This chapter should be cited as follows:
Phillips N, Solouki S, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.420003

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 12

Infections in gynecology

Volume Editors: Professor Francesco De Seta, Department of Medical, Surgical and Health Sciences, Institute for Maternal and Child Health, University of Trieste, IRCCS Burlo Garofolo, Trieste, Italy
Dr Pedro Vieira Baptista, Lower Genital Tract Unit, Centro Hospitalar de São João and Department of Gynecology-Obstetrics and Pediatrics, Faculdade de Medicina da Universidade do Porto, Portugal

Chapter

Urinary Tract Infections in Women

First published: March 2024

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INTRODUCTION

Urinary tract infections (UTIs) are bacterial infections, which may be isolated to the bladder or lower urinary tract (cystitis, urethritis) or ascend to the kidneys (pyelonephritis). Conventionally, uncomplicated UTIs include only acute cystitis in non-pregnant women without co-morbid conditions like diabetes, immunocompromised state or in-dwelling catheters. Complicated infections include those involving the upper urinary tract, and any infection in pregnant, elderly, those with co-morbid conditions or any structural or immunocompromised state.¹ Other definitions include pyelonephritis as uncomplicated, in non-pregnant women, with no associated systemic symptoms such as fevers, chills or costovertebral angle tenderness, regardless of structural or co-morbid conditions.² Most textbooks and guidelines use this definition.

The differentiation and recognition of complicated versus uncomplicated infection will direct differences in diagnostic testing, in- versus out-patient therapy, choice of antibiotics, duration of treatment and subsequent follow-up.

A high degree of suspicion and active treatment of UTI can be critical in at-risk patients, who may not present with typical urinary symptoms. Left untreated, especially in the compromised or aging population, progression to pyelonephritis, bacteremia, septicemia, renal abscess, renal or muti-organ failure may occur. In the aging population, these latter complications may be the presenting symptoms.

This chapter aims to review the incidence, predisposing factors, interventions and implications of both uncomplicated acute cystitis and complicated disease, based on the characteristics of the infection and the characteristics of the patient.

ACUTE UNCOMPLICATED URINARY TRACT INFECTIONS: CYSTITIS

Definition

A UTI is defined as uncomplicated if it involves the lower urinary tract in a non-pregnant woman with a normally structured and functioning urinary tract, normal kidney function and no co-morbidities, which would promote or lead to complications from the infection.¹ Some definitions include pyelonephritis in women who meet the same criteria as considered uncomplicated.³ This discussion will refer to the more conventional definition and discuss lower UTIs only.

Epidemiology

Uncomplicated UTIs are the most common out-patient infection in the United States, affecting 40–60% of women at least once in their lifetime. The most recent estimated cost to the US health care system (2010) with UTIs exceeded two billion dollars.⁴ UTIs are estimated to affect 150 million people each year worldwide.⁵ The overall incidence of UTIs increases with age, despite a peak in sexually active women between 14 and 35 years.⁶ In this same approximate age group (16–35) women are 35 times more likely to experience acute cystitis than men, likely related to anatomical differences and behavioral factors, as discussed below.⁷

Pathophysiology

In women with no obvious risk factors, UTI susceptibility is multifactorial, with the most likely mechanism being the high levels of potentially pathogenic bacteria in the rectum and vagina. This, combined with the short distance between the rectum and the urethral meatus, and urethra to bladder epithelium confers access of these bacteria to the latter. Sexual activity facilitates this transport, explaining the high rate of UTIs in sexually active women. Condom or spermicide use is a risk factor for UTI, but there is little evidence to support 'poor hygiene', such as wiping back to front or not wiping with each urination as a risk factor. A 2022 questionnaire-based survey showed delayed voiding increased the risk of UTIs (potentially related to less frequent flushing of bacterial colonizers of the urethral meatus).⁸

The vaginal microbiome plays a yet undefined role in both the promotion and protection against acute cystitis. As the initial bacterial destination from the rectum on the way to the urethra, the vaginal lactobacilli dominant microbiome may act as an antimicrobial defense system. As such, loss of lactobacilli (related to menopause, antibiotic use, contraception) may contribute to UTIs.⁴ This remains an area for both ongoing research and potential prevention and treatment modalities.

Evaluation

Acute cystitis generally presents with urinary frequency, urgency, and dysuria with or without gross hematuria. In the absence of vaginal symptoms of discharge or itching, these symptoms are specific for UTI in up to 90% of cases.⁹ Therefore, in healthy women with these symptoms no further diagnostic testing is warranted. Both the American College of Obstetricians and Gynecologists (ACOG) and the European Association of Urology recommend against the use of culture and sensitivity tests prior to treatment of an uncomplicated UTI.¹⁰ In women with non-specific symptoms or in older females, where urine incontinence, lower pelvic pain or feeling “unwell” can be a presenting symptom, urinalysis and culture are indicated.

Management

Management of acute cystitis can be started empirically based on symptoms and likely pathogens. Escherichia coli remains the cause of acute community-acquired cystitis in 75–95% of cases, followed by Klebsiella pneumoniae. Proteus mirabilis and other bacteria, such as Staphylococcus saprophyticus may also be etiologic agents.¹¹ First-line treatment includes trimethoprim/sulfa, nitrofurantoin, fosfomycin, or pivmecillinam, based on efficacy and safety data. In the absence of contraindications, such as allergy or high local multidrug-resistant (MDR) bacteria, any of these agents is acceptable. If treatment with one agent has been used in the prior 3 months, another agent may be chosen. However, as fosfomycin retains activity against many MDR bacteria, some authors recommend limiting its use to prevent potential increased resistance.¹² E. coli resistance to trimethoprim-sulfa and fluroquinolones has increased globally and is more common in those with recent antibiotic use, health care exposures, or travel to countries with high MDR bacteria rates. Beta-lactams may be considered in cases of allergy or suspicion of resistance to other treatments, and fluroquinolones may be an acceptable alternative.¹³

Symptomatic improvement after treatment for acute cystitis is sufficient. Repeat cultures for test of cure should be reserved for ongoing or recurrent symptoms. In cases where hematuria was present in initial urinalysis, a repeat urinalysis should be performed to confirm resolution.

ASYMPTOMATIC BACTERIURIA

Definition

Asymptomatic bacteriuria is defined as a single bacterium species present in a concentration of >10⁵ colony forming unite (cfu)/mL in a clean catch urine specimen collected from someone with no urinary symptoms.¹⁴ To make the diagnosis, a second clean-catch specimen 2 weeks later is used to confirm a similar colony count with the same bacterium species, whereas a single catheterized specimen with similar results is sufficient. The presence or absence of pyuria, in the absence of symptoms, should not influence the decision to treat.

Epidemiology

In general, asymptomatic bacteriuria increases with age, with estimates of about 3% in women between 15 and 24, increasing to 20–50% in women older than 80.¹⁵ However, these numbers vary depending on the population, with healthy premenopausal women estimated to be 1–5%, healthy postmenopausal women (50–70) 3–9%; those over 70 but in the community 15%, and long-term care residents up to 25–50%. Men, in general, are less likely to have asymptomatic bacteriuria, ranging from 0.7% in the general population up to 50% in those in long-term residences.¹⁶

Pathophysiology

The pathophysiology of asymptomatic bacteriuria is not fully understood, although both pathogen and host factors may be involved. Pathogens may be less virulent, may be unable to attach to the uroepithelium, or may be transient (especially in young healthy girls or after sexual activity). Host factors may include receptor alterations with decreased ability for mucosal attachment, producing a “carrier state.” Finally, microbiome studies have shown a similarity of the vaginal microbiome in the bladder, although this research is preliminary in nature.¹⁷

Management

Treatment of asymptomatic bacteriuria is not indicated, except for pregnant women, those undergoing a urological procedure or those with a recent renal transplant, generally defined as within the previous 1–3 months.¹⁴

There is no evidence of benefit in treating asymptomatic bacteriuria, out of the contexts previously referred. Conversely, there are many consequences of treatment, including adverse medical events (allergic reactions, development of gastrointestinal side effects, development of Clostridioides difficile), increased health care cost, or development of antibiotic resistance.¹⁸

Clear guidelines exist for treatment of asymptomatic bacteriuria.¹⁴ These are summarized below:

• Pregnant women should be screened for asymptomatic bacteriuria early in pregnancy and treated appropriately.
• Patients undergoing endourological procedures associated with mucosal trauma (e.g., transurethral surgery; ureteroscopy, including lithotripsy and percutaneous nephrolithotomy) should be screened for asymptomatic bacteriuria before the procedure and treated appropriately.
• Patients who have undergone a renal transplant more than 1 month before, should not be screened or treated for asymptomatic bacteriuria (3 months according to some authors).
• Screening for or treatment of asymptomatic bacteriuria in any other population (including the elderly, those with indwelling catheters, or with other co-morbidities like diabetes) is not recommended.

SPECIAL POPULATIONS (URINARY TRACT INFECTIONS [AND ASYMPTOMATIC BACTERIURIA] IN PREGNANCY)

UTIs and asymptomatic bacteriuria in pregnant women require separate discussion, based on differences in physiology, treatment recommendations, risks and outcomes.

Definition

Asymptomatic bacteriuria is defined as a high colony count of bacteria in a woman without symptoms of UTI. Most guidelines recommend screening all pregnant women for asymptomatic bacteriuria at least once in early pregnancy.^14,19 Although by diagnostic criteria, two consecutive clean catch specimens with the same organism with a colony count of ≥10⁵ cfu/mL are required for definition, a single result will generally prompt treatment in pregnancy. Office-based urinalysis is not sufficient for the diagnosis of asymptomatic bacteriuria.

Epidemiology

Asymptomatic bacteriuria is estimated to occur in up to 15% of cases, with the highest incidence in the first trimester.

In the absence of treatment, asymptomatic bacteriuria will progress to acute cystitis in as many as 20 to 35% of pregnant women. This risk is reduced by 70 to 80% if bacteriuria is eradicated.²⁰

Pathophysiology

The physiologic changes of pregnancy, such as bladder wall relaxation, incomplete bladder emptying, and ureteral dilatation may facilitate the ascent of bacteria to the upper urinary tract. Treatment of asymptomatic bacteriuria, therefore, is also instrumental in the prevention of pyelonephritis. As in non-pregnant women, E. coli is the most common species recovered in both asymptomatic and symptomatic bacteriuria.

Management

Treatment should be directed towards the isolated pathogen and its sensitivities, with consideration of safety of antibiotic agents in pregnancy. Beta-lactams, nitrofurantoin, and fosfomycin, as in non-pregnant women are frequent first-line options. Nitrofurantoin is not preferred in the first trimester, although its use is acceptable if alternatives are not available. Full-course therapy versus shorter or single-dose therapy has been shown to be more effective in eradication of asymptomatic bacteriuria (with the exception of fosfomycin).²¹

The role of re-screening and re-treating asymptomatic bacteriuria in pregnancy is controversial, although generally performed in clinical practice. The Infectious Disease Society of America, the American Academy of Pediatrics, and the American College of Obstetrics and Gynecology feel more data are needed to determine the benefit of this practice.^14,22 In high-risk patients, such as those with sickle cell trait, diabetes, history or high risk for preterm labor or renal anomalies, re-screening may be appropriate.

Group B streptococcus (GBS) bacteriuria in pregnancy is a marker of heavy genital colonization and increased risk of pregnancy complications, including postpartum endometritis, and warrants intrapartum prophylaxis. Asymptomatic colony counts of 10⁵ cfu/mL should be treated. However, treatment of asymptomatic GBS bacteriuria at colony counts less than 10⁵ cfu/mL remains controversial, as it may reflect genital rather than urine colonization. At least two older studies however have shown improved pregnancy outcomes with treatment of GBS at any colony count.^23,24

ACUTE CYSTITIS IN PREGNANCY

Epidemiology

Acute cystitis in pregnancy has an estimated incidence of 1–2% and presents with similar symptoms as in non-pregnant women. Also, as in non-pregnant women, E. coli is the most common pathogen, isolated in culture in 70% of cases of both UTI and pyelonephritis.²⁵

Management

Confirmation of a UTI should be obtained by culture and sensitivity testing, but empiric treatment can be started prior to obtaining results, and adjusted as needed. Some authors suggest that in symptomatic pregnant women, lower colony counts (10³ cfu/mL versus 10⁵) should be considered positive and treated, especially if E. coli is detected, to prevent progression to pyelonephritis.²⁶ If symptoms are highly suggestive of UTI, then empiric treatment may be considered with cephalosporins, cefpodoxime, amoxicillin-clavulanate or fosfomycin. Nitrofurantoin and trimethoprim-sulfamethoxazole are generally not used during the first trimester or near term, but are appropriate if other options are not feasible. If symptoms resolve, repeated culture is not necessary.

For those women with recurrent UTIs (generally defined as three or more infections in pregnancy, or two in close succession), prophylaxis through the remainder of the pregnancy is usually initiated, despite the lack of studies validating that approach. The medication for prophylaxis should be based on prior sensitivities, but low-dose nitrofurantoin (50–100 mg nightly) or cephalexin (250–500 mg nightly) are common regimens. If UTIs occur following intercourse, the use of post-coital antibiotic prophylaxis is appropriate.

URINARY TRACT INFECTIONS IN THE ELDERLY

Elderly patients are at particularly high risk of UTIs due to many factors, including, but not limited to, incontinence, immobility, cognitive impairment.²⁷ In addition, they are postmenopausal, have a higher rate of dysfunctional or reconstructed lower urinary tracts, indwelling catheters, and high rates of institutional living.²⁸ However, urinary growth of bacteria in the absence of urinary tract symptoms (i.e., asymptomatic bacteriuria) is also common and represents a commensal colonization.²⁸

A diagnosis of symptomatic UTI in older women generally requires the presence of localized genitourinary symptoms, pyuria, and a urine culture with an identified urinary pathogen.^28,29

Epidemiology

UTIs are the second-most common infection in elderly women living in the community, and the most common cause of infection in hospitalized elderly women or those in long-term care.³⁰

Some population-based studies report an annual prevalence of symptomatic UTIs after 65 years old up to 5–12.8%,^30,31,32 this incidence also increases with age.^33,34

Pathophysiology

The pathophysiology of UTIs in aging women is complex. As in the younger population, UTIs are significantly more common in adult women than men, possibly because of their shorter urethra, which permits easier passage of bacteria from the intestine.^35,36

However, in many ways, risk factors for symptomatic UTIs in the elderly differ from those in the younger population. Low estrogen status and vaginal atrophy is hypothesized to predispose to UTIs due to higher pH environment, less hostile to pathogenic bacteria. Age-related changes in immune function (immunosenescence), exposure to nosocomial pathogens, a higher number of comorbidities, and history of UTIs are also factors. Individuals with previous symptomatic UTIs have a 4–7-fold greater risk for future UTIs.^29,35,36

Institutionalized elderly women generally have even more comorbidities and cognitive deficits, or indwelling urinary catheters. The presence of bowel and/or bladder incontinence, functional disability, and dementia are also significantly associated with UTI or persistent asymptomatic bacteriuria.³⁷ Antimicrobial therapy is indicated for symptomatic UTI only.^28,38

However, in the setting of asymptomatic bacteriuria, as in other populations, antimicrobial treatment is generally not indicated and may even be harmful. Asymptomatic bacteriuria may protect against superinfecting with asymptomatic UTI.

Evaluation

Many elderly women do not present with the classic localized genitourinary symptoms of UTIs, such as dysuria, urinary frequency, and urgency. UTIs in elderly patients may instead manifest as confusion or delirium, increased lethargy, blunted fever response, new-onset incontinence, or anorexia.^29,30,39

Patients should be evaluated through medical and pelvic/urinary tract and surgical history. Baseline urinary tract and bowel symptoms should be asked (dysuria, nocturia, incontinence, constipation, diarrhea, fecal incontinence). Personal history of antibiotic-related problems and prior urine cultures and sensitivities should be assessed. Triggers should be recognized (bowel and/or bladder incontinence, functional disability, dementia, diabetes mellitus, chronic indwelling catheter). Physical examination should be performed to identify any structural or functional abnormalities (for example, genital prolapse or elevated post void residue). A baseline urinalysis and urine culture should be performed.

Cystoscopy and upper tract genitourinary imaging should only be performed if a patient’s history or presentation suggests an underlying cause for UTIs, such as a history of bladder or pelvic surgery or history or symptoms of nephrolithiasis.

Management

Careful antibiotic planning is especially critical in older populations to reduce their risk of acquiring difficult-to-treat multidrug-resistant organisms and avoid common sequalae of antibiotic therapy on vaginal and gastrointestinal tracts.⁴⁰

European Association of Urology (EAU) guidelines on urological infections recommend fosfomycin, nitrofurantoin, pivmecillinam, or cephalosporins as first-line treatment for uncomplicated cystitis in adult women.²⁸ The European Medical Agency (EMA) advises special caution with quinolones or fluoroquinolones in the elderly due to their higher risk of tendon injury.

Elderly patients with UTIs are at high risk for developing urosepsis, especially those who are frail, depend on assistance for daily living, suffer from dementia, or are bedridden. Guidelines recommend immediate and empirical antimicrobial therapy with broad antimicrobial coverage against all likely causative pathogens. Antimicrobial treatment can be adapted once culture results become available.

In the appropriate clinical setting, antimicrobials may be given as continuous low-dose prophylaxis for 3–6 months to prevent recurrent UTIs. Regimens include nitrofurantoin, fosfomycin, cephalexin, or cefaclor.²⁸ Sulfamethoxazole-trimethoprim should be avoided because of its pulmonary and hepatic toxicity. Further research is needed to better understand the implications of prophylaxis on treatment-related adverse events, development of resistance, and quality of life in this population.³³

As in all populations, overuse and misuse of antimicrobials contributes to the continued increase of resistance, which is a serious public health threat. The development of this resistance is greatest within the first month post-treatment, and this effect could be maintained for up to 1 year.⁴¹ As such, the paradigm of empirical antibiotic therapy for symptomatic UTIs is being challenged, underlining the need for alternative treatment strategies.

Cranberry products have been used widely for many years. A putative mechanism of action is preventing the adherence of P-fimbriated E. coli to uroepithelial cells on the bladder wall by proanthocyanidins contained in cranberries.⁴² Nevertheless, the results from meta-analyses and a subsequent placebo-controlled randomized controlled trial do not support the use of cranberry products for prevention of UTI.²⁸

Oral non-antimicrobial prophylactic treatment for recurrent UTIs, based on lyophilized E. coli bacterial lysate (OM-89 vaccine), was developed more than 30 years ago. Some studies show a significant decrease in the number of infections and a better quality of life, nevertheless randomized controlled trials are required before any definitive conclusion about the efficacy of OM-89 in UTIs.⁴³

Vaginal estrogens have been shown to reduce the number of episodes in postmenopausal women with recurrent UTIs.⁴⁴ But, as with OM-89, additional well-controlled studies of estrogen in UTI are required before any conclusions can be drawn.

A systematic review evaluated a range of non-antibiotic approaches to manage uncomplicated UTIs including cranberry products, Canephron N (a phytodrug), probiotics (Lactobacillus spp.), non-steroidal anti-inflammatory drugs (ibuprofen, diclofenac), D-mannose, estrogens, vitamins (C and D), and immunotherapy. The overall conclusion was that the evidence was insufficiently conclusive to recommend non-antibiotic options in place of antibiotic usage, although incorporating some of these measures in the management strategy of UTIs may contribute to avoidance of antimicrobial resistance.⁴⁵

URINARY TRACT INFECTIONS IN SPECIAL POPULATIONS (NOSOCOMIAL, CATHETER ASSOCIATED)

Introduction

In this section we will include nosocomial urinary tract infections (UTIs) and catheter associated since there are vast similarities among these patients. UTIs are among the more frequent types of nosocomial infection, along with lower respiratory infections and post-operative wound infections. Hospital-acquired and device-associated infections are a major challenge to patient safety, tend to be associated with resistant strains, and place a huge economic burden all around the world..⁴⁶

A UTI is said to be "nosocomial" or "nosocomially acquired" (NUTI or NAUTI) when it is acquired in any health care institution or, more generally, when it is related to patient management.⁴⁷ Virtually, all health care associated UTIs are caused by instrumentation of the urinary tract. Catheter-associated urinary tract infections are commonly called CAUTI.

In this setting, if asymptomatic bacteriuria is untreated, 20–40% of cases can progress to acute UTI.⁴⁸

Epidemiology

Between 15% and 25% of hospitalized patients may receive short-term indwelling urinary catheters.⁴⁹ This practice contributes to increased infections and subsequent infectious complications, including death. Sometimes the indication for bladder catheterization is not considered adequate and continuation is considered unnecessary in up to 30%. A closed drainage system is used in most of the patients. Opening of the closed drainage system is the most frequent major error in catheter management.⁵⁰ The simple presence of an indwelling urethral catheter allows continuous access of organisms to the urinary tract.

Multivariate analyses have emphasized that the duration of catheterization is the most important risk factor for the development of nosocomial/catheter-associated bacteriuria.^51,52 Other risk factors include colonization of the drainage bag, catheter and periurethral segment, diabetes mellitus, female gender, impaired kidney function, poor quality of catheter care, including its insertion outside of an operating room, and lack of antimicrobial therapy.^53,54,55

Pathophysiology

As previously stated, the pathophysiology is likely complex, but UTIs are significantly more common in adult women than in men.⁴⁰ Several studies have shown that bladder distention and bladder contractions (frequently present in patients with intermittent catheterization) can cause decreased blood flow, resulting in ischemia of the bladder wall, which increases mucosal tears and facilitates the ability of the bacteria that have colonized the bladder to invade the submucosa and start a UTI. Likewise, the urethral catheter can inhibit or bypass certain defense mechanisms that would normally prevent or minimize bacteria-epithelial cell interactions (glycosaminoglycan layer and biofilm formation). The source of microorganisms causing CAUTI can be endogenous, typically via meatal, rectal, or vaginal colonization, or exogenous, such as via contaminated equipment or health care staff´s hands.

Microbial pathogens can enter the urinary tract either by the extraluminal route, via migration along the outside of the catheter in the periurethral mucous sheath, or by the intraluminal route, via movement along the internal lumen of the catheter from a contaminated collection bag or catheter-drainage tube junction. Bacteria can enter the urinary tract in catheterized patients at the time of catheter insertion. This is especially common in patients who have inadequate cleansing of the perineum and distal urethra, especially in those on intermittent clean catheterization where only a limited attempt is made to cleanse the "entry points" before introducing the catheter. It is, however, doubtful whether such cleansing is in general of any benefit, but in hospitalized patients the introduction of organisms at the time of catheterization could be critical. Up to 20% of individuals are colonized immediately after catheterization.^51,52

The maximum number of days in hospitalized patients that an indwelling catheter should stay before replacement is unclear. In these circumstances, clinical wisdom should be advised, and when a major UTI symptom is present, substitution should be recommended. Additionally, avoiding the leg bag over distention and kinking of the catheter, will prevent bladder wall overdistention and consequent ischemia, and ultimately infection.

The five most commonly isolated microorganisms in nosocomial/catheter associated UTIs are E. coli (35.3%), Enterococcus spp. (15.2%), Candida spp. (12.9%), Klebsiella spp. (9.8%), and Pseudomonas aeruginosa (5.4%). A polymicrobial infection occurs in an average of 14.1% of infection cases (13.1% in European countries versus 16% in non-European countries; P>0.05).⁵⁰

Antimicrobial resistance among urinary pathogens is an ever-increasing problem. In Western countries, E. coli is resistant to fluoroquinolones in 8–48% of cases and to third-generation cephalosporins in 3–43%. Infections with K. pneumoniae are particularly common in hospitals among vulnerable individuals. Like E. coli, K. pneumoniae acquires resistance to multiple antibacterial drugs mainly through horizontal transfer of mobile genetic elements such as transposons or plasmids. Klebsiella spp. are an emerging problem because the extended spectrum beta lactamase (ESBL) positive strains are resistant to all extended beta-lactam antibacterial drugs such as cephalosporins. Although for these strains the carbapenems are the main remaining treatment option, K. pneumonia is also the main trigger of infections caused by carbapenem-resistant bacteria worldwide (up to 68%).⁵⁶

Evaluation

A high degree of suspicion for UTI should be maintained, as many patients with complicated UTIs do not present with localized genitourinary symptoms such as dysuria, urinary frequency, and urgency. Fevers, lethargy, or change in mental status should prompt a full evaluation, including urine evaluation.

Patients should be evaluated through medical and pelvic/urinary tract and surgical history. Baseline urinary tract and bowel symptoms should be asked (dysuria, nocturia, incontinence, constipation, diarrhea, fecal incontinence). Personal history of antibiotic-related problems and prior urine cultures and sensitivities should be assessed. Triggers should be recognized (bowel and/or bladder incontinence, functional disability, dementia, diabetes mellitus, chronic indwelling catheter). Physical examination should be performed to identify any structural or functional (e.g., prolapse or elevated post void residue) abnormalities. A baseline urinalysis and urine culture should be performed.

Upper tract genitourinary imaging should be performed if a patient’s history suggests an underlying cause for UTIs, such as an history of bladder or pelvic surgery, or of nephrolithiasis.

Management

In patients with nosocomial urinary tract infections, who may have indwelling urinary catheters and highly resistant pathogens, the perception that bacterial susceptibilities are unimportant may not necessarily be accurate. Thus, clinical judgment and the patient’s response to therapy dictate the degree to which susceptibility data are used for the direct treatment of symptomatic urinary tract infections in hospitalized patients.⁵⁷

The increasing antimicrobial resistance of uropathogens is challenging the paradigm of empirical antibiotic therapy for symptomatic UTIs, underlining the need for alternative treatment strategies.

Regarding catheters or collecting systems it is important to highlight some key points:

• Minimize urinary catheter use and duration.
• Hydrophilic catheters are preferable to standard catheters for patients in intermittent catheterization.
• Perform aseptic insertion of urinary catheter and maintain a closed drainage system.
• Urinary catheter systems should be sealed.
• Instillation of antiseptic or antimicrobial solutions into urinary drainage bags is not recommended.
• Unless clinical indications exist (patients with bacteriuria upon catheter removal post urologic surgery), do not use systemic antimicrobials routinely as prophylaxis for UTI in patients requiring either short- or long-term catheterization.

Bacterial colonization of the bladder is common in those with both neurogenic and non-neurogenic bladders. This colonization likely has a positive effect by inhibiting colonization of pathogenic bacteria. Therefore, judicious use of antibiotics for symptomatic UTIs is important to prevent disruption of a one’s microbiome and to avoid the development of more resistant organisms. According to the Cochrane database, for patients using intermittent catheterization, there is limited evidence suggesting that antibiotic prophylaxis decreases the rate of bacteriuria (asymptomatic or symptomatic).⁵⁸

However, if these patients have recurrent symptomatic UTIs, antimicrobials may be considered as continuous low-dose prophylaxis for 3–6 months. Regimens include nitrofurantoin, fosfomycin, cephalexin, or cefaclor.²⁸ Sulfamethoxazole-trimethoprim should be avoided because it is associated with pulmonary and hepatic toxicity. Further research is needed to better understand the implications of prophylaxis on treatment-related adverse events, development of resistance, and quality of life in this population.³³

Maintaining a “quiet” bladder is crucial with treatments like anticholinergic medications or onabotulinum toxin A. Prevention of bladder stones is also vital.⁵⁹ For individuals with recurrent symptomatic UTIs, in addition to the above, ruling out anatomical problems and urinary calculi, as well as trying to change the environment (urinary acidification) is also important. Newer strategies under development to help prevent CAUTIs include “strengthening the host” with prebiotics/probiotics, blocking adhesions to the host/bladder urothelium, bacterial biofilm inhibition, and immunobiotherapy.⁶⁰

RECURRENT URINARY TRACT INFECTIONS

Definition

Recurrent urinary tract infections (UTIs) are commonly defined as two or more culture-proven acute uncomplicated cystitis episodes within a 6 month period or three or more infections in a 12 month period, in an otherwise healthy adult.⁶¹

Epidemiology

They are common in females,³⁶ and reported incidence is from 1–27%.^62,63,64 Risk factors are similar to those of acute simple cystitis and include increased intercourse frequency, and spermicide use.⁶⁵ In postmenopausal women, factors like urinary incontinence, cystocele, and elevated postvoid residual appear to be risk factors.⁶⁶ There is likely genetic predisposition, as suggested by increased risk in women whose mothers have a history of UTIs, and younger age (15 or younger) at first UTI.⁶⁷

Pathophysiology

The pathophysiology is likely complex, but like episodic acute cystitis episodes is likely due to contamination of the vagina and periurethral areas with fecal microbiota. Colonization with E. coli appears to predispose women to higher likelihood of recurrence. Low estrogen status and vaginal atrophy is hypothesized to predispose to UTIs due to higher pH environment, which is less protective.

Evaluation

A thorough history should be obtained, including medical and pelvic/urinary tract surgical history, baseline urinary habits and symptoms and urinary tract infection symptoms should be asked (dysuria, nocturia, incontinence), bowel symptoms (constipation, diarrhea, fecal incontinence), antibiotic-related problems (prior or current antibiotic use, C. difficile, allergies). Prior urine cultures and sensitivities should be reviewed and triggers (sexual intercourse, fecal incontinence) identified.

Pelvic exam should be performed to identify any structural (e.g., prolapse or urethral diverticulum) or functional (elevated post void residual) abnormalities. And baseline urinalysis (and reflex urine culture) should be performed to determine presence of hematuria, discharge and bacteriuria.

Cystoscopy and upper tract genitourinary imaging should not be routinely done, unless there are elements in the patient’s history that suggest there may be an underlying abnormality, such as a history of bladder or pelvic surgery (e.g., midurethral sling),⁶⁸ history of nephrolithiasis or repeated presence of P. mirabilis UTI, which is associated with stone formation. Additionally, if a patient does not respond appropriately to their treatment, for example, rapid recurrence of their UTI or poor symptomatic response despite appropriate antibiotic therapy, it is reasonable to offer them further diagnostic evaluation.

Management

Behavioral modifications

Voiding and wiping habits and increased urinary tract infections do not appear to have a clear relationship, this intervention has been suggested with success in some women.⁶⁷ A simple intervention of consuming at least 1.5 liter of water per daily does appear to reduce of rate of UTIs in women.⁶⁹

• Birth control
  • Spermicides-based and barrier contraceptives also appear to be associated with increased UTIs and switching to other forms of birth control is recommended.^70,71
• Vaginal estrogen therapy
  • As opposed to systemic estrogen therapy, vaginal estrogen therapy has been shown to reduce the number of UTI episodes in peri and postmenopausal women with recurrent UTIs.^44,72 There is some evidence that topical estradiol cream may be superior to other vaginal formulations however there is no clear superiority to any formulation.⁷³
• Supplements:
  • Non-antibiotic preventative methods play a very important role in an age of increasing antibiotic resistance and given the known side effects of antibiotics. Evidence of the efficacy of cranberry extract supplements is mixed but is considered harmless with minimal side effect profile and therefore is a reasonable recommendation in women with recurrent UTIs given its possible benefit.^42,74 Probiotics are recommended by many providers, however prior studies have failed to show their clear efficacy.⁷⁵ According to at least one trial consumption of daily d-mannose prophylaxis appears to significantly reduce the risk of UTIs.⁷⁶ That same study showed that there was no statistically significant difference in UTI rate between patients who used d-mannose (2000 mg once daily) versus nitrofurantoin prophylaxis (50 mg once daily) over a 6-month period and is supported by a metanalysis evaluating its efficacy.⁷⁷
• Bacteriostatic agent:
  • Methenamine-hippurate is a bacteriostatic agent. A multi-center randomized control trial comparing methenamine to antibiotic prophylaxis demonstrated that methenamine is non-inferior and is a reasonable alternative.⁷⁸
• Antibiotics:
  • Patient-initiated antibiotics in select patients. Choice of empiric antibiotics should be nitrofurantoin (for 5 days), trimethoprim/sulfamethoxazole (for 3 days) or fosfomycin (one packet) based on local antibiogram. Antibiotics should generally not exceed 7 days. Providers should not perform test of cure, unless patient has persistent symptoms.⁶¹
  • Postcoital antibiotics have shown to be effective and generally consist of taking a single dose of antibiotics either immediately before or after intercourse.^79,80
  • Prophylactic antibiotics: multiple randomized controlled trials comparing daily antibiotic prophylaxis with sulfamethoxazole-trimethoprim, nitrofurantoin, or fosfomycin (one packet every 10 days) compared to placebo have demonstrated that the former have reduced incidence of recurrent UTI episodes. Side effects (nitrofurantoin, trimethoprim/sulfamethoxazole), and resistance have to be taken into consideration. Nitrofurantoin is associated with rare pulmonary and hepatic toxicity.⁸¹ Once antibiotics were discontinued, UTIs tend to recur. Fluoroquinolones should be avoided when possible due to adverse side effects and risk of tendon rupture.

COMPLICATED URINARY TRACT INFECTIONS (PYELONEPHRITIS)

Definition

Complicated UTIs are is defined as those that extend beyond the bladder, typically exhibiting systemic effects such as fever, sepsis, or clinical evidence of pyelonephritis (flank pain or costovertebral tenderness).

Epidemiology

Complicated UTIs are more common in patients with underlying immune conditions (e.g., poorly controlled diabetes mellitus or acquired immunodeficiency syndrome (AIDS)) and genitourinary abnormalities (e.g., nephrolithiasis or stents in place). Pyelonephritis is estimated to occur in 15–17 per 10,000 non-pregnant adult women, and up to 20–30% of pregnant women annually. Young sexually active women between the ages of 15 and 29 are at the highest risk outside of pregnancy.^82,83

Pathophysiology

Pyelonephritis is usually the result of an ascending infection from the bladder. Similar to acute simple cystitis, the most common organism is E. coli, although other Gram-negative bacteria of the fecal microbiota, such as Proteus, Klebsiella, and Enterobacter spp. may also be responsible.⁸²

Evaluation

Suspicion should arise in patients with signs of acute cystitis (dysuria, frequency, urgency, suprapubic pain) who also have fever, chills or flank pain and non-specific symptoms, such as nausea and vomiting. It is important to note that pyelonephritis can present without lower urinary tract symptoms in about 20% of patients.⁸⁴

Physical exam is crucial for diagnosis of pyelonephritis, as it is typically a clinical diagnosis. On exam suprapubic and/or costovertebral tenderness may be elicited.

Urinalysis and urine culture should always be requested. On urinalysis, evidence of pyuria and nitrites support the diagnosis. White cell casts may suggest a renal origin of the infection. Urine culture is important for evidence of growth and for antibiotic sensitivity. Occasionally, urinalysis and urine culture may be negative if the infection does not communicate with the bladder due to an obstruction (stone or stricture). A complete blood count and metabolic profile will help assess the severity of infection as well as detect renal compromise.

Imaging is generally not indicated for diagnosis of complicated urinary tract infection. It can be helpful in instances where nephrolithiasis, an obstructing calculus or an abscess is suspected, and is recommended in patients who do not respond after 48–72 hours of treatment. Renal ultrasound is acceptable; however, abdominopelvic computed tomography with and without contrast typically has the highest sensitivity for capturing those abnormalities.^85,86 Edema and infiltrative changes can be supportive of pyelonephritis, however normal imaging does not rule out pyelonephritis.

Management

In cases of acute complicated urinary tract infection rapid initiation and choice of antibiotics is critical. Urine culture is important as it can dictate necessary adjustments to antibiotic therapy.

Most patients with acute complicated UTIs can be managed as out-patients after brief evaluation with or without administration of one dose of parenteral antibiotics followed by completion of an oral course of antibiotics. Patients who must be admitted to hospital for treatment include those with signs of sepsis, persistently high fevers, inability to take oral medications or if urinary obstruction is suspected. In pregnancy, severe pyelonephritis can result in complications such as sepsis or acute respiratory distress syndrome in an estimated 20%, and admission until afebrile for 24 hours is recommended.⁸⁷ Housing or financial insecurity should be considered before out-patient treatment is considered.⁸⁸

The choice of empiric antibiotics is dictated by a variety of factors and includes prior documented urine cultures, local antibiogram, allergies, and interactions. The most common initial agents include parenteral ceftriaxone, or piperacillin-tazobactam or alternatively fluoroquinolones. In regions with a >10% incidence of fluoroquinolone resistance or with any alternative regimen, a single initial dose of a parental agent may be considered.^12,89 Oral agents for treatment of acute complicated UTIs include trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, cepodoxime, cefdinir or cefadroxil with typical duration being 7–10 days. Agents such as nitrofurantoin should not be used for acute complicated UTIs as it does not have extra-vesical penetrance.^84,88

Follow up on urine culture to verify proper antibiotic was selected. If no improvement is noted within 48–72 hours, reassessment is recommended and the use of imaging should be considered. Pregnant women who have experienced pyelonephritis have a 6–8% chance of recurrence within the remainder of the pregnancy and suppression with cephalexin (250–500 mg at bedtime) or nitrofurantoin (50–100 mg at bedtime), during the remainder of the pregnancy, can be considered despite the lack of data.⁹⁰

PRACTICE RECOMMENDATIONS

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