Thomas M. Hooton

Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship

Timothy H. Dellit, Robert C. Owens, John E. McGowan, Jr., Dale N. Gerding, Robert A. Weinstein, John P. Burke, W. Charles Huskins, David L. Paterson, Neil O. Fishman, Christopher F. Carpenter, P. J. Brennan, Marianne Billeter, and Thomas M. Hooton Harborview Medical Center and the University of Washington, Seattle; Maine Medical Center, Portland; Emory University, Atlanta, Georgia; Hines Veterans Affairs Hospital and Loyola University Stritch School of Medicine, Hines, and Stroger (Cook County) Hospital and Rush University Medical Center, Chicago, Illinois; University of Utah, Salt Lake City; Mayo Clinic College of Medicine, Rochester, Minnesota; University of Pittsburgh Medical Center, Pittsburgh, and University of Pennsylvania, Philadelphia, Pennsylvania; William Beaumont Hospital, Royal Oak, Michigan; Ochsner Health System, New Orleans, Louisiana; and University of Miami, Miami, Florida

International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases

A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults

1. The diagnosis of asymptomatic bacteriuria should be based on results of culture of a urine specimen collected in a manner that minimizes contamination (A-II) (table 1). • For asymptomatic women, bacteriuria is defined as 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts 10 cfu/mL (B-II). • A single, clean-catch voided urine specimen with 1 bacterial species isolated in a quantitative count 10 cfu/mL identifies bacteriuria in men (BIII). • A single catheterized urine specimen with 1 bacterial species isolated in a quantitative count 10 cfu/mL identifies bacteriuria in women or men (A-II). 2. Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment (A-II). 3. Pregnant women should be screened for bacteriuria by urine culture at least once in early pregnancy, and they should be treated if the results are positive (A-I). • The duration of antimicrobial therapy should be

Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America

Guidelines for the diagnosis, prevention, and management of persons with catheter-associated urinary tract infection (CA-UTI), both symptomatic and asymptomatic, were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic criteria, strategies to reduce the risk of CA-UTIs, strategies that have not been found to reduce the incidence of urinary infections, and management strategies for patients with catheter-associated asymptomatic bacteriuria or symptomatic urinary tract infection. These guidelines are intended for use by physicians in all medical specialties who perform direct patient care, with an emphasis on the care of patients in hospitals and long-term care facilities.

DIAGNOSIS AND TREATMENT OF UNCOMPLICATED URINARY TRACT INFECTION

Acute uncomplicated urinary tract infection is one of the most common problems for which young women seek medical attention and accounts for considerable morbidity and health care costs. Acute cystitis or pyelonephritis in the adult patient should be considered uncomplicated if the patient is not pregnant or elderly, if there has been no recent instrumentation or antimicrobial treatment, and if there are no known functional or anatomic abnormalities of the genitourinary tract. Most of these infections are caused by E. coli, which are susceptible to many oral antimicrobials, although resistance is increasing to some of the commonly used agents. Review of the published data suggests that a 3-day regimen is more effective than a single-dose regimen for all antimicrobials tested. Regimens with trimethoprim-sulfamethoxazole seem to be more effective than those with beta lactams, regardless of the duration. Because of increasing resistance to trimethoprim-sulfamethoxazole, an alternative regimen such as nitrofurantoin (in a 7-day regimen), a fluoroquinolone, or an oral third-generation cephalosporin may be a better empiric choice in some areas. Acute pyelonephritis caused by highly virulent uropathogens in an otherwise healthy woman may be considered an uncomplicated infection. The optimal treatment duration for acute uncomplicated pyelonephritis has not been established, but 10- to 14-day regimens are recommended. We prefer to use antimicrobials that attain high renal tissue levels, such as a fluoroquinolone, trimethoprim-sulfamethoxazole, or an aminoglycoside, for pyelonephritis. Acute uncomplicated cystitis or pyelonephritis in healthy adult men is uncommon but is generally caused by the same spectrum of uropathogens with the same antimicrobial susceptibility profile as that seen in women.

Increasing antimicrobial resistance and the management of uncomplicated community-acquired urinary tract infections.

Uncomplicated community-acquired urinary tract infections (UTIs) are among the most common infections in women, accounting for more than 8 million office visits per year in the United States as well as significant morbidity and health care costs (1). Current management of these infections is usually empirical, without the use of a urine culture or susceptibility testing to guide therapy. The rationale for this approach is based on the narrow and predictable spectrum of etiologic agents that cause acute cystitis and their susceptibility patterns (2). However, as with many community-acquired infections, antimicrobial resistance among the pathogens that cause community-acquired UTIs is increasing (3-6). As the problem of antimicrobial resistance becomes more widespread, the use of narrow-spectrum, inexpensive antimicrobial agents becomes less feasible, affecting both the cost of and access to health care for patients. In addition, such infections as uncomplicated community-acquired UTI, which have traditionally been readily treatable, are now becoming therapeutic challenges. Perhaps the most significant change in resistance among uropathogens has been the increase in the prevalence of resistance to trimethoprimsulfamethoxazole (TMPSMX), the current drug of choice in the United States for empirical therapy for uncomplicated UTI in women. In addition, TMPSMX resistance has been associated with concurrent resistance to other antibiotics, resulting in multidrug-resistant uropathogens (7, 8). However, although several reports have focused on changing patterns of in vitro resistance of uropathogens to TMPSMX, the clinical significance of this resistance has not been well studied. Therefore, implications for health care providers are not yet clear. This review highlights the problem of antimicrobial resistance in acute uncomplicated community-acquired UTI, focusing on TMPSMX resistance, and summarizes the few available data regarding clinical outcomes associated with in vitro resistance. Finally, we outline recommendations for empirical treatment of uncomplicated UTI in a period of evolving antimicrobial resistance. Etiologic Agents in Uncomplicated Community-Acquired UTIs Although susceptibility patterns have changed, the spectrum of agents causing community-acquired UTI has remained relatively constant. Escherichia coli accounts for 75% to 90% of cases; Staphylococcus saprophyticus accounts for 5% to 15% (particularly in younger women); and enterococci and nonE. coli aerobic gram-negative rods, such as Klebsiella species and Proteus mirabilis, account for the remaining 5% to 10% (2, 9). Although less well studied, the spectrum of agents causing uncomplicated pyelonephritis is similar to that causing acute cystitis (10, 11). Pharmacologic Issues The antimicrobial agents used to treat uncomplicated community-acquired UTIs include the -lactams, TMPSMX, nitrofurantoin, fosfomycin, and the fluoroquinolones. All of these agents achieve high urinary concentrations, usually greatly exceeding the expected serum levels (Table 1). Of note, susceptibility breakpoints from the National Committee for Clinical Laboratory Standards are based on serum rather than urine concentrations of these antimicrobial agents, except for nitrofurantoin and fosfomycin, which are exclusively used for treatment of cystitis (12). Table 1. Pharmacokinetic Characteristics of Selected Antimicrobial Agents Used To Treat Community-Acquired Urinary Tract Infections The aminopenicillins, ampicillin and amoxicillin, and most cephalosporins are rapidly excreted into the urine and attain high urinary concentrations (Table 1) (12-15). The peak serum and urinary concentrations of amoxicillin are higher than those achieved with a similar dose of ampicillin (12). In the 1970s, ampicillin was commonly used for treatment of acute cystitis. However, because of increasing in vitro resistance, as well as lower efficacy and more adverse effects than are seen with other available UTI antimicrobial agents, the -lactams in general are no longer recommended for empirical UTI therapy (1). In certain settings, such as during pregnancy or when enterococci are suspected, ampicillin or amoxicillin may still be an appropriate choice for acute UTI (1). The combination of TMP and SMX has been shown to be synergistic against a variety of organisms, including such aerobic gram-negative rods as E. coli (16). This combination has been used for treatment of UTI for more than two decades, although the commonly used 3-day regimen has not been formally approved by the U.S. Food and Drug Administration. After a single oral dose of one double-strength tablet (TMP, 160 mg; SMX, 800 mg), the peak urine concentrations are approximately 35 and 3 to 4 times higher, respectively, than serum levels (Table 1). Trimethoprim also concentrates in prostatic tissue at levels 2 to 3 times higher than those found in serum (12). Nitrofurantoin is one of the oldest urinary antiinfective agents in use. The macrocrystalline formulation requires frequent dosing (every 6 hours); however, a modified monohydratemacrocrystal form delays gastric uptake and allows twice-daily dosing. Nitrofurantoin is used primarily for treatment of cystitis because it does not attain appreciable serum levels (Table 1). It is 90% renally excreted, and therefore the urine concentration is very high, making it an effective urinary anti-infective agent for most gram-positive and gram-negative uropathogens (17). Fosfomycin tromethamine is a phosphonic acid derivative that is newly licensed for treating uncomplicated cystitis caused by E. coli or Enterococcus faecalis (18). It is not approved for use for cystitis caused by S. saprophyticus or for treatment of pyelonephritis. It achieves very high concentrations in the urine and persists in the urine for more than 24 hours (Table 1). The fluoroquinolones each have individual pharmacodynamic properties (12, 19, 20). The first fluoroquinolones widely used for treatment of UTI, namely norfloxacin, ciprofloxacin, ofloxacin, and levofloxacin, all have excellent bioavailability and achieve high urinary concentrations (Table 1). Their penetration into prostatic and renal tissue is also excellent. Some of the newer fluoroquinolones, such as sparfloxacin and trovafloxacin, are not excreted in high urinary concentrations and thus should not be used for treatment of uncomplicated pyelonephritis or complicated UTI. The fluoroquinolones also have a significant postantibiotic effect against gram-negative organisms (12). In Vitro Susceptibility Data Many recent studies have reported the resistance profiles of uropathogens to antimicrobial agents commonly used to treat UTI (3-8). Much of this in vitro data comes from laboratory-based surveys that often do not define the sex, age, clinical syndrome, or location (inpatient vs. outpatient) of the patients from whom the urine specimens are collected. Therefore, the reported rates of resistance may vary depending on whether the study sample consists primarily of outpatients with uncomplicated UTIs or patients with complicated nosocomial UTIs. The data presented here focus on studies that clearly define the study sample as women with uncomplicated community-acquired UTI. Although susceptibility profiles vary by each specific organism and antimicrobial combination, some general trends have clearly emerged. Resistance of E. coli and other uropathogens to -lactams, such as ampicillin, and the first-generation cephalosporins has continued to increase in the past decade and now approaches 40% in most studies (3, 6). Most gram-negative uropathogens are still susceptible to the combination of amoxicillinclavulanate, but the expense and gastrointestinal side effects of this drug make it a less desirable choice for empirical treatment of uncomplicated UTI (2). Moreover, it has been suggested that the failure rate with this drug is high when the uropathogen is resistant to ampicillin but susceptible to amoxicillinclavulanate (22). Nitrofurantoin and the fluoroquinolones have retained in vitro activity against most E. coli isolates that cause uncomplicated community-acquired UTI (>99% in most studies) (Table 2). However, nitrofurantoin is less active against nonE. coli gram-negative rods (3, 6) and inactive against Proteus and Pseudomonas species. The fluoroquinolones have had consistently high activity against essentially all gram-negative uropathogens seen in women with uncomplicated community-acquired UTI but are active against only 60% to 70% of enterococci, depending on the study (3, 6). Both nitrofurantoin and the fluoroquinolones retain good in vitro activity against S. saprophyticus (6), although increased failure rates have been reported with the use of single doses of fluoroquinolones to treat S. saprophyticusrelated UTIs (1). Table 2. in Vitro Susceptibility of Escherichia coli from U.S. Studies of Urinary Tract Infection As mentioned, the most substantial change in resistance prevalence has been to TMPSMX. Resistance to TMPSMX among uropathogens in the community was relatively infrequent in the United States in the early 1990s (Table 2). At that time, McCarty and colleagues (9) conducted a multicenter trial of low-dose ciprofloxacin compared with standard-dose ofloxacin and TMPSMX for treatment of acute uncomplicated cystitis in women. They reported only a 7% prevalence of TMPSMX resistance among the E. coli isolates. The rates of resistance did not increase to levels that might compromise clinical effectiveness until the mid-1990s (Table 2). We conducted a cross-sectional survey of urine isolates from a well-defined sample of outpatient women in western Washington State who had acute uncomplicated cystitis. We found that the prevalence of TMPSMX resistance among E. coli was 9% in 1992 but had increased to 18% by 1996, the last year of the study (3). Of interest, in a California student health sample, Dyer and coworkers found that the prevalence of UTI isolate

A prospective study of risk factors for symptomatic urinary tract infection in young women.

BACKGROUND Although acute urinary tract infections are common in young women, the associated risk factors have not been defined prospectively. METHODS We recruited sexually active young women who were starting a new method of contraception at a university health center or a health maintenance organization (HMO) and monitored them for six months for symptomatic urinary tract infections. Daily diaries and serial interviews were used to collect data on potential risk factors. RESULTS Among 796 women, the incidence of urinary tract infections per person-year was 0.7 in the university cohort (mean age, 23 years; n = 348) and 0.5 in the HMO cohort (mean age, 29; n = 448). In both cohorts, there were strong dose-response relations between the risk of infection and both recent use of a diaphragm with spermicide (respective relative risks for one, three, and five days of use in the past week, 1.42, 2.83, and 5.68 in the university cohort, P<0.001; and 1.29, 2.14, and 3.54 in the HMO cohort, P=0.04) and recent sexual intercourse (respective relative risks for one, three, and five days with intercourse in the past week, 1.37, 2.56, and 4.81 in the university cohort, P<0.001; and 1.24, 1.91, and 2.96 in the HMO cohort, P=0.002). The risk of acute infection was also associated with a history of recurrent infection (relative risk, 5.58 in the university group and 2.10 in the HMO group) but not with cervical-cap use, ABO-blood-group nonsecretor phenotype, or delayed postcoital voiding. CONCLUSIONS Among sexually active young women the incidence of symptomatic urinary tract infection is high, and the risk is strongly and independently associated with recent sexual intercourse, recent use of a diaphragm with spermicide, and a history of recurrent urinary tract infections.

Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection

Background Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI. Methods and Findings We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria. Conclusions The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.

Risk Factors for Recurrent Urinary Tract Infection in Young Women

To define host factors associated with an increased risk of recurrent urinary tract infection (RUTI), a case-control study was conducted in 2 populations: university women and health maintenance organization enrollees. Case patients were 229 women 18-30 years old with RUTIs; control subjects were 253 randomly selected women with no RUTI history. In a multivariate model, independent risk factors for RUTI included recent 1-month intercourse frequency (odds ratio [OR], 5.8; 95% confidence interval [CI], 3.1-10.6 for 4-8 episodes), 12-month spermicide use (OR, 1.8; 95% CI, 1.1-2.9), and new sex partner during the past year (OR, 1.9; 95% CI, 1.2-3.2). Two newly identified risk factors were age at first urinary tract infection (UTI) </=15 years (OR, 3.9; 95% CI, 1.9-8.0) and UTI history in the mother (OR, 2.3; 95% CI, 1.5-3.7). Blood group and secretor phenotype were not associated with RUTI. In young women, risk factors for sporadic UTI are also risk factors for recurrence. Two predictors suggest that genetic/long-term environmental exposures also predispose to RUTI.

Recurrent urinary tract infection in women

Recurrent urinary tract infections (UTI) are common among young healthy women even though they generally have anatomically and physiologically normal urinary tracts. Women with recurrent UTI have an increased susceptibility to vaginal colonization with uropathogens, which is due to a greater propensity for uropathogenic coliforms to adhere to uroepithelial cells. Risk factors for recurrent UTI include sexual intercourse, use of spermicidal products, having a first UTI at an early age, and having a maternal history of UTIs. Inherited factors may be important in some women with recurrent UTI. Many factors thought to predispose to recurrent UTI in women, such as pre- and post-coital voiding patterns, frequency of urination, wiping patterns, and douching have not been proven to be risk factors for UTI. In contrast to the predominantly behavioral risk factors for young women, mechanical and/or physiological factors that affect bladder emptying are most strongly associated with recurrent UTI in healthy postmenopausal women. The management of recurrent UTI is the same as that for sporadic UTI except that the likelihood of infection with an antibiotic resistant uropathogen is higher in women who have received recent antimicrobials. Strategies to prevent recurrent UTI in young women should include education about the association of recurrent UTI with frequency of sexual intercourse and the usage of spermicide-containing products. Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment with antimicrobials have all been demonstrated to be effective in managing recurrent uncomplicated UTIs in women. Estrogen use is very effective in preventing recurrent UTI in post-menopausal women. Exciting new approaches to prevent recurrent UTI include the use of probiotics and vaccines. Further understanding of the pathogenesis of UTI will lead to more effective and safer methods to prevent these frequent infections.