Urinary tract infections (UTIs) include simple acute cystitis (infection of the bladder/lower urinary tract) and pyelonephritis (infection of the kidney/upper urinary tract). The pathogenesis of UTI begins with the colonization of the vaginal introitus or urethral meatus by uropathogens from the fecal flora, followed by ascension via the urethra into the bladder. Pyelonephritis develops when pathogens ascend to the kidneys via the ureters. Pyelonephritis can also be caused by seeding of the kidneys from bacteremia. Some cases of pyelonephritis may be associated with the seeding of the kidneys from bacteria in the lymphatics.
This course will review the approach to women and men with typical symptoms of cystitis when there is no concern that the infection has extended beyond the bladder which, is simple acute cystitis. When there is concern that the infection has possibly extended beyond the bladder (e.g., when there is flank pain or other features suggestive of pyelonephritis, pelvic, or perineal pain (in men), fever, and other signs of systemic illness, including sepsis), this is defined as a complicated UTI. This approach to categorizing UTI differs from other conventions.
The term “simple acute cystitis” refers to an acute UTI presumed to be confined to the bladder. Such infections lack signs or symptoms that suggest an infection extending beyond the bladder or systemic infection.
If any of the following signs or symptoms are present in pyuria and bacteriuria, this patient is considered to have a complicated acute UTI and should be managed differently. These signs and symptoms suggest an infection extending beyond the bladder (Hooton & Gupta, 2021):
If the patient has no concerning symptoms of an upper UTI or systemic infection, they may not have a complicated acute UTI (Hooton & Gupta, 2021).
This following list of patients should be followed closely because they have a lower threshold for management as a complicated acute UTI (Hooton & Gupta, 2021). These patients may have more subtle signs and symptoms suggestive of more extensive infection. Many patients with significant urologic abnormalities come to clinical attention for a complicated acute UTI because of signs/symptoms consistent with a complicated acute UTI as defined here, rather than features of simple cystitis alone. Pregnant women and renal transplant recipients are unique populations with unique management considerations and thus are not included in these categories (Hooton & Gupta, 2021):
Women categorized as having acute uncomplicated cystitis would fall under the definition of simple acute cystitis. Simple acute cystitis or pyelonephritis in a nonpregnant premenopausal woman without underlying urologic abnormalities is acute uncomplicated UTI. Complicated acute UTI has been defined as cystitis or pyelonephritis in a patient with underlying urologic abnormalities. Individuals who do not fit into either category have often been treated as having a complicated UTI.
Another approach to treatment is based on the presumed extent of infection and severity of illness. A complicated acute UTI is a more serious infection than simple acute cystitis. Thus, the efficacy of an antimicrobial agent is of greater importance and certain agents used for simple acute cystitis should not be used for a complicated acute UTI because they do not achieve adequate tissue levels, which is important for a cure. Risk for infection with drug-resistant organisms is a consideration in the antibiotic selection for both simple acute cystitis and complicated acute UTIs.
|Simple Acute Cystitis|
|Complicated Acute UTI||Acute UTI accompanied by signs or symptoms that suggest an extension of infection beyond the bladder: |
|Special populations with unique management considerations|
Simple acute cystitis among women is extremely common. Among otherwise healthy women, risk factors for simple acute cystitis include (Hooton & Gupta, 2021; Hooton & Calderwood, 2020):
Simple acute cystitis occurs in a very small proportion of men between 15 and 50 years of age. The incidence is approximately five to eight UTIs per year per 10,000 young to middle-aged men. Among otherwise healthy men, risk factors associated with simple acute cystitis include (Hooton & Gupta, 2021; Hooton & Calderwood, 2020):
Other comorbidities in both men and women which increase the risk factors for simple acute cystitis include (Hooton & Gupta, 2021; Hooton & Calderwood, 2020):
UTIs are caused by both Gram-negative and Gram-positive bacteria, as well as by certain fungi. Uropathogens include (Hooton & Gupta, 2021):
In the absence of antimicrobial or health care exposures, other gram-negative and gram-positive species may infrequently be isolated in simple acute cystitis.
The microbial spectrum of simple acute cystitis in patients with recent antimicrobial or other health care exposures may be broader and also include other gram-negative bacilli such as (Hooton & Gupta, 2021):
Culture and susceptibility testing are essential for management in patients who have such risk factors. Resistance to E. coli can be a major issue.
Among otherwise healthy nonpregnant women, the isolation of organisms such as lactobacilli, enterococci, Group B streptococci, and coagulase-negative staphylococci other than S. saprophyticus from voided midstream urine most commonly represents contamination of the urine specimen. Nevertheless, it may be appropriate to consider these organisms the likely causative agent in symptomatic women when found in voided midstream urine at high counts and with pure growth (i.e., without growth of other bacteria).
Expected susceptibility patterns of E. coli should be the basis for the empiric antimicrobial selection for simple acute cystitis. Increasing rates of resistance have been reported globally.
Risk factors for UTI with resistant organisms include (Hooton & Gupta, 2021):
When there are no clear risk factors for resistance, nitrofurantoin, fosfomycin, and pivmecillinam are appropriate first-line agents for simple acute cystitis. Resistance rates for first and second-generation oral cephalosporins and amoxicillin-clavulanic acid are regionally variable but generally <10%. Fluoroquinolone resistance rates have been <10% in most parts of North America and Europe, but there has been a clear trend of increasing resistance over time.
When interpreting these data, it is important to remember that passive laboratory-based surveillance methods tend to overestimate true resistance rates since they are skewed by urine cultures obtained from patients who may have failed initial therapy or who have specific risk factors for resistance, such as recent travel or antimicrobial use.
Trimethoprim-Sulfamethoxazole (TMP-SMX) is the agent for which there is the most data to guide clinical use. Identified risk factors for resistance in women with simple acute cystitis include (Hooton & Gupta, 2021):
Studies have suggested that a 20% resistance prevalence should be the threshold at which TMP-SMX should not be used for empiric treatment of simple acute cystitis (Hooton & Gupta, 2021).
For other antimicrobial agents, there is insufficient data to determine the resistance levels at which the likelihood of failure outweighs the potential benefits. The decision to prescribe an appropriate antibiotic agent depends on the discretion of the individual practitioner. Additionally, practitioners need to understand that local resistance rates reported in hospital antibiograms are often skewed by cultures of samples obtained from hospitalized patients or those with complicated infections and may not accurately predict susceptibilities in women with simple acute community-acquired cystitis, in whom resistance rates tend to be lower (Hooton & Gupta, 2021).
Image 1: Female Anatomy
Image 2: Male Anatomy
The classic clinical manifestations of simple acute cystitis in both sexes include:
Fever, chills, rigors, and other signs of systemic illness raise the possibility of pyelonephritis or other complications of a UTI and, thus, are not compatible with a diagnosis of simple acute cystitis.
An important thing to note for women is the presence/absence of vaginal symptoms (e.g., vaginal pruritus or discharge). The probability of simple acute cystitis is greater than 50% in women with any of these symptoms and greater than 90% in women with dysuria and frequency without vaginal discharge or irritation. Hematuria is also often observed. Symptoms of simple acute cystitis can occasionally be subtle and more difficult to tease out, especially in older women (Hooton & Gupta, 2021; Hooten & Calderwood, 2020).
Older women can have several nonspecific urinary symptoms (such as chronic dysuria or urinary incontinence) that mimic symptoms of simple acute cystitis, even when there is no evidence of UTI. A systematic review of studies evaluating UTI diagnosis among community-dwelling adults older than 65 suggested that symptoms such as chronic urinary nocturia, incontinence, and a general sense of lack of well-being were common and nonspecific for UTI. Women should be asked about fevers/chills and flank pain.
Suppose fever (>99.9°F/37.7°C), other signs or symptoms of systemic illness (including chills, rigors, or marked fatigue or malaise beyond baseline), flank pain, or CVA tenderness are present. In this case, the patient should be evaluated and managed as potentially having a complicated UTI.
Acute dysuria (less than one-week duration), new or worsening urinary urgency, new incontinence, frequency, gross hematuria, and suprapubic pain or tenderness are considered discriminating symptoms. Fever is also a discriminating feature, although it is common to consider patients with cystitis symptoms and fever to have a complicated UTI. Among debilitated patients, many generalized signs or symptoms, e.g., falls, changes in functional status, and mental status, are not reliable predictors of bacteriuria or cystitis.
Although cloudy or smelly urine may be associated with bacteriuria, as demonstrated in nursing home residents, there is no evidence treating patients with only these complaints as having a UTI before the onset of usual cystitis symptoms is indicated. Color and odor of urine are influenced by ingestion of certain foods, dehydration, and other noninfectious factors. Consequently, increased fluid intake and careful observation are reasonable initial approaches to patients who complain of changes in odor or color of urine (Hooton & Gupta, 2021; Hooten & Calderwood, 2020).
Prostatitis should be considered in men presenting with cystitis symptoms that are recurrent or are accompanied by pelvic or perineal pain or fever.
Physical examination is often not essential for the diagnosis, but if performed, should include assessment for (Hooton & Gupta, 2021; Hooten & Calderwood, 2020):
In addition, specifically for female patients, a pelvic examination is indicated if symptoms or signs suggesting vaginitis or urethritis are present. Among sexually active young women, a pelvic examination should be performed, particularly if symptoms are not convincing for a UTI, to evaluate for cervical motion or uterine tenderness, which would be suggestive of pelvic inflammatory disease (PID).
For male patients, urethritis must be considered in sexually active men. An examination should include assessing for penile ulcerations as well as urethral discharge. A digital rectal examination should be performed on men who present with pelvic or perineal pain or fever symptoms to evaluate for a tender or edematous prostate that would suggest acute prostatitis.
Suppose fever (>99.9°F/37.7°C), other signs or symptoms of systemic illness (including chills, rigors, or marked fatigue or malaise beyond baseline), flank pain, or CVA tenderness are present. In this case, these signs and symptoms are not compatible with a diagnosis of simple acute cystitis and raise the possibility of pyelonephritis, prostatitis, or other complications of a UTI. These patients should be evaluated and managed as potentially having a complicated UTI.
For most women with suspected simple acute cystitis, particularly those with classic symptoms, no additional testing is warranted to make the diagnosis.
If additional testing is warranted, the following diagnostics can be ordered (Hooton & Gupta, 2021; Hooten & Calderwood, 2020):
When indicated, urinalysis (either by microscopy or by dipstick) for evaluation of pyuria is a valuable laboratory diagnostic test for UTI. It is not indicated in women with typical symptoms of simple acute cystitis (the diagnosis can reliably be made on symptoms alone). Still, it can be helpful in cases in which the clinical presentation is not typical.
Pyuria is present in almost all men and women with simple acute cystitis, but its absence strongly suggests an alternative diagnosis.
Apart from the classic features listed above, features that should prompt urine testing include:
Chronic urinary nocturia, chronic incontinence, general malaise, and cloudy or malodorous urine are nonspecific findings that should not routinely rapid urine testing to evaluate cystitis. Urine is not routinely tested in elderly or debilitated patients with nonspecific mental or functional status changes in the absence of focal urinary tract symptoms.
Hydration, careful observation, and assessment for other potential contributing factors are advocated. If fever is also present, evaluation for infection, including complicated UTI, is warranted.
The most accurate method for assessing pyuria is to examine an unspun, voided midstream urine specimen under the microscope with a hemocytometer.
An abnormal result is ≥10 leukocytes/microliter. However, this laboratory test is usually not available to the clinician. White blood cell casts in the urine, although rare, are diagnostic of upper tract infection rather than simple acute cystitis, thus indicating a complicated UTI.
The presence of hematuria is helpful since it is common in UTI but not in urethritis or vaginitis. However, hematuria is not a predictor for complicated infection and does not alter the approach to therapy.
Dipsticks are commercially available strips that detect the presence of leukocyte esterase (an enzyme released by leukocytes, reflecting pyuria) and nitrite (reflecting the presence of Enterobacteriaceae, which convert urinary nitrate to nitrite). The dipstick test is most accurate for predicting UTI when positive for either leukocyte esterase or nitrite, with a sensitivity of 75% and a specificity of 82%. However, results of the dipstick test provide little useful information when the clinical history is strongly suggestive of UTI.
Urine culture and susceptibility testing should be performed on patients with risk factors for more serious infection or who are at risk for an infection with a resistant organism, such as those with:
Urine culture and susceptibility testing are generally unnecessary in women with simple acute cystitis but should be performed in patients at risk for infection with a resistant organism.
Additional diagnostics can include (Hooton & Gupta, 2021; Hooten & Calderwood, 2020):
In women with simple acute cystitis, the causative organisms and their antimicrobial susceptibility profiles are frequently predictable. Consequently, routine cultures for such infections are often not necessary for management decisions. Given the increasing prevalence of antimicrobial resistance among uropathogens, obtaining a urine culture before initiation of therapy is warranted in patients who have risk factors for antimicrobial resistance, as well as in patients at risk for more serious infection (e.g., those with underlying urologic abnormalities, immunocompromising conditions, and poorly controlled diabetes mellitus).
Suppose voided urine cultures are sent to the laboratory. In this case, the practitioner should ask the laboratory to quantify E. coli, if it grows, to at least 103 colony-forming units/mL to improve specificity. Moreover, E. coli should not necessarily be considered a contaminant if it grows in mixed flora since almost any growth of E. coli in voided urine in a symptomatic patient reflects bladder growth. Growth of organisms generally thought to be contaminants (lactobacilli, enterococci, Group B streptococci, and non-saprophyticus coagulase-negative staphylococci) may be considered causative when found in voided midstream urine at high counts and with pure growth.
The clinical diagnosis of simple acute cystitis is made in a patient who presents with typical urinary signs and symptoms (i.e., dysuria, urinary frequency, urgency, suprapubic pain, etc.). The diagnosis is supported by pyuria on microscopy or dipstick and bacteriuria on urinalysis and culture for patients with atypical urinary symptoms.
The clinical diagnosis of simple acute cystitis excludes (Hooten & Gupta, 2021):
The presence of any of these features suggests pyelonephritis or extension of the infection beyond the bladder and is thus considered a complicated acute UTI. A lower threshold is considered in patients with risk factors for more serious infection as having complicated acute UTI, for example, if they have more subtle signs or symptoms of a possible upper tract or systemic infection. Such risk factors include (Hooten & Gupta, 2021):
Bacteriuria with or without pyuria in the absence of any symptom that could be attributable to a UTI is called asymptomatic bacteriuria (Fekete & Hooten, 2021) and generally does not warrant treatment in nonpregnant patients who are not undergoing urologic procedures.
Both infectious and noninfectious processes can cause symptoms of dysuria, frequency, urgency, suprapubic pain, and hematuria (Hooten & Gupta, 2021). The following differential diagnoses should also be considered (Hooten & Gupta, 2021):
β-lactam antibiotics (beta-lactam antibiotics) are a class of broad-spectrum antibiotics consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Bacteria often develop resistance to β-lactam antibiotics by synthesizing a β-lactamase, an enzyme that attacks the β-lactam ring. To overcome this resistance, β-lactam antibiotics are often given with β-lactamase inhibitors such as clavulanic acid (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
|Beta-lactamase inhibitor combination|
Fluoroquinolones, which contain a fluorine atom in their chemical structure, are effective against Gram-negative and Gram-positive bacteria (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Co-trimoxazole antibiotic is a combination of trimethoprim and sulfamethoxazole (TMP-SMX). It has a greater effect when given together than when given separately because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations. When they enter the body, their concentration in the blood and tissues is roughly one-to-twenty — the exact ratio required for a peak synergistic effect between the two (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Fosfomycin is a novel class of antibacterial with a chemical structure unrelated to other known antibiotics. It is a bactericidal drug that disrupts cell wall synthesis by inhibiting phosphoenolpyruvate synthetase and thus interferes with the production of peptidoglycan (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Nitrofurantoin monohydrate macrocrystal is bactericidal. The mechanism of action is unique and complex. The drug works by damaging bacterial DNA since its reduced form is highly reactive. Rapid reduction of nitrofurantoin inside the bacterial cell by flavoproteins (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA, pyruvate metabolism, and other macromolecules within the cell (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
All antimicrobial agent dosages presuppose normal renal function.
Simple acute cystitis in men is uncommon and there are no comparative antimicrobial treatment trials from which to draw evidence-based recommendations. The approach to management is based on indirect evidence from trials in women and more limited data in men (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Although simple acute cystitis in men is generally classified in the literature as a complicated UTI, it is reasonable to consider a healthy man without a neurogenic bladder who has mild to moderate dysuria, urinary frequency, and urgency, with no symptoms or signs of infection outside the bladder, as having simple acute cystitis. For empiric antimicrobial treatment of such men, one of the first-line regimens recommended for women is advocated (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
The choice should be individualized based on patient circumstances (allergy, tolerability, and expected adherence), local community resistance prevalence, availability, and cost.
If the patient has taken one of the agents in the preceding three months, a different one should be selected. Based on data on UTI in women, empiric TMP-SMX should be avoided if the regional prevalence of resistance is known to exceed 20%. Nitrofurantoin or fosfomycin is particularly useful if multidrug resistance (MDR) is documented or suspected. As in women, beta-lactams can be used cautiously if other options are inappropriate because of allergy/intolerance or concerns about resistance.
Nitrofurantoin, fosfomycin, and beta-lactams do not achieve reliable tissue concentrations in the prostate and may not adequately treat subclinical prostatitis.
Consequently, for men who have more severe cystitis symptoms or concern about early involvement of the prostate, the following therapeutic agents are recommended for empiric therapy since they achieve more reliable tissue concentrations (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
Once susceptibility testing results are available, subsequent therapy should be tailored as appropriate.
No studies have evaluated the optimal duration of antimicrobial therapy in men with simple acute cystitis. Fluoroquinolones can be given for five days and other agents can be given for seven days. Fosfomycin is given as a single dose, but there is no experience with using this regimen in men with simple acute cystitis.
In men with simple acute cystitis who have no signs or symptoms suggestive of pyelonephritis or prostatitis (e.g., fever, flank pain, pelvic pain, prostatic tenderness on a digital rectal exam if this part of the examination is performed), a seven-day or shorter course of an antimicrobial to which the infecting strain is susceptible is likely to be sufficient (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
In a large retrospective study of 33,336 male veterans who received antimicrobial therapy for a UTI, as identified through billing codes (and not necessarily specified as simple or uncomplicated), there was no difference in the risk of early (less than 30 days after a prior UTI) or late (30 days or longer after a prior UTI) recurrence between those who received a short (seven days or less) or long (more than seven days) course of antimicrobials (Hooten & Gupta, 2021; Hooten & Calderwood, 2020). Moreover, in a multivariate analysis, there was a nonsignificant trend toward increased risk in the incidence of Clostridioides difficile infection among patients who received a longer course of therapy. In a subsequent database study of 573 men attending outpatient clinics, treatment for more than seven days was associated with a higher risk of recurrence when men with urologic abnormalities, immunocompromising conditions, prostatitis, pyelonephritis, nephrolithiasis, and benign prostatic hyperplasia were excluded from the analysis. Because of the inherent limitations in the interpretation of retrospective studies, prospective studies are warranted to elucidate further the benefits and harms of shorter- versus longer-duration treatment for UTIs in men (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Patients are at higher risk for a Multi-Drug Resistant (MDR) gram-negative organism if they have any of the following occurring in the prior three months (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
One of the first-line antimicrobial regimens should be chosen for empiric therapy of simple acute cystitis in patients who do not have risk factors for an MDR gram-negative infection (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
For patients who have reasons to avoid all these options (either because of allergies, intolerances, or a history of a urinary isolate resistant to these agents within the prior three months), an alternative option should be chosen (see below).
The preferred agents for empiric therapy of simple acute cystitis are nitrofurantoin monohydrate/macrocrystals, TMP-SMX, fosfomycin, and, if available, pivmecillinam because of the favorable balance between efficacy and adverse effects (including the risk of selecting for resistant organisms). None of the first-line agents outweigh the others in the efficacy/adverse effects balance, except that resistance is more likely with TMP-SMX and that pivmecillinam (and possibly fosfomycin) is somewhat less effective.
The optimal antimicrobial in one region may be different from that in another depending on resistance prevalence. As such, the choice among them should be individualized based on patient circumstances (allergy, tolerability, and expected adherence), local community resistance prevalence, availability, cost, and patient and provider threshold for failure. If the patient has taken one of the agents in the preceding three months, a different one should be selected.
If all of these are appropriate based on patient circumstances and prior urinary isolates, nitrofurantoin or TMP-SMX is suggested rather than Fosfomycin or pivmecillinam. Fosfomycin is usually reserved for suspected MDR infections or when other first-line agents cannot be used. It retains activity against many MDR isolates and overuse may increase resistance rates. Pivmecillinam is somewhat less effective but is commonly used in Europe because of its low risk for resistance.
The following information provides details on dosing, expected efficacy, and additional reasons for avoidance of first-line antimicrobials (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
These antimicrobial options and suggested treatment durations for simple acute cystitis are the same for any adult woman with simple acute cystitis, regardless of age.
A systematic review of studies evaluating treatment of cystitis in community-dwelling adults’ ≥65 years of age concluded that the optimal regimens are the same as those recommended for younger adults and that shorter antimicrobial courses (three to six days) resulted in similar outcomes as longer ones (7 to 14 days). However, since these studies excluded women with urinary tract abnormalities, immunocompromising conditions, or poorly controlled diabetes mellitus, it is reasonable to use a longer duration of therapy (e.g., 7 days) in women with such comorbidities (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
The patient should be treated as having a complicated acute UTI (which includes pyelonephritis) if there is diagnostic uncertainty regarding cystitis versus early pyelonephritis. The use of nitrofurantoin, fosfomycin, and pivmecillinam should be avoided in such cases because they do not achieve adequate renal tissue levels.
If any factors (such as allergies or intolerances or concern for resistance) preclude using the above first-line antimicrobials, oral beta-lactams are appropriate options. Acceptable beta-lactam agents include (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
Ampicillin or amoxicillin should not be used for empiric treatment, given the high prevalence of resistance to these agents. Suppose an Enterococcus or Group B Streptococcus grows as the only isolate on culture and is determined to cause simple acute cystitis. In that case, amoxicillin is usually the preferred agent, as long as the isolate is susceptible. In general, beta-lactams are second-line agents because they are less effective and have more potential adverse effects than other UTI antimicrobials. If beta-lactams cannot be used because of severe allergy, appropriate alternative fluoroquinolone antibiotics include (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
Multiple randomized trials have demonstrated that fluoroquinolones are very effective for treating simple acute cystitis and that fluoroquinolones are more effective than beta-lactams. However, increasing rates of resistance mitigate the utility of the fluoroquinolone class. Furthermore, because of concerns about the adverse effects of fluoroquinolones, the risk-benefit balance for simple acute cystitis favors the use of fluoroquinolones only if other agents (including beta-lactams) cannot be used. When possible, fluoroquinolones should be reserved for more serious infections than simple acute cystitis. If a fluoroquinolone is used, patients should be advised about the uncommon but potentially serious musculoskeletal and neurologic adverse effects.
Suppose a patient has reasons not to use any of the first-line agents, beta-lactams, or fluoroquinolones. In that case, a urine culture and susceptibility test should be performed and an antimicrobial agent should be chosen based on those results. Studies among women without comorbidities have suggested that deferring antimicrobial therapy until these results are available is a safe strategy for simple acute cystitis.
If there are concerns about deferring antimicrobials (e.g., because of significant bladder symptoms), it is reasonable to treat empirically with an agent (e.g., first-line option, beta-lactam, or fluoroquinolone) that was initially avoided because of concerns for possible resistance while awaiting culture results. Alternately, if there are concerns about potential treatment failure with oral agents in patients with risk factors for more serious infection (e.g., an underlying urologic condition or immunocompromising condition), the patient can be treated with an initial intravenous agent.
A urine culture and susceptibility testing should be obtained first for patients with risk factors for an MDR gram-negative infection.
For empiric treatment, unless the patient has a history of an isolate with documented resistance to these agents in the prior three months, oral options include (Hooten & Gupta, 2021; Hooten & Calderwood, 2020):
If all of these are appropriate options based on patient circumstances (allergies, intolerances, drug interactions) and prior urinary isolates, nitrofurantoin is suggested. The use of fosfomycin should be reserved for documented MDR gram-negative infections or when nitrofurantoin is not an option and pivmecillinam is not as effective. In the US, resistance to all oral options is still uncommon among outpatients with E. coli cystitis.
Studies have suggested that nitrofurantoin, fosfomycin, and pivmecillinam retain clinical activity against some MDR organisms, including ESBL-producing isolates. For example, in a case-control study including 113 patients with ESBL-producing E. coli UTIs, no resistance to fosfomycin was detected, and clinical cure rates were high (93%). Some studies have evaluated a higher dose of fosfomycin (e.g., 3 g once every 2 to 3 days for 3 doses) for infections due to MDR organisms. Still, there is no evidence that this has greater efficacy than single-dose therapy (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Suppose none of these can be used because of resistance or other concerns. In this case, antimicrobial therapy should be deferred until a regimen can be selected based on culture and susceptibility testing results. Studies among women without comorbidities have suggested that deferring antimicrobial therapy until these results are available is a safe strategy for simple acute cystitis.
Increasing antimicrobial resistance is found with simple acute cystitis that has a low risk of progression in patients without risk factors for serious infection. Antimicrobial sparing management strategies for some women with simple acute cystitis are of increasing interest but warrant further study before they can be routinely employed.
Delaying antimicrobial therapy while awaiting urine culture results appears reasonable in women without comorbidities if empiric therapy is complicated by resistance or drug intolerance. Substituting anti-inflammatory agents for antimicrobial therapy has also been evaluated but cannot be recommended as an initial approach to managing symptomatic simple acute cystitis. Additional studies are necessary.
Symptoms of simple acute cystitis should respond to antimicrobial therapy within 48 hours. Dysuria is usually diminished within a few hours after the start of antimicrobial therapy. Analgesics can be used in the interim for symptom relief in women with mild to moderate symptoms. For some patients with severe dysuria, a urinary analgesic such as over-the-counter oral phenazopyridine three times daily as needed may be useful. A two-day course of phenazopyridine is usually sufficient to allow time for symptomatic response to antimicrobial therapy and minimize inflammation. Phenazopyridine should not be used chronically since it may mask clinical symptoms requiring clinical evaluation.
In many cases, patients with underlying functional or anatomic urinary tract abnormalities have systemic symptoms of UTI. Abnormalities include an indwelling catheter, urethral stent, neurogenic bladder, and nephrolithiasis. Consequently, these patients are managed as having a complicated UTI. It is reasonable to treat those who appear to have only simple acute cystitis without upper tract or systemic symptoms as previously outlined cautiously, because these patients were not included in efficacy studies of the regimens used for simple acute cystitis. Monitor them carefully for treatment failure.
The initial urine cultures should be followed to ensure that the empirically chosen regimen was appropriate. Furthermore, since the antimicrobial durations listed above have not been well studied in patients with urologic dysfunction, a longer duration of therapy (e.g., one to two weeks, depending on the agent chosen) is reasonable. It is also reasonable to have a lower threshold to treat such patients with a complicated UTI (e.g., for more subtle symptoms of pyelonephritis or systemic infection). Additionally, other treatment measures in addition to antimicrobial therapy may be warranted. These include:
Follow-up urine cultures are not needed in patients with simple acute cystitis whose symptoms resolve on antimicrobials. For patients who had hematuria on initial presentation, a urinalysis should be repeated several weeks following antimicrobial therapy to evaluate for persistent hematuria.
Patients who have persistent symptoms after 48 to 72 hours of appropriate antimicrobial therapy or have recurrent symptoms within a few weeks of treatment should have an additional evaluation for other potential conditions causing those symptoms and for factors that might be compromising clinical response, including urine culture and empiric treatment with another antimicrobial agent. Subsequent treatment should be tailored to the susceptibility profile of the isolated causative organism. If symptoms persist in the setting of appropriate antimicrobial therapy, urologic assessment and radiographic imaging (generally with computed tomography) may be appropriate to evaluate for anatomic abnormalities that would interfere with response to antimicrobial treatment (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Dedicated urologic evaluation is probably unnecessary in healthy young men with no obvious complicating factors who have a single episode of simple acute cystitis that responds promptly to antimicrobial treatment. Men with persistent or recurrent simple acute cystitis should be evaluated for predisposing features or causative factors (prostatic hypertrophy or other urinary tract obstruction). In particular, recurrent infection with the same strain of bacteria should prompt evaluation for chronic prostatitis (Hooten & Gupta, 2021; Hooten & Calderwood, 2020).
Ms. Vinge is a 63-year-old, retired, Caucasian female who reports the acute onset of urinary frequency and urgency with gross hematuria beginning 0830 this morning. She denies fever, chills, rigors, flank pain, and CVA tenderness. She denies vaginal discharge or itching and reports no sexual activity in the past ten years. LMP 1999. No travel outside of the country since 2009.
Past Medical History:
No known drug allergies
Midstream urine culture was collected and sent to the lab.
Results of urine culture showed Escherichia coli > 103 colony-forming units/mL.
The patient is considered to be at low risk for antimicrobial resistance.
TMP-SMX 160/800 mg orally ordered twice daily x 3 days.
Follow-up with MD scheduled in 1 week.
The term “simple acute cystitis” refers to an acute infection confined to the bladder in a nonpregnant individual. Such infections lack features that suggest the infection extends beyond the bladder, such as fever (>99.9°F/37.7°C), other signs or symptoms of systemic illness (including chills, rigors, and marked fatigue or malaise beyond baseline), flank pain, and CVA tenderness. This definition is distinct from traditional categorizations of UTI and is more focused on the clinical presentation and severity of illness.
Escherichia coli is the most frequent microbial cause of simple acute cystitis, with occasional infections caused by other species of Enterobacteriaceae, such as Klebsiellapneumoniae and Proteus mirabilis, and other bacteria, such as Staphylococcus saprophyticus. The microbial spectrum of simple acute cystitis in patients with recent antimicrobial or other health care exposures may be broader and include other gram-negative bacilli (e.g., Pseudomonas), enterococci, and staphylococci. Increasing rates of resistance in uropathogens have been reported globally.
Simple acute cystitis occurs in a small number of men between 15 and 50 years of age. Symptomatic UTI is much less common in men than women due to longer urethral length, drier periurethral environment (with less frequent colonization around the urethra), and antibacterial substances in prostatic fluid.
Risk factors for UTI with resistant organisms include recent antimicrobial use, health care exposures, and travel to parts of the world where MDR organisms are prevalent.
The classic clinical manifestations of simple acute cystitis in both sexes consist of dysuria, urinary frequency, urinary urgency, and suprapubic pain. Symptoms of simple acute cystitis can be difficult to assess in older or debilitated women, who have several nonspecific urinary symptoms (such as chronic dysuria or urinary incontinence) that could mimic symptoms of simple acute cystitis.
For women with classic symptoms of cystitis, no additional testing is warranted to make the diagnosis. For women with atypical urinary symptoms, the diagnosis is supported by pyuria and bacteriuria on urinalysis and culture.
The diagnosis of simple acute cystitis can be made in a man who presents with typical urinary symptoms, pyuria, and bacteriuria on urine culture without fever or other systemic symptoms, pelvic or perineal pain, CVA tenderness, and other features suggestive of pyelonephritis or acute prostatitis.
Laboratory diagnostic tools for cystitis consist of urinalysis (either by microscopy or by dipstick) and urine culture with susceptibility data. A urine culture should be performed for all men and women with symptoms suggestive of simple acute cystitis.
The selection of an antimicrobial regimen for simple acute cystitis depends on the likelihood of infection with an MDR gram-negative isolate. Before initiation of therapy, urine culture and susceptibility testing are warranted for patients with risk factors for antimicrobial resistance or more serious infection (e.g., those with underlying urologic abnormalities, immunocompromising conditions, and poorly controlled diabetes mellitus).
For patients who do not have risk factors for an MDR gram-negative infection, the first-line antimicrobial agents include:
If all of these medications are appropriate options based on patient circumstances, local resistance rates, and prior urinary isolates, nitrofurantoin or TMP-SMX is suggested first rather than fosfomycin or pivmecillinam.
Oral beta-lactams are appropriate alternative options for those who cannot use any of the first-line antimicrobials. If beta-lactams cannot be used, a fluoroquinolone is reasonable. These, however, should be reserved for more serious infections than simple acute cystitis, if possible, because of concerns for adverse effects.
For patients who have risk factors for an MDR gram-negative infection or have a history of an isolate with documented resistance to these agents in the past three months, oral options include:
If all of these are appropriate options based on patient circumstances, local resistance rates, and prior urinary isolates, nitrofurantoin is preferred. Culture and susceptibility results should be used to guide directed therapy.
Antimicrobial therapy should be deferred until a regimen can be selected based on culture and susceptibility testing results if none of the above options are appropriate because of resistance or other concerns. Studies among women without comorbidities have suggested that deferring antimicrobial therapy until these results are available is a safe strategy for simple acute cystitis. However, suppose there is concern about deferring antimicrobial therapy (e.g., because of bothersome symptoms or risk factors for more serious infection). In that case, options include using one of the oral regimens for simple acute cystitis that was not chosen because of the possibility of resistance or using an initial dose of a parenteral agent, as used in complicated acute UTI.
Patients who have simple acute cystitis in the setting of underlying functional or anatomic urinary tract abnormalities (such as an indwelling catheter, urethral stent, neurogenic bladder, history of nephrolithiasis) may warrant more frequent intermittent catheterization, changing out an indwelling catheter, or urologic/urogynecologic consultation. Additionally, a longer duration of antimicrobial therapy is appropriate since shorter durations have not been well studied in such patients (Fekete, 2021).
Patients who have persistent symptoms after 48 to 72 hours of empiric antimicrobial therapy or have recurrent symptoms within a few weeks of treatment should have urine submitted for culture and susceptibility testing. If symptoms persist during appropriate antimicrobial therapy, radiographic imaging to evaluate for anatomic abnormalities is appropriate.
Men with recurrent simple acute cystitis should undergo evaluation for prostatitis. Urologic evaluation is probably unnecessary in healthy young men with no obvious complicating factors who have a single episode of simple acute cystitis that responds promptly to antimicrobial treatment.
Fever, chills, or malaise suggest a complicated UTI (including pyelonephritis) or bacterial prostatitis. In particular, pelvic or perineal pain, pain radiating to the tip of the penis, or obstructive symptoms such as dribbling and hesitancy (due to acute urinary retention) in a man with symptoms of simple acute cystitis, suggest bacterial prostatitis.
Chronic prostatitis should be considered in all men with simple acute cystitis, particularly in those men who have recurrent infections. Urethritis must be considered in sexually active men, and diagnostic tests for Neisseria gonorrhoeae and Chlamydia trachomatis are warranted.
Empiric antimicrobial therapy in men with simple acute cystitis includes:
Beta-lactams are an alternative. However, if there are severe simple acute cystitis symptoms or concern about early involvement of the prostate, a fluoroquinolone is preferred.
Once susceptibility testing results are available, subsequent therapy should be tailored as appropriate. The duration depends on the agent used (fluoroquinolones are given for five days, fosfomycin is given as a single dose, and other agents are given for seven days).
CEUFast, Inc. is committed to furthering diversity, equity, and inclusion (DEI). While reflecting on this course content, CEUFast, Inc. would like you to consider your individual perspective and question your own biases. Remember, implicit bias is a form of bias that impacts our practice as healthcare professionals. Implicit bias occurs when we have automatic prejudices, judgments, and/or a general attitude towards a person or a group of people based on associated stereotypes we have formed over time. These automatic thoughts occur without our conscious knowledge and without our intentional desire to discriminate. The concern with implicit bias is that this can impact our actions and decisions with our workplace leadership, colleagues, and even our patients. While it is our universal goal to treat everyone equally, our implicit biases can influence our interactions, assessments, communication, prioritization, and decision-making concerning patients, which can ultimately adversely impact health outcomes. It is important to keep this in mind in order to intentionally work to self-identify our own risk areas where our implicit biases might influence our behaviors. Together, we can cease perpetuating stereotypes and remind each other to remain mindful to help avoid reacting according to biases that are contrary to our conscious beliefs and values.