guidelines.

PYELONEPHRITIS
Since patients with pyelonephritis have tissue-invasive disease, the treatment regimen chosen should have a very high likelihood of eradicating the causative organism and should reach therapeutic
blood levels quickly. High rates of TMP-SMX-resistant E. coli in patients with pyelonephritis have made fluoroquinolones the first-line therapy for acute uncomplicated pyelonephritis. Whether the fluoroquinolones are given orally or parenterally depends on
the patient’s tolerance for oral intake. A randomized clinical trial demonstrated that a 7-day course of therapy with oral ciprofloxacin (500 mg twice daily, with or without an initial IV 400-mg dose) was highly effective for the initial management of pyelonephritis in the outpatient setting. Oral TMP-SMX (one double-strength
tablet twice daily for 14 days) also is effective for treatment of acute uncomplicated pyelonephritis if the uropathogen is known to be susceptible. If the pathogen’s susceptibility is not known and TMPSMX is used, an initial IV 1-g dose of ceftriaxone is recommended.

Oral β-lactam agents are less effective than the fluoroquinolones and should be used with caution and close follow-up. Options for parenteral therapy for uncomplicated pyelonephritis include fluoroquinolones, an extended-spectrum cephalosporin with or without an aminoglycoside, or a carbapenem. Combinations of a β-lactam
and a β-lactamase inhibitor (e.g., ampicillin-sulbactam, piperacillintazobactam) or a carbapenem (imipenem-cilastatin, ertapenem, meropenem) can be used in patients with more complicated histories, previous episodes of pyelonephritis, anticipated antimicrobial resistance, or recent urinary tract manipulations; in general, the treatment of such patients should be guided by urine culture results.
The treatment of very resistant organisms may require the use of newer, very broad-spectrum agents, in consultation with infectious disease specialists. Once the patient has responded clinically, oral
therapy should be substituted for parenteral therapy.

UTI IN PREGNANT WOMEN
Nitrofurantoin, ampicillin, and the cephalosporins are considered
relatively safe in early pregnancy. One retrospective case-control study suggesting an association between nitrofurantoin and birth defects has not been confirmed. Sulfonamides should clearly be
avoided both in the first trimester (because of possible teratogenic effects) and near term (because of a possible role in the development of kernicterus). Fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. Ampicillin and the cephalosporins have been used extensively in pregnancy and are he drugs of choice for the treatment of asymptomatic or symptomatic UTI in this group of patients. Generally, pregnant women with
ASB are treated for 4–7 days in the absence of evidence to support
single-dose therapy. For pregnant women with overt pyelonephritis, parenteral β-lactam therapy with or without aminoglycosides is the standard of care.

UTI IN MEN
Since the prostate is involved in the majority of cases of febrile UTI in men, the goal in these patients is to eradicate the prostatic infection as well as the bladder infection. A 7- to 14-day course
of a fluoroquinolone or TMP-SMX is recommended if the uropathogen is susceptible; clinical practice is tending toward the shorter, 7-day duration to reduce antibiotic exposure. If acute
bacterial prostatitis is suspected, antimicrobial therapy should be
initiated after urine and blood are obtained for cultures. Therapy can be tailored to urine culture results and should be continued for 2–4 weeks. For documented chronic bacterial prostatitis, a 4- to
6-week course of antibiotics is often necessary. Recurrences, which are not uncommon in chronic prostatitis, often warrant a 12-week course of treatment.

COMPLICATED UTI
Complicated UTI occurs in a heterogeneous group of patients,
many with structural and functional abnormalities of the urinary tract and kidneys. The range of species and their susceptibility to antimicrobial agents are likewise heterogeneous. As a consequence,
therapy for complicated UTI must be individualized and guided by urine culture results. Frequently, a patient with complicated UTI will have prior urine-culture data that can be used to guide empirical therapy while current culture results are pending. Xanthogranulomatous pyelonephritis is treated with nephrectomy. Percutaneous
drainage can be used as the initial therapy in emphysematous pyelonephritis and can be followed by elective nephrectomy as needed.
Papillary necrosis with obstruction requires intervention to relieve the obstruction and to preserve renal function.

ASYMPTOMATIC BACTERIURIA
Treatment of ASB does not decrease the frequency of symptomatic infections or complications except in pregnant women, persons undergoing urologic surgery, and perhaps neutropenic patients and renal transplant recipients. Treatment of ASB in pregnant women and patients undergoing urologic procedures should be directed
by urine culture results. In all other populations, screening for and treatment of ASB are discouraged. The majority of cases of catheter-associated bacteriuria are asymptomatic and do not warrant
antimicrobial therapy.

CATHETER-ASSOCIATED UTI
Multiple institutions have released guidelines for the treatment of CAUTI, which is defined by bacteriuria and symptoms in a catheterized patient. The signs and symptoms either are localized to
the urinary tract or can include otherwise unexplained systemic manifestations, such as fever. The accepted threshold for bacteriuria to meet the definition of CAUTI is ≥103 CFU/mL of urine, while the threshold for bacteriuria to meet the definition of ASB is ≥105 CFU/mL.
As catheters provide a conduit for bacteria to enter the bladder, bacteriuria is inevitable with long-term catheter use. The typical signs and symptoms of UTI, including pain, urgency, dysuria, fever,
peripheral leukocytosis, and pyuria, have less predictive value for the diagnosis of infection in catheterized patients. Furthermore, the presence of bacteria in the urine of a patient who is febrile and
catheterized does not necessarily mean that the patient has CAUTI, and other explanations for the fever should be considered.
The etiology of CAUTI is diverse, and urine culture results are essential to guide treatment. Fairly good evidence supports the practice of catheter change during treatment for CAUTI. The goal is to remove biofilm-associated organisms that could serve as a nidus for reinfection. Pathology studies reveal that many patients with long-term catheters have occult pyelonephritis. A randomized trial in persons with spinal cord injury who were undergoing intermittent catheterization found that relapse was more common after 3 days of therapy than after 14 days. In general, a 7- to 14-day course of antibiotics is recommended, but further studies on the optimal duration of therapy are needed.
The best strategy for prevention of CAUTI is to avoid insertion of unnecessary catheters and to remove catheters once they are no
longer necessary. Quality-improvement collaboratives that have addressed technical aspects of CAUTI prevention (such as avoidance of inappropriate catheterization) as well as team communication strategies have shown the benefit of this approach in decreasing
CAUTI in both acute- and long-term-care settings. Antimicrobial catheters impregnated with silver or nitrofurazone have not been shown to provide significant clinical benefit in terms of reducing rates of symptomatic UTI. Evidence is insufficient to recommend suprapubic catheters and condom catheters as alternatives to indwelling urinary catheters as a means to prevent bacteriuria.
However, intermittent catheterization may be preferable to longterm indwelling urethral catheterization in certain populations (e.g., spinal cord–injured persons) to prevent both infectious and
anatomic complications.

CANDIDURIA
The appearance of Candida in the urine is an increasingly common complication of indwelling catheterization, particularly for
patients in the intensive care unit, those taking broad-spectrum antimicrobial drugs, and those with underlying diabetes mellitus.
In many studies, >50% of urinary Candida isolates have been found to be non-albicans species. The clinical presentation varies from a laboratory finding without symptoms to pyelonephritis and even
sepsis. Removal of the urethral catheter results in resolution of candiduria in more than one-third of asymptomatic cases. Treatment of asymptomatic patients does not appear to decrease the frequency
of recurrence of candiduria. Therapy is recommended for patients who have symptomatic cystitis or pyelonephritis and for those who are at high risk for disseminated disease. High-risk patients include those with neutropenia, those who are undergoing urologic manipulation, those who are clinically unstable, and low-birth-weight infants. Fluconazole (200–400 mg/d for 7–14 days) reaches high levels in urine and is the first-line regimen for Candida infections of the urinary tract. Although instances of successful eradication of candiduria by some of the newer azoles and echinocandins have
been reported, these agents are characterized by only low-level urinary excretion and thus are not recommended. For Candida isolates with high levels of resistance to fluconazole, oral flucytosine and/or parenteral amphotericin B are options. Bladder irrigation with
amphotericin B generally is not recommended.

Question 30

■ PREVENTION OF RECURRENT UTI IN WOMEN

Answer 30

Recurrence of uncomplicated cystitis in reproductive-age women is common, and a preventive strategy is indicated if recurrent UTIs are interfering with a patient’s lifestyle. The threshold of two or more symptomatic episodes per year is not absolute; decisions about interventions should take the patient’s preferences into account.
Three prophylactic strategies are available: continuous, postcoital, and patient-initiated therapy. Continuous prophylaxis and postcoital prophylaxis usually entail low doses of TMP-SMX or nitrofurantoin.
These regimens are all highly effective during the period of active antibiotic intake. Typically, a prophylactic regimen is prescribed for 6 months and then discontinued, at which point the rate of recurrent UTI often returns to baseline. If bothersome infections recur, the prophylactic program can be reinstituted for a longer period. Selection of
resistant strains in the fecal flora has been documented in studies of women taking prophylactic antibiotics for 12 months.
Patient-initiated therapy involves supplying the patient with materials for urine culture and with a course of antibiotics for self-medication at the first symptoms of infection. The urine culture is refrigerated and delivered to the physician’s office for confirmation of the diagnosis.

When an established and reliable patient–provider relationship exists, the urine culture can be omitted as long as the symptomatic episodes respond completely to short-course therapy and are not followed by relapse.
Non-antimicrobial prevention is increasingly being studied. Lactobacillus probiotics are one appealing approach to UTI prevention, but there is a paucity of data to support this strategy. Similarly, studies of cranberry products for UTI prevention have produced mixed results.
Varied dosing and product composition between studies remain an issue for providing clinical guidance.

Question 31

PROGNOSIS

Answer 31

Cystitis is a risk factor for recurrent cystitis and pyelonephritis. ASB is common among elderly and catheterized patients but does not in itself increase the risk of death. The relationships among recurrent UTI, chronic pyelonephritis, and renal insufficiency have been widely studied. In the absence of anatomic abnormalities such as reflux, recurrent infection in children and adults does not lead to chronic pyelonephritis
or to renal failure.

Moreover, infection does not play a primary role in chronic interstitial nephritis; the primary etiologic factors in this condition are analgesic abuse, obstruction, reflux, and toxin exposure. In the presence of underlying renal abnormalities (particularly obstructing stones), infection as a secondary factor can accelerate renal parenchymal damage.