Urinary Tract Infection – Recurrent and Complicated

Author: Dr Anthony J. Schaeffer University of Chicago 2008-07-28

Recurrent and complicated urinary tract infections occur in both men and women, are a common cause of morbidity, and can lead to significant mortality. Management of these infections requires careful assessment of past history, risk factors, and a thorough evaluation of the urinary tract. This Knol discusses these urinary tract infections, how they occur, common misconceptions about them, and strategies for prevention and treatment.

Introduction 

Recurrent urinary tract infections (UTIs) fall into one of two categories:

1. Reinfection occurs after successful therapy for a UTI, is caused by bacteria from outside the urinary tract and characterized by varying, delayed recurrence with different strains.
2. Relapse is caused by bacteria that persist within the urinary tract despite antimicrobial therapy and characterized by rapid recurrence with the same strain.

The above distinction is important because patients with reinfection require minimal evaluation and various types of medical management. Conversely, a pattern of relapse warrants careful urologic evaluation to subsequently reduce or correct any underlying abnormalities.

What is a Complicated UTI? 

About 25% of healthy women have reinfections associated with the same bacterial strains (Escherichia coli [E. coli], Staphylococcus saprophyticus) and risk factors (sexual intercourse, spermicide use, low vaginal estrogen, and genetic predisposition) that cause acute, uncomplicated cystitis (an inflammation of the bladder). Healthy young men may also have reinfection with the same strains and risk factors (lack of circumcision, or intercourse with a woman with a UTI) that cause acute, uncomplicated cystitis. In most of these women and some of these men, the infections are uncomplicated (the urinary tract has normal structure and function) and are cured and prevented by antimicrobial therapy.

Sometimes – typically in some young women, most elderly women, and most men – UTIs are complicated. This means the urinary tract is functionally and structurally abnormal, the host is compromised, and/or the bacteria have increased virulence factors and/or antimicrobial resistance (Table 1). These factors increase the chance of acquiring bacteria and decrease the effectiveness of therapy.

The spectrum of presenting symptoms for complicated infections ranges from simple cystitis (characterized by frequent, urgent, and painful urination) to severe kidney or prostate infection (fever, chills, flank pain, or irritative, obstructive voiding) and life-threatening bloodstream infections (urosepsis [urine entering other body tissue]). Since these symptoms may not be obvious initially, a high index of suspicion and careful assessment of outcomes is required.

Unlike those that are uncomplicated, complicated UTIs are caused by a broad range of bacteria including E. coli, other gram-negative bacteria (including Proteus, Klebsiella, and pseudomonas species), and gram-positive bacteria (enterococci and staphylococci). Since many of these strains originate from patients who have been exposed to antimicrobials and/or from a hospital or nursing care environment, the bacteria tend to be more virulent and resistant to antimicrobial therapy than strains associated with the uncomplicated UTIs.

As with uncomplicated infections, urinalysis will demonstrate white blood cells and bacteria in the urine. Urine cultures must be obtained prior to initiating therapy in order to identify the pathogen and antimicrobial susceptibility. Cultures should also be obtained during therapy to determine efficacy, and after therapy to identify relapsing infections.

Evaluation of Recurrent Urinary Tract Infections 

In most women with symptoms of UTI, and in many men with symptoms of prostatitis or chronic pelvic pain syndrome, initial antimicrobial therapy is used without a culture that confirms a bacterial infection. Therefore, in patients with recurrent symptoms, it is imperative to document that the UTI symptoms are due to bacterial infections. If repeated cultures obtained during symptomatic episodes show no evidence of infection, then urologic referral is required to rule out other causes of symptoms such as bladder stones, interstitial cystitis, chronic pelvic pain syndrome, or bladder cancer.

When to Evaluate for Complicated Infection 

The majority of women with documented recurrent UTIs have a normal urinary tract (uncomplicated recurrent cystitis, uncomplicated reinfections); these patients only rarely have an underlying structural or functional abnormality. In these instances, urinary tract imaging and/or referral to a urologist is unnecessary.

However, further evaluation should be entertained to rule out abnormalities if a woman has a history of childhood UTI or a pattern of recurring infections with the same bacterial strain. This is particularly important if the infections occur at close intervals, suggesting that relapse from a focus of bacterial persistence within the urinary tract is responsible for the recurring UTIs (Table 1).

In older men, recurring UTIs are usually complicated, justifying imaging and urologic evaluation. However, in young men, an alternative approach is to assess the response to therapy. If they respond promptly and do not recur, a urologic evaluation can be deferred.

Patients with the other risk factors should be considered to have complicated UTIs and undergo imaging and evaluation by specialists (urologist, infectious disease, etc.) as indicated.

Management of Recurrent UTIs 

As noted above, distinguishing between relapse and reinfection is an important first step in managing UTIs, as recurring events identified as a relapse can usually be cured by surgical removal or correction of the infection’s focus. Conversely, patients with reinfections who do not have any alterable urologic abnormalities will require long-term medical management.

Relapsing Urinary Tract Infections 

Rapid recurrence of a UTI is indicative of a relapsing infection, and should be evaluated to determine if the infection is from the same strain of bacteria. Imaging, usually a CT scan, may reveal an abnormality in the urinary tract (such as a stone), or a congenital or acquired obstruction that impedes flow of urine (such as ureteral pelvic junction obstruction or enlargement of the prostate gland); these findings warrant urologic evaluation. In men, chronic bacterial prostatitis should be considered (see Knol “Prostatitis”). Determining whether the abnormality is associated with bacterial persistence within the UTI is key; if there is a link, surgical removal or correction of the underlying abnormality generally prevents future relapse. This relationship can be either readily apparent or subtle. More severe abnormalities (such as Staghorn calculus, described below) are usually more apparent; with those that are more subtle, special tests can be performed to localize the infection to the abnormality. For example, ureteral catheters can be placed in the kidney to collect urine and establish the relationship between a stone in the kidney and bacterial persistence. Similarly, a prostate localization culture can determine if a patient has chronic bacterial prostatitis.

A classic example of bacterial persistence is an infection stone, typically formed by Proteus mirabilis. Persistent infection with Proteus leads to a high urinary pH, precipitation of crystals, and formation of an infection stone that incorporates bacteria within. Once the process is initiated, it can become exceedingly difficult to eradicate the bacteria from the stone, thus resulting in its continuing growth, possibly filling the kidney collecting system with stone material (previously mentioned Staghorn calculus). Surgical removal of the stone can stop relapsing infections.

Reinfections in Women 

Reinfection is defined as two or more symptomatic UTIs in six months or three or more episodes within 12 months. Prior history of infection, medical comorbidities, use of antimicrobials, sexual history and use of spermicides should be reviewed. In most women, examination to rule out urethral diverticulum (an outpouching) and assessment of post-void residual urine will suffice. Some women with a narrow urethral opening (meatus) may benefit from a dilation to improve bladder emptying. However, there is no evidence that repeated dilation of the urethra is indicated and/or beneficial in women with recurring infections.

Since diaphragm-spermicide use has been associated with increased risk of UTIs, spermicides should be discontinued and other forms of contraception used.

Women with estrogen depletion who topically apply estradiol cream can effectively reduce reinfections [1].

Reinfections in men are uncommon, except as noted in younger individuals. Even in these instances, underlying abnormalities such as urethral stricture can be apparent; thus, particularly if the patient does not respond promptly to therapy or experiences recurrent infections, a minimal urologic evaluation such as urethroscopy (a tube with a camera) should be considered. For more information on reinfection in men, see Knol “Prostatitis.”

Abnormal Communication with the Urinary Tract (Fistula) 

The possibility of a communication between the bladder and the bowel or vagina is a rare condition, but one that should be considered when the patient has a history of air in the urine (pneumaturia), stool in the urine (fecaluria), diverticulitis, previous pelvic surgery, or radiation therapy. With these conditions, urologic referral, imaging and cystoscopy (a test that looks at the inner lining of the bladder and urethra) are required.

Antimicrobial Therapy

In women with reinfections three approaches are recommended: 

1. Low-dose continuous prophylaxis
2. Post-intercourse prophylaxis 
3. Self-start intermittent therapy

Low-Dose Continuous Prophylaxis

The success of prophylaxis depends on the ability of the antimicrobial agent to achieve concentrations in the urine or vaginal mucosa high enough to prevent bacterial growth but low enough to prevent bacterial resistance in the bowel flora (the mixture of organisms found at any site in the body). Continuous, low-dose prophylaxis should be initiated when eradication of an active infection is confirmed by urine culture several weeks after antimicrobial therapy is discontinued. These low-dose antimicrobials are usually taken orally once daily at bedtime.

The antimicrobial agents of choice are listed below:
 

Trimethoprim-sulfamethoxazole or trimethoprim

• Secreted into the vaginal fluid and eradicates gram-negative bacteria from the vaginal flora with minimal effect on the bowel flora

 Nitrofurantoin

• Does not enter the bowel flora and is present for a short time in high concentrations in the urine
• Pulmonary reactions are rare adverse occurrences, but if a patient on long-term therapy develops a chronic cough, the drug should be discontinued and a chest radiograph obtained

 Fluoroquinolones

• Enter the urine and vaginal fluid
• They are expensive and can only be used in non-pregnant women 
• Their role in prophylaxis should be limited to situations when antimicrobial resistance or patient intolerance to the aforementioned drugs occurs 
• Achilles tendonitis and rupture has been associated with these drugs

 Cephalexin

• In low doses, achieves a bacteria-killing urinary level, but bowel flora resistance does not develop
• Although no drugs are approved for use during pregnancy, it appears to be a safe choice for prophylaxis during this time

Other adverse events associated with these drugs are listed in the article “Urinary Tract Infections in Women - Uncomplicated.”

These prophylactic regimens are generally continued for six to 12 months, but in many instances have been used successfully for many years. Randomized, placebo-controlled trials have shown 95% reduction in recurrent reinfections with all of these agents [2]. Adverse affects, most commonly gastrointestinal symptoms, rash, and yeast vaginitis, occur in 0-40% of patients and vary with the agents [3].

If a patient has symptomatic episodes during prophylaxis, a culture should be obtained and a full therapeutic dose administered using the prophylactic agent or another antimicrobial agent used to treat the infection. If a patient experiences symptomatic reinfections immediately after completion of prophylactic therapy, reinstitution of nightly prophylaxis is effective and results in no increased adverse effects.

Post-Intercourse Prophylaxis

Post-intercourse prophylaxis with a single-dose of those antimicrobial agents used for low-dose prophylaxis (trimethoprim-sulfamethoxazole or trimethoprim, nitrofurantoin, cephalexin or the fluoroquinolones) will effectively reduce the incidence of reinfections.

Self-Start Intermittent Therapy

A patient is given a dip slide culture device and a prescription for three days of antimicrobial therapy. When she has symptoms of UTI, a culture is performed and therapy initiated. Fluoroquinolones are ideal for self-start therapy because they have a broader spectrum of activity for prophylaxis compared to any of the other oral agents; nitrofurantoin and trimethoprim or trimethoprim-sulfamethoxazole are acceptable alternatives.

The culture is brought to the office. If the culture is positive and the patient is asymptomatic, urinalysis is performed to confirm resolution of the infection. The patient is then resupplied with the culture device and another prescription.

If the patient’s symptoms do not respond to initial antimicrobial therapy, susceptibility testing of the initial culture is performed and therapy adjusted accordingly.

If symptomatic events are not associated with positive cultures, urologic evaluation should be performed to rule out other causes of bladder irritation such as interstitial cystitis, neurogenic bladder dysfunction, or even carcinoma in situ (cancer).

Patient-initiated therapy without culture is another alternative, but if symptomatic events occur frequently and do not respond to empiric therapy cultures should be obtained.

Other Strategies for Treating Reinfection

Cranberry juice contains proanthocyanicidins that block adherence of pathogens to uroepithelial cells in vitro. Some randomized trials in low-risk patients have shown efficacy of cranberry juice or cranberry concentrate tablets, but others have shown no benefit. The actual cranberry content of tablets varies substantially, which may account for their unpredictable efficacy. There is no clinically proven evidence that cranberry products are effective for the treatment of UTIs.

Other factors such as wiping patterns, use of hot tubs, hygiene and types of undergarments have not been shown to predispose women to recurrent UTIs and, thus, there are no guidelines or specific instructions regarding these factors.

Acute Pyelonephritis 

Acute pyelonephritis is an upper tract (kidney) infection which can progress from lower tract (cystitis) whether it is an isolated or recurrent infection. The clinical spectrum for this condition ranges from cystitis with mild flank pain to severe gram-negative sepsis and death. In healthy young women, episodes can be associated with a normal urinary tract (acute uncomplicated pyelonephritis), but in all other cases, acute pyelonephritis should be judged as complicated until proven otherwise.

Presentation

The classic presentation of acute pyelonephritis is an abrupt onset of fever of 100º F or greater, chills, and flank pain or tenderness. These upper tract signs are usually accompanied by lower tract symptoms of dysuria (pain while urinating), and increased urinary frequency and urgency. Patients may also experience gastrointestinal tract symptoms such as pain, nausea, vomiting, and diarrhea. A physical examination often reveals tenderness to deep palpation in the flank.

Diagnosis

A presumptive diagnosis is made by urinalysis which reveals numerous white blood cells and bacteria. Urine culture should be obtained in all patients. Blood cultures are positive in about 25% of cases of uncomplicated pyelonephritis in women but they generally replicate the bacteria found in urine culture, therefore do not need to be obtained for women with uncomplicated pyelonephritis. However, they should be done in men and women with severe toxicity or risk factors (such as pregnancy) that require hospitalization. E. coli cause about 80% of cases and research has shown that these bacteria have special structures (P fimbriae) that allow the bacteria to adhere to the upper urinary tract.

Imaging

Acute pyelonephritis is assumed to be uncomplicated in young, healthy women with no risk factors. However, if there is any reason to suspect a problem, or if the patient will not have reasonable access to imaging should there be a change in her status, we prefer renal sounds for computed tomography (CT) to rule out obstruction or stones. In women with known or suspected complicated pyelonephritis, and in all men, CT provides excellent assessment of the status of the urinary tract, and the severity and extent of the infection.

Management

Initially, patients with pyelonephritis can be subdivided into three groups:

1. Uncomplicated infection that does not warrant hospitalization
2. Uncomplicated infection in patients with normal urinary tract who are ill enough to warrant hospitalization for parenteral (injection or IV) therapy
3. Complicated infections

Antimicrobials

Broad spectrum antimicrobial therapy should be instituted until the results of culture and susceptibility testing (to understand antimicrobial resistance) is available. For patients managed as outpatients because their illness is less severe and they are able to tolerate fluid intake, initial single-dose parenteral therapy or initial oral therapy can be followed by oral therapy in the outpatient setting. Patients with uncomplicated pyelonephritis but more severe symptoms, nausea and vomiting, and those with complicated pyelonephritis require initial parenteral therapy. Symptoms will usually improve over the next several days; when they do, the patient can be switched to oral therapy based on susceptibility testing.

Parenteral and/or oral fluoroquinolones are particularly excellent choices for group one patients. If a patient fails to improve during the initial outpatient treatment of uncomplicated pyelonephritis, has an uncomplicated infection but is sufficiently ill to require hospitalization, or has complicated pyelonephritis, the patient should be admitted and treated with intravenous antimicrobial agents. A parenteral fluoroquinolone aminoglycoside with or without ampicillin – or extended spectrum cephalosporin with or without an aminoglycoside – is recommended [4] (Table 2). 

Any substantial obstruction must be relieved expediently by the safest and simplest means. Most commonly, this is done by passing a tube into the kidney (percutaneous nephrostomy) or advancing a ureteral catheter from the bladder to the kidney.

 

Initial Therapy

Patients with uncomplicated pyelonephritis should be treated with parenteral or oral therapy for 10-14 days. Patients with complicated pyelonephritis should be treated for seven days with parenteral therapy and then switched to parenteral oral therapy for a total of 14-21 days [4] (Figure 1). 

 Responses to Therapy

Most patients will see their fever abate and respond to therapy within 48-72 hours. If their symptoms persist or progress while on therapy, radiologic evaluation is necessary to determine if the infection has become more extensive, such as development of a renal (kidney) or perirenal abscess. 

Follow-Up

Repeat urine culture should be performed on and 10-14 days after therapy to determine that there is a microbiologic cure. About 25% of individuals with acute pyelonephritis will relapse after therapy. These individuals are usually cured by another 14-day course of therapy but occasionally longer therapy is indicated [5].

To find resolution to the acute event, patients with underlying abnormalities should be evaluated for possible correction.

Other Complicated UTI 

Because of the various presentations, bacteria, underlying abnormalities, and a lack of controlled studies, there are no specific guidelines for antimicrobial therapy. Empiric therapy for patients with mild to moderate illness can utilize oral fluoroquinolones. Sicker patients will require parenteral broad spectrum antimicrobial therapy. Drug combinations of ampicillin plus gentamicin, cephalosporin, and aztreonam should be considered. Efforts to remediate or reduce the underlying abnormalities within the UTI and improve the status of the host are essential for good outcomes. Generally, 10-14 days of therapy is necessary but longer therapy may be indicated in select patients, such as those with pseudomonas and other difficult-to-treat organisms.

Key Points 

• UTIs are mediated by bacterial virulence and host defense mechanisms. These factors predispose a patient to a UTI and influence the infection’s severity; modification of these factors can reduce a patient’s susceptibility to a UTI, as well as its severity 
• Recurrent infections are usually uncomplicated reinfections and can be effectively managed by continuous prophylaxis, post-coital prophylaxis or self-start therapy at home. A minimal urologic evaluation is reasonable. Imaging studies are not required in most healthy women with recurrent UTIs 
• Rapid reinfection with the same strain in women and all men with recurrent infection warrant radiologic imaging studies; CT provides the best anatomic data on the potential site, cause and extent of bacterial persistence 
• Patients with bacterial persistence can usually be cured of recurrent infections by identification and surgical removal or correction of the focus of infection 
• Uncomplicated pyelonephritis in women with mild illness who tolerate oral therapy can be treated as an outpatient for 14 days. Sicker patients who are initially hospitalized should receive parenteral therapy then switch to oral therapy for a total of 14-21 days 
• Complicated UTIs require careful assessment of the urinary tract and correction of abnormalities. Risk factors must be addressed. In general, empiric broad spectrum antimicrobial regimens should be initiated and then tailored based on susceptibility and continued for at least 14 days

More Information 

Web Resources

• American Family Physician ( http://www.aafp.org/afp/990301ap/1225.html)
• Medline Plus Online Medical Encyclopedia (http://www.nlm.nih.gov/medlineplus/ency/article/000522.htm)

Books  

• Icon Heath Publications, The Official Patient's Sourcebook on Urinary Tract Infection: A Revised and Updated Directory for the Internet Age.
• Calvin M. Kunin, Urinary Tract Infections: Detection, Prevention, and Management.

References

1. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329(11):753-6.
2. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents 2001;17(4):259-68.
3. Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003;349(3):259-66.
4. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999;29(4):745-58.
5. Stamm WE. Recent developments in the diagnosis and treatment of urinary tract infections. West J Med 1982;137(3):213-20.