Urinary Tract Infections

Prim Care Clin Office Pract 35 (2008) 345–367

Urinary Tract Infections Dimitri M. Drekonja, MDa,b,*, James R. Johnson, MDa,b a

Minneapolis Veterans Affairs Medical Center, Infectious Diseases (111F), 1 Veterans Drive, Minneapolis, MN 55417, USA b Division of Infectious Diseases and International Medicine, University of Minnesota, MMC 250, 420 Delaware Street S.E., Minneapolis, MN 55455, USA

Urinary tract infection (UTI) is among the most frequently encountered bacterial infections in the office setting. In addition, UTI is a major cause of hospital admissions, is responsible for significant morbidity and mortality, and has a large associated economic burden, with estimated annual costs in the United States ranging from $1.6 to $2.5 billion [1,2]. The spectrum of severity ranges from asymptomatic bacteriuria to septic shock with multiorgan system failure. Because UTI occurs so frequently and can cause serious sequelae or lead to unnecessary testing and antimicrobial exposure if managed inappropriately, all practicing physicians should be able to diagnose and manage different types of UTI properly. This review addresses the clinical spectrum of UTI; the etiology, microbiology, diagnosis, and treatment of various UTI syndromes; and the areas of uncertainty in the field. Prostatitis, a related topic, is reviewed elsewhere [3,4].

Acute uncomplicated cystitis in women Acute cystitis, also known as lower UTI, is an acute bacterial infection of the urinary bladder or urethra. The term uncomplicated refers to the absence of known predisposing conditions that affect the microbiology, incidence, and recurrence rates of UTI (Table 1), as discussed in a subsequent section of this article. Uncomplicated cystitis occurs most commonly among women of childbearing age. Characteristic symptoms include dysuria, urinary frequency or urgency, suprapubic pain, and, sometimes, low back pain.

* Corresponding author. Minneapolis Veterans Affairs Medical Center, Infectious Diseases (111F), 1 Veterans Drive, Minneapolis, MN 55417. E-mail address: [email protected] (D.M. Drekonja). 0095-4543/08/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.pop.2008.01.001

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Table 1 Underlying conditions that define a urinary tract infection as complicated Category

Specific condition

Anatomic/functional

Solitary kidney Polycystic kidney(s) Instrumentation Indwelling or intermittent catheter Ureteral stent Percutaneous nephrostomy tube Vesicoureteral reflux Surgical reconstruction Ileal diversion Bladder augmentation Renal transplant Duplicated collecting system Enlarged prostate Calculi Neurogenic bladder Ureteral obstruction other than calculi Tumor Fibrosis Stricture Diabetes mellitus Chronic renal failure

Obstruction

Medical

Escherichia coli causes 75% to 90% of episodes, and Staphylococcus saprophyticus causes 5% to 15% of cases. Less common pathogens include enterococci and gram-negative bacilli other than E coli, such as Klebsiella species and Proteus mirabilis [5]. Risk factors for uncomplicated cystitis include sexual intercourse, use of spermicide-based contraception, delayed postcoital micturition, and a history of recent UTI [6,7]. Other infections that should be considered in the differential diagnosis are urethritis attributable to Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus (HSV) and vaginitis attributable to Candida or Trichomonas species. Vaginal discharge or irritation lowers the probability of UTI and should prompt consideration of urethritis or vaginitis. A recent meta-analysis that examined specific combinations of symptoms demonstrated that the presence of dysuria and urinary frequency, combined with the absence of vaginal discharge or irritation, had a positive likelihood rate for UTI of greater than 90%, whereas a history of vaginal discharge or irritation significantly reduced the likelihood of UTI [8]. Microbiologic confirmation of UTI relies on demonstrating significant bacteriuria or funguria in a voided midstream urine sample. Traditionally, 105 colony-forming units per milliliter (cfu/mL) has been the threshold for defining a positive (ie, ‘‘significant’’) culture result. Use of this criterion excludes a substantial proportion of women who have resolution of typical UTI symptoms when given antimicrobial therapy on the basis of a urine

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culture showing lower numbers of cfu/mL, however [9,10]. The most recent Infectious Disease Society of America (IDSA) guidelines on the treatment of uncomplicated cystitis recommend a threshold criterion of 103 or greater cfu/mL of a typical uropathogen [11]. This definition provides 80% sensitivity and 90% specificity for detecting UTI. Urine cultures are often not performed in patients who are suspected of having uncomplicated cystitis, however. This is appropriate because of the high positive predictive value of the typical symptom complex, the predictable spectrum of causative organisms, the costs associated with routinely testing for such a common condition, the availability of rapid and inexpensive diagnostic tests for surrogate markers of infection, and the fact that culture results usually become available only after the therapeutic decision has been made and, in many instances, therapy has been completed. Urinalysis with microscopy, urine Gram’s stain, and rapid leukocyte esterase (LE) testing by dipstick are the most commonly used rapid diagnostics that can provide useful information at the point of care. Pyuria is a sensitive indicator of UTI, being found in virtually all cases in which a positive urine culture is obtained in the setting of acute urinary symptoms [12]. The LE dipstick test for detecting pyuria is also a sensitive marker for UTI, although slightly less so than microscopy (range of reported sensitivity: 75%–96%) [12]. A negative LE test result in a patient who has symptoms of UTI should prompt microscopy for pyuria. If microscopy or LE testing reveals pyuria, empiric therapy directed at the typical pathogens of cystitis can be prescribed with good evidence of safety, efficacy, and cost-effectiveness [13], without a need for urine culture. A disadvantage of not routinely obtaining urine cultures in cases of suspected uncomplicated cystitis, however, is that the microbiology of this entity is suboptimally defined. If the results of LE testing and microscopy are negative but the suspicion of UTI is high, urine culture should be obtained before initiating therapy. There is no utility in obtaining a posttreatment urine culture in the absence of symptoms. Antimicrobial therapy for uncomplicated cystitis is often chosen empirically. Major factors to be considered in selecting a drug are the microbiology of this entity and the local prevalence of resistant organisms. Other relevant considerations include the agent’s frequency of administration, effect on vaginal and bowel flora, side effect profile, safety record, and cost. Several agents can be used effectively to treat uncomplicated cystitis in women as single-dose or short-course regimens (Table 2). In general, single-dose regimens have higher recurrence rates and lower rates of clinical success than do multiday regimens, whether success is defined microbiologically or by clinical symptoms [14]. Seven-day treatment courses have higher success rates and lower rates of recurrent UTI than single-dose therapy but are associated with more adverse drug events (ADEs). Three-day regimens of trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones have shown equal clinical efficacy to longer courses, with no increase in

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Table 2 Antimicrobial agent, dose, dosing interval, and duration for the treatment of uncomplicated cystitis in women Drug and dose

Dosing interval

Duration

Comments

Amoxicillin, 250 or 500 mg Amoxicillin-clavulanate, 250/125 mg or 500/125 mg

q8 hours (250 mg) to q12 hours (500 mg) q8 hours (250/125 mg) to q12 hours (500/125 mg)

7 days 7 days

Cefixime, 400 mg

q24 hours

7 days

Ciprofloxacin, 250 mg

q12 hours

3 days

Ciprofloxacin, 500 mg, extended release Fosfomycin, 3 g

q24 hours

3 days

Single dose

NA

Levofloxacin, 250 mg

q24 hours

3 days

Nitrofurantoin monohydrate or macrocrystals, 100 mg

q12 hours

5–7 days

Trimethoprim, 100 mg

q12 hours

3 days

TMP-SMX, 160/800 mg

q12 hours

3 days

Useful in pregnancy and for enterococcal UTI Alternative with TMP-SMZ and fluoroquinolone resistance Not available in the United States currently Use sparingly (avoid resistance) Use sparingly (avoid resistance) Third line, resistance uncommon Use sparingly (avoid resistance) Alternative if TMP-SMZ allergy, or local TMP-SMZ resistance prevalence is greater than 20% For patients with sulfa allergy Preferred if local TMP-SMZ resistance prevalence is less than 20%

Abbreviations: q, every; TMP-SMX, trimethoprim-sulfamethoxazole.

ADEs over single-dose regimens [15,16]. Accordingly, to avoid unnecessary fluoroquinolone use, a 3-day course of TMP-SMX is the recommended empiric therapy for uncomplicated cystitis in women if TMP-SMX resistance is unlikely [11,17]. Treatment options when the anticipated prevalence of resistance to TMP-SMX exceeds 20% are discussed next. Alternatives to TMP-SMZ must be considered if patient intolerance or microbial resistance is a concern. Fluoroquinolones are well studied and exhibit comparable efficacy to TMP-SMX for uncomplicated cystitis, including as 1-, 3-, 5-, and 7-day regimens [18–20]. Ciprofloxacin is the most commonly used fluoroquinolone for UTI in the United States [21]; norfloxacin, ofloxacin, and levofloxacin are also efficacious. Ciprofloxacin’s extensive track record and current availability in an inexpensive generic formulation recommend it if a fluoroquinolone is to be used. Nitrofurantoin has not performed as well as TMP-SMX or fluoroquinolones in 3-day regimens, leading to a recommendation for 7-day therapy for acute cystitis [22].

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In a recent study, however, 5 days of nitrofurantoin was clinically and microbiologically equivalent to 3 days of TMP-SMX, allowing shortened treatment with no apparent increase in failures [23]. Alternatively, fosfomycin, given as a single 3-g oral dose, has shown reasonable efficacy in treating UTI and is another option if TMP-SMX cannot be used [24]. b-Lactam agents have not performed as well as other available agents, even with extended treatment courses, and so cannot be recommended unless no alternatives are available [16]. Antimicrobial resistance has increasingly complicated the treatment of UTI, with the prevalence of resistance to TMP-SMX and fluoroquinolones among uropathogens having reached critical levels in many parts of the world. In the United States, the prevalence of TMP-SMX resistance in E coli as reported by hospital laboratories varies by region, exceeding 20% in certain areas [25]. In other parts of the world, the problem is more severe, with resistance prevalences of nearly 35% in some areas of Southern Europe and greater than 75% in India [26,27]. A widely disseminated E coli clonal group (clonal group A) has been implicated in the spread of TMP-SMX resistance within the United States and internationally [28,29]. Fluoroquinolone resistance has been limited in the United States to date, with a nationwide surveillance study showing a prevalence of 2.5% among E coli clinical isolates in 2001 [25]. Regional prevalence values as high as 37% have been reported in Europe, however, and as high as 69% in India [26,27]. It is sometimes assumed that high urine levels of TMP-SMX allow clinical success, even with organisms showing in vitro resistance to this agent. Multiple studies, prospective and retrospective, have documented unacceptably high clinical and microbiologic failure rates when TMP-SMX was used to treat TMP-SMX–resistant organisms, however [25,30,31]. For example, within a cohort of women with uncomplicated cystitis from Michigan, among those treated with TMP-SMX, the clinical failure rate was 45% if the urine organism was resistant to TMP-SMX compared with only 4% for susceptible strains [31]. Given the increased prevalence of TMP-SMX resistance, and its dramatic impact on therapeutic response, predicting TMP-SMX resistance is clinically important if empiric use of TMP-SMX is considered. Retrospective cohort and case-control studies have demonstrated that use of an antibiotic in the past 3 months, especially TMP-SMX, is the most reliable predictor of TMP-SMX resistance, with Hispanic ethnicity also being predictive in one locale [32–34]. In contrast, a recent prospective study identified foreign travel and Asian race but not recent personal or household antibiotic use as independent predictors of TMP-SMZ resistance [35]. Accordingly, it may be reasonable to use TMP-SMX for empiric therapy of acute uncomplicated cystitis if the local resistance prevalence to TMP-SMX among uropathogens does not exceed 20% and if the patient has not recently traveled internationally or taken TMP-SMX and is not from a resistance-associated ethnic or racial group. In contrast, when resistance is prevalent, or if the

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patient exhibits personal risk factors for TMP-SMX resistance, 5- to 7-day therapy with nitrofurantoin and 3-day therapy with a fluoroquinolone are reasonable alternatives. Given the value of fluoroquinolones in the treatment of pyelonephritis and complicated UTI (as discussed in subsequent sections of this article), however, fluoroquinolones may best be regarded as second-line alternatives after nitrofurantoin. Single-dose fosfomycin can be considered but is less likely to succeed than 3-day therapy with a fluoroquinolone or TMP-SMX [14,23]. The disappointing clinical performance of amoxicillin-clavulanate [22] suggests that it should be used only if TMPSMZ, nitrofurantoin, and fluoroquinolones cannot be used. Recurrent urinary tract infection Recurrent UTI is a common clinical problem, with 27% to 40% of women experiencing a new episode of cystitis within 6 months after an initial episode [36]. The subsequent UTI episode can be attributable to the initial pathogen (from either reintroduction from an external reservoir or internal persistence within the host) or to a different organism. The proportion of recurrent UTI episodes that represent same-strain versus different-strain recurrence varies considerably among studies [37,38]. The most obvious external reservoirs that could produce same-strain recurrence are the host’s own vaginal and fecal microflora. In some women with same-strain recurrence, however, the causative organism cannot be found at these sites, suggesting an alternate reservoir [39]. In some instances, the UTI strain is present in the colonic flora of family members, including pets, who thus may provide an external reservoir of the organism from which it could be reintroduced into the patient [40]. Alternatively, uropathogenic E coli has been demonstrated to invade the bladder epithelium in a mouse UTI model, suggesting a possible persisting intracellular reservoir from which organisms could re-emerge to cause recurrent UTI. Whether this phenomenon contributes to recurrent UTI in humans is undefined [41]. Although anatomic or functional abnormalities of the urinary tract definitely predispose to UTI, they are quite uncommon among otherwise healthy women with seemingly uncomplicated recurrent UTI [42], making routine imaging of the urinary system a low-yield practice among such patients. In contrast, risk factors for recurrent uncomplicated UTI in women include use of diaphragms and spermicides for contraception, vaginal intercourse, onset of UTI before the age of 15 years, and a maternal history of UTI [43,44]. A genetic basis for recurrent UTI is suggested by data showing higher rates of UTI in women who are nonsecretors of blood-group antigens [45,46]. These women have specific E coli–binding glycolipids on their vaginal and urinary epithelial cells that are absent in women who do secrete blood-group antigens [47]. The microbiology of recurrent uncomplicated cystitis is generally similar to that of uncomplicated cystitis. (Indeed, because cultures are more likely

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to be obtained for recurrent UTI episodes, the organisms causing this entity are probably overrepresented in the studies of the microbiology of uncomplicated cystitis.) E coli predominates, followed by S saprophyticus, enterococci, and non–E coli gram-negative bacilli. A urine culture should be considered in the setting of recurrent UTI, particularly after recent antimicrobial therapy, to ensure that the new organism is susceptible to the empirically chosen antimicrobial. Treatment for an initial episode of recurrent uncomplicated cystitis is relatively straightforward. As the number and frequency of recurrences increase, however, the optimal strategy becomes less clear. Because recent use of TMP-SMX is a predictor of having a resistant organism, it may be reasonable to avoid repeated empirical courses of TMP-SMX for recurrent cystitis. Nitrofurantoin, fluoroquinolones, fosfomycin, and amoxicillinclavulanate are options for empiric therapy of recurrent cystitis. Culture and susceptibility testing results, when available, can be used to tailor therapy for the present episode and to guide drug selection for a possible subsequent episode. The optimal place for fluoroquinolones in the overall management scheme is unclear, given the risk for selecting resistant strains and thereby limiting treatment options for future episodes of cystitis or more severe infections, such as pyelonephritis. Depending on the patient’s pattern and frequency of recurrence, consideration can be given to any of three different antimicrobial-based preventive approaches, including continuous prophylaxis, postcoital prophylaxis, and patient-initiated therapy. Continuous prophylaxis with low-dose TMPSMX effectively reduced the risk for UTI over a 5-year period, with little evidence for developing UTI attributable to resistant organisms [48]; thus, this approach can be considered if UTI occurs frequently, without relation to sexual activity. In another study, daily TMP-SMX, trimethoprim, and nitrofurantoin all performed similarly well compared with placebo for preventing UTI over 6 months. Prophylaxis reduced the overall number of UTI episodes, although more infections attributable to resistant non–E coli gramnegative bacilli occurred [49]. Because these two studies were from the 1980s, their applicability in today’s era of increased antimicrobial resistance is uncertain; newer studies are needed. Postcoital prophylaxis reduces the frequency of UTI recurrences among women with a history of recurrent UTI. This approach often involves significantly less antimicrobial consumption than does continuous prophylaxis. Particularly for patients with a history of UTI onset after sexual intercourse, it is a reasonable preventive strategy [50]. Patient-initiated single-dose therapy on symptom onset also is effective and is an attractive option if recurrences are infrequent and are not associated with coitus [51]. No comparative data exist to recommend one strategy over another. Therefore, in the individual patient, cost, frequency, recurrence pattern, and patient preference should be considered when selecting a strategy.

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The most studied nonantimicrobial option for prevention of recurrent UTI is consumption of cranberry juice (or tablets). A recent Cochrane Database Systematic Review concluded that this did reduce the incidence of symptomatic UTI [52]. Dropout rates in the reviewed studies were high, however, suggesting that although effective, this intervention may not be tolerated by all patients [52]. Pending the results of additional trials, motivated patients who have recurrent UTI and prefer nonantimicrobial therapy can be advised that daily intake of cranberry juice is an option that may provide some benefit with minimal risk.

Acute pyelonephritis The term pyelonephritis indicates infection of the kidney and renal pelvis. Although renal involvement can be confirmed by a variety of imaging methods [53], the diagnosis is usually made clinically, based on the presence of characteristic signs and symptoms in a patient with laboratory evidence of UTI. The hallmark clinical manifestations of pyelonephritis include fever and flank (costovertebral angle) pain and tenderness. A wide spectrum of associated symptoms may occur, including dysuria, nausea, vomiting, abdominal pain, and, in extreme cases, severe sepsis or septic shock. In a patient with voiding symptoms consistent with cystitis, the presence also of nausea, vomiting, flank pain, and vital sign abnormalities (eg, fever, tachycardia, tachypnea, hypotension) should prompt consideration of pyelonephritis. The microbiology of pyelonephritis is similar to that of uncomplicated cystitis, except that S saprophyticus rarely causes pyelonephritis. E coli remains the most common pathogen overall, accounting for more than 80% of cases [52]. Other Gram-negative bacilli, including Proteus, Klebsiella, and Citrobacter species, are encountered less frequently. Gram-positive organisms cause only a small proportion of cases, with enterococci and Staphylococcus aureus predominating. Because of the greater severity of illness and broader range of possible pathogens in pyelonephritis than in cystitis, obtaining a pretreatment urine culture is mandatory. Blood cultures should be obtained as part of the evaluation of any febrile illness if the diagnosis is uncertain; however, if a patient clearly has pyelonephritis, urine culture almost always captures the causative organism. Positive blood cultures are observed in 15% to 20% of cases of pyelonephritis [54,55] but do not influence management. In patients suspected of having pyelonephritis, additional tests can help to establish a presumptive diagnosis and guide empiric therapy. Urinalysis almost always shows pyuria. Gram’s staining of unspun urine often shows Gram-negative bacilli; the presence of Gram-positive organisms should prompt consideration of a treatment regimen active against enterococci and, possibly, S aureus. A few patients who have pyelonephritis have fewer than 105 cfu/mL in their urine [55], and thus a negative urine Gram’s stain.

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Therefore, this finding should not lead clinicians to exclude the diagnosis, if clinically suspected. Imaging has little role in the initial management of pyelonephritis but may be important later. Treatment for pyelonephritis has undergone substantial changes over the years. Whereas in the past, patients who have pyelonephritis typically received long-term inpatient parenteral antimicrobial therapy, today, most such patients are treated with oral therapy as outpatients. For treating pyelonephritis, an antimicrobial is needed that achieves adequate levels not just in urine but in serum and the renal parenchyma. Accordingly, nitrofurantoin and fosfomycin, which are approved by the US Food and Drug Administration (FDA) for treating cystitis, have no role in pyelonephritis. Additionally, given the greater severity of illness in pyelonephritis, selection of an initial regimen to which the infecting organism is susceptible takes on additional importance. Accordingly, TMP-SMX should not be used routinely for empiric therapy of pyelonephritis. It may be a reasonable choice in selected patients with mild symptoms, however, if the local prevalence of TMP-SMX resistance among uropathogens is quite low or if the patient’s urine organism is known to be susceptible. The optimal initial antimicrobial regimen for pyelonephritis depends on the setting (inpatient or outpatient), severity of symptoms, local resistance patterns, and patient’s recent antimicrobial use history. Indications for hospital admission include nausea, vomiting, hypotension, or tachycardia that does not resolve promptly with volume repletion in the emergency department, suggesting more severe systemic disease, and inability of the patient to seek follow-up care should symptoms worsen. In the absence of these factors or other evidence of more severe disease, most patients can be safely managed with oral therapy, with or without an initial parenteral antimicrobial dose in the emergency department [13]. If the patient is hospitalized, parenteral therapy is reasonable initially. Well-studied regimens include ceftriaxone [56], ciprofloxacin [30], and ampicillin combined with gentamicin (Table 3) [54]. The latter regimen can be used for enhanced activity against enterococci if the urine Gram’s stain shows Gram-positive cocci. Newer evidence indicates that for women with mild to moderately severe pyelonephritis, the duration of therapy can be shorter that the traditional 2 weeks. Talan and colleagues [30] showed that such women had significantly higher cure rates with 7 days of ciprofloxacin (99%) than with 14 days of TMP-SMX (89%), with the failures in the latter group being attributable to TMP-SMX resistance. A more recent study of short-course fluoroquinolone therapy found that levofloxacin (750 mg/d) given for 5 days was not inferior to 10 days of ciprofloxacin (500 mg given twice daily) [57]. It is unknown whether ciprofloxacin would be similarly effective if given for 5 days. Other agents (ie, b-lactams, TMP-SMX) have had higher failure rates with short-course therapy; thus, they should be given for 10 to 14 days [58,59].

Dosing interval

Route of administration

Duration of therapy

Comments

Amoxicillin, 875 mg

q12 hours

Oral

10–14 days

Amoxicillin-clavulanate, 875/125 mg

q12 hours

Oral

10–14 days

Ampicillin, 1 ga

q6 hours

Intravenous

Variableb

Ampicillin-sulbactam, 1.5–3 g Aztreonam, 1 g

q6–q8 hours q8–q12 hours

Intravenous Intravenous

Variableb Variableb

Cefepime, 1 g Ceftriaxone, 1 g Ciprofloxacin, 400 mg Ciprofloxacin, 500 mg Gentamicin, 3–5 mg/kgc

q8–q12 hours q24 hours q12 hours q12 hours q24 hours

Intravenous Intravenous Intravenous Oral Intravenous

Variableb Variableb Variableb 7 days Variableb

Imipenem, 500 mg

q8 hours

Intravenous

Variableb

Levofloxacin, 250 or 750 mg Piperacillin-tazobactam, 3.375 g TMP-SMX, 160/800 mg

q24 hours

Intravenous or oral

q6 hours

Intravenous

7–10 days (250 mg), 5 days (750 mg) Variableb

Useful in pregnancy and for enterococcal UTI; many E coli are resistant Useful in pregnancy and for enterococcal UTI; many E coli are resistant Combined with gentamicin for enterococcal activity Many E coli are resistant Alternative for penicillin or cephalosporin allergy Anti-Pseudomonas activity Initial therapy Initial therapy Initial or continuation therapy Initial therapy (often combined with ampicillin) Initial therapy (for complicated or severe disease) Initial or continuation therapy

q8–q12 hours

Intravenous/oral

10–14 days

Initial therapy (complicated or severe infection) Initial/continuation therapy; many E coli are resistant

Abbreviation: q, every. a Combined with gentamicin if used for empiric therapy. b It is expected that most patients can be transitioned from an intravenous regimen to an oral regimen (see text for details). c Can be combined with ampicillin if the suspicion for enterococci is high.

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Drug and dose

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Table 3 Antimicrobial agent, dose, dosing interval, route of administration, and duration for the treatment of uncomplicated pyelonephritis in women

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Improvement is generally rapid with pyelonephritis, with most patients experiencing significantly improved or resolved signs and symptoms, including fever, within 48 to 72 hours after initiation of effective antimicrobial therapy. Patients who fail to improve within this interval, or whose status worsens on therapy, should be reassessed, including with repeated urine and blood cultures to evaluate for the possible emergence of resistance or an alternate pathogen, and urinary tract imaging should be considered. CT is the preferred imaging modality, although ultrasonography is a reasonable alternative if CT is not readily available. Ultrasound has the benefit of avoiding exposure to ionizing radiation and intravenous contrast, whereas CT is more sensitive in detecting anatomic and functional abnormalities in acute pyelonephritis [53]. Perinephric abscess, intrarenal abscess, and emphysematous pyelonephritis are the most severe local complications of pyelonephritis. If any of these conditions, or obstruction leading to hydronephrosis is detected, urologic consultation is warranted. A more detailed discussion of the management of these severe sequelae is provided in relevant reviews [60,61]. Complicated urinary tract infection Complicated UTI refers to UTI occurring in patients who have an underlying predisposing condition, whether medical, functional, or anatomic, that (1) increases the risk for initial infection and recurrence, (2) reduces the effectiveness of therapy, or (3) shifts the spectrum of causative microorganisms toward more antimicrobial-resistant but less virulent strains than those encountered in uncomplicated cystitis and pyelonephritis. The distinction between complicated and uncomplicated UTI can be confusing and is somewhat arbitrary, with different investigators having inconsistently included or excluded various conditions as defining a UTI as complicated. Also potentially confusing is the practice of describing adverse sequelae of infections as complications, whereas, by tradition for UTI, the term complicated refers to predisposing conditions. Among the more commonly encountered predisposing conditions that are considered to render a UTI complicated are diabetes, neurogenic bladder, indwelling catheter use, and urinary obstruction of any cause (see Table 1). Presence of a resistant microorganism is insufficient of itself for UTI to be regarded as complicated, because, with appropriate antimicrobial therapy, the duration and outcome of illness should be unaffected. Although according to this definition, many UTIs in men or the elderly are complicated, the patient being male or elderly, per se, does not necessarily make the UTI complicated; some men and elderly individuals can be considered to have uncomplicated UTI and can be treated accordingly (as discussed in a subsequent section in this article). Unfortunately, little evidence is available from clinical trials to inform management approaches for complicated UTI. Still, several general

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recommendations can be made, including the use of pretreatment urine cultures, broader spectrum empiric therapy than is used in uncomplicated UTI, and extended duration of therapy. To obtain a pretreatment urine culture seems prudent, because the spectrum of pathogens (and associated antimicrobial resistance profiles) in complicated UTI is more diverse than in uncomplicated UTI [13]. Fluoroquinolones are a reasonable choice for empiric therapy; however, to limit the development of fluoroquinolone resistance, a switch to a narrower spectrum agent should be considered if the culture shows that the urine organism is susceptible. Optimal duration of therapy is also undefined, but expert opinion suggests that treatment courses of 10 to 14 days are advisable [13,62]. It is unclear if routine posttreatment urine cultures have a role in complicated UTI. Although their routine use has been advocated [13], this entails a large cost to detect asymptomatic bacteriuria, an entity that usually is not treated, as discussed elsewhere in this article [62,63].

Urinary tract infection in men Historically, all cases of UTI in men have been classified as complicated [64]. More recent evidence suggests that men with symptoms of cystitis who are not known to have any of the predisposing conditions associated with complicated UTI (see Table 1) can be regarded as having uncomplicated UTI and can receive shorter term treatment than traditionally used for complicated UTI [65,66]. Risk factors for cystitis in men include a history of insertive anal intercourse, lack of circumcision, and having a sexual partner who is colonized vaginally with uropathogenic E coli [67]. Treatment of uncomplicated UTI in men can be achieved with a 7-day course of TMP-SMX, trimethoprim, or a fluoroquinolone [4]. It is unknown if the 1-, 3-, and 5-day regimens used for uncomplicated cystitis in women are effective in men; appropriate studies could assist in limiting costs and antimicrobial use. Complicated UTI in men generally refers to UTI occurring in the presence of an underlying urologic abnormality, often an enlarged prostate, although all the conditions listed in Table 1 are relevant. Principles and duration of therapy are similar to those of other complicated UTIs as discussed previously. An additional issue in men with UTI is the prostatic penetration of the antimicrobial agent. Fluoroquinolones are attractive for use in men with UTI for this reason. Routine use of fluoroquinolones to treat urinary symptoms in men predictably increases selection for fluoroquinolone-resistant organisms, however. TMP-SMX also achieves adequate prostatic tissue levels, whereas most b-lactams do not. Same-strain recurrent UTI in men may be attributable to repeated seeding of the urinary system from a persisting prostatic focus, eradication of which may require extended treatment courses (eg, 6 weeks) [4]. An in-depth discussion of prostatitis can be found in several reviews of this topic [3,4].

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Urinary tract infection in the elderly Urinary infections in the elderly are often considered to be complicated, although evidence to support this concept is lacking. Postmenopausal women with UTI who are otherwise healthy, ambulatory, and living independently probably can be regarded as having uncomplicated infection and treated accordingly, although data specifically addressing this question are limited [68]. Other postmenopausal women with UTI, particularly those who have any of the conditions listed in Table 1, are considered to have complicated UTI and should be approached as discussed previously.

Catheter-associated urinary tract infection Catheter-associated urinary tract infection (CAUTI), that is, UTI related to use of an indwelling urinary catheter, is the most common type of nosocomial infection in the United States and the most common source of gramnegative septicemia in hospitals [40]. It affects primarily hospitalized patients but can occur in any catheterized individual, including community dwellers and long-term care facility residents. Microbial colonization of the (normally sterile) urinary tract develops in a time-dependent manner in the presence of an indwelling catheter, whether the catheter enters through the urethra, a suprapubic tract, or other percutaneous channel (eg, nephrostomy tubes) [69]. Pyuria occurs in a high proportion of catheterized patients who have bacteriuria or funguria, including those who seem to be clinically well, and is of no clinical significance. Most patients who have catheter-associated bacteriuria or funguria experience no ill effects from the microorganisms present in their urine and should not receive antimicrobial therapy. (Although the term CAUTI is often applied to such patients, this erroneously implies that they have an infectious disease in need of antimicrobial therapy, a misconception that leads to considerable unnecessary antimicrobial use). Still, an estimated 10% to 25% of patients who have catheter-associated bacteriuria or funguria develop signs or symptoms of infection [70–72], including fever, leukocytosis, or suprapubic discomfort, suggesting symptomatic UTI. A small subset exhibits severe sepsis or septic shock and has organisms isolated from the bloodstream that correspond to those present in the urine. The reported frequency of catheter-associated urosepsis varies among studies. Older studies suggested that it occurred in 1% to 4% of patients who have CAUTI. In a recent study of 1497 catheterized patients who were followed prospectively, however, only 4 (1.8%) of 224 with bacteriuria or funguria developed bloodstream infection attributable to an organism that corresponded with the concurrent urine organism. Moreover, in 2 of these patients, the organism was also isolated from an indwelling intravascular device, obscuring the true primary source of bacteremia [73].

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Although asymptomatic catheter-associated bacteriuria or funguria should not be treated, it is reasonable to treat symptomatic infections. Deciding which patients actually have symptomatic CAUTI can be challenging, however, because the prevalence of bacteriuria or funguria among catheterized individuals is high and genitourinary symptoms typical of UTI may be caused by the catheter itself [73]. Likewise, infection-related systemic manifestations (eg, fever, malaise, leukocytosis) are quite nonspecific and may be caused by any number of processes. It becomes a matter of clinical judgment what constellation of symptoms should be considered evidence of symptomatic UTI when encountered together with a positive urine culture. In CAUTI, as in other forms of UTI, use of an arbitrary numerical cutoff to indicate a positive or negative culture result is not supported by good evidence. On the contrary, in catheterized patients, low levels of bacteriuria or funguria usually reach counts of 105 cfu/mL within several days in the absence of antimicrobial therapy [74]. The microbiology of CAUTI is highly diverse. In addition to E coli, various other Gram-negative bacilli (including Pseudomonas) and enterococci, staphylococci, and Candida species are commonly encountered. [75,76]. Gram-negative bacilli typically enter the bladder by ascending from the drainage bag within the lumen of the catheter, whereas perineal organisms, such as enterococci, staphylococci, and Candida, do so by ascending in the space between the catheter and the urethra [71]. The primary solution to CAUTI is prevention. To this end, every effort should be made to use indwelling catheters sparingly (ie, to insert them only when no alternative suffices and to remove them promptly when they are no longer indicated). Special reminder systems can assist with this process and are necessary because providers are commonly unaware of which of their patients have an indwelling catheter and many catheters lack a clear indication for use [72]. Condom catheters are an option for male patients, although leakage and discomfort can occur, and the incidence of UTI, albeit lower than with indwelling catheters [77], is still appreciable. Other alternatives include absorbent undergarments, which can be used for simple urinary incontinence, and straight intermittent catheterization, which addresses urinary retention, including from bladder outlet obstruction. Either is preferable to an indwelling urethral catheter with respect to infection risk, restraint, and patient comfort [78,79]. Biofilm formation on catheters is regarded as an important aspect of the pathogenesis of CAUTI. Encrustation with microbial glycocalix material, urinary salts, and Tamm-Horsfall protein creates an environment within which microbes can survive inaccessible to antimicrobial therapy. To prevent this process, among other strategies, special coatings have been applied to catheters, patients have been deliberately colonized with an avirulent bacterial strain to prevent the incursion of pathogens [80], and catheters have been exchanged on various schedules. None of these approaches has yet demonstrated a convincing decrease in clinically significant UTI, although

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catheters coated with silver or nitrofurazone have been shown to decrease catheter-associated bacteriuria or funguria during short-term catheterization in selected populations [81].

Asymptomatic bacteriuria or funguria Asymptomatic bacteriuria (ie, a positive urine culture unaccompanied by clinical manifestations) is defined operationally as two consecutive voided urine specimens with isolation of the same bacterial strain in concentrations greater than 105 cfu/mL in women, or a single such specimen in a man [82], in the absence of symptoms or other clinical manifestations of UTI. Urine is sterile in most young healthy adults; the incidence of detectable bacteriuria is only 0.5 to 0.7 episodes per person-year among asymptomatic female subjects aged 18 to 40 years [83]. However, the prevalence of asymptomatic bacteriuria is higher in other populations, ranging from 20% among ambulatory elderly women and from 15% to 50% among the institutionalized elderly to virtually 100% among patients with long-term indwelling catheters [84]. Specific risk factors for asymptomatic bacteriuria that were identified in a study of almost 800 women included diabetes mellitus, sexual intercourse, and the use of a diaphragm or spermicide for contraception, but not a history of prior UTI or blood group secretor status [83]. The lack of clinical significance of asymptomatic bacteriuria has been repeatedly established, and current IDSA guidelines on asymptomatic bacteriuria recommend against treatment except in specific narrowly defined situations [82]. Because of the high prevalence of asymptomatic bacteriuria in the elderly [85], a positive urine culture of itself does not establish the diagnosis of clinically significant UTI. In numerous studies, treatment of asymptomatic bacteriuria in elderly individuals or patients with diabetes had no beneficial effect on subsequent urinary symptoms or mortality but caused adverse drug effects and selected for resistant organisms [86]. The attribution of nonspecific clinical manifestations, such as weakness and anorexia, to UTI in a patient who has bacteriuria or funguria but no localizing urinary tract symptoms may lead to unnecessary antimicrobial therapy and to incomplete investigation for the actual cause of the manifestations [87]. The two clinical situations in which treatment of asymptomatic bacteriuria or funguria is recommended are (1) before urologic surgery involving mucosal disruption and (2) during pregnancy. Flexible fiberoptic cystoscopy without biopsy is analogous (with respect to infection risk) to placing a urinary catheter, a procedure for which eradication of asymptomatic bacteriuria is not recommended. If a biopsy or other mucosal disruption is anticipated during cystoscopy, however, urine should be rendered sterile before the procedure. Treatment of asymptomatic bacteriuria in pregnancy is discussed next.

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Urinary tract infection in pregnancy UTI is a common and important occurrence during pregnancy. Infection of the lower tract (asymptomatic bacteriuria and cystitis) and upper tract (pyelonephritis) is of concern. Although neither cystitis nor asymptomatic bacteriuria is more common among pregnant women compared with agematched nonpregnant women, the risk for progression from either of these entities to pyelonephritis is significantly increased [88]. The reason for this higher risk for pyelonephritis is unclear but may relate to pregnancy-related anatomic and physiologic changes within the urinary tract [89]. Pyelonephritis during pregnancy threatens the mother and the fetus, making prompt diagnosis and treatment of its precursor UTI syndromes essential. The microbiology of UTI in pregnancy resembles that seen in nonpregnant women of similar ages. E coli predominates, followed by S saprophyticus, group B Streptococcus, Klebsiella species, and other enteric Gram-negative bacilli [88]. Screening of all pregnant women for asymptomatic bacteriuria is currently recommended, with the optimal timing for screening considered to be at 16 weeks of gestation [90]. Two voided specimens with greater than 105 cfu/mL provide 95% specificity for asymptomatic bacteriuria, whereas a single positive specimen provides only 80% specificity [90]. If the initial screen is negative, and there is no history of prior UTI or known urologic abnormality, the chance of developing asymptomatic bacteriuria during the remainder of pregnancy is small and no further screening is necessary. If a history of past UTI or a urologic abnormality is present, screening should be repeated throughout the pregnancy, although the optimal frequency of urine sampling is undefined. Acute cystitis and asymptomatic bacteriuria should be treated similarly during pregnancy as in other women. As with all pharmacotherapy given to a pregnant woman, care must be taken in selecting a regimen that is safe for the mother and the fetus. In addition, dosing adjustments may be needed because of pregnancy-associated changes in physiology and pharmacokinetics, including increased volume of distribution and creatinine clearance. Because of these factors, the mainstays of therapy for cystitis in pregnancy have been penicillins, cephalosporins, and nitrofurantoin. Penicillins are nonteratogenic and have been used extensively in pregnancy. Amoxicillin can be given orally and is active against many of the typical pathogens of cystitis. However, with increasing resistance, particularly in E coli, susceptibility testing should be done to ensure in vitro activity. Penicillin is active against group B Streptococcus and should be used to treat such cases to help limit the use of broad-spectrum agents [91]. In the case of a significant penicillin allergy, clindamycin is a suitable alternative. Cephalosporins have been widely used, are nonteratogenic, and are mainstays of therapy in cystitis and pyelonephritis during pregnancy. The most frequently prescribed oral agent is cephalexin [90], whereas parenteral options include cefazolin, ceftriaxone, and ceftazidime. Rapid clearance of

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cephalexin is thought to explain in part its inferior performance when compared with TMP-SMX or fluoroquinolones in nonpregnant patients; the increased creatinine clearance observed during pregnancy may make treatment failure even more likely [90]. Nitrofurantoin is well tolerated during the first and second trimesters of pregnancy, and development of resistance has been rare despite decades of use. Limitations include the inherent resistance of certain genera (Pseudomonas and Proteus), although these are uncommon causes of UTI in pregnancy. In addition, a theoretic risk exists of fetal hemolytic anemia when nitrofurantoin is used to treat UTI in a patient with G6PD deficiency [92], making this a less attractive option during the later weeks of pregnancy [91]. Other drugs that can be used cautiously in pregnancy include TMP-SMX and aminoglycosides. Both components of TMP-SMX may be harmful during the first trimester, and sulfamethoxazole may precipitate kernicterus during the third trimester by displacing maternal bilirubin from albumin. Aminoglycosides have a theoretic risk for fetal nephro- and ototoxicity, although the absence of documented cases and the excellent renal penetration of these agents recommend them for pyelonephritis of pregnancy, especially if resistance precludes the use of other antimicrobials [88,90]. Fluoroquinolones and tetracyclines are contraindicated during pregnancy because of potential effects on fetal skeletal elements and teeth [90]. Pyelonephritis during pregnancy occurs most commonly during the third trimester and manifests much as in nonpregnant women, with fever, flank pain, dysuria, and vomiting. Most, if not all, pregnant women with pyelonephritis should be admitted to the hospital for parenteral antimicrobial therapy and observation. Additional information is available in recent reviews of this topic [88,90]. Urinary tract infection in children UTI is important among pediatric patients because of its relatively frequent occurrence and association with underlying urologic abnormalities. Symptoms of UTI are variable in young children, and include fever, irritability, lethargy, and altered feeding. Fever is the most common presenting symptom, and the American Academy of Pediatrics (AAP) recommends that all children younger than the age of 2 years with unexplained fever be evaluated for UTI [93]. In a cohort of young children (aged 1–12 months) presenting to an emergency department with fever, 5% were diagnosed with UTI [94], with UTI being equally likely in those who were versus were not suspected of having UTI. Among older children, symptoms of UTI are similar to those encountered in adults, except that incontinence occurs more frequently. The cumulative incidence of UTI is greater among girls than boys, with approximately 3% of prepubertal girls and 1% of prepubertal boys being

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diagnosed with UTI [95]. Certain children are at higher risk for UTI, including uncircumcised boys, diabetic children, and girls who are sexually active. Children with structural and functional urinary tract abnormalities, including vesicoureteral reflux, may have persistence of bacteriuria once it becomes established [95]. Diagnosis of pediatric UTI requires a urine culture, preferably obtained by means of suprapubic aspiration or urethral catheterization [93]. Midstream collection, although a reasonably accurate method for diagnosing UTI in adults, often detects periurethral colonization in young children. The age at which children can cooperate sufficiently to submit a clean-catch specimen is undefined. The use of a perineal bag to obtain a specimen is plagued by high false-positive rates; thus, although this may be useful for ruling out UTI, a positive result is ambiguous. The AAP recommends suprapubic aspiration or urethral catheterization for obtaining urine for culture and urinalysis [93]. A suprapubic aspirate is considered to indicate infection if it yields any Gram-negative bacilli or greater than 2000 cfu/mL of Gram-positive organisms. A catheterized specimen is considered to represent infection if greater than 105 cfu/mL of organisms are isolated and is suspicious for infection if greater than 104 cfu/mL are present [95]. Presumed lower UTIs in children can be treated with a variety of oral agents, including trimethoprim, TMP-SMX, nitrofurantoin, and cephalosporins. Fluoroquinolones have traditionally been avoided because of fears of cartilage toxicity; however, a growing body of evidence indicates that short-course therapy is safe and well tolerated [96]. The optimal duration of drug therapy is unclear. Traditionally, courses of 7 to 14 days have been used. A meta-analysis comparing short-duration (2- to 4-day) versus long-duration (7- to 14-day) therapy showed no benefit to longer therapy, however, and, currently, a 3-day course of therapy is considered adequate for older children [97]. Longer courses are still recommended for children younger than 2 years of age [96]. If the pathogen isolated is susceptible to the antimicrobial chosen for therapy and clinical symptoms resolve, there is no evidence that documenting eradication by posttreatment urine culture is beneficial. Most children with pyelonephritis or febrile UTI can be treated orally, with or without an initial parenteral antimicrobial dose. Those younger than the age of 2 years, or who appear toxic or are intolerant of oral therapy, should be admitted for observation and treatment [96]. Ten to 14 days of culture-guided therapy should be given, whether orally, parenterally, or a combination thereof [93]. Ampicillin, ceftriaxone, cefotaxime, gentamicin, and tobramycin have been used successfully for pediatric pyelonephritis. The AAP recommends urinary tract imaging with ultrasound and an evaluation for vesicoureteral reflux after a first episode of UTI for all children younger than the age of 2 years, whereas imaging is optional for older children [93,98]. Children awaiting urinary tract imaging after a UTI episode should receive continuous antimicrobial prophylaxis until the imaging

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studies are complete [93]. Further discussion of the management of pediatric UTI is provided by recent reviews of this topic [93,96].

Summary UTI, with its diverse clinical syndromes and affected host groups, remains one of the most common but widely misunderstood and challenging infectious diseases encountered in clinical practice. Antimicrobial resistance is a leading concern, with few oral options available to treat infections caused by Gram-negative organisms resistant to TMP-SMX and fluoroquinolones, especially for patients who have upper tract disease. Efforts should be made not to detect or treat asymptomatic bacteriuria and funguria; to ensure an appropriate duration of therapy for symptomatic infections; and to limit the use of broad-spectrum agents, especially fluoroquinolones, if narrower spectrum agents are available. Evidence-based guidelines for the management of cystitis and asymptomatic bacteriuria are available [11,82,93]. Further research is needed regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development of new antimicrobials (particularly oral agents) for drug-resistant UTI.

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