InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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, Clostridium difficile Infection, Including Pseudomembranous Colitis Type of Test Relative Sensitivitya Relative Specificitya Comment Stool culture for C. difficile ++++ +++ Most sensitive test; specificity of ++++ if the C. difficile isolate tests positive for toxin; with clinical data, is diagnostic of CDI; turnaround time too slow for practical use Cell culture cytotoxin test on stool +++ ++++ With clinical data, is diagnostic of CDI; highly specific but not as sensitive as stool culture; slow turnaround time


InternalMed_Harrison

InternalMed_Harrison. Cell culture cytotoxin test on stool +++ ++++ With clinical data, is diagnostic of CDI; highly specific but not as sensitive as stool culture; slow turnaround time Enzyme immunoassay for toxin A or ++ to +++ +++ With clinical data, is diagnostic of CDI; rapid results, but not as sen-toxins A and B in stool sitive as stool culture or cell culture cytotoxin test Enzyme immunoassay for C. difficile +++ to ++++ +++ Detects glutamate dehydrogenase found in toxigenic and non-common antigen in stool toxigenic strains of C. difficile and other stool organisms; more sensitive and less specific than enzyme immunoassay for toxins; rapid results Nucleic acid amplification tests for ++++ ++++ Detect toxigenic C. difficile in stool; newly approved for clinical test- C. difficile toxin A or B gene in stool ing, but appears to be more sensitive than enzyme immunoassay toxin testing and at least as specific


InternalMed_Harrison

InternalMed_Harrison. C. difficile toxin A or B gene in stool ing, but appears to be more sensitive than enzyme immunoassay toxin testing and at least as specific Colonoscopy or sigmoidoscopy + ++++ Highly specific if pseudomembranes are seen; insensitive compared with other tests aAccording to both clinical and test-based criteria. ++++, >90%; +++, 71–90%; ++, 51–70%; +, ~50%.


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InternalMed_Harrison. 860 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. Initial episode, mild to moderate Metronidazole (500 mg tid × 10–14 d) Vancomycin (125 mg qid × 10–14 d) may be more effective than metronidazole. Fidaxomicin (200 mg bid × 10 d) is another alternative. Initial episode, severe Vancomycin (125 mg qid × 10–14 d) Indicators of severe disease may include leukocytosis (≥15,000 white blood cells/μL) and a creatinine level ≥1.5 times the premorbid value. Fidaxomicin is an alternative. Initial episode, severe compli-Vancomycin (500 mg PO or via nasogastric tube) plus Severe complicated or fulminant CDI is defined as severe CDI cated or fulminant metronidazole (500 mg IV q8h) plus consider with the addition of hypotension, shock, ileus, or toxic megacolon. The duration of treatment may need to be >2 weeks and is Rectal instillation of vancomycin (500 mg in 100 mL of dictated by response. Consider using tigecycline (50 mg IV q12h normal saline as a retention enema q6–8h) after a 100-mg loading dose) in place of metronidazole.


InternalMed_Harrison

InternalMed_Harrison. First recurrence Same as for initial episode Adjust treatment if severity of CDI has changed with recurrence. Consider fidaxomicin, which significantly decreases the likelihood of additional recurrences. Second recurrence Vancomycin in taper/pulse regimen Typical taper/pulse regimen: 125 mg qid × 10–14 d, then bid × 1 week, then daily × 1 week, then q2–3d for 2–8 weeks. Multiple recurrences Consider the following options: The only controlled studies that included patients with one or more recurrent CDI episodes were with vancomycin and S. boulardii, which showed borderline significance compared with vancomycin plus placebo, and fecal microbiota transplantation, boulardii (500 mg bid × 28 d) which was highly significant compared with a high-dose course (125 mg qid × 10–14 d); then stop vanco-of vancomycin. (The vancomycin taper was not compared.) mycin and start rifaximin (400 mg bid × 2 weeks) aAll agents are given orally unless otherwise specified.


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InternalMed_Harrison. strain of C. difficile. None of these biotherapeutic approaches has been approved by the FDA for use in the United States. Other nonFDA-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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 secondand 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. urinary Tract Infections, 162 Pyelonephritis, and Prostatitis Kalpana Gupta, Barbara W. Trautner 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Urinary Tract Infections, Pyelonephritis, and Prostatitis 862 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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 twoto 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 Type of organism Genetic background Infection, colonization, or elimination HostOrganism Behavioral factors Underlying disease Tissue-specific receptors Presence of virulence factors Expression of virulence factors


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InternalMed_Harrison. Infection, colonization, or elimination HostOrganism Behavioral factors Underlying disease Tissue-specific receptors Presence of virulence factors Expression of virulence factors FIGURE 162-1 Pathogenesis of urinary tract infection. The relationship among specific host, pathogen, and environmental factors determines the clinical outcome. immunocompetent patient implies either genital contamination or potentially widespread visceral dissemination.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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)


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 863 exfoliation of uroepithelial cells, with the attached E. coli organisms carried away in the urine. APPROACH TO THE PATIENT: 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.


InternalMed_Harrison

InternalMed_Harrison. 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 that of a patient who undergoes a screening urine culture for a reason unrelated to the genitourinary tract and is incidentally found to have bacteriuria. The presence of systemic signs or symptoms such as fever, altered mental status, and leukocytosis in the setting of a positive urine culture does not merit a diagnosis of symptomatic UTI unless other potential etiologies have been considered. 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 is generally an indication that the upper urinary tract is involved. Fever also is an indication of invasive infection of either the kidney or the prostate.


InternalMed_Harrison

InternalMed_Harrison. 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 and 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


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InternalMed_Harrison. 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. 162-2). Xanthogranulomatous pyelonephritis occurs when chronic urinary obstruction (often by stag-horn calculi), together with chronic infection, leads to suppurative destruction of renal tissue (Fig. 162-3). 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 situation should be suspected when a patient has continued fever and/or bacteremia despite antibacterial therapy.


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


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InternalMed_Harrison. 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. Complicated UTI presents as a symptomatic episode of cystitis or pyelonephritis in a man or woman with an anatomic predisposition to infection, with a foreign body in the urinary tract, or with factors predisposing to a delayed response to therapy.


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. FIGURE 162-3 Xanthogranulomatous pyelonephritis. A. This photograph shows extensive destruction of renal parenchyma due to longstanding 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.)


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InternalMed_Harrison. Acute onset of Back pain Nausea/vomiting Fever Cystitis symptoms Acute onset of urinary symptoms Dysuria Frequency Urgency Non-localizing systemic symptoms of infection Fever Altered mental status Leukocytosis Positive urine culture in the absence of Urinary symptoms Systemic symptoms related to the urinary tract Recurrent acute urinary symptoms Male with perineal, pelvic, or prostatic pain All other patients Woman with unclear history or risk factors for STD Otherwise healthy woman who is not pregnant, clear history Patient who is pregnant, is a renal transplant recipient, or will undergo an invasive urologic procedure Otherwise healthy woman who is not pregnant Patient with urinary catheter All other patients All other patients Otherwise healthy woman who is not pregnant Male No obvious non-urinary cause Consider acute prostatitis Urinalysis and culture Consider urology evaluation Consider uncomplicated cystitis or STD Dipstick, urinalysis, and culture STD evaluation, pelvic exam


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InternalMed_Harrison. non-urinary cause Consider acute prostatitis Urinalysis and culture Consider urology evaluation Consider uncomplicated cystitis or STD Dipstick, urinalysis, and culture STD evaluation, pelvic exam Consider uncomplicated cystitis No urine culture needed Consider telephone management Consider complicated UTI, CAUTI, or pyelonephritis Urine culture Blood cultures Exchange or remove catheter if present Consider complicated UTI Urinalysis and culture Address any modifiable anatomic or functional abnormalities Consider uncomplicated pyelonephritis Urine culture Consider outpatient management Consider ASB Screening and treatment warranted Consider pyelonephritis Urine culture Blood cultures Consider ASB No additional workup or treatment needed Consider CA-ASB No additional workup or treatment needed Remove unnecessary catheters Consider recurrent cystitis Urine culture to establish diagnosis Consider prophylaxis or patient-initiated management Consider chronic bacterial prostatitis


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InternalMed_Harrison. needed Remove unnecessary catheters Consider recurrent cystitis Urine culture to establish diagnosis Consider prophylaxis or patient-initiated management Consider chronic bacterial prostatitis Meares-Stamey 4-glass test Consider urology consult


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InternalMed_Harrison. Urinary Tract Infections, Pyelonephritis, and Prostatitis 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.


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InternalMed_Harrison. disease. Either nitrite or leukocyte esterase positivity can be interpreted differ in men (highly specific) and in noncatheterized nursing home as a positive result. Blood in the urine also may suggest a diagnosis of residents (highly sensitive). UTI. A dipstick test negative for both nitrite and leukocyte esterase Urine microscopy reveals pyuria in nearly all cases of cystitis and in the same type of patient should prompt consideration of other hematuria in ~30% of cases. In current practice, most hospital laboratoexplanations for the patient’s symptoms and collection of urine for ries use an automated system rather than manual examination for urine culture. A negative dipstick test is not sufficiently sensitive to rule out microscopy. A machine aspirates a sample of the urine and then classifies bacteriuria in pregnant women, in whom it is important to detect all the particles in the urine by size, shape, contrast, light scatter, volume, and episodes of bacteriuria. Performance


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InternalMed_Harrison. classifies bacteriuria in pregnant women, in whom it is important to detect all the particles in the urine by size, shape, contrast, light scatter, volume, and episodes of bacteriuria. Performance characteristics of the dipstick test other properties. These automated systems can be overwhelmed by high 866 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 twoor 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Asymptomatic Bacteriuria The diagnosis of ASB involves both micro-biologic 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 multidrugresistant 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.


InternalMed_Harrison

InternalMed_Harrison. 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 TMPSMX 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. aMicrobial response as measured by reduction of bacterial counts in the urine.


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InternalMed_Harrison. aMicrobial response as measured by reduction of bacterial counts in the urine. Note: Efficacy rates are averages or ranges calculated from the data and studies included in the 2010 Infectious Diseases Society of America/European Society of Clinical Microbiology and Infectious Diseases Guideline for Treatment of Uncomplicated UTI. TMP-SMX, trimethoprim-sulfamethoxazole; DS, double-strength.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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-totreat 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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, ticarcillinclavulanate, 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 7to 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 4to 6-week course of antibiotics is often necessary. Recurrences, which are not uncommon in chronic prostatitis, often warrant a 12-week course of treatment.


InternalMed_Harrison

InternalMed_Harrison. 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 Urinary Tract Infections, Pyelonephritis, and Prostatitis 868 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.


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InternalMed_Harrison. 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. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 longterm 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.


InternalMed_Harrison

InternalMed_Harrison. 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 7to 14-day course of antibiotics is recommended, but further studies on the optimal duration of therapy are needed.


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 longterm indwelling bladder catheter is a well-documented risk factor for bladder cancer. Chronic bacteriuria resulting in chronic inflammation is one possible explanation


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InternalMed_Harrison. patients, use of a longterm 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.


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InternalMed_Harrison. Sexually Transmitted Infections: overview and Clinical Approach Jeanne M. Marrazzo, King K. Holmes CLASSIFICATION AND EPIDEMIOLOGY Worldwide, most adults acquire at least one sexually transmitted infec-163 tion (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,


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. In all societies, STIs rank among the most common of all infectious diseases, with >30 infections now classified as pre dominantly 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Sexual Transmission Repeatedly Described but Not Well Defined or Not the Predominant Mode Transmitted by Sexual Contact Involving Oral-Fecal Exposure; of Declining Importance in Men Who Have Sex with Men Shigella spp. Hepatitis A virus Giardia lamblia Campylobacter spp. aIncludes protozoa, ectoparasites, and fungi. bAmong U.S. patients for whom a risk factor can be ascertained, most hepatitis B virus infections are transmitted sexually.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. In industrialized countries, fear of HIV infection since the mid1980s, 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. Sexually Transmitted Infections: Overview and Clinical Approach 870 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 HIVserodiscordant 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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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InternalMed_Harrison. STD care and management begin with risk assessment and proceed to clinical assessment, diagnostic testing or screening, treatment, and prevention. Indeed, the routine care of any patient begins with risk assessment (e.g., for risk of heart disease, cancer). STD/HIV risk assessment is important in primary care, urgent care, and emergency care settings as well as in specialty clinics providing adolescent, HIV/ AIDS, prenatal, and family planning services. STD/HIV risk assessment guides detection and interpretation of symptoms that could reflect an STD; decisions on screening or prophylactic/preventive treatment; risk reduction counseling and intervention (e.g., hepatitis B vaccination); and treatment of partners of patients with known infections. Consideration of routine demographic data (e.g., gender, age, area of residence) is a simple first step in STD/HIV risk assessment. For example, national guidelines strongly recommend routine screening of sexually active females ≤25 years of


InternalMed_Harrison

InternalMed_Harrison. (e.g., gender, age, area of residence) is a simple first step in STD/HIV risk assessment. For example, national guidelines strongly recommend routine screening of sexually active females ≤25 years of age for C. trachomatis infection. Table 163-3 provides a set of 11 STD/HIV risk-assessment questions that clinicians can pose verbally or that health care systems can adapt (with yes/no responses) into a routine self-administered questionnaire for use in clinics. The initial framing statement gives permission to discuss topics that may be perceived as sensitive or socially unacceptable by providers and patients alike.


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InternalMed_Harrison. Risk assessment is followed by clinical assessment (elicitation of information on specific current symptoms and signs of STDs). Confirmatory diagnostic tests (for persons with symptoms or signs) or screening tests (for those without symptoms or signs) may involve microscopic examination, culture, antigen detection tests, nucleic acid amplification tests (NAATs), or serology. Initial syndrome-based treatment should cover the most likely causes. For certain syndromes, results of rapid tests can narrow the spectrum of this initial therapy (e.g., saline microscopy of vaginal fluid for women with vaginal discharge, Gram’s stain of urethral discharge for men with urethral discharge, rapid plasma reagin test for genital ulcer). After the institution of treatment, STD management proceeds to the “4 Cs” of prevention and control: contact tracing (see “Prevention and Control of STIs,” below), ensuring compliance with therapy, and counseling on risk reduction, including condom promotion and


InternalMed_Harrison

InternalMed_Harrison. the “4 Cs” of prevention and control: contact tracing (see “Prevention and Control of STIs,” below), ensuring compliance with therapy, and counseling on risk reduction, including condom promotion and provision.


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InternalMed_Harrison. Consistent with current guidelines, all adults should be screened for infection with HIV-1 at least once and more frequently if they are at elevated risk for acquisition of this infection. Urethritis in men produces urethral discharge, dysuria, or both, usually without frequency of urination. Causes include Neisseria gonorrhoeae, AIDS HIV types 1 and 2 Urethritis: males Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum (subspecies urealyticum), Trichomonas vaginalis, HSV Epididymitis C. trachomatis, N. gonorrhoeae Lower genital tract infections: females Cystitis/urethritis C. trachomatis, N. gonorrhoeae, HSV Mucopurulent cervicitis C. trachomatis, N. gonorrhoeae, M. genitalium Vulvitis Candida albicans, HSV Vulvovaginitis C. albicans, T. vaginalis Acute pelvic inflammatory N. gonorrhoeae, C. trachomatis, disease BV-associated bacteria, M. genitalium, group B streptococci


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InternalMed_Harrison. Vulvovaginitis C. albicans, T. vaginalis Acute pelvic inflammatory N. gonorrhoeae, C. trachomatis, disease BV-associated bacteria, M. genitalium, group B streptococci Infertility N. gonorrhoeae, C. trachomatis, BV-associated bacteria Ulcerative lesions of the HSV-1, HSV-2, Treponema pallidum, genitalia Haemophilus ducreyi, C. trachomatis (LGV strains), Klebsiella (Calymmatobacterium) granulomatis Complications of pregnancy/ Several agents implicated puerperium Intestinal infections Proctitis C. trachomatis, N. gonorrhoeae, HSV, T. pallidum Proctocolitis or enterocolitis Campylobacter spp., Shigella spp., Entamoeba histolytica, Helicobacter spp., other enteric pathogens Enteritis Giardia lamblia Acute arthritis with urogenital N. gonorrhoeae (e.g., DGI), C. trachomatis infection or viremia (e.g., reactive arthritis), HBV Genital and anal warts HPV (30 genital types) Mononucleosis syndrome CMV, HIV, EBV Hepatitis Hepatitis viruses, T. pallidum, CMV, EBV Neoplasias


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InternalMed_Harrison. Squamous cell dysplasias and HPV (especially types 16, 18, 31, 45) cancers of the cervix, anus, vulva, vagina, or penis Kaposi’s sarcoma, body-cavity HHV-8 lymphomas T cell leukemia HTLV-1 Hepatocellular carcinoma HBV Tropical spastic paraparesis HTLV-1 Scabies Sarcoptes scabiei Pubic lice Pthirus pubis Abbreviations: BV, bacterial vaginosis; CMV, cytomegalovirus; DGI, disseminated gonococcal infection; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HHV-8, human herpesvirus type 8; HPV, human papillomavirus; HSV, herpes simplex virus; HTLV, human T cell lymphotropic virus; LGV, lymphogranuloma venereum. C. trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis, HSV, and adenovirus.


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InternalMed_Harrison. C. trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis, HSV, and adenovirus. Until recently, C. trachomatis caused ~30–40% of cases of nongonococcal urethritis (NGU), particularly in heterosexual men; however, the proportion of cases due to this organism has probably declined in some populations served by effective chlamydial-control programs, and older men with urethritis appear less likely to have chlamydial infection. HSV and T. vaginalis each cause a small proportion of NGU cases in the United States. Recently, multiple studies have consistently implicated M. genitalium as a probable cause of many Framing Statement: In order to provide the best care for you today and to understand your risk for certain infections, it is necessary for us to talk about your sexual behavior. Screening Questions: Do you have any reason to think you might have a sexually transmitted infection? If so, what reason?


InternalMed_Harrison

InternalMed_Harrison. Screening Questions: Do you have any reason to think you might have a sexually transmitted infection? If so, what reason? For all adolescents <18 years old: Have you begun having any kind of sex yet? STD History: (3) Have you ever had any sexually transmitted infections or any genital infections? If so, which ones? Sexual Preference: (4) Have you had sex with men, women, or both? Injection Drug Use: Have you ever injected yourself (“shot up”) with drugs? (If yes, have you ever shared needles or injection equipment?) Have you ever had sex with a gay or bisexual man or with anyone who had ever injected drugs? Characteristics of Partner(s): Has your sex partner had any sexually transmitted infections? If so, which ones? Has your sex partner had other sex partners during the time you’ve been together? STD Symptoms Checklist: (9) Have you recently developed any of these symptoms?


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InternalMed_Harrison. Has your sex partner had other sex partners during the time you’ve been together? STD Symptoms Checklist: (9) Have you recently developed any of these symptoms? Sexual Practices, Past 2 Months (for patients answering yes to any of the above questions, to guide examination and testing): Now I’d like to ask what parts of your body may have been sexually exposed to an STD (e.g., your penis, mouth, vagina, anus). Query about Interest in STD Screening Tests (for patients answering no to all of the above questions): Would you like to be tested for HIV or any other STDs today? (If yes, clinician can explore which STD and why.) Source: Adapted from JR Curtis, KK Holmes, in KK Holmes et al (eds): Sexually Transmitted Diseases, 4th ed. New York, McGraw-Hill, 2008. Chlamydia-negative cases. Fewer studies than in the past have implicated Ureaplasma; the ureaplasmas have been differentiated into U. urealyticum and Ureaplasma parvum, and a few studies suggest that


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InternalMed_Harrison. U. urealyticum—but not U. parvum—is associated with NGU. Coliform bacteria can cause urethritis in men who practice insertive anal intercourse. The initial diagnosis of urethritis in men currently includes specific tests only for N. gonorrhoeae and C. trachomatis; it does not yet include testing for Mycoplasma or Ureaplasma species. The following summarizes the approach to the patient with suspected urethritis: 1. Establish the presence of urethritis. If proximal-to-distal “milking” of the urethra does not express a purulent or mucopurulent discharge, even after the patient has not voided for several hours (or preferably overnight), a Gram’s-stained smear of an anterior urethral specimen obtained by passage of a small urethrogenital swab 2–3 cm into the urethra usually reveals ≥5 neutrophils per 1000× field in areas containing cells; in gonococcal infection, such a smear usually reveals gram-negative intracellular diplococci as well. Alternatively, the centrifuged sediment of the


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InternalMed_Harrison. per 1000× field in areas containing cells; in gonococcal infection, such a smear usually reveals gram-negative intracellular diplococci as well. Alternatively, the centrifuged sediment of the first 20–30 mL of voided urine—ideally collected as the first morning specimen— can be examined for inflammatory cells, either by microscopy showing ≥10 leukocytes per high-power field or by the leukocyte esterase test. Patients with symptoms who lack objective evidence of urethritis may have functional rather than organic problems and generally do not benefit from repeated courses of antibiotics.


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InternalMed_Harrison. 2. Evaluate for complications or alternative diagnoses. A brief history 871 and examination will exclude epididymitis and systemic complications, such as disseminated gonococcal infection (DGI) and reactive arthritis. Although digital examination of the prostate gland seldom contributes to the evaluation of sexually active young men with urethritis, men with dysuria who lack evidence of urethritis as well as sexually inactive men with urethritis should undergo prostate palpation, urinalysis, and urine culture to exclude bacterial prostatitis and cystitis. 3.


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InternalMed_Harrison. Evaluate for gonococcal and chlamydial infection. An absence of typical gram-negative diplococci on Gram’s-stained smear of urethral exudate containing inflammatory cells warrants a preliminary diagnosis of NGU, as this test is 98% sensitive for the diagnosis of gonococcal urethral infection. However, an increasing proportion of men with symptoms and/or signs of urethritis are simultaneously assessed for infection with N. gonorrhoeae and C. trachomatis by “multiplex” NAATs of first-voided urine. The urine specimen tested should consist of the first 10–15 mL of the stream, and, if possible, patients should not have voided for the prior 2 h. Culture or NAAT for N. gonorrhoeae may yield positive results when Gram’s staining is negative; certain strains of N. gonorrhoeae can result in negative urethral Gram’s stains in up to 30% of cases of urethral infection. Results of tests for gonococcal and chlamydial infection predict the patient’s prognosis (with greater risk for recurrent NGU if


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InternalMed_Harrison. urethral Gram’s stains in up to 30% of cases of urethral infection. Results of tests for gonococcal and chlamydial infection predict the patient’s prognosis (with greater risk for recurrent NGU if neither chlamydiae nor gonococci are found than if either is detected) and can guide both the counseling given to the patient and the management of the patient’s sexual partner(s).


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InternalMed_Harrison. 4. Treat urethritis promptly while test results are pending. Table 163-4 summarizes the steps in management of sexually active men with urethral discharge and/or dysuria.


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InternalMed_Harrison. In practice, if Gram’s stain does not reveal gonococci, urethritis is treated with a regimen effective for NGU, such as azithromycin or doxycycline. Both are effective, although azithromycin may give better results in M. genitalium infection. If gonococci are demonstrated by Gram’s stain or if no diagnostic tests are performed to exclude gonorrhea definitively, treatment should include parenteral cephalosporin therapy for gonorrhea (Chap. 181) plus oral azithromycin, primarily for additive activity against N. gonorrhoeae given concerns about evolving antibiotic resistance. Azithromycin also treats C. trachomatis, which often causes urethral co-infection in men with gonococcal urethritis. Ideally, sexual partners should be tested for gonorrhea and chlamydial infection; regardless of whether they are tested for these infections, however, they should receive the same regimen given to the male index case. Patients with confirmed persistence or recurrence of urethritis after treatment