Introduction
Urinary tract infection (UTI) is one of the most common infectious diseases, both in ambulatory and hospital settings, and is a major cause of antimicrobial use. This is especially relevant in the era of increasing antimicrobial resistance, and in particular, resistance developing in the Gram-negative organisms, which cause most UTI episodes. In many locations, it is increasingly difficult to select an empiric agent for UTI treatment that is reliably active, without major toxicities, and with robust evidence from clinical trials. Additional challenges in treating UTI are recognizing the distinct clinical syndromes included within the broad category of UTI and being aware of key management differences such as drug selection, therapy duration, and route of administration. The spectrum of distinct entities included under the umbrella of “UTI” ranges from simple cystitis, to pyelonephritis, to life-threatening urosepsis, making appropriate treatment of UTI more challenging than often appreciated.
Finally, it is critical to recognize that 30% to 50% of “UTI” episodes are actually asymptomatic bacteriuria mistakenly labeled as UTI and that any antimicrobial therapy given to these patients confers the risk of harm with no benefit. This chapter will focus on practical definitions of the commonly encountered UTI syndromes and highlight important principles of diagnosis and treatment for each entity.
Microbiology
Escherichia coli is the most important organism in the UTI world, but its relative importance fluctuates based on the specific UTI syndrome and the age and sex of the patient. In the case of uncomplicated cystitis in a premenopausal woman, E. coli is the causative organism for >90% of cases, with the remainder accounted for by Staphylococcus saprophyticus and a smattering of non– E. coli Enterobacteriaceae. Defining clonal strains of E. coli and their epidemiology is an ongoing area of research and is clinically relevant in that rapid expansion of specific clones can lead to widespread emergence of clinically relevant phenotypes, such as fluoroquinolone resistance and extended-spectrum β-lactamase production, both of which are important to consider when choosing empiric antimicrobial therapy, especially in a critically ill patient. In postmenopausal women, and especially in elderly men, non– E. coli organisms become more common causes of UTI. Although E. coli is still the most common organism isolated from the urine of symptomatic patients, in many cases, it is only a plurality, with non– E. coli organisms together comprising a majority. The specific organisms are not crucial to commit to memory, but a few general principles should be noted. Gram-negative organisms predominate, including Enterobacteriaceae such as Klebsiella , Enterobacter , and Citrobacter , but others such as Pseudomonas aeruginosa are also encountered, especially in patients with recent hospital exposure. Gram-positive organisms are less likely, but enterococci can be isolated from men, and Staphylococcus aureus should also be considered in a patient with hospital exposure.
Other than knowing the relative importance of Gram-negative organisms, the most important tools for a provider regarding UTI treatment is knowledge of how to access a current antibiogram and the ability to obtain a urine Gram stain to help guide empiric therapy. The urine Gram stain can be particularly useful in a patient with a prior history of methicillin-resistant S. aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) colonization; if such a patient presents with symptoms of pyelonephritis, a urine Gram stain showing only Gram-negative bacilli eliminates the need for empiric therapy targeting those previously isolated organisms and can greatly simplify therapy. Consulting a local antibiogram is essential in selecting an optimal empiric therapy for all UTI syndromes, but in particular for high-acuity syndromes such as pyelonephritis and urosepsis. At a facility where resistance to fluoroquinolones among Gram-negative organisms is below 10%, ciprofloxacin for a patient hospitalized with pyelonephritis is reasonable. If the same patient were to present at a facility with fluoroquinolone resistance rates for Gram-negatives exceeding 25%, ciprofloxacin as empiric therapy would be a questionable choice and could lead to harm.
Sex Differences
The epidemiology of UTI differs by sex, with UTI being far more common in premenopausal women relative to similarly aged men. The shorter urethra in women is believed to contribute to the increased risk of UTI, with bacteria having a shorter distance to travel to reach the bladder. Among postmenopausal women and similarly aged men, rates of UTI are comparable, largely due to rising incidence among men. This is attributed to the increasing frequency of prostatic hypertrophy and to the development of other comorbid conditions such as renal calculi, other prostatic diseases such as cancer, diabetes mellitus, chronic kidney disease, and others. This accumulation of conditions negates the protection accorded by the longer male urethra and whatever other factors may account for the lower rate of UTI in younger men relative to their female counterparts.
Sex differences are relevant in both the diagnosis and treatment of UTI. As mentioned previously, the microbiology of UTI in men is varied and unpredictable, such that a urine culture should always be obtained. In women, the microbiology is so predictable that in the absence of high rates of resistance, a urine culture is superfluous for UTI managed in the ambulatory setting. Among hospitalized patients, urine culture is advisable for all patients with a UTI syndrome to ensure active therapy in these acutely ill patients. Treatment differences between men and women include the fact that known or suspected prostatic involvement may influence drug selection (ideally with an agent known to penetrate prostatic tissue) and that treatment duration is generally longer for men than for women.
Classification of Urinary Tract Infections
What is a urinary tract infection?
In broad terms, a UTI is the presence of bacteria in the urinary tract with corresponding symptoms and signs. Importantly, although much is made about a specific numeric threshold for bacteria in a urine sample that indicates a true UTI, it is critical to note that patients can be symptomatic with relatively low numbers of bacteria in their urine and completely asymptomatic with high-count bacteriuria (generally defined as >100,000 colony-forming units/milliliter [cfu/mL]). In patients who are neurologically intact and without an indwelling catheter, symptoms of UTI can include frequency, urgency, dysuria, flank pain, pelvic discomfort, suprapubic pain, and acute hematuria. Other less specific symptoms can also be present, including fevers, chills, and rigors. Different UTI syndromes typically present with a subset of these symptoms, which will be reviewed in detail later and are summarized in Table 11.1 .
| UTI Syndrome | Characteristic Symptoms | Typical Findings | Urinalysis | Urine Culture |
|---|---|---|---|---|
| Cystitis (uncomplicated and complicated) | Dysuria, frequency, urgency | Suprapubic tenderness | Pyuria | Microbial growth |
| Pyelonephritis | Fever, flank pain, malaise, nausea, vomiting | CVA tenderness | Pyuria | Microbial growth |
| Urosepsis | Fever, altered mental status | Varied, including hemodynamic instability | Pyuria | Microbial growth |
| Bacteriuria/pyuria of undetermined clinical significance | Nonurinary symptoms without signs of systemic illness | Often absent or trivial findings | Pyuria | Microbial growth |
| Asymptomatic bacteriuria | None | None | Pyuria | Microbial growth |
Among patients with neurologic deficits such as multiple sclerosis, spinal cord injury (SCI), and stroke, some symptoms of UTI may not be present or may be reported differently. For instance, a patient with an incomplete SCI at the T10 spinal cord level is not likely to report dysuria, but may report malaise or increased spasticity. Similarly, a patient with a chronic indwelling urinary catheter will not report frequency and may not be able to report dysuria. Patients lacking the ability to accurately report symptoms can also be challenging—this includes sedated patients in the intensive care unit and those with cognitive impairments that preclude accurate reporting of symptoms. These special populations need to be evaluated carefully, and sometimes clinicians must decide whether an unusual symptom such as increased muscle spasticity is representative of a UTI or simply a temporal coincidence.
What is not a urinary tract infection?
Bacterial growth in the urine without corresponding symptoms is not a UTI, but instead reflects asymptomatic bacteriuria (ASB). In research settings this has been defined as >100,000 cfu/mL of the same organism isolated in two urine samples obtained at least 1 week apart, but a clinically more practical definition is any bacterial growth reported on a urine culture obtained from an asymptomatic patient. Despite guidelines from the Infectious Diseases Society of America that recommend no antimicrobial treatment for ASB outside of two specific scenarios (in pregnant women and before urologic surgery), treatment of ASB that is incorrectly labeled as UTI accounts for a substantial portion of UTIs that are treated with antimicrobials. An abnormal urinalysis or urine culture in an asymptomatic patient is not a UTI.
Specific Syndromes
Uncomplicated Cystitis
A 24-year-old woman presents with 24 hours of dysuria and frequency. She is afebrile and without abnormal findings on physical examination, including no vaginal discharge. She reports vaginal intercourse two to four times weekly with a single male partner and uses condoms with spermicide for all episodes. She has no history of UTI or sexually transmitted infections.
The concept of “complicated” and “uncomplicated” in the field of UTI generates considerable confusion, in part because there is some disagreement regarding whether certain features suffice to classify an episode as complicated. In this setting, “complicated” refers to factors that increase the risk of UTI, make eradication of the infection more difficult, broaden the spectrum of causative organisms, or increase the risk of UTI recurrence. Factors that most UTI experts agree upon as conferring “complicated” status include renal calculi, presence of a urinary catheter, abnormal urinary tract anatomy, anatomic or physiologic obstruction (e.g., prostatic hypertrophy or neurogenic bladder, respectively), recent instrumentation, and diabetes. Male sex is a factor that is sometimes invoked as a complicating factor, but agreement is not universal. Certain medications for diabetes can confer an increased risk for UTI, most notably the sodium–glucose cotransporter-2 inhibitors, which are widely used.
The patient in the clinical vignette is presenting with a clear case of cystitis, or what is sometimes described as “lower urinary tract infection.” Symptoms are directly referable to the site of infection—the urinary bladder. Systemic symptoms such as fevers or rigors are not present, and there is no indication of pyelonephritis (aka upper urinary tract infection ) such as flank pain or costovertebral tenderness on examination. Because the patient is sexually active, sexually transmitted infections should be considered, but the lack of vaginal discharge and the history of condom use makes this less likely. Use of spermicide has been linked to an increased risk of UTI through alteration in the normal bacterial flora of the vagina. The suggested diagnostic workup includes a urinalysis and possibly a urine culture. Urinalysis findings suggestive of infection include the presence of white blood cells (or a surrogate marker of white blood cells such as leukocyte esterase), nitrates, and bacteria. If the local antibiogram demonstrates low levels or resistance to first-line agents for cystitis, a urine culture is unlikely to add value. However, if resistance to first-line agents exceeds 20%, or if there is a reason to suspect a more resistant organism such as recent antimicrobial use, then a urine culture should be obtained.
Recommended treatment for cystitis includes nitrofurantoin, fosfomycin, and trimethoprim–sulfamethoxazole ( Table 11.2 ). Fluoroquinolones are not recommended for simple cystitis, despite excellent efficacy. This is because cystitis is typically a self-limiting disease, and widespread use of an oral agent with extended Gram-negative activity will limit its utility for more serious infections by increasing selection for fluoroquinolone-resistant strains. Moreover, increasing recognition of the adverse events caused by fluoroquinolones (hypoglycemia and hyperglycemia, tendon pain and rupture, neuropathy, QT prolongation, and increased rate of aortic aneurysms) have further added to the impetus to avoid these drugs for uncomplicated cystitis, and the US Food and Drug Administration specifically states to not use fuoroquinolones for uncomplicated cystitis. Patients with mild symptoms could be offered symptomatic treatment with ibuprofen and increased fluid intake, particularly if there is a compelling reason to avoid antibiotics (allergy, recent Clostridium difficile infection, etc.). The patient described in the vignette could be treated with nitrofurantoin, trimethoprim–sulfamethoxazole, or fosfomycin, based on her preferences for multiday or single-dose therapy.
| UTI Syndrome | Antimicrobial Dose, Route, and Duration | Comments |
|---|---|---|
| Uncomplicated cystitis | Nitrofurantoin macrocrystals 100 mg PO twice daily for 5 days TMP/SMZ 160/800 mg PO twice daily for 3 days Fosfomycin 3 g PO once | If treating a man as uncomplicated, consider treating for 7 days |
| Complicated cystitis | Nitrofurantoin macrocrystals 100 mg PO twice daily for 7–14 days TMP/SMZ 160/800 mg PO twice daily for 7–14 days Ciprofloxacin 500 mg PO twice daily for 7–14 days Fosfomycin 3 g PO every 3 days for two to three doses | For most cases, opting for shorter-duration therapy is preferred. Men with slow-to-resolve symptoms may need longer treatment duration. Fosfomycin dosing beyond once daily is poorly studied. |
| Pyelonephritis and febrile UTI | Ciprofloxacin 500 mg PO twice daily for 7 to 14 days Ceftriaxone 1 g IV once daily Piperacillin/tazobactam 3.375 grams IV q6h Ampicillin 2 grams IV q4h | If fluoroquinolone resistance exceeds 10%–20%, consider initial dose of ceftriaxone Ampicillin monotherapy suitable if Enterococcus suspected from urine Gram stain Step-down to oral agent to complete 7–14 days therapy |
| Urosepsis | Piperacillin/tazobactam 3.375 g IV q6h plus gentamicin 5 mg/kg/day Meropenem 500 mg IV q6h | Adding gentamicin is suggested for areas with high rates of resistance or for critically ill patients Step-down to oral agent to complete 7–14 days therapy, if possible |
| Bacteriuria/pyuria of undetermined clinical significance | Unknown if treatment needed | If opting to treat, regimens for complicated cystitis or pyelonephritis are reasonable |
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