Continuing Education Activity

Recurrent urinary tract infections (UTIs) are a common cause of morbidity, especially in young women. Defined as 2 or more acute UTIs within 6 months or 3 in a year, recurrent UTIs should be differentiated from relapsing infections that involve identical organisms and may suggest an infectious cause. Recurrent UTIs can be easily treated, and further episodes prevented with appropriate care. This activity reviews the etiology of recurrent urinary tract infections, their evaluation, and the differentiating blood and urinary tests that may narrow a differential diagnosis. The article outlines the diagnosis, treatment, and prophylaxis of recurrent UTIs. Since the recurrence occurs more frequently in women, discussing the anatomical considerations and best practice hygiene guidelines is vital. An interprofessional team comprising primary care clinicians and specialists aware of the social factors in patient compliance is necessary.

Objectives:

• Identify the etiology of recurrent urinary tract infections.

• Differentiate the presentation of a patient with recurrent urinary tract infections compared to relapsing UTIs.

• Implement the management considerations for patients with recurrent urinary tract infections consistent with current guidelines.

• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients affected by recurrent urinary tract infections.

Introduction

Recurrent urinary tract infections (UTIs) are defined as 2 episodes of acute bacterial cystitis, along with associated symptoms within the last 6 months or 3 episodes within the previous year.[1] Recurrent UTIs are much more common in the female population. The cost of treating urinary tract infections in the United States alone is about 3.5 billion dollars annually.[2]

A UTI is traditionally defined as >100,000 colony-forming units CFU/ml of urine associated with typical acute symptoms of dysuria, urgency, frequency, or suprapubic pain.[3] However, more than 100 CFUs of E. coli with specific acute urinary symptoms have a positive predictive value of about 90%, indicating that a lower CFU threshold is more appropriate in diagnosing simple and recurrent UTIs.[4] 

Etiology

Several conditions may predispose both men and women to an increased risk of UTIs.

• Anatomical defects that lead to stasis, obstruction, or urinary reflux increase predisposition to recurrent urinary tract infections.
• Atrophic vaginitis
• Bladder diverticula, especially those that do not drain well.
• Cystoceles and pelvic organ prolapse are important risk factors for recurrent UTIs in women.[5]
• Functional defects, like overactive bladder and urinary incontinence, tend to lead to recurrent infections.[6] 
• Inadequate or incomplete treatment of the initial acute cystitis.[7]
• Increasing bacterial resistance to antibiotics.
• Older men can often develop urinary tract infections due to outlet obstruction or neurogenic bladder, causing urinary stasis and incomplete bladder emptying, which predisposes them to an increased risk of UTIs.
• Recurrent urinary tract infections may be commonly seen in sexually active women without any identifiable structural abnormality or another predisposing condition.
• Several other lesions may predispose to recurrent UTIs, including intraluminal (bladder stones, neoplasms, indwelling catheters, stents, foreign bodies), intramural (ureteral stenosis/strictures), and extramural lesions (inflammatory mass, fibrosis, extrinsic mass effect, or neoplasm).[8]
• Ureteroceles
• Urinary fistula
• Urolithiasis
• Vesicoureteric reflux (VUR) is identified in up to 40% of children being investigated for a first UTI.[9][10]

Immunodeficiency alone typically does not lead to isolated recurrent UTIs.

Epidemiology

Approximately 1 in 3 women suffer an uncomplicated urinary tract infection (UTI) before the age of 24.[11] 

The lifetime prevalence of at least 1 symptomatic UTI in women is estimated to be over 50%, with about 26% of women demonstrating a recurrence during 6 months of follow-up after treatment of the initial UTI.[12] 

In a study in the primary care setting, 53% of women over 55 years of age, and 36% of younger women reported a recurrence within 1 year.[1] 

Pathophysiology

Recurrent urinary tract infections are usually new infections with different bacterial organisms. If the infection persists despite treatment, it may indicate an untreated source, such as an abscess, urinary stone, or prostatitis. The source of these recurrent infections is the same as for any uncomplicated cystitis.

Typically, the rectal bacterial flora contaminates the periurethral area and urethra. From there, bacteria can quickly ascend and reach the bladder. Research demonstrates a complex relationship between the intestinal, vaginal, and urinary microbiome, which is not well understood.[13]

Three-quarters of recurrent UTIs are caused by Escherichia coli. Other commonly found organisms include Enterococcus faecalis, Klebsiella, Proteus mirabilis, or Staphylococcus.[14]

It is important to differentiate rapid reinfection (a different organism) from a relapse (the same organism not completely treated). A relapse is further defined as a recurrence within 2 weeks of completing therapy with the same organism. Reinfection occurs if a new infection, even from the same organism, is diagnosed more than two weeks after treatment.

Most recurrent UTIs typically seen in medical offices and clinics are reinfections and do not warrant an extensive urological evaluation or imaging. Indications for imaging include persistent hematuria, a history of kidney stones, repeatedly finding Proteus (often associated with urolithiasis), and relapsing infections.

Menopause and atrophic vaginitis cause the number of protective vaginal lactobacilli to decrease.[5] Bladder contractions tend to become less forceful, leading to higher post-void residual volumes predisposing to recurrent UTIs.

The numbers of Lactobacilli in the vagina naturally decline. The contraction of the bladder weakens with age, leading to difficulties in complete emptying.

Risk factors for recurrent UTIs are listed below. Of these, the most significant include the use of a diaphragm with spermicide, menopause, untreated atrophic vaginitis, and frequent sexual intercourse. Spermicides and lack of estrogen effect will disrupt the normal vaginal flora, while sexual intercourse tends to introduce vaginal bacteria into the urethra and bladder. Genetic factors are likely if a sister or mother has a history of frequent UTIs.

Risk Factors for Recurrent Infections

• Any spermicide use within the previous year, primarily if used with a diaphragm
• Atrophic vaginitis
• Bladder diverticula
• Bladder fistula
• Chronic diarrhea
• Cystocele
• Diabetes
• First UTI before 16 years of age
• Genetic predisposition (usually through bacterial/vaginal mucosal adherence factors)
• A higher frequency of sexual intercourse (>twice a week) triples the UTI risk
• History of 5 or more UTIs
• Inadequate fluid intake (low urinary volumes)
• Increased post-void residual urine (incomplete bladder emptying >150 mL)
• Mother or sister with a history of frequent or multiple UTIs
• New or multiple sexual partners
• Short anal to urethral meatus distance
• Urethral diverticula
• Urinary incontinence
• Use of spermicide-coated condoms [5][15][16][17][18][19][20][21][22][23]

Personal Hygiene Factors

• Failing to use a gentle, liquid soap when washing the vaginal area
• Not cleaning the urethral area first when washing
• Not using clean, soft washcloths to clean the vaginal area when washing
• Not using vaginal estrogen, when appropriate, in post-menopausal women
• Not washing hands before wiping the vaginal area after voiding
• Taking baths instead of showers
• Wiping and washing the vaginal area (incorrectly) from back to front or more than once

History and Physical

A complete history and physical are necessary. Acute simple cystitis presents with urinary frequency or urgency symptoms, dysuria, and suprapubic pain. The probability of cystitis is greater than 90% in women with dysuria and frequency without vaginal discharge or irritation.[24] The presence of fever, chills, rigors, marked fatigue, or malaise suggests that the infection has extended beyond the bladder and is now regarded as acute complicated cystitis. 

Clinical features of pyelonephritis include fever, chills, flank pain, costovertebral angle tenderness, nausea, and vomiting.[25] Symptoms of cystitis are often, but not universally, present in patients with pyelonephritis. Women with recurrent UTIs should have a pelvic examination to check for cystoceles, vaginitis, vaginal atrophy, and prolapse of pelvic organs.[3] 

A study of 113 women found that hematuria and urgency as symptoms during an initial urinary infection were the strongest predictors of a second UTI.[12] 

Men who have recurrent episodes of cystitis should undergo an evaluation for prostatitis. At the same time, elderly or debilitated patients may present with more generalized symptoms of infection (like fever and chills) or a change in mental status without any precise localization to the urinary tract. 

To confirm a diagnosis of recurrent UTIs, there should be documentation of positive urine cultures associated with appropriate urinary symptoms.[3] If clean catch urine samples are suspicious for contamination (especially in women), consideration should be given to obtaining a catheterized specimen.[3]

In women who have very rapid recurrences of cystitis after treatment, clinical clues should attempt to classify cystitis as reinfection (i.e., new infection after the previous one was wholly eradicated) or a relapse (i.e., re-emergence of the previous infection, which was incompletely eradicated).

A recurrence is termed reinfection if the interval between two episodes is greater than two weeks, if a different uropathogenic strain is documented, or if a sterile culture (with the patient off antibiotics) was documented between 2 UTI episodes. If the interval between the 2 episodes is less than 2 weeks, it is a relapse. Relapsing infections often require additional evaluation with urological imaging.

Evaluation

The typical patient with recurrent UTIs does not require cystoscopy or urological imaging.[3][26]

In women with a history of recurrent UTI with typical symptoms, no further urological evaluation is necessary other than a urine culture and sensitivity. However, the diagnosis of recurrent cystitis can be made clinically. Urine cultures should be performed in severe infection or if there is a high risk of antibiotic resistance (multidrug-resistant isolate, recent inpatient admission, recent antibiotic use, a history of travel to India, Israel, Spain, or Mexico).

Urine cultures are also necessary to differentiate recurrent infections (repeat infections with different organisms) from relapsing (identical organisms on culture). Relapsing infections suggest a persistent source of bacterial inoculation, such as an abscess, chronic bacterial prostatitis, or an infected stone. The American Urological Association Guidelines on recurrent urinary tract infections in women recommend obtaining a urinalysis and urine culture with each episode of acute cystitis.[3]

Urological imaging is advised for only a select group of women. Indications for urological imaging include relapsing infections, persistent hematuria after treatment, a history of stone passage, or repeated isolation of Proteus from the urine, often associated with renal stones. Preferred imaging modalities include renal ultrasonography or, ideally, a CT scan of the abdomen and pelvis.

Various sampling methods have been described to establish the diagnosis of UTI in the pediatric population. However, obtaining the urine sample utilizing suprapubic aspiration or catheterization might result in lower contamination and more reliable results. Moreover, if the urine sample is collected through a plastic bag, several steps are required to rule out the possibility of UTI, including dipstick evaluation and microscopic analysis.

The presence of leukocyte esterase and nitrite on a urinary dipstick and the possibility of pyuria and bacteriuria should be excluded to rule out the impression of a UTI. Utilizing a clean, voided midstream urine sample for the diagnosis is limited to toilet-trained children and individuals.[27]

Patients with negative urinary cultures who have persistent symptoms should be evaluated for other causes, such as atypical organisms, interstitial cystitis, endometriosis, atrophic vaginitis, trauma, urethral pathology, neoplasms, diverticula, strictures, medication side effects, and vaginitis.[28][29][30]

Performing a cystoscopy solely for the diagnosis of recurrent UTIs is rarely indicated as it might induce an ascending lower urinary tract infection.[31][32] Cystoscopy is rarely helpful when utilized routinely; however, it might be useful in a few clinical situations, including post-operative exclusion and management of possible ureteral injuries, to evaluate incomplete bladder emptying or to identify possible bladder calculi.

The optimal recommended type of irrigation fluid used during cystoscopy has been investigated. For instance, in the 8-month-long study of the joined Cleveland health system clinics, a significantly higher rate of UTIs was found in those patients who had undergone cystoscopy with 10% dextrose and water irrigation compared to normal saline.[33] All cystoscopies were planned to exclude intraoperative ureteral injuries during complicated urogynecology procedures.

Treatment / Management

Treatment for Simple UTIs

Acute uncomplicated UTIs are primarily managed in the outpatient setting.[7] Women with typical symptoms of acute cystitis can be prescribed antibiotic therapy over the telephone.[34] A urine culture is recommended to optimize antibiotic therapy in cases of initial treatment failure and high-risk patients. The decision for hospitalization should be taken on a case-by-case basis. Most patients with persistent fever, pain, inability to take oral medicines or poor medication adherence should be managed inpatient.

Management of simple cystitis is relatively straightforward. Urine cultures should be obtained before initiating therapy:

• For patients treated for cystitis in the past 3 months, urine culture and susceptibility testing should be obtained to guide antibiotic therapy due to the increased risk of antibiotic resistance.
• Patients with complicated cystitis or pyelonephritis should also have urine cultures before initiating empiric antibiotics.

The first-line options for empiric antibiotic therapy for simple cystitis are:

• Nitrofurantoin 100 mg twice daily orally for 5 to 7 days. It should be avoided in suspected pyelonephritis (due to poor tissue penetration) or if creatinine clearance is <30 mL/min.
• Trimethoprim-sulfamethoxazole 160/800 mg twice daily orally for 3 days. It should be avoided if the local resistance rate exceeds 20%.
• Fosfomycin, as a single oral dose of 3 g. 
• Pivmecillinam (not available in the US but commonly used in Europe) is the agent of choice for UTIs in Nordic countries. Avoid this agent in suspected pyelonephritis due to poor tissue penetration.[35]

Oral beta-lactams are the next best choice if the above options cannot be used. Amoxicillin-clavulanate 500 mg twice daily, cefdinir 300 mg twice daily, cefadroxil 500 mg twice daily, and cefpodoxime 100 mg twice daily are each given for 5 to 7 days. Ampicillin or amoxicillin should be avoided due to high rates of resistance.[36][37] If the beta-lactams cannot be used, fluoroquinolones such as levofloxacin 250 to 500 mg daily, ciprofloxacin 250 to 500 mg twice daily, or norfloxacin 400 mg twice daily for three days, are good alternatives. Fluoroquinolones are contraindicated in pregnancy and should be avoided where possible to minimize the development of quinolone resistance.

For inpatient management of patients with risk factors for multi-drug resistant (MDR) pathogen infection, carbapenems (imipenem 500 mg IV q6, meropenem 1g IV q8, or doripenem 500 mg q8 are used). If no risk factors for MDR are present, ceftriaxone 1 gram IV daily or piperacillin-tazobactam 3.375 grams IV q6 can be used. Fluoroquinolones (ciprofloxacin or levofloxacin), both oral and parenteral, are also good alternatives. Carbapenems (as above) and vancomycin are typically used for critically ill patients. Aminoglycosides may also be used selectively, depending on urine culture, sensitivity results, and local antibiotic susceptibility patterns.  

Symptoms should respond to antibiotic therapy within 48 hours of initiation of therapy. Suppose no improvement is noticed within the first 48 hours after starting therapy. In that case, a repeat urine culture should be obtained along with urologic imaging to rule out complications such as an obstructing urinary stone, hydronephrosis, urinary retention, renal abscess, or pyelonephritis.

Clinicians should not generally perform a post-treatment test of cure urinalysis or urine culture in asymptomatic patients. Repeat urine cultures should be obtained to guide further management when UTI symptoms persist following antimicrobial therapy.

Preferred agents for UTIs in patients with renal failure include carbapenems, cephalosporins, doxycycline, fosfomycin, penicillins, and quinolones. Intravesical instillation of an antibiotic solution, such as gentamicin, may also be used in patients with severe renal impairment.[38] For patients with end-stage renal failure, quinolones (ciprofloxacin, levofloxacin) are the first-line agents for UTIs, with cefdinir or cefpodoxime as backup therapy.[39][40] For prophylaxis, the preferred antimicrobials are trimethoprim alone and fosfomycin.[38] 

Treatment for Recurrent UTIs

Recommended treatments for recurrent UTIs include maximizing personal hygiene factors, avoiding spermicides, wiping correctly, increasing fluid intake and hydration, using vaginal estrogens if appropriate, etc. The effectiveness of lifestyle changes in personal hygiene in reducing recurrent UTIs has not been conclusively demonstrated. However, recommending improved hygiene has no negative consequences and might be of some benefit.[15][19] The use of probiotics is unclear, as clinical trials to date have inconclusive evidence.[41] 

When conservative measures fail to control recurrent UTIs, commonly recommended initial non-antibiotic prophylactic therapies include the following:

Cranberry products are recommended as first-line prophylactic agents, but their efficacy is somewhat controversial as, so far, a benefit has not yet been definitively and conclusively established.[42] Cranberries are thought to work by providing proanthocyanidins, decreasing bacterial adherence to the urothelium. While this sounds reasonable and is an attractive hypothesis, commercially available cranberry products have limited amounts of proanthocyanidins. The American Urological Association Guidelines suggest using this treatment but advise patients that its effectiveness is uncertain and alternative measures may be necessary.[3][43]

D-mannose has been proposed as an aid in recurrent cystitis due to its ability to bind to bacterial surface ligands, which decreases the adherence of infecting organisms to the urothelial mucosa.[44] While there is some evidence of a reduction in recurrent infections from D-mannose, definitive studies have not yet been done, and optimal dosages are still undetermined, but 500 mg BID is commonly suggested.[42]

Methenamine prophylaxis has been suggested, along with vitamin C, to help acidify the urine.[42] If the urinary pH remains acidic, preferably <5.5, the bladder converts the methenamine to formaldehyde.[45] A recent systematic review found methenamine to be an effective and well-tolerated prophylactic antimicrobial agent, avoiding the need for systemic antibiotics and their potential side effects.[46] A separate multi-institutional, clinical randomized trial study compared methenamine to trimethoprim for UTI prophylaxis and found the same rate of recurrences for both after 1 year.[47]

Although some studies have failed to prove a long-term benefit, the majority show efficacy, indicating that further use and study of methenamine is warranted, particularly given recent trends demonstrating increasing antibiotic resistance.[48][49][50] Methenamine should not be used if the glomerular filtration rate (GFR) is <10 mL/min.[51]

Vaginal estrogen has been shown to reduce recurrent UTIs in postmenopausal women and should be used when appropriate in addition to other prophylactic measures.[48]

A "care bundle" including behavioral and lifestyle modifications, probiotics, D-mannose, and cranberry products was used for 6 months in 47 patients with recurrent UTIs. Women in the study reduced their rate of UTIs by 76%, and antibiotic use dropped by over 90%.[52] Such a combination of non-antibiotic therapy appears quite promising as being effective, avoiding the potential side effects of antibiotic use, and minimizing bacterial resistance. However, further research with larger sample sizes using different components is needed to confirm and determine the optimal ingredients and dosages.[52][53]

Antibiotic prophylaxis will generally successfully control recurrent UTIs, but alternative non-antibiotic means are recommended first.[54] This approach limits the development of bacterial resistance, eliminates antibiotic-related side effects, and reduces costs.[54] 

Antibiotic prophylaxis is reasonable when other more conservative measures fail or there is evidence of multiple rapid recurrences. Antibiotic prophylaxis is never appropriate in patients who have permanent catheters or nephrostomies, as this will rapidly lead to highly resistant organisms.

There are several ways antibiotic prophylaxis for recurrent UTIs can be administered.

• Post-coital prophylaxis is appropriate for women with frequent episodes of cystitis that are associated with sexual activity.

• Self-directed therapy, where patients start a short course of antibiotics at the first sign or symptom of a UTI, is another option. Such an approach is reasonable if the patient is sufficiently educated about infection symptoms and will reliably follow instructions.[3] A urine culture should still be obtained before starting treatment, if possible. Efficacy appears equal to continuous low-dose prophylaxis regimens with fewer GI side effects.[20][55] If this fails, then a continuous prophylactic treatment protocol will be needed.

• Long-term low-dose antibiotic prophylaxis is the gold standard method of recurrent UTI prevention but also requires the highest level of patient compliance, has a long duration of therapy (at least 6 months), and risks increasing antibiotic resistance. It should be used in the most intractable cases where more conservative measures have failed or cannot be effectively utilized. (See below.)

Surveillance urine testing and cultures in asymptomatic patients are not recommended. Asymptomatic patients, even high-risk patients in nursing homes and diabetics, do not benefit from an additional evaluation, and any bacteriuria should not be treated without symptoms.[3] (This recommendation does not apply to pregnant women or patients about to have urinary tract surgery.)

If a recurrent UTI patient develops an acute UTI, a urine culture should be obtained, and an alternate antibiotic agent should be used to treat the infection. The duration of treatment should generally be no longer than a week.[3] If the urine cultures show resistance to all available oral agents, then parenteral antibiotics may be required. Fosfomycin may be an acceptable agent in such circumstances. An infectious disease consultation is suggested in such situations. The duration of therapy should generally be no more than 1 week.[3] 

Long-term, Low-dose Antibiotic Prophylaxis

Continuous long-term prophylactic antibiotics typically use lower dosages than acute cystitis therapy. Therefore, this approach is called the long-term, low-dose therapy protocol. The antibiotic selection is based on the patient's culture and sensitivity results. Initial evaluation of the effectiveness of prophylaxis is suggested at 3 months. If effective, a 6 to 12-month duration is typical. Unfortunately, many individuals will revert to their prior pattern of infections once prophylaxis stops.[56][57] 

Some experts will recommend continuing prophylaxis for up to 2 or more years in selected patients.[58][59] In such cases, nitrofurantoin, SMX-TMP, and trimethoprim are preferred agents. Quinolones are not preferred for prophylaxis because of the risk of increasing bacterial resistance; however, they can be used if no other option is available.

Suppose it is determined that a quinolone antibiotic is needed for prophylaxis. In that case, norfloxacin is preferred as it has less tissue penetration outside the urinary tract than other quinolones but maintains good urinary levels. This would typically be selected only when other first-line agents cannot be used.[60]

Some patients have continued low-dose prophylaxis for years, but this practice has not been scientifically studied or validated. Potential side effects of long-term, low-dose antibiotic usage would include gastrointestinal, hepatic, and pulmonary issues.[61]

Beta-lactams can be used but tend to rapidly change GI flora, carry a risk of pseudomembranous colitis (Clostridia), provoke bacterial resistance, and stimulate yeast overgrowth.

There is limited data on the use of fosfomycin for UTI prophylaxis, but it may be appropriate in selected situations.[62] Prophylactic regimens are not written in stone; agents can be changed to help maintain efficacy. In patients with chronic, permanent catheters, a short course of 1 to 3 days of antibiotic prophylaxis can reduce the incidence of symptomatic UTIs. This approach may suit severely immunocompromised patients and possibly those with persistent infections after catheter changes. However, it is not recommended routinely due to the expected increase in antibiotic use and worsening bacterial resistance patterns.[63]

There are some negative aspects to antibiotic prophylaxis. There is the added cost and inconvenience of taking additional medication. There are possible allergies and medication cross-reactivities. Yeast superinfections and Clostridia overgrowth in the gastrointestinal tract may increase, and continuous prophylaxis promotes the emergence of more resistant urinary pathogens.[64][65]

Long-term, low-dose antibiotic prophylaxis is effective but requires high patient compliance and risks resistance.[56]

Preferred Antibiotic Agents for Recurrent UTI Prophylaxis

• Nitrofurantoin at 50 to 100 mg HS daily
• SMX-TMP at 40/200 mg HS daily
• Trimethoprim at 100 mg HS daily

Second-line Agents That are Less Preferred for Prophylaxis

• Cephalexin at 125 mg or 250 mg HS daily
• Cefaclor at 250 mg HS daily
• Fosfomycin at 3 gm every 10 days
• Norfloxacin at 400 mg HS daily

UTI Prophylaxis in Renal Failure

Patients with significant renal failure (GFR <30 mL/min.) cannot take nitrofurantoin, methenamine, or sulfa medications for prophylaxis. Preferred agents for prophylaxis in such situations include: [66]

• Trimethoprim at 100 mg HS daily
• Fosfomycin at 3 gm every 10 days
• Quinolone at a reduced dosage (less preferred)

Differential Diagnosis

Differential diagnosis to consider and rule out include the following:

• Atrophic vaginitis - Thinning, drying, and inflammation of the vaginal tissues, frequently leading to urinary symptoms due to loss of estrogen.
• Overactive bladder - Frequency and urgency with no evidence of infection.
• Painful bladder syndrome - Diagnosis of exclusion. Dysuria, frequency, urgency, but no evidence of infection.
• Pelvic inflammatory disorder - Lower abdominal or pelvic pain, fever, cervical discharge, with cervical motion tenderness.
• Prostatitis - Consider in men. May present with pain during ejaculation and tender prostate on digital rectal examination.
• Urethritis - Urinalysis shows pyuria but no bacteria. Common in sexually active women.
• Urolithiasis - Bladder or distal ureteral calculi can cause similar symptoms, and nephrolithiasis may be an infected focus.
• Vaginitis - The presence of vaginal discharge, odor, pruritus, and dyspareunia. No frequency or urgency.

Prognosis

Most recurrent UTIs have no long-term sequelae, and patients recover fully. The mortality associated with acute uncomplicated cystitis in women is negligible. However, in terms of morbidity, each episode of UTI results in a loss of 1.2 days of attendance at class or work. Younger patients without preexisting comorbidities have the best prognosis.

Some factors associated with a worse prognosis may include older age, recent urinary instrumentation, recent hospitalization or antibiotic therapy, preexisting diabetes mellitus, sickle cell anemia, or chronic renal disease.[67] UTIs occurring in the setting of specific anatomical abnormalities such as renal calculi, obstruction, hydronephrosis, colovesical fistula, neurogenic bladder, renal failure, or bladder exstrophy also have a worse prognosis.

Complications

Risk factors for complications include urinary tract obstruction, recent urinary tract instrumentation, older age, and patients with diabetes mellitus (particularly for emphysematous pyelonephritis and papillary necrosis).

Acute pyelonephritis can also be complicated by the infection progressing to a renal abscess, perinephric abscess, papillary necrosis, or emphysematous pyelonephritis. This may present a lack of improvement in symptoms after 48 hours of appropriate antibiotic therapy and requires further evaluation with urological imaging. Patients with complicated UTIs can present directly with bacteremia, sepsis, multiple organ system failure, or acute renal failure.

Deterrence and Patient Education

Several preventive measures can be taken to reduce further recurrences of UTIs. Patients should be advised to increase fluid intake to at least 2 liters daily. In a study on 140 women, increased water intake resulted in decreased incidence of cystitis episodes by 1.5 (95% CI 1.2-1.8) (mean 1.7 versus 3.2) episodes.[68] 

Topical vaginal estrogen is recommended in postmenopausal women with vulvovaginal atrophy (genitourinary syndrome of menopause) to reduce the risk of future UTIs, provided there are no contraindications to estrogen therapy.

Other behavioral modifications include wiping from front to back, using clean liquid soap, avoiding reusable luffas and sponges for soap application when bathing, and early postcoital voiding.[69] There is no conclusive evidence on the beneficial role of cranberry juice in reducing episodes of recurrent UTI, but some still recommend it.[70]

Antibiotic prophylaxis should only be offered after other preventive modalities and only in women with a confirmed diagnosis of recurrent cystitis. In some situations, the adverse effects of antibiotic prophylaxis may outweigh the risk of recurrent UTIs, as cystitis rarely results in a poor outcome. The adverse effects may include direct drug toxicity, development of resistance, alteration of the microbiome, and/or Clostridioides difficile infection.

In women with cystitis episodes associated with sexual activity, postcoital antibiotics may be advised to reduce the risk of adverse effects without compromising the drug's efficacy or promotion of antibiotic resistance.[71][72] In other cases, continuous prophylaxis may be used. The drugs used in continuous as well as postcoital prophylaxis are largely similar. The need for antibiotic prophylaxis should be reevaluated after 6 months.

Summary of Personal Hygiene Recommendations

In many women, recurrent UTIs may be affected by inadequate or suboptimal personal hygiene. Controlled studies have not proven significant efficacy in reducing recurrent urinary tract infections purely from personal hygiene lifestyle modifications.[15][19] Still, it is recommended to teach optimal personal hygiene, including wiping front to back, avoiding baths, using only newly laundered soft cotton or microfiber washcloths, using non-toxic liquid soap, washing hands before wiping, cleaning the private area before the rest of the body to avoid contamination of the perineum, etc.

Since many women feel uncomfortable hearing such advice from men or male clinicians, many patients should have the suggestions reviewed by a female nurse or written down in a guide, which can be read privately at home. 

The following information covers what should be imparted to patients so they understand their condition and its conservative management: 

Preventing Urinary Tract Infections

Urinary tract infections (UTIs) are prevalent, especially in women. About 50% of all women will have at least one such infection in their lifetimes. While a UTI is usually just bothersome with symptoms such as burning on urination, urinary frequency, urgency, nocturia, hematuria (blood in the urine), and odor, it is possible for a urinary tract infection to progress. It affects the kidneys or other organs, which can be serious.

When a patient has 3 or more urinary tract infections within 1 year, it is termed a recurrent infection, and a medical review may be recommended. The following changes are recommended:

Wash hands before wiping: Patients should wash their hands before urinating or at least before using the toilet. They should also wash their hands before they get into the shower to avoid passing germs from their hands back to their body near the vaginal area.

Wipe front to back: Always wipe from the front to the back after urinating. The patient should start from the front and push down and away towards the rectum. Most urinary infections are from bacteria that normally live around the rectum and anus. Therefore, any wiping motion that starts near the rectum and then approaches the urethral area will move potentially dangerous bacteria closer to the bladder and urinary tract. Patients should also wipe the same way, front to back, after a bowel movement. 

When wiping, only wipe once: Using toilet paper after urination is acceptable. However, the patient must wipe once, or they may add more bacteria to the urethral area. Sterile baby wipes are cleaner than toilet paper and can be carried in their purse outside the home. As a general rule, anything safe for babies can also be used in the delicate area around the vagina and urethral opening.

Avoid baths: Bathwater is full of dirt and bacteria from the skin. Sitting in a tub allows the bacteria to reach the urethra. Remind the patient that the water they wouldn't drink shouldn't be used to clean their urethra. Suppose the patient absolutely must take a bath instead of a shower. In that case, they should avoid any bubble baths or other cosmetic bath additives, which tend to be irritating to the delicate skin of the vaginal mucosa. Instruct the patient to take showers instead.

Avoid luffas and all reusable sponges: Luffas and other reusable sponges, including nylon, cannot be adequately cleaned or sterilized once used, so they retain bacteria. They are also used repeatedly for days, weeks, or even months, during which they can accumulate more and more bacteria and germs. Women who are susceptible to infections, particularly urinary tract infections, should avoid using reusable items that are heavily contaminated.

Use a gentle liquid soap when washing: Bar soap will always have bacteria due to exposure to the air and bathroom environment. A body wash is fine for regular skin cleaning, but regular body wash is too harsh for the gentle tissue of the vagina and urethral area. It is important to avoid using products with unnecessary perfumes, astringents, creams, or other possibly irritating chemicals. The patient may use gentle baby soap or shampoo for the urethral area.

Use washcloths: The best and cleanest way to apply soap is to use a clean, soft cotton or microfiber washcloth. The washcloths can be placed into a clean, resealable plastic bag immediately after they are washed and dried, as they are cleanest from the dryer. The patient may want a second washcloth to finish their shower after adequately cleaning the urethral area.    

Clean the urethral area first: The bladder is the only body area infected if not cleaned properly. It should be washed before a washcloth or hands have picked up any dirt, germs, or bacteria from other body parts. When surgeons perform surgery, they clean the surgical site before moving to the surrounding area. The same principle applies to cleaning the bladder area. 

How to wash - summary: Wash your hands before showering. Wet the washcloth, add some clean liquid soap, and clean the urethral area first with a single front-to-back wipe with the washcloth. Rinse well without directly spraying the area. The washcloth used to clean the urethral area should be used only once before laundering and not for any other purpose.

Douches and other personal hygiene products: In most cases, a vinegar and water douche or a douche with iodine or benzalkonium chloride is helpful if carried out correctly at appropriate intervals. The patient should not use any feminine hygiene sprays, cosmetics, perfumes, medicated towelettes, or similar products in the vagina or urethral area unless approved by the clinician.

Use tampons for periods: Tampons are advised during menstrual periods rather than sanitary napkins or pads. A tampon can help maintain better hygiene and reduce bacterial growth compared to a sanitary pad.

Avoid long intervals between urinations: The patient should try to empty their bladder every 4 hours during the day, even if they don't feel the urge to void. The urge to void should be promptly answered, if possible. 

Don’t wear tight clothes:  Avoid wearing pantyhose, bathing suits, or tight slacks for prolonged periods. All of these can cause the skin around the vagina to fold into the body, potentially introducing more bacteria around the urethra.  

Drink more water: Start with 1 extra glass with each meal. If the patient's urine appears any darker than a very pale yellow, this could mean that they are not drinking enough and should increase their fluid intake. Cranberry juice is helpful in patients with urinary tract infections but can be substituted with other beverages.

Take some extra vitamin C and drink cranberry juice: The clinician may recommend additional vitamin C. This may help increase the body’s resistance to infection. Extra vitamin C that the system cannot use immediately will be released into the urine, which helps block bacterial growth. As noted earlier, cranberry juice or pills may be of benefit in reducing urinary tract infections. 

Avoid irritating foods like caffeine: Symptoms of bladder irritation may be aggravated by caffeine, regular coffee, tea, alcohol, “hot” spices, aspartame, chocolate, cola drinks, and high-potassium foods like bananas and oranges.

Avoid activities that increase the risk of bladder infections:  Prolonged bicycling, motorcycling, horseback riding, and similar physical activities and exercises may increase the risk of bladder infections. When engaging in physical activity and exercise, patients should frequently empty their bladders and drink plenty of water and other fluids. Sexual activity may also increase the risk.

Take special precautions after sexual activity:  After intercourse, instruct the patient to empty their bladder and drink 2 extra glasses of water. After sexual activity, clinicians may advise some patients to take a urinary antiseptic or antibiotic.

An estrogen vaginal cream may increase resistance to bladder infections: Clinicians may suggest an estrogen cream for the vagina if the patient has had menopause, even if they are already on an oral estrogen supplement or patch. The vaginal cream will help keep the tissues around the urethra healthy and more resistant to infection.

Take antibiotics only as prescribed: If the clinician has prescribed medication or antibiotics as prophylaxis, patients should follow their instructions carefully. They must be aware that medications may be necessary for up to a year or more, depending on the nature and severity of the UTI. For some patients, a small amount of a urinary antibiotic or antiseptic taken daily at bedtime will prevent most urinary infections, give the bladder a chance to heal, and restore its natural resistance. Other patients may only need antibiotics when they think they are getting an infection. 

If patients follow these suggestions and get an infection anyway: Despite these precautions, they must seek medical help promptly if they get an infection. A urine specimen is typically requested by a clinician. Patients should seek prompt help for excessive vaginal discharge or other signs of vaginal inflammation and infection. Patients may be started on an antibiotic at this time, and compliance is crucial. Sometimes, the clinician may request additional tests such as kidney X-rays or a direct bladder examination with a telescope (cystoscopy). Sterilization of washcloths may be the next step where simpler measures are inadequate.

Sterilizing Washcloths for Home Use

The clinician may recommend sterilizing washcloths for washing and personal hygiene to help prevent recurrent urinary tract infections. This extra step is probably unnecessary for most patients with recurrent infections, but it can benefit the more severe or resistant cases. Patients should use only those washcloths purchased for this purpose and remember to wipe correctly from front to back.

Home Sterilization of Washcloths

1. Wash the washcloths with hot water and soap or detergent. If the patient doesn’t have a washer, they can use soap and hot water in a sink.
2. Boil the washcloths in water for at least 20 minutes.
3. Take the washcloths out of the water and allow them to dry, or use the clothes dryer.
4. When dry, place each washcloth in a separate, sealable, microwave-safe plastic bag such as a ziplock bag.
5. The bags should be left open and not sealed yet.
6. Place the bags in the microwave. In the center of the microwave, put a large glass of cold water. The washcloths should not be placed in the water.
7. Put the microwave on high for 5 minutes. Replace the glass of cold water (now very hot) with a new glass of cold water and microwave on high for 5 minutes. 
8. Let the bags cool, then close them. The washcloths are now sterile inside a sterile bag.

This technique will kill the germs and bacteria on the washcloths using microwave radiation for sterilization. Without the glass of cold water to absorb the heat, the bags would melt, and the washcloths would catch fire.

Tips for Preventing Infections

• Wipe in the correct direction, from front to back.
• Wash hands before using washcloths, tissues, or toilet paper for wiping or washing.
• Use a clean, gentle liquid soap because it tends to be much cleaner than bar soap.
• Only wipe once with each washcloth or tissue. 
• When washing, clean the bladder area first to prevent bacteria contamination from other body parts.
• Don’t use these washcloths for anything except to clean the area around the urethra.
• Drink extra water and take vitamin C. Drink cranberry juice or take cranberry pills. 
• The patient can consider using an estrogen cream twice a week (or as prescribed by the clinician) if they are past menopause.

Pearls and Other Issues

Experimentally, vaccines to reduce the recurrence of urinary tract infections have been developed from whole bacterial cells. Still, they have been marginally successful, and the beneficial effect disappears after just a few weeks.[73][74][75] Sublingual mucosal polybacterial vaccines were recently studied in immunocompromised patients with promising results in reducing recurrent infections.[76] A bioconjugate vaccine from various E. coli genotypes works better with a longer-lasting effect. Yet, another promising experimental vaccine focuses on E. coli type 1 fimbrial adhesion protein.[77][78] 

Pilicides and mannosides are also designed to interfere with bacterial adhesion to the urothelium and may be particularly useful in patients with chronic Foley catheters.[79] Another approach uses oral immunostimulants for E. coli. This is already commercially available in Europe but not the U.S. and has demonstrated a reduction in E. coli recurrences of 95%.[80] 

The use of non-steroidal anti-inflammatory agents (NSAIDs) to modify host defenses is being studied experimentally to reduce recurrent UTIs.[81][82]

Fecal microbiota transfer, which transplants metabolites and microorganisms from the fecal material of a healthy donor, appears promising, and bacteriophage therapy, which targets pathogenic bacteria with specific viruses, is also being explored as a possible future therapy for recurrent UTIs.[54]

Enhancing Healthcare Team Outcomes

Recurrent UTIs often have a typical presentation of dysuria, urinary frequency or urgency, and suprapubic pain with or without fever, chills, flank pain, hematuria, costovertebral angle tenderness, and nausea/vomiting. The diagnosis is usually not in question. But, according to the literature, a gap exists in the clinician and patient's perception of the symptom severity, which may be attributed to misinformation, misconceptions, or miscommunication.[83]

Recurrent UTIs require management from an interprofessional healthcare team that includes clinicians (MDs, DOs, PAs, NPs), nurses, and pharmacists, coordinating their efforts and sharing case information to achieve optimal outcomes with the fewest adverse events.

The primary care clinician is usually the first point of medical contact in the care of a patient with a UTI. A proper history and physical exam should be conducted on patients with recurrent UTIs. In several situations, it may be imperative to involve a urologist, an infectious disease specialist, or a nephrologist, as deemed necessary, according to the severity.

In cases of suspected urinary tract obstruction, the radiologist plays a critical role in determining the cause through imaging. Urology should be consulted if an obstruction is confirmed.

Nurses are also vital members of the interprofessional group as they will monitor the patient's vital signs and assist with educating the patient and family.[84]  The pharmacist should ensure that the right antibiotics are chosen on a case-by-case basis. 

The presentation in pregnant women may be complicated as widespread inflammation can be mistaken for obstetrical pain. In such cases, the first point of contact may be an obstetrician. 

A unique aspect of managing recurrent UTIs is in the self-diagnosis and self-treatment of UTIs by the patient. This can be done if the patient is motivated, has a good relationship with the clinician, is reliable and compliant with treatment recommendations, and has documented recurrent UTIs. This approach has been demonstrated to have similar efficacy as conventional therapy in selected patients.[55]

The American Urological Association (AUA) Guidelines are evidence-based recommendations for recurrent UTIs reviewed by an interprofessional expert committee. The current guidelines, published in 2019, have been developed after an exhaustive review of the current medical literature from peer-reviewed journals.[3] The only non-antibiotic-based therapies for recurrent UTIs currently recommended by the AUA Guidelines are cranberry prophylaxis and vaginal estrogen.[3]