Urinary Tract Infection in Women

Transcription

1 WOMEN S HEALTH Urinary Tract Infection in Women Linda French, MD ABSTRACT PURPOSE: To review the epidemiology, diagnosis, and treatment of urinary tract infection (UTI) in women. EPIDEMIOLOGY: UTI is the most commonly diagnosed bacterial infection in women. Uncomplicated cystitis rarely leads to major morbidity or mortality, but economic costs and impact on quality of life are considerable. Populations at increased risk of complications include older women, pregnant women, and women who have diabetes, are immunocompromised, or have anatomic or functional disorders of the urinary tract. REVIEW SUMMARY: A presumptive diagnosis of uncomplicated UTI can be made based on history alone, or with limited diagnostic testing such as dipstick urinalysis. Culture should be obtained if the patient has risk factors for complicated disease, presumed treatment failure, or frequent recurrences. A 3-day course of trimethoprim-sulfamethoxazole has been recommended as the preferred initial treatment for uncomplicated UTI as long as resistance to the drug remains sufficiently low. Other options for first-line treatment include ofloxacin, nitrofurantoin macrocrystals, and cephalexin. Women with frequent recurrences may use continuous prophylaxis, postcoital prophylaxis, or self-treatment of recurrent episodes. Cranberry juice or pills reduce recurrences. In postmenopausal women intravaginal estrogen can reduce recurrences. TYPE OF AVAILABLE EVIDENCE: Meta-analyses, controlled trials, cohort studies, case-control studies, and nationally recognized and foreign treatment guidelines. GRADE OF AVAILABLE EVIDENCE: Fair to good. CONCLUSION: Diagnosis of UTI based on suggestive history alone is safe but leads to overtreatment. In regard to treatment, there is concern about emerging antibiotic resistance. Future research should include head-to-head trials of inexpensive generic antibiotics for the treatment of UTIs. (Adv Stud Med. 2006;6(1):24-29) Urinary tract infection (UTI) is defined as the symptomatic presence of microbial pathogens within the urinary tract, typically the lower urinary tract (bladder) unless otherwise specified. Symptoms generally include dysuria and increased frequency of urination. Flank pain and fever, on the other hand, suggest involvement of the upper urinary tract. An uncomplicated UTI shows no signs or symptoms of an upper UTI (pyelonephritis) and occurs in a person without abnormalities that confer an increased risk of upper infection. Complicated UTI refers to suspected upper UTI or increased risk of upper UTI, which may lead to serious morbidity such as sepsis or abscess. Structural or functional abnormalities of the urinary tract and recent instrumentation of the urinary tract all confer increased risk of upper UTI. Uncomplicated pyelonephritis refers to upper UTI in a person without structural or functional abnormalities Dr French is Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, East Lansing, Michigan. Conflict of Interest: Dr French reports having no financial or advisory relationships with corporate organizations related to this activity. Off-Label Product Discussion: Dr French does not include discussion of off-label or unapproved uses of products. Address correspondence to: Linda French, MD, B101 Clinical Center, College of Human Medicine, Michigan State University, East Lansing, MI Linda.French@hc.msu.edu. 24 Vol. 6, No. 1 January 2006

2 URINARY TRACT INFECTION of the urinary tract. Asymptomatic bacteriuria (ASB) refers to the asymptomatic presence of pathogens in the urine. EPIDEMIOLOGY UTI is considered to be the most common bacterial infection in adult women, as well as in the general population. The diagnosis of UTI was given at almost 7 million office visits and 1 million emergency department visits in 1997 according to National Ambulatory Medical Care Survey data. 1 By age 24 nearly one third of women will receive a course of antibiotic treatment with a diagnosis of UTI, as will nearly half of women at some time during their reproductive years 2 ; this increases to about 60% in women of older age. 3 However, it is not possible to obtain true population incidence rates because UTI often is treated in the ambulatory setting without diagnostic testing to verify the diagnosis. In addition, many women with UTI may not seek treatment. Uncomplicated UTI in women generally is believed to be a relatively benign and self-limited condition. However, its effect on quality of life is substantial. Each episode of UTI is associated with a mean of 6 symptomatic days and 1 missed workday. 2 Progression of uncomplicated UTI to pyelonephritis and sepsis is possible but unlikely in otherwise healthy, nonpregnant women. PATHOGENESIS The initial step in the pathogenesis of UTI is colonization of the vaginal introitus with uropathogens from the fecal flora. The urethra in women is relatively short compared with that of men, making infection predominant in women as the bacteria gain access to the urinary tract via ascending migration through the urethra. Additional genetic, biologic, and behavioral host factors in certain women contribute to susceptibility as described below. Adherence to the uroepithelium is a key factor in pathogenesis. The fimbriae or pili of Escherichia coli allow adherence to the epithelial cells. The type 1 pili of some strains of E coli that are commonly associated with UTI contain the adhesion molecule FimH, which attaches to host uroepithelial cells through specific adhesion receptors. Other uropathogens adhere via different mechanisms. MICROBIOLOGY The most common pathogens isolated in uncomplicated UTI have remained relatively constant. E coli accounts for approximately 80% of infections, followed by Staphylococcus saprophyticus (5% to 15%). 4,5 Other uropathogens in uncomplicated UTI include enterococci and gram-negative rods such as Klebsiella, Proteus, Enterobacter, Psueudomonas, and Serratia. It should be noted that dysuria and urinary frequency do not distinguish UTI from urethritis due to Chlamydia trachomatis. Chlamydial infection also may be asymptomatic. Routine screening is recommended by the US Preventive Services Task Force (USPSTF) for sexually active women under age 26 who are at highest risk for chlamydial infection, as well as for older women whose sexual history suggests risk for sexually transmitted infections. RISK FACTORS Some female populations are at increased risk of morbidity and mortality from UTI, and so are considered to have complicated UTI. Populations at increased risk of UTI and pyelonephritis include infants, older women, pregnant women, and patients with diabetes, immunodeficiency, or those with underlying urologic and neurologic abnormalities. Considerations for the diagnosis and treatment of UTI in special populations of women are addressed separately below. Among otherwise healthy women of reproductive age risk factors for UTI include spermicides and barrier contraceptive methods, coital frequency, and new sexual partners. 6-8 UTI frequently occurs within 48 hours after sexual intercourse. 9,10 Intercourse is associated with transient bacteriuria 11 and nonoxynol-9 is known to enhance adherence of E coli to epithelial cells. 12 Recent antibiotic therapy has been associated with UTI, which likely is related to replacement of the normal vaginal lactobacilli with uropathogenic flora. DIAGNOSIS HISTORY AND PHYSICAL EXAMINATION A systematic review 13 of history and physical examination findings to predict diagnosis of UTI in women of reproductive age suggested that the most helpful combination of factors includes presence of dysuria and absence of vaginal discharge or irritation, which had a positive likelihood ratio (LR) of 25 and a probability of positive culture of 77%. On the other hand, absence of dysuria and presence of vaginal discharge or irritation provided a negative LR of 0.3 and a probability of positive culture of 4%. Other individual findings that increased the likelihood of UTI in women who reported dysuria were frequency, hematuria, back pain, and fever, each with a positive LR between 1.5 and 2.0. Among women with a history of recurrent UTI, self-diagnosis had a positive LR of 4.0. Limitations of this review include the relatively small number of studies that met inclusion criteria and the diversity of studies pooled. History and physical findings that suggest pyelonephritis include fever, nausea and vomiting, flank pain, and costovertebral tenderness. URINALYSIS In a systematic review of dipstick urinalysis 14 pres- Johns Hopkins Advanced Studies in Medicine 25

3 WOMEN S HEALTH ence of either leukocyte esterase or nitrites was calculated to have a positive LR of 4.2 whereas the absence of both yielded a negative LR of 0.3. Nitrites are produced by coliform bacteria, but not by S saprophyticus or enterococci. A negative dipstick urinalysis has sufficient specificity to rule out UTI in women of reproductive age. The addition of dipstick urinalysis to history and physical examination improves physicians diagnostic accuracy of UTI, especially in cases with moderate pretest probability. 15 Urine clarity has been shown to be a simple and accurate test to rule out UTI in a pediatric population. 16 If urine in a test tube was clear enough that newsprint could be seen as well through it as through water, the negative LR of UTI was 0.1. The generalizability of visual inspection of urine to rule out UTI requires a confirmatory study in adult women. CULTURE In current office practice the diagnosis and treatment of uncomplicated UTI do not require urine culture unless there is lack of response to therapy or frequent recurrence. Culture should be taken when complicating factors exist including suspected pyelonephritis. A midstream, clean catch urine sample has been considered the standard method for obtaining a sample from women for urine culture. However, a study compared results of samples obtained in nonsterile containers without any preparation with standard clean catch samples obtained after use of a bactericidal wipe and showed similar rates of contamination and colony counts. 17 Unrefrigerated urine supports the growth of bacteria, therefore if a delay of 2 hours or more is expected in transport the specimen should be refrigerated at 4 C. The colony count to diagnose UTI has traditionally been 10 5, however, diagnosis using a lower count of 10 2 currently is recommended because 30% to 50% of symptomatic women with any growth of pathogens on culture will have colony counts below Laboratories often use methods such as semiquantitative microscopy to screen out samples that are likely to produce negative cultures in order to minimize expense and improve turnaround time. Blood cultures are warranted only in cases of pyelonephritis severe enough for hospitalization or where there is suspicion of sepsis. IMAGING STUDIES Urologic evaluation and imaging should be considered in cases of pyelonephritis in which fever persists beyond 72 hours or with multiple episodes of pyelonephritis. Otherwise, imaging for evaluation of the urinary tract with ultrasound, excretory urography, or cystography has a low yield in adult women. 19 A single episode of pyelonephritis is not associated with a clinically significant risk of urologic abnormality. 20 TREATMENT UNCOMPLICATED CYSTITIS More than 90% of women will experience symptom relief within 3 days following start of antimicrobial therapy. 21,22 Phenazopyridine for 1 or 2 days may be used to reduce symptoms. This compound is available over the counter. The Infectious Diseases Society of America (IDSA) published treatment guidelines in 1999 for uncomplicated UTI and acute pyelonephritis in women. 23 The drug of choice for UTI per those guidelines is a 3-day course of trimethoprim-sulfamethoxazole (TMP-SMZ), and suggested alternative therapies are 3-day courses of trimethoprim alone or ofloxacin. The Institute for Clinical Systems Integration also suggests nitrofurantoin as a suitable first-line alternative. One-day treatments are discouraged as less effective, and longer treatments discouraged as increasing risk of adverse effects without improving effectiveness. Other fluoroquinolones are not recommended as first-line drugs unless the community has documented resistance to TMP-SMZ of 10% to 20% or more as a result of expense and concern about the potential for promoting resistance. British recommendations suggest trimethoprim alone, 200 mg twice a day for 3 days, as the first choice and include other choices of inexpensive generic antibiotics, cephalexin 500 mg 3 times daily for 3 days and nitrofurantoin macrocrystals 100 mg twice a day for 7 days. 24 Increasing in vitro resistance of E coli to TMP-SMZ has been documented in many communities in different geographic locations, ranging from 10% in the northeastern United States to 22% in the west. 25,26 Resistance to TMP-SMZ has been associated with any current antibiotic use and recent use of TMP-SMZ. 27 Some authors therefore are now advocating fluoroquinolones as first-line antibiotics for uncomplicated UTI. However, laboratory data are not likely to be representative of primary care practice because many women with uncomplicated UTI are successfully treated without urine cultures. In vitro resistance also may underestimate clinical ineffectiveness as a result of a high concentration of antibiotics in the urine. One Scandinavian study documents better than expected clinical effectiveness of TMP- SMZ than in vitro sensitivities would suggest. 28 Nitrofurantoin is an antibiotic traditionally used for treating UTI. It achieves high concentration in urine, but not renal tissue. Resistance of E coli to this antibiotic has remained low although about 20% of non-e coli strains show in vitro resistance. 29 The treatment regimen is traditionally 7 days and shorter durations have not been adequately studied. Nitrofurantoin macrocrystals have a more gradual absorption and thus a longer half-life allowing for twice-daily instead of 4- times-daily dosing. Little research has been conducted using this newer form of the drug to treat UTI. 26 Vol. 6, No. 1 January 2006

4 URINARY TRACT INFECTION Cephalexin and other cephalosporins were not recommended by the IDSA because of concerns about resistance and disruption of the vaginal flora. 23 However, cephalexin was successfully used as the antibiotic of choice 70% of antibiotic prescriptions in a large US study of telephone management for uncomplicated UTI in women. 30 Fosfomycin is approved as therapy for UTI as a single 3-g dose. It provides microbial cure similar to a 5-day course of trimethoprim 31 or a 7-day course of nitrofurantoin. 32 However, fosfomycin is costly and not recommended by the IDSA as first-line treatment. 23 PYELONEPHRITIS Oral treatment for 7 to 14 days may be given in the outpatient setting for women with acute pyelonephritis without complicating factors. 23,24 Amoxicillin or amoxicillin-clavulanate are additional antibiotic choices if pyelonephritis is caused by a gram-positive bacteria such as S saprophyticus. For women presenting to the emergency department with acute pyelonephritis, an initial dose of gentamicin or ceftriaxone followed by oral therapy has been advocated. 33 RECURRENT URINARY TRACT INFECTIONS The most important predictor of recurrence after an episode of UTI in a young woman is a history of other episodes. 6,7 Among 285 college women diagnosed with UTI almost 25% experienced a recurrence within 6 months. 6 The type and duration of antibiotic therapy was not associated with recurrence. 6 Some women are genetically predisposed to recurrent UTI. For example, Lewis blood group nonsecretors, about 25% of the general population, have an increased likelihood of recurrent UTI. 34 Increased susceptibility in nonsecretors is believed to be related to increased ability of fimbriated bacteria such as E coli to adhere to uroepithelial cells. Recurrences are frequently by identical strain of E coli, implying that there may be unique adaptation of the strain to the individual host. Women with 3 or more recurrences annually may be offered 1 of 3 treatments: continuous prophylaxis, self-treatment of recurrences, or a single dose of antibiotic taken after intercourse as a prophylactic measure. Continuous prophylaxis is administered as a single daily dose, usually at bedtime. Antimicrobials shown to reduce recurrences to 0.3 or fewer per year include TMP-SMZ 40 mg/200 mg, TMP 100 mg, norfloxacin 200 mg, and nitrofurantoin macrocrystals 50 mg to 100 mg. 35 Unfortunately, the baseline pattern of recurrent UTI is typically observed when prophylaxis is discontinued. 36 Patient self-treatment of recurrences involves much less use of antibiotics and is therefore less costly. 37,38 Postcoital use of antibiotic prophylaxis is effective for women who experience recurrent UTI and have a temporal association with intercourse. 39 Voiding after sexual intercourse has shown inconsistent results in prevention of recurrent UTI, but may be recommended as a simple, no-cost practice. Cranberry juice and tablets containing the active ingredient, proanthocyanidin, can reduce the rate of recurrences by about 50%. 40 The mechanism of action for this is through inhibition of adherence of the E coli fimbriae. Approaches for prevention of recurrences without evidence to support effectiveness include lactobacillus drink 41 and direction of perineal wiping. 42 ECONOMICS The direct costs associated with communityacquired UTI in the general population are estimated at nearly $2 billion annually. 43 Telephone-based protocols for diagnosis and treatment of uncomplicated UTI are safe, effective, and reduce costs. 30,44,45 The principal concern with this approach is overtreatment of women who do not truly have a UTI. Addition of dipstick urinalysis adds little cost and would decrease unnecessary antibiotic prescriptions. 45 Whether or not telephone protocols are used, inexpensive generic antibiotics such as TMP-SMZ are the most cost-effective first-line therapies for uncomplicated UTI. 46 SPECIAL POPULATIONS POSTMENOPAUSAL WOMEN Postmenopausal women have vaginal flora with high ph in which uropathogens may predominate. For postmenopausal women with recurrent UTI intravaginal use of low-dose estrogen has been shown to reduce recurrences. 47,48 FRAIL OLDER ADULTS Risk factors for symptomatic UTI among older women include anatomic and functional abnormalities of the genitourinary tract such as decreased mental status, urinary incontinence, cystocele, and postvoiding residual. 49,50 UTI in older women with septicemia may present with nonspecific features. In one study of patients older than 50 years of age with UTI and culture-proven bacteremia, clinical features of confusion, cough, and dyspnea all were more common than were new urinary symptoms, which occurred in only 20%. 51 The urinary tract as a source of infection should not be overlooked as a possible source of serious illness in aging women. On the other hand, treatment of ASB in older women is not generally recommended. Older women have a high prevalence of ASB up to 25% in institutionalized environments among those without indwelling catheters. 52,53 Serial urine cultures demonstrate a high turnover, with patients who have positive cultures becoming negative and those with negative cultures becoming positive. 53 In Johns Hopkins Advanced Studies in Medicine 27

5 WOMEN S HEALTH older women with lower UTI a 3-day course of antibiotics is optimal by promoting compliance and reduction of adverse events. 54 PREGNANCY Pregnancy confers an increased risk of pyelonephritis in women with ASB, which is related at least in part to the relative obstruction of the ureters. A history of recurrent UTI is the most important risk factor for pyelonephritis in pregnancy among otherwise healthy women. 55 In addition to maternal morbidity, an association has been established between UTI in pregnancy and later developmental delay in the offspring. 56,57 Screening for bacteriuria in pregnancy and antibiotic treatment of those women who screen positive has been recommended by the USPSTF. Observational data from one institution suggest that the impact of this approach reduces the incidence of pyelonephritis by a little more that 1 percentage point, from 1.8% to 0.6%, with number needed to screen of 83 to prevent 1 case of pyelonephritis. 58 A repeat culture is recommended to assure clearing after treatment of a UTI in pregnancy. Serial cultures on a monthly basis are a usual practice after treatment of pyelonephritis in pregnancy. DIABETES MELLITUS Women with diabetes are a population at increased risk of ASB, UTI, and most importantly a 5- to 10-fold increase in risk of pyelonephritis. 59 Patients with diabetes also are at increased risk of complications of pyelonephritis, including renal abscess, emphysematous pyelonephritis, and pyelitis. E coli is the most common pathogen, but Klebsiella sp, group B streptococci, enterococci, and nonalbicans Candida all are more frequent in this population. The relative impairment of polymorphonuclear leukocyte and other aspects of immune system function in patients with diabetes contribute to susceptibility. Anatomic and functional abnormalities of the urinary tract also may contribute. NEUROLOGIC ABNORMALITIES Women with spinal cord injuries and other neurologic abnormalities requiring catheterization have high rates of ASB and an increased risk of UTI. Common uropathogens are E coli, Psuedomonas, and Proteus mirabilis. In women with multiple sclerosis up to 74% have ASB, and episodes of symptomatic UTI may be associated with subsequent multiple sclerosis relapses, acute exacerbations, and neurologic progression of disease. 60 RESEARCH DIRECTIONS Future research should include head-to-head trials of regimens for the treatment of acute uncomplicated UTI. In particular, evaluation is needed of generic antibiotics including cephalexin and shorter, 3- to 5-day courses of nitrofurantoin macrocrystals. Additional research is warranted as to the role of vaginal flora and other biologic host variables in susceptibility to UTI. Vaccine development is another proposed area of research. CONCLUSION UTI in women is a condition seen commonly in primary care practice. Increasing antibiotic resistance among common uropathogens is the most important emerging concern for patients with UTI. Appropriate treatment of individual women should be balanced with the population-based need to avoid further exacerbation of antibiotic resistance. REFERENCES 1. Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, Vital Health Stat :i-iv, Foxman B, Barlow R, D Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol. 2000;10: Molander U, Arvidsson L, Milsom I, Sandberg T. A longitudinal cohort study of elderly women with urinary tract infections. 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