| Drug | Dose and duration | Comments |
|---|---|---|
| First-line agents | ||
| TMP–SMX | 1 DS (160/800-mg) tablet twice daily for 3 days | First-line agents unless ≥10–20% rate of Escherichia coli resistance to TMP–SMX locally, history of antibiotic use, within past 3 months, or history of recent hospitalization FDA pregnancy category C; avoid in third trimester |
| Nitrofurantoin (monohydrate macrocrystals) | 100 mg twice daily for 7 days | May be less effective than TMP–SMX Consider for patients with mild to moderate symptoms, and with ≥10–20% rate of E. coli resistance to TMP–SMX locally, sulfa allergy, or antibiotic use other than nitrofurantoin within past 3 months FDA pregnancy category B |
| Fosfomycin | 3 g as single dose | May be less effective than TMP–SMX Consider for patients with mild to moderate symptoms, and with ≥10–20% rate of E. coli resistance to TMP–SMX locally, sulfa allergy, or antibiotic use other than fosfomycin within past 3 months FDA pregnancy category B |
| Second-line agents | ||
| β-lactams (e.g., amoxicillin-clavulanate, cephalosporins) | 3–7 days (dose depends on individual agent) | There are less efficacy data for these agents compared to data for first-line agents and fluoroquinolones Consider β-lactams if ≥10–20% rate of E. coli resistance to other agents and rates of resistance to selected β-lactams ≤ 20% Amoxicillin or ampicillin should not be used as monotherapy for empiric treatment FDA pregnancy category B |
| Fluoroquinolones Ciprofloxacin Levofloxacin | 250 mg twice daily for 3 days 250 mg daily for 3 days | Consider fluoroquinolones if ≥10–20% rate of E. coli resistance to TMP–SFX locally, patient allergy to other agents, and antibiotic use other than fluoroquinolones within past 3 months FDA pregnancy category C |
Note: Antibiotic dose recommendations assume normal renal function.
Abbreviations: TMP–SMX = trimethoprim–sulfamethoxazole; DS = double strength; FDA = Food and Drug Administration.
Pathogenesis
The pathogenesis of most upper and lower UTIs is related to the ability of microorganisms to establish colonization in the periurethral area and to ascend into the urinary tract, causing infection. These organisms are typically derived from the gastrointestinal tract or vagina. After colonization, the ensuing events that lead to infection are not entirely understood but likely depend upon virulence factors of the organism, and host anatomy and immune response. Urinary catheters can facilitate both colonization and infection. They are commonly colonized by periurethral flora that migrate along the catheter surface. Interactions between the catheter and infecting or colonizing organisms facilitate adhesion to the catheter and production of a biofilm, which aids certain microorganisms in evading host defenses. Rarely, UTIs may occur through a hematogenous route of infection.
The majority of upper and lower UTIs are monomicrobial. Escherichia coli is the most common pathogen, causing 70% to 90% of all UTIs. Other members of the Enterobacteriaceae family such as Klebsiella, Proteus, and Enterobacter species are also common UTI pathogens. Among the gram-positive organisms, Staphylococcus saprophyticus and Enterococcus species are the most frequently identified pathogens. Other bacteria, such as Pseudomonas, Serratia, and Candida species can be seen more frequently in association with indwelling urinary catheters, and polymicrobial UTIs can also occur in this setting. A polymicrobial infection in the absence of a urinary catheter may suggest an enterovesical fistula or contamination during the specimen collection process. Candida albicans is the most common etiologic agent in fungal UTIs, but other Candida species are becoming increasingly common. Several sexually transmitted infections (STIs), including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and genital herpes simplex virus infection, can cause urethritis, which mimics symptoms of UTI. Therefore, appropriate diagnostic evaluation for STIs should also be performed as part of a UTI workup in sexually active patients, especially if another pathogen is not isolated.
Lower UTI: cystitis
Typical symptoms of lower UTIs include dysuria, urinary frequency, urgency, and, occasionally, hematuria or suprapubic pain. The presence of fever or flank pain should raise the concern for pyelonephritis. In addition to history and physical examination findings, laboratory tests are often used in the diagnosis of cystitis.
Diagnosis
The diagnosis of cystitis can be made using a combination of clinical and laboratory criteria. Some symptoms, including dysuria, urinary frequency, and hematuria, increase the likelihood of UTI. The absence of dysuria or back pain and presence of vaginal irritation or discharge decrease the likelihood of UTI. Women with at least one symptom have at least a 35% to 50% likelihood of having cystitis. The presence of dysuria and urinary frequency combined with the absence of vaginal discharge increases the likelihood of UTI to greater than 90%. Patients with a high pretest probability for cystitis and no complicating factors should be treated empirically without additional testing. Patients with a lower pretest probability should have diagnostic testing performed. In these patients, the diagnosis of cystitis can be evaluated using urine dipstick, microscopy, and/or culture.
In ambulatory settings, urine dipstick testing has largely replaced microscopy to diagnose UTI because it is cheaper, faster, and more convenient. Dipstick testing can detect the presence of leukocyte esterase, an enzyme released by white blood cells, and nitrites, by-products of nitrate metabolism produced by Enterobacteriaceae. A positive test for either leukocyte esterase or nitrite has a sensitivity of 75% and specificity of 82%. Because of the limited sensitivity and specificity of the dipstick test, the dipstick may be most useful for rapid rule-out of UTI among women with a moderate to low pretest likelihood of infection, such as minimally symptomatic patients or those with both bladder and vaginal symptoms. Urine microscopy has a higher sensitivity and specificity compared to the dipstick test. Hemocytometer (counting chamber) measurement of urine leukocytes in an unspun specimen provides the most accurate assessment of pyuria, which is defined as a leukocyte count ≥10 leukocytes/mm3. Pyuria is present in almost all women with cystitis in the absence of neutropenia. Another method of urinalysis involves the microscopic examination of urine sediment from centrifuged samples. The accuracy of this method depends on the skill of the operator and the level of procedural standardization. The presence of bacteriuria on urine microscopy can also be used to assess the presence of UTI, but it is often difficult to interpret, given the ease of specimen contamination with periurethral flora during collection, as well as the overgrowth of bacteria that may result from the improper handling of specimens. Therefore, bacteriuria alone in the absence of pyuria should not be used to make the diagnosis of UTI.
Urine culture is not necessary in most otherwise healthy women with cystitis because the causative organisms and their susceptibility patterns are predictable. However, urine cultures should be obtained in patients with refractory symptoms, recurrent UTIs, suspected pyelonephritis, or complicated UTI. Urine cultures should also be obtained in patients with history of, or risk factors for, antibiotic-resistant pathogens, including in those patients with recent antibiotic use, recent hospitalization, or residence in a long-term care facility. Although suprapubic aspiration or straight catheterization has the best chance of minimizing contamination, midstream, or “clean-catch,” urine collection remains the most practical method of obtaining urine samples. Quantitative urine cultures are the gold standard for microbiologic diagnosis of UTIs. Growth, identification, and susceptibility testing of the pathogen can offer the most effective means for establishing infection and determining appropriate antimicrobial therapy. Traditionally, bacteriuria with ≥105 colony-forming units (CFU) of bacteria per milliliter of urine has been considered diagnostic. This threshold was extrapolated from studies of pyelonephritis and asymptomatic bacteriuria in women. However, based on more recent studies, lower colony counts (102 to 104 CFU/mL) in association with signs and symptoms of cystitis have also been accepted as diagnostic. The quantitative threshold for UTIs in men remains unclear, but many authorities recommend a lower threshold of 103 CFU/mL.
Therapy
Treatment of uncomplicated cystitis can be accomplished with a short course of an effective antimicrobial agent. Because therapy is typically started in the absence of a culture or before culture results become available, understanding common pathogens and local susceptibility patterns is essential. Given that E. coli is the predominant UTI pathogen, its susceptibility patterns typically drive empiric antibiotic choices. Table 65.1 outlines general treatment recommendations for uncomplicated cystitis.
In many areas, resistance rates for nitrofurantoin, fosfomycin, and trimethoprim–sulfamethoxazole (TMP–SMX) are less than 10%. Therefore, these drugs have become the recommended first-line empiric agents for uncomplicated cystitis. However, the rates of resistance vary considerably by geographic region and can exceed 20% in some areas. In particular, the rapidly increasing rate of resistance of E. coli to TMP–SMX has raised significant concern about its empiric use for UTI. In vitro and mathematical modeling studies suggest that TMP–SMX should not be used when local resistance rates exceed 20%. Individual risk factors for resistance should also be considered before using TMP–SMX for empiric therapy. Studies have suggested that the highest risk of UTI caused by TMP–SMX-resistant E. coli is associated with recent TMP–SMX or other systemic antibiotic use. Other risk factors include recent hospitalization, residence in a long-term care facility, and travel outside the United States within the last 3 to 6 months.
The potential benefits of nitrofurantoin and fosfomycin use for UTI treatment include that both have a relatively narrow spectrum of activity, have little in vitro resistance, and that neither achieve high concentrations outside the urinary tract. Both nitrofurantoin and fosfomycin have been studied only for treatment of lower UTIs, and as they do not achieve high drug concentration levels in the upper urinary tract, they should not be used to treat upper UTIs. Nitrofurantoin used for 5 days has similar clinical cure rates as TMP–SMX used for 3 days. Fosfomycin can be administered as a single dose for uncomplicated cystitis, and it is a reasonable first-line therapy. A few small studies suggest clinical cure rates may be slightly inferior when fosfomycin is compared with other first-line agents. One potential disadvantage of fosfomycin is that most microbiology laboratories do not perform routine fosfomycin susceptibility testing and require a special request to do so. Fosfomycin retains in vitro activity against many multidrug-resistant organisms, including extended-spectrum β
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