Clostridium difficile Infection, Including Pseudomembranous Colitis

The mainstay of treatment is adequate rehydration. The treatment of cholera and other dehydrating diarrheal diseases was revolutionized by the promotion of oral rehydration solution (ORS), the efficacy of which depends on the fact that glucose-facilitated absorption of sodium and water in the small intestine remains intact in the presence of cholera toxin. The use of ORS has reduced mortality rates for cholera from >50% (in untreated cases) to <1%. A number of ORS formulas have been used. Initial preparations were based on the treatment of patients with cholera and included a solution containing 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate (or 2.9 g of sodium citrate), 1.5 g of potassium chloride, and 20 g of glucose (or 40 g of sucrose) per liter of water. Such a preparation can still be used for the treatment of severe cholera. Many causes of secretory diarrhea, however, are associated with less electrolyte loss than occurs in cholera. Beginning in 2002, the World Health Organization recommended a “reduced-osmolarity/reduced-salt” ORS that is better tolerated and more effective than classic ORS. This preparation contains 2.6 g of sodium chloride, 2.9 g of trisodium citrate, 1.5 g of potassium chloride, and 13.5 g of glucose (or 27 g of sucrose) per liter of water. ORS formulations containing rice or cereal as the carbohydrate source may be even more effective than glucose-based solutions. Patients who are severely dehydrated or in whom vomiting precludes the use of oral therapy should receive IV solutions such as Ringer’s lactate.

Although most secretory forms of traveler’s diarrhea (usually due to enterotoxigenic or enteroaggregative E. coli or to Campylobacter) can be treated effectively with rehydration, bismuth subsalicylate, or antiperistaltic agents, antimicrobial agents can shorten the duration of illness from 3–4 days to 24–36 h. Changes in diet have not been shown to have an impact on the duration of illness, while the efficacy of probiotics continues to be debated. Most individuals who present with dysentery (bloody diarrhea and fever) should be treated empirically with an antimicrobial agent (e.g., a fluoroquinolone or a macrolide) pending microbiologic analysis of stool. Individuals with shigellosis should receive a 3- to 7-day course. Individuals with Campylobacter infection often benefit from antimicrobial treatment as well. Because of widespread resistance of Campylobacter to fluoroquinolones, especially in parts of Asia, a macrolide antibiotic such as erythromycin or azithromycin may be preferred for this infection.

Treatment of salmonellosis must be tailored to the individual patient. Since administration of antimicrobial agents often prolongs intestinal colonization with Salmonella, these drugs are usually reserved for individuals at high risk of complications from disseminated salmonellosis, such as young children, patients with prosthetic devices, elderly patients, and immunocompromised persons. Antimicrobial agents should not be administered to individuals (especially children) in whom enterohemorrhagic E. coli infection is suspected. Laboratory studies of enterohemorrhagic E. coli strains have demonstrated that a number of antibiotics induce replication of Shiga toxin–producing lambdoid bacteriophages, thereby significantly increasing toxin production by these strains. Clinical studies have supported these laboratory results, and antibiotics may increase by twentyfold the risk of hemolytic-uremic syndrome and renal failure during enterohemorrhagic E. coli infection. A clinical clue in the diagnosis of the latter infection is bloody diarrhea with low fever or none at all.

PROPHYLAXIS

Improvements in hygiene to limit fecal-oral spread of enteric pathogens will be necessary if the prevalence of diarrheal diseases is to be significantly reduced in developing countries. Travelers can reduce their risk of diarrhea by eating only hot, freshly cooked food; by avoiding raw vegetables, salads, and unpeeled fruit; and by drinking only boiled or treated water and avoiding ice. Historically, few travelers to tourist destinations adhere to these dietary restrictions. Bismuth subsalicylate is an inexpensive agent for the prophylaxis of traveler’s diarrhea; it is taken at a dosage of 2 tablets (525 mg) four times a day. Treatment appears to be effective and safe for up to 3 weeks, but adverse events such as temporary darkening of the tongue and tinnitus can occur. A meta-analysis suggests that probiotics may lessen the likelihood of traveler’s diarrhea by ~15%. Prophylactic antimicrobial agents, although effective, are not generally recommended for the prevention of traveler’s diarrhea except when travelers are immunosuppressed or have other underlying illnesses that place them at high risk for morbidity from gastrointestinal infection. The risk of side effects and the possibility of developing an infection with a drug-resistant organism or with more harmful, invasive bacteria make it more reasonable to institute an empirical short course of treatment if symptoms develop. If prophylaxis is indicated, the nonabsorbed antibiotic rifaximin can be considered.

The possibility of exerting a major impact on the worldwide morbidity and mortality associated with diarrheal diseases has led to intense efforts to develop effective vaccines against the common bacterial and viral enteric pathogens. An effective rotavirus vaccine is currently available. Vaccines against S. typhi and V. cholerae also are available, although the protection they offer is incomplete and/or short lived. At present, there is no effective commercially available vaccine against Shigella, enterotoxigenic E. coli, Campylobacter, nontyphoidal Salmonella, norovirus, or intestinal parasites.

DEFINITION

Clostridium difficile infection (CDI) is a unique colonic disease that is acquired most often in association with antimicrobial use and the consequent disruption of the normal colonic microbiota. The most commonly diagnosed diarrheal illness acquired in the hospital, CDI results from the ingestion of spores of C. difficile that vegetate, multiply, and secrete toxins, causing diarrhea and pseudomembranous colitis (PMC) in the most severe cases.

ETIOLOGY AND EPIDEMIOLOGY

C. difficile is an obligately anaerobic, gram-positive, spore-forming bacillus whose spores are found widely in nature, particularly in the environment of hospitals and chronic-care facilities. CDI occurs frequently in hospitals and nursing homes (or shortly after discharge from these facilities) where the level of antimicrobial use is high and the environment is contaminated by C. difficile spores.

Clindamycin, ampicillin, and cephalosporins were the first antibiotics associated with CDI. The second- and third-generation cephalosporins, particularly cefotaxime, ceftriaxone, cefuroxime, and ceftazidime, are frequently responsible for this condition, and the fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) are the most recent drug class to be implicated in hospital outbreaks. Penicillin/β-lactamase-inhibitor combinations such as ticarcillin/clavulanate and piperacillin/tazobactam pose significantly less risk. However, all antibiotics, including vancomycin and metronidazole (the agents most commonly used to treat CDI), carry a risk of subsequent CDI. Rare cases are reported in patients without prior antibiotic exposure.

C. difficile is acquired exogenously—most frequently in the hospital or nursing home, but also possibly in the outpatient setting—and is carried in the stool of both symptomatic and asymptomatic patients. The rate of fecal colonization is often ≥20% among adult patients hospitalized for >1 week; in contrast, the rate is 1–3% among community residents. Community-onset CDI without recent hospitalization, nursing home residence, or outpatient health-care contact probably accounts for ≤10% of all cases. The risk of C. difficile acquisition increases in proportion to the length of hospital stay. Asymptomatic fecal carriage of C. difficile in healthy neonates is very common, with repeated colonization by multiple strains in infants (<1 year old), but associated disease in these infants is extremely rare if it occurs at all. Spores of C. difficile are found on environmental surfaces (where the organism can persist for months) and on the hands of hospital personnel who fail to practice good hand hygiene. Hospital epidemics of CDI have been attributed to a single C. difficile strain and to multiple strains present simultaneously. Other identified risk factors for CDI include older age, greater severity of underlying illness, gastrointestinal surgery, use of electronic rectal thermometers, enteral tube feeding, and antacid treatment. Use of proton pump inhibitors may be a risk factor, but this risk is probably modest, and no firm data have implicated these agents in patients who are not already receiving antibiotics.

PATHOLOGY AND PATHOGENESIS

Spores of toxigenic C. difficile are ingested, survive gastric acidity, germinate in the small bowel, and colonize the lower intestinal tract, where they elaborate two large toxins: toxin A (an enterotoxin) and toxin B (a cytotoxin). These toxins initiate processes resulting in the disruption of epithelial-cell barrier function, diarrhea, and pseudomembrane formation. Toxin A is a potent neutrophil chemoattractant, and both toxins glucosylate the guanosine triphosphate (GTP)–binding proteins of the Rho subfamily that regulate the actin cell cytoskeleton. Data from studies using molecular disruption of toxin genes in isogenic mutants suggest that toxin B is the more important virulence factor. This possibility, if confirmed, might account for the occurrence of clinical disease caused by toxin A–negative strains. Disruption of the cytoskeleton results in loss of cell shape, adherence, and tight junctions, with consequent fluid leakage. A third toxin, binary toxin CDT, was previously found in only ~6% of strains but is present in all isolates of the widely recognized epidemic NAP1/BI/027 strain (see “Global Considerations,” below); this toxin is related to C. perfringens iota toxin. Its role in the pathogenesis of CDI has not yet been defined.

The pseudomembranes of PMC are confined to the colonic mucosa and initially appear as 1- to 2-mm whitish-yellow plaques. The intervening mucosa appears unremarkable, but, as the disease progresses, the pseudomembranes coalesce to form larger plaques and become confluent over the entire colon wall (Fig. 161-1). The whole colon is usually involved, but 10% of patients have rectal sparing. Viewed microscopically, the pseudomembranes have a mucosal attachment point and contain necrotic leukocytes, fibrin, mucus, and cellular debris. The epithelium is eroded and necrotic in focal areas, with neutrophil infiltration of the mucosa.

FIGURE 161-1   Autopsy specimen showing confluent pseudomembranes covering the cecum of a patient with pseudomembranous colitis. Note the sparing of the terminal ileum (arrow).

Patients colonized with C. difficile were initially thought to be at high risk for CDI. However, four prospective studies have shown that colonized patients who have not previously had CDI actually have a decreased risk of CDI. At least three events are proposed as essential for the development of CDI (Fig. 161-2). Exposure to antimicrobial agents is the first event and establishes susceptibility to C. difficile infection, most likely through disruption of the normal gastrointestinal microbiota. The second event is exposure to toxigenic C. difficile. Given that the majority of patients do not develop CDI after the first two events, a third event is clearly essential for its occurrence. Candidate third events include exposure to a C. difficile strain of particular virulence, exposure to antimicrobial agents especially likely to cause CDI, and an inadequate host immune response. The host anamnestic serum IgG antibody response to toxin A of C. difficile is the most likely third event that determines which patients develop diarrhea and which patients remain asymptomatic. In all probability, the majority of people first develop antibody to C. difficile toxins when colonized asymptomatically during the first year of life or after CDI in childhood. Infants are thought not to develop symptomatic CDI because they lack suitable mucosal toxin receptors that develop later in life. In adulthood, serum levels of IgG antibody to toxin A increase more in response to infection in individuals who become asymptomatic carriers than in those who develop CDI. For persons who develop CDI, development of increasing levels of antitoxin A during treatment correlates with a lower risk of recurrence of CDI. A clinical trial using monoclonal antibodies to both toxin A and toxin B in addition to standard therapy showed rates of recurrence significantly lower than those obtained with placebo plus standard therapy.

FIGURE 161-2   Pathogenesis model for hospital-acquired Clostridium difficile infection (CDI). At least three events are integral to C. difficile pathogenesis: (1) Exposure to antibiotics establishes susceptibility to infection. (2) Once susceptible, the patient may acquire nontoxigenic (nonpathogenic) or toxigenic strains of C. difficile as a second event. (3) Acquisition of toxigenic C. difficile may be followed by asymptomatic colonization or CDI, depending on one or more additional events (e.g., an inadequate host anamnestic IgG response to C. difficile toxin A).

GLOBAL CONSIDERATIONS

Rates and severity of CDI in the United States, Canada, and Europe increased markedly after the year 2000. Rates in U.S. hospitals tripled between 2000 and 2005. In 2005, hospitals in Montreal, Quebec, reported rates four times higher than the 1997 baseline, with directly attributable mortality of 6.9% (increased from 1.5%). An epidemic strain, variously known as toxinotype III, REA type BI, polymerase chain reaction (PCR) ribotype 027, and pulsed-field type NAP1 and thus collectively designated NAP1/BI/027, is thought to account for much of the increase in incidence and has been found in North America, Europe, and Asia. It is now recognized that two clones of NAP1/BI/027 originated in the United States and Canada and spread to the United Kingdom, Europe, and Asia. The epidemic organism is characterized by (1) an ability to produce 16–23 times as much toxin A and toxin B as control strains in vitro; (2) the presence of a third toxin (binary toxin CDT); and (3) high-level resistance to all fluoroquinolones. New strains have been and probably will continue to be implicated in outbreaks, including a strain (toxinotype V, ribotype 078) commonly found in food animals that also carries binary toxin and has been associated with high mortality risk in human infections. In the past 5 years, rates of CDI in the United Kingdom have markedly decreased, and the frequency of the NAP1/BI/027 strain in the countries of the European Union has likewise decreased. However, there has been no evidence of decreased rates of CDI or a decreased incidence of NAP1/BI/027 in North America; the latter strain still causes 25–35% of all CDIs in most regions of the United States.

CLINICAL MANIFESTATIONS

Diarrhea is the most common manifestation caused by C. difficile. Stools are almost never grossly bloody and range from soft and unformed to watery or mucoid in consistency, with a characteristic odor. Patients may have as many as 20 bowel movements per day. Clinical and laboratory findings include fever in 28% of cases, abdominal pain in 22%, and leukocytosis in 50%. When adynamic ileus (which is seen on x-ray in ~20% of cases) results in cessation of stool passage, the diagnosis of CDI is frequently overlooked. A clue to the presence of unsuspected CDI in these patients is unexplained leukocytosis, with ≥15,000 white blood cells (WBCs)/μL. Such patients are at high risk for complications of C. difficile infection, particularly toxic megacolon and sepsis.

C. difficile diarrhea recurs after treatment in ~15–30% of cases, and this figure may be increasing. Recurrences may represent either relapses due to the same strain or reinfections with a new strain. Susceptibility to recurrence of clinical CDI is likely a result of continued fecal-microbiota disruption caused by the antibiotic used to treat CDI.

DIAGNOSIS

The diagnosis of CDI is based on a combination of clinical criteria: (1) diarrhea (≥3 unformed stools per 24 h for ≥2 days) with no other recognized cause plus (2) toxin A or B detected in the stool, toxin-producing C. difficile detected in the stool by PCR or culture, or pseudomembranes seen in the colon. PMC is a more advanced form of CDI and is visualized at endoscopy in only ~50% of patients with diarrhea who have a positive stool culture and toxin assay for C. difficile. Endoscopy is a rapid diagnostic tool in seriously ill patients with suspected PMC and an acute abdomen, but a negative result in this examination does not rule out CDI.

Despite the array of tests available for C. difficile and its toxins (Table 161-1), no single traditional test has high sensitivity, high specificity, and rapid turnaround. Most laboratory tests for toxins, including enzyme immunoassays, lack sensitivity. However, testing of multiple additional stool specimens is not recommended. Nucleic acid amplification tests, including PCR assays, have now been approved for diagnostic purposes and appear to be both rapid and sensitive while retaining high specificity. Testing of asymptomatic patients is not recommended except for epidemiologic study purposes. In particular, so-called tests of cure following treatment are not recommended because >50% of patients continue to harbor the organism and toxin after diarrhea has ceased and test results do not always predict recurrence of CDI. Thus these results should not be used to restrict placement of patients in long-term-care or nursing home facilities.

PRIMARY CDI

When possible, discontinuation of any ongoing antimicrobial administration is recommended as the first step in treatment of CDI. Earlier studies indicated that 15–23% of patients respond to this simple measure. However, with the advent of the current epidemic strain and the associated rapid clinical deterioration of some patients, prompt initiation of specific CDI treatment has become the standard. Empirical treatment is appropriate if CDI is strongly suspected on clinical grounds. General treatment guidelines include hydration and the avoidance of antiperistaltic agents and opiates, which may mask symptoms and possibly worsen disease. Nevertheless, antiperistaltic agents have been used safely with vancomycin or metronidazole for mild to moderate CDI.

Oral administration of vancomycin, fidaxomicin, or metronidazole is recommended for CDI treatment. IV vancomycin is ineffective for CDI, and fidaxomicin is available only for oral administration; when IV metronidazole is administered, fecal bactericidal drug concentrations are achieved during acute diarrhea; however, in the presence of adynamic ileus, IV metronidazole treatment of CDI has failed. Two large clinical trials comparing vancomycin and fidaxomicin indicated comparable resolution of diarrhea (~90% of patients) as well as significantly reduced rates of recurrent CDI with fidaxomicin from rates with vancomycin. In previous randomized trials, diarrhea response rates to oral therapy with vancomycin or metronidazole were ≥94%, but four observational studies found that response rates for metronidazole had declined to 62–78%. Although the mean time to resolution of diarrhea is 2–4 days, the response to metronidazole may be much slower. Treatment should not be deemed a failure until a drug has been given for at least 6 days. On the basis of data for shorter courses of vancomycin and the results of two large-scale clinical trials, it is recommended that vancomycin, fidaxomicin, and metronidazole be given for at least 10 days. Metronidazole is not approved for CDI by the U.S. Food and Drug Administration (FDA), but most patients with mild to moderate illness respond to 500 mg given by mouth three times a day for 10 days; extension of the treatment period may be needed for slow responders. In addition to the reports of increases in metronidazole failures, a prospective, randomized, double-blind, placebo-controlled study has demonstrated the superiority of vancomycin over metronidazole for treatment of severe CDI. The severity assessment score in that study included age as well as laboratory parameters (elevated temperature, low albumin level, or elevated WBC count), documentation of PMC by endoscopy, and treatment of CDI in the intensive care unit. Although a validated severity score is not available, it is important to initiate treatment with oral vancomycin for patients who appear seriously ill, particularly if they have a high WBC count (>15,000/μL) or a creatinine level that is ≥1.5 times higher than the premorbid value (Table 161-2). In addition, a randomized blinded trial compared a toxin-binding polymer, tolevamer, with two antibiotic regimens for treatment of CDI and showed that vancomycin was superior to metronidazole for all patients regardless of severity. Small randomized trials of nitazoxanide, bacitracin, rifaximin, and fusidic acid for treatment of CDI have been conducted. These drugs have not been extensively studied, shown to be superior, or approved by the FDA for CDI, but they provide potential alternatives to vancomycin, fidaxomicin, and metronidazole.

RECURRENT CDI

Overall, ~15–30% of successfully treated patients experience recurrences of CDI, either as relapses caused by the original organism or as reinfections following treatment. Rates of CDI recurrence are significantly lower among patients treated with fidaxomicin rather than vancomycin. Rates of recurrence are comparable with vancomycin and metronidazole. Recurrence rates are higher among patients ≥65 years old, those who continue to take antibiotics while being treated for CDI, and those who remain in the hospital after the initial episode of CDI. Patients who have a first recurrence of CDI have a high rate of second recurrence (33–65%). In the first recurrence, re-treatment with metronidazole is comparable to treatment with vancomycin (Table 161-2), and fidaxomicin is superior to vancomycin in reducing the risk of further recurrences in patients who have had one recurrence. Recurrent CDI, once thought to be relatively mild, has now been documented to pose a significant (11%) risk of serious complications (shock, megacolon, perforation, colectomy, or death within 30 days). There is no standard treatment for multiple recurrences, but long or repeated metronidazole courses should be avoided because of potential neurotoxicity. The use of vancomycin in tapering doses or with pulse dosing every other day for 2–8 weeks may be the most practical approach to treatment of patients with multiple recurrences. Other approaches include the administration of vancomycin followed by the yeast Saccharomyces boulardii; the administration of vancomycin followed by a fecal microbiota transplant given via nasoduodenal tube, colonoscope, or enema; and the intentional colonization of the patient with a nontoxigenic strain of C. difficile. None of these biotherapeutic approaches has been approved by the FDA for use in the United States. Other non-FDA-approved antibiotic strategies include (1) sequential treatment with vancomycin (125 mg four times daily for 10–14 days) followed by rifaximin (400 mg twice daily for 14 days) and (2) treatment with nitazoxanide (500 mg twice daily for 7 days). IV immunoglobulin, which has also been used with variable success, presumably provides antibodies to C. difficile toxins.

SEVERE COMPLICATED OR FULMINANT CDI

Fulminant (rapidly progressive and severe) CDI presents the most difficult treatment challenge. Patients with fulminant disease often do not have diarrhea, and their illness mimics an acute surgical abdomen. Sepsis (hypotension, fever, tachycardia, leukocytosis) may result from severe CDI. An acute abdomen (with or without toxic megacolon) may include signs of obstruction, ileus, colon-wall thickening and ascites on abdominal CT, and peripheral-blood leukocytosis (≥20,000 WBCs/μL). With or without diarrhea, the differential diagnosis of an acute abdomen, sepsis, or toxic megacolon should include CDI if the patient has received antibiotics in the past 2 months. Cautious sigmoidoscopy or colonoscopy to visualize PMC and abdominal CT are the best diagnostic tests in patients without diarrhea.

Medical management of fulminant CDI is suboptimal because of the difficulty of delivering oral fidaxomicin, metronidazole, or vancomycin to the colon in the presence of ileus (Table 161-2). The combination of vancomycin (given via nasogastric tube and by retention enema) plus IV metronidazole has been used with some success in uncontrolled studies, as has IV tigecycline in small-scale uncontrolled studies. Surgical colectomy may be life-saving if there is no response to medical management. If possible, colectomy should be performed before the serum lactate level reaches 5 mmol/L. The incidence of fulminant CDI requiring colectomy appears to be increasing in the evolving epidemic; however, morbidity and death associated with colectomy may be reduced by performing instead a laparoscopic ileostomy followed by colon lavage with polyethylene glycol and vancomycin infusion into the colon via the ileostomy.

PROGNOSIS

The mortality rate attributed to CDI, previously found to be 0.6–3.5%, has reached 6.9% in recent outbreaks and rises progressively with increasing age. Most patients recover, but recurrences are common.

PREVENTION AND CONTROL

Strategies for the prevention of CDI are of two types: those aimed at preventing transmission of the organism to the patient and those aimed at reducing the risk of CDI if the organism is transmitted. Transmission of C. difficile in clinical practice has been prevented by gloving of personnel, elimination of the use of contaminated electronic thermometers, and use of hypochlorite (bleach) solution for environmental decontamination of patients’ rooms. Hand hygiene is critical; hand washing is recommended in CDI outbreaks because alcohol hand gels are not sporicidal. CDI outbreaks have been best controlled by restricting the use of specific antibiotics, such as clindamycin and second- and third-generation cephalosporins. Outbreaks of CDI due to clindamycin-resistant strains have resolved promptly when clindamycin use is restricted. Future preventive strategies are likely to include use of monoclonal antibodies, vaccines, and biotherapeutics containing live organisms that will restore colonization protection in the microbiota.

Urinary tract infection (UTI) is a common and painful human illness that, fortunately, is rapidly responsive to modern antibiotic therapy. In the preantibiotic era, UTI caused significant morbidity. Hippocrates, writing about a disease that appears to have been acute cystitis, said that the illness could last for a year before either resolving or worsening to involve the kidneys. When chemotherapeutic agents used to treat UTI were introduced in the early twentieth century, they were relatively ineffective, and persistence of infection after 3 weeks of therapy was common. Nitrofurantoin, which became available in the 1950s, was the first tolerable and effective agent for the treatment of UTI.

Since the most common manifestation of UTI is acute cystitis and since acute cystitis is far more prevalent among women than among men, most clinical research on UTI has involved women. Many studies have enrolled women from college campuses or large health maintenance organizations in the United States. Therefore, when reviewing the literature and recommendations concerning UTI, clinicians must consider whether the findings are applicable to their patient populations.

DEFINITIONS

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. However, ASB occurs in the absence of symptoms attributable to the bacteria in the urinary tract and does not usually require treatment, while UTI has more typically been assumed to imply symptomatic disease that warrants antimicrobial therapy. Much of the literature concerning UTI, particularly catheter-associated infection, does not differentiate between UTI and ASB. In this chapter, the term UTI denotes symptomatic disease; cystitis, symptomatic infection of the bladder; and pyelonephritis, symptomatic infection of the kidneys. Uncomplicated UTI refers to acute cystitis or pyelonephritis in nonpregnant outpatient women without anatomic abnormalities or instrumentation of the urinary tract; the term complicated UTI encompasses all other types of UTI. Recurrent UTI is not necessarily complicated; individual episodes can be uncomplicated and treated as such. Catheter-associated bacteriuria can be either symptomatic (CAUTI) or asymptomatic.

EPIDEMIOLOGY AND RISK FACTORS

Except among infants and the elderly, 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 to 4.8 with five episodes of intercourse in the preceding week. 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 common 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 clear 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 pods of infecting organisms within the bladder epithelium have been demonstrated in animal models of UTI, but the importance 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 or to the sloughing of the protective outer bladder epithelial layer in response to bacterial attachment during acute cystitis. 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 preterm birth and perinatal death of the fetus and with pyelonephritis in the mother. A Cochrane meta-analysis found that treatment of ASB in pregnant women decreased the risk of pyelonephritis by 75%.

The majority of men with UTI have a functional or anatomic abnormality of the urinary tract, most commonly urinary obstruction secondary 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 also 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.

Women with diabetes have been found to have a two- to threefold higher rate of ASB and UTI than women without diabetes; there is insufficient evidence to make a corresponding statement about men. Increased duration of diabetes and the use of insulin rather than oral medication are also associated with a higher 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.

ETIOLOGY

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 Europe and Brazil. 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 are also important pathogens in complicated UTI. Data on etiology and resistance are generally obtained from laboratory surveys and should be understood in the context that organism identification is performed only in cases in which urine is sent for culture—i.e., typically, when complicated UTI or pyelonephritis is suspected. The available data demonstrate a worldwide increase in the resistance of E. coli to antibiotics commonly used to treat UTI. North American and European surveys from women with acute cystitis have documented resistance rates of >20% to trimethoprim-sulfamethoxazole (TMP-SMX) and to ciprofloxacin in some regions. In community-acquired infections, the increased prevalence of uropathogens producing extended-spectrum β-lactamases has left few oral options for therapy. 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.

PATHOGENESIS

The urinary tract can be viewed as an anatomic unit united 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. 162-1). 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 true infection. In the simplest of terms, anything that increases the likelihood of bacteria entering the bladder and staying there increases the risk of UTI.

FIGURE 162-1   Pathogenesis of urinary tract infection. The relationship among specific host, pathogen, and environmental factors determines the clinical outcome.

Bacteria can also 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 noninstrumented immunocompetent patient implies either genital contamination or potentially widespread visceral dissemination.

Environmental Factors  •  VAGINAL ECOLOGY   In women, vaginal ecology is an important environmental factor affecting the risk of UTI. 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 microflora 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.

Host Factors 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 non-secretors 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 response genes (e.g., those coding for Toll-like receptors and the interleukin 8 receptor) also have been linked to recurrent UTI and pyelonephritis. Polymorphisms in the interleukin 8–specific receptor gene CXCR1 are associated with increased susceptibility to pyelonephritis. Lower-level expression of CXCR1 on the surface of neutrophils impairs neutrophil-dependent host defense against bacterial invasion of the renal parenchyma.

Microbial Factors 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, hairlike 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 uroplakins on the luminal surface of bladder uroepithelial cells. The binding of type 1 fimbriae of E. coli to receptors on uroepithelial cells initiates a complex series of signaling events that leads to apoptosis and exfoliation of uroepithelial cells, with the attached E. coli organisms carried away in the urine.

FIGURE 162-2   Emphysematous pyelonephritis. Infection of the right kidney of a diabetic man by Escherichia coli, a gas-forming, facultative anaerobic uropathogen, has led to destruction of the renal parenchyma (arrow) and tracking of gas through the retroperitoneal space (arrowhead).

FIGURE 162-3   Xanthogranulomatous pyelonephritis. A. This photograph shows extensive destruction of renal parenchyma due to long-standing suppurative inflammation. The precipitating factor was obstruction by a staghorn calculus, which has been removed, leaving a depression (arrow). The mass effect of xanthogranulomatous pyelonephritis can mimic renal malignancy. B. A large staghorn calculus (arrow) is seen obstructing the renal pelvis and calyceal system. The lower pole of the kidney shows areas of hemorrhage and necrosis with collapse of cortical areas. (Images courtesy of Dharam M. Ramnani, MD, Virginia Urology Pathology Laboratory, Richmond, VA.)

DIAGNOSTIC TOOLS

History The diagnosis of any of the UTI syndromes or ASB begins with a detailed history (Fig. 162-4). 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 self-diagnosis 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. Similarly, 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.

FIGURE 162-4   Diagnostic approach to urinary tract infection (UTI). STD, sexually transmitted disease; CAUTI, catheter-associated UTI; ASB, asymptomatic bacteriuria; CA-ASB, catheter-associated ASB.

When the patient’s history is applied as a diagnostic tool, it is important to recall 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.

The 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. 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 the host’s polymorphonuclear leukocytes in the 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 the same 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. Performance characteristics of the dipstick test differ in men (highly specific) and in noncatheterized nursing home residents (highly sensitive).

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 is the diagnostic “gold standard” for UTI; unfortunately, however, culture results do not become available until 24 h after the patient’s presentation. 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.

DIAGNOSIS

The approach to diagnosis is influenced by which of the clinical UTI syndromes is suspected (Fig. 162-4).

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. These recommendations are made with the caveat that no factors associated with complicated UTI, such as pregnancy, are known to be present.

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. If the diagnosis is unclear, localization cultures using the two- or four-glass Meares-Stamey test (urine collection after prostate massage) should be undertaken to differentiate between bacterial and nonbacterial prostatic syndromes, and the patient should be referred to a urologist. 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 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.

Asymptomatic Bacteriuria   The diagnosis of ASB involves both microbiologic and clinical criteria. The microbiologic criterion is usually ≥10⁵ bacterial CFU/mL except in catheter-associated disease, in which ≥10² CFU/mL is the cutoff. The clinical criterion is that the person has no signs or symptoms referable to UTI.

Antimicrobial therapy is warranted for any symptomatic UTI. The choice of antimicrobial agent and the dose and 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. 162-4). 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 white women who are at low risk for 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. Antibiotic resistance among uropathogens causing uncomplicated cystitis has since 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. Outbreaks of Clostridium difficile infection offer an example of collateral damage in the hospital environment. The implication of collateral damage in this context 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 change 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.

Several effective therapeutic regimens are available for acute uncomplicated cystitis in women (Table 162-1). Well-studied first-line agents include TMP-SMX and nitrofurantoin. Second-line agents include fluoroquinolone and β-lactam compounds. Single-dose fosfomycin treatment for acute cystitis is widely used in Europe but has produced mixed results in randomized trials. There is increasing experience with the use of fosfomycin against UTIs (including complicated infections) caused by multidrug-resistant E. coli. 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 other therapies 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%. 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. 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. Since this drug affects bacterial metabolism in multiple pathways, several mutational steps are required for the development of resistance. 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, similar microbiologic and clinical efficacies are noted with a 5-day course of nitrofurantoin or a 3-day course of TMP-SMX for treatment of women with 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.

Most fluoroquinolones are highly effective as short-course therapy for cystitis; the exception is moxifloxacin, which may not reach adequate urinary levels. The fluoroquinolones commonly used for UTI include ofloxacin, ciprofloxacin, and levofloxacin. The main concern about fluoroquinolone use for acute cystitis is 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. Fluoroquinolone use is also a factor driving the emergence of C. difficile outbreaks in hospital settings. Most experts now call for restricting fluoroquinolones to specific instances of uncomplicated cystitis in which other antimicrobial agents are not suitable. Quinolone use in certain populations, including adults >60 years of age, has been associated with an increased risk of Achilles tendon rupture.

Except for pivmecillinam, β-lactam agents generally have not performed as well as TMP-SMX 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. A proposed role for intracellular biofilm communities is intriguing. 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.

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.

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 TMP-SMX 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, ticarcillin-clavulanate, piperacillin-tazobactam) or imipenem-cilastatin can be used in patients with more complicated histories, previous episodes of pyelonephritis, or recent urinary tract manipulations; in general, the treatment of such patients should be guided by urine culture results. 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 the drugs of choice for the treatment of asymptomatic or symptomatic UTI in this group of patients. 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. 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 (other than that discussed above) occurs in a heterogeneous group of patients with a wide variety of 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 awaited. 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, while the threshold for bacteriuria to meet the definition of ASB is ≥10⁵ CFU/mL.

The formation of biofilm—a living layer of uropathogens—on the urinary catheter is central to the pathogenesis of CAUTI and affects both therapeutic and preventive strategies. Organisms in a biofilm are relatively resistant to killing by antibiotics, and eradication of a catheter-associated biofilm is difficult without removal of the device itself. Furthermore, because 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 predict 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.

In the setting of long-term catheter use, systemic antibiotics, bladder-acidifying agents, antimicrobial bladder washes, topical disinfectants, and antimicrobial drainage-bag solutions have all been ineffective at preventing the onset of bacteriuria and have been associated with the emergence of resistant organisms. The best strategy for prevention of CAUTI is to avoid insertion of unnecessary catheters and to remove catheters once they are no longer necessary. Evidence is insufficient to recommend suprapubic catheters and condom catheters as alternatives to indwelling urinary catheters as a means to prevent CAUTI. However, intermittent catheterization may be preferable to long-term indwelling urethral catheterization in certain populations (e.g., spinal cord–injured persons) to prevent both infectious and anatomic complications. Antimicrobial catheters impregnated with silver or nitrofurazone have not been shown to provide significant clinical benefit in terms of reducing rates of symptomatic UTI.

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 an asymptomatic laboratory finding 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. Treatment 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 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.

PREVENTION OF RECURRENT UTI IN WOMEN

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, a fluoroquinolone, 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.

PROGNOSIS

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, 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. In spinal cord–injured patients, use of a long-term indwelling bladder catheter is a well-documented risk factor for bladder cancer. Chronic bacteriuria resulting in chronic inflammation is one possible explanation for this observation.

CLASSIFICATION AND EPIDEMIOLOGY

Worldwide, most adults acquire at least one sexually transmitted infection (STI), and many remain at risk for complications. Each year, for example, an estimated 14 million persons in the United States acquire a new genital human papillomavirus (HPV) infection, and many of these individuals are at risk for genital neoplasias. Certain STIs, such as syphilis, gonorrhea, HIV infection, hepatitis B, and chancroid, are most concentrated within “core populations” characterized by high rates of partner change, multiple concurrent partners, or “dense,” highly connected sexual networks—e.g., involving sex workers and their clients, some men who have sex with men (MSM), and persons involved in the use of illicit drugs, particularly crack cocaine and methamphetamine. Other STIs are distributed more evenly throughout societies. For example, chlamydial infections, genital infections with HPV, and genital herpes can spread widely, even in relatively low-risk populations.

In general, the product of three factors determines the initial rate of spread of any STI within a population: rate of sexual exposure of susceptible to infectious people, efficiency of transmission per exposure, and duration of infectivity of those infected. Accordingly, efforts to prevent and control STIs aim to decrease the rate of sexual exposure of susceptibles to infected persons (e.g., through individual counseling and efforts to change the norms of sexual behavior and through a variety of STI control efforts aimed at reducing the proportion of the population infected), to decrease the duration of infectivity (through early diagnosis and curative or suppressive treatment), and to decrease the efficiency of transmission (e.g., through promotion of condom use and safer sexual practices, through use of effective vaccines, and recently through male circumcision).

In all societies, STIs rank among the most common of all infectious diseases, with >30 infections now classified as predominantly sexually transmitted or as frequently sexually transmissible (Table 163-1). In developing countries, with three-quarters of the world’s population and 90% of the world’s STIs, factors such as population growth (especially in adolescent and young-adult age groups), rural-to-urban migration, wars, limited or no provision of reproductive health services for women, and poverty create exceptional vulnerability to disease resulting from unprotected sex. During the 1990s in China, Russia, the other states of the former Soviet Union, and South Africa, internal social structures changed rapidly as borders opened to the West, unleashing enormous new epidemics of HIV infection and other STIs. Despite advances in the provision of highly effective antiretroviral therapy worldwide, HIV remains the leading cause of death in some developing countries, and HPV and hepatitis B virus (HBV) remain important causes of cervical and hepatocellular carcinoma, respectively—two of the most common malignancies in the developing world. Sexually transmitted herpes simplex virus (HSV) infections now cause most genital ulcer disease throughout the world and an increasing proportion of cases of genital herpes in developing countries with generalized HIV epidemics, where the positive-feedback loop between HSV and HIV transmission is a growing, intractable problem. Despite this consistent link, randomized trials evaluating the efficacy of antiviral therapy in suppressing HSV in both HIV-uninfected and HIV-infected persons have not demonstrated a protective effect against acquisition or transmission of HIV. The World Health Organization estimated that 448 million new cases of four curable STIs—gonorrhea, chlamydial infection, syphilis, and trichomoniasis—occurred in 2005. Up to 50% of women of reproductive age in developing countries have bacterial vaginosis (arguably acquired sexually). All of these curable infections have been associated with increased risk of HIV transmission or acquisition.

In the United States, the prevalence of antibody to HSV-2 began to fall in the late 1990s, especially among adolescents and young adults; the decline is presumably due to delayed sexual debut, increased condom use, and lower rates of multiple (four or more) sex partners, as is well documented by the U.S. Youth Risk Behavior Surveillance System. The estimated annual incidence of HBV infection has also declined dramatically since the mid-1980s; this decrease is probably attributable more to adoption of safer sexual practices and reduced needle sharing among injection drug users than to use of hepatitis B vaccine, for which coverage among young adults (including those at high risk for this infection) initially was very limited. Genital HPV remains the most common sexually transmitted pathogen in this country, infecting 60% of a cohort of initially HPV-negative, sexually active Washington state college women within 5 years in a study conducted from 1990 to 2000. The scale-up of HPV vaccine coverage among young women has already shown promise in reducing the incidence of infection with the HPV types included in the vaccines and of conditions associated with these viruses.

In industrialized countries, fear of HIV infection since the mid-1980s, coupled with widespread behavioral interventions and better-organized systems of care for the curable STIs, initially helped curb the transmission of the latter diseases. However, foci of hyperendemic transmission persist in the southeastern United States and in most large U.S. cities. Rates of gonorrhea and syphilis remain higher in the United States than in any other Western industrialized country.

In the United States, the Centers for Disease Control and Prevention (CDC) has compiled reported rates of STIs since 1941. The incidence of reported gonorrhea peaked at 468 cases per 100,000 population in the mid-1970s and fell to a low of 98 cases per 100,000 in 2012. With increased testing and more sensitive tests, the incidence of reported Chlamydia trachomatis infection has been increasing steadily since reporting began in 1984, reaching an all-time peak of 457.6 cases per 100,000 in 2011. The incidence of primary and secondary syphilis per 100,000 peaked at 71 cases in 1946, fell rapidly to 3.9 cases in 1956, ranged from ~10 to 15 cases through 1987 (with markedly increased rates among MSM and African Americans), and then fell to a nadir of 2.1 cases in 2000–2001 (with rates falling most rapidly among heterosexual African Americans). Unfortunately, since 1996, with the introduction of highly active antiretroviral therapy, the increased use of “serosorting” (i.e., the avoidance of unprotected sex with HIV-serodiscordant partners but not with HIV-seroconcordant partners, a strategy that provides no protection against STIs other than HIV infection), and an ongoing epidemic of methamphetamine use, gonorrhea, syphilis, and chlamydial infection have had a remarkable resurgence among MSM in North America and Europe, where outbreaks of a rare type of chlamydial infection (lymphogranuloma venereum [LGV]) that had virtually disappeared during the AIDS era have occurred. In 2012, ~75% of primary and secondary syphilis cases reported to the CDC were in MSM. These developments have resulted in a high degree of co-infection with HIV and other sexually transmitted pathogens (particularly syphilis and LGV), primarily among MSM.

MANAGEMENT OF COMMON SEXUALLY TRANSMITTED DISEASE (STD) SYNDROMES

Although other chapters discuss management of specific STIs, delineating treatment based on diagnosis of a specific infection, most patients are actually managed (at least initially) on the basis of presenting symptoms and signs and associated risk factors, even in industrialized countries. Table 163-2 lists some of the most common clinical STD syndromes and their microbial etiologies. Strategies for their management are outlined below. Chapters 225e and 226 address the management of infections with human retroviruses.

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