Management of Urinary Tract Infections in Women

US Pharm. 2007;32(9):26-33.

According to a 2007 report released by the National Institutes of Health, urinary tract infections (UTIs) cost Americans approximately $3.5 billion a year, making UTI one of the five most expensive urologic health problems in the United States.^1,2 About half of all women will experience at least one UTI during their lifetime, with 25% of women experiencing a recurrent infection usually within six months of the initial infection.^1,3 This leads to more than 8.3 million physician office visits per year.^2,4 More than 100,000 hospital admissions are due to UTI primarily for acute pyelonephritis, an infection of the kidneys. ⁵ UTIs occur most frequently in women ages 18 to 24, with a rate of 17.5%.⁶

The majority of UTI cases are classified as uncomplicated and are easily treated with a short course of antibiotics.⁷ However, not all cases present with symptoms. For example, pregnant women may have asymptomatic bacteriuria, which can develop into a UTI. If a UTI is not treated promptly, the infection may cause permanent damage to the bladder and kidneys.⁸ Therefore, it is important to recognize the signs and symptoms of a UTI to ensure its proper treatment management.

By definition, a UTI is a bacterial infection of the urinary tract. The urinary tract consists of the urethra, bladder, ureters, and kidneys, which are considered sterile areas. Bacteria  can enter any of these anatomical locations and produce an active infection. UTIs will generally affect either the lower or the upper urinary tract.⁹ The most common cases of UTI are due to infection of the lower urinary tract involving the bladder, and are known as cystitis . In contrast, acute pyelonephritis is an infection of the upper urinary tract. Acute cystitis and acute pyelonephritis are generally considered uncomplicated when these infections occur in healthy, nonpregnant adult women of childbearing age.¹⁰ A UTI in any other female patient population, including postmenopausal women and pregnant women, is considered complicated.¹⁰

Many women will experience a recurrent UTI, which is classified as a relapse or a reinfection , depending on when it occurs in relation to the initial infection. If the recurrent infection occurs within two weeks of completion of treatment, it is considered a relapse caused by the original pathogen. If the recurrent infection occurs after this time, then it can be due to the same pathogen or a different pathogen; this is known as a reinfection.¹¹

Pathogenesis and Risk Factors
Women commonly experience UTIs for several reasons. A primary reason is the anatomy of the female genitourinary system. Women have a short urethra in comparison to men, which makes it easier for bacteria to travel up to the bladder. In addition, a womanurethra is in close proximity to the rectum, allowing for fecal flora to travel to the urethra much more easily. Sexual intercourse can also aid in the migration of uropathogens to the urethra and bladder, resulting in an infection. For young women, sexual activity is the highest risk factor for UTIs and increases the risk by severalfold.⁶ In addition, the use of diaphragms and spermicides has been associated with an increased risk of UTI.⁷ Spermicides have an antibacterial effect that may reduce lactobacilli, a normal component of the periurethral flora.¹¹ Lactobacilli work by producing hydrogen peroxide and lactic acid, which provides a pH that is toxic to uropathogens, inhibits bacterial growth, and blocks sites of attachment.¹¹

Some women are more susceptible to UTIs, such as postmenopausal women due to estrogen deficiency, which reduces lactobacilli colonization in the vaginal area.¹¹ Individuals with a history of UTIs, diabetes, sickle cell disease or sickle cell trait, or kidney stones have an increased risk. In addition, those who are immunocompromised or have any illness that can paralyze the bladder or decrease the ability to fully empty the bladder are at higher risk of UTI. ^8,12 Women of low socioeconomic status are also at greater risk for having a UTI.¹³

The most common pathogen in UTIs is Escherichia coli--both in upper and lower tract infections--accounting for approximately 85% of all cases.¹⁰ Staphylococcus saprophyticus is also a common pathogen, accounting for about 10% of infections in young women.¹⁴ Other pathogens include the Proteus species, Klebsiella species, Enterobacter species, Pseudomonas species, and group B beta-hemolytic streptococcus. Enterococci are less common gram-positive pathogens and are often found in complicated UTI.^10,14,15

Clinical Presentation and Diagnosis
Recognizing the signs and symptoms is the initial approach in diagnosing a UTI. Typical symptoms of a UTI include an urgent and frequent need to urinate, pain or burning upon urination, blood in the urine, and suprapubic pain.⁷ Vaginitis (yeast infection) and urethritis (inflammation of the urethra) can also present with burning upon urination. In these instances, a physical examination may be necessary if the diagnosis is questionable.⁷ If flank pain (pain in one side of lower back), fever, chills, nausea, and vomiting are also present, then the patient may have pyelonephritis.

In order to confirm the diagnosis of UTI, a urine sample needs to be obtained from the patient by the "clean catch" method. This involves cleaning the external genitalia and voiding for a few seconds before the sample is collected. This technique is used to avoid bacterial contamination from the skin. The sample can then be used for microscopic urinalysis, dipstick assay, or urine culture.¹¹ Urine dipstick is most often used in the office setting because it is convenient, easy to use, and provides quick results.¹¹ When a urine dipstick reveals positive leukocyte esterase, this is indicative of pyuria , which is the most significant laboratory diagnostic sign of a positive UTI result. Urine samples can also be evaluated for the presence of nitrites, proteins, and blood--all of which can contribute to a diagnosis of UTI. A nitrite-positive dipstick can reveal Enterobacteriaceae in the sample. ¹⁰ However, not all cases of UTIs are nitrite positive, because only certain bacteria can reduce nitrate to nitrite.¹⁰ In addition, a nitrite dipstick may reveal a false-negative result if the sample has a low count of bacteria due to inadequate sensitivity of the dipstick test.¹⁰ White blood cells in the urine may indicate an upper UTI. Urine cultures are usually not obtained in cases of acute uncomplicated cystitis because the causative organisms and their microbial susceptibility profiles are often predictable.¹⁰ However, in patients who may have a complicated or recurrent UTI, or when diagnosis is questionable, urine cultures are taken to prove that an infection is present and to determine which antibiotics to use.

Treatment of Acute Uncomplicated Cystitis
According to the practice guidelines developed by the Infectious Diseases Society of America (IDSA), a three-day course of double-strength trimethoprim-sulfamethoxazole (TMP-SMX) can be recommended as first-line therapy in cases of uncomplicated cystitis in nonpregnant women.⁵ Due to the widespread use of TMP-SMX for UTIs and upper respiratory tract infections and as prophylaxis against Pneumocystis carinii pneumonia in patients with HIV, there has been an increase in the number of pathogens that are resistant to TMP-SMX. ¹⁶ Therefore, this medication may not be the best therapy for all cases of UTI. For example, a patient with a history of recent hospitalization or one who used TMP-SMX in the previous three months may have resistance to TMP-SMX. ¹⁰ Therefore, TMP-SMX is only recommended in areas where resistance to E coli strains is less than 20%.

Fluoroquinolones are considered highly effective in cystitis, but due to their cost and clinical effectiveness in the treatment of complicated UTIs and prostatitis, use should be reserved to prevent emerging resistance. Fluoroquinolones like ciprofloxacin and/or levofloxacin can be used instead of TMP-SMX when resistance or a sulfonamide allergy is present. Additional alternatives would include a seven-day course of nitrofurantoin or single-dose fosfomycin. However, fosfomycin is not recommended in UTIs caused by S saprophyticus . According to the IDSA guidelines, studies have shown that older women, in comparison to women of childbearing age, and individuals with infections caused by S saprophyticus tend to have lower eradication rates with a three-day course of antibiotics, particularly fluoroquinolones.⁵ Therefore, it is recommended that older women and those who have S saprophyticus–causinginfections receive treatment with a seven-day course of antibiotics.⁵

Clinical symptoms of acute uncomplicated cystitis will usually resolve in one to three days after initiation of therapy; however, the full prescribed course of antibiotics should be taken to completely resolve the infection.⁷ Additionally, providers may prescribe phenazopyridine, a urinary analgesic, to their patients to help alleviate the pain that is often associated with UTIs. In conjunction with antibiotics, this medication is usually needed for only one to two days. It is important to counsel patients that phenazopyridine may cause a dark orange discoloration to urine and tears. Therefore, contact lenses should not be used during phenazopyridine therapy. This drug can also cause gastrointestinal discomfort, rash, headaches, and hemolytic reactions in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹⁷ This medication requires dosage adjustment in patients with renal impairment and should be avoided in individuals whose creatinine clearance is less than 50 mL/minute. Since phenazopyridine is also available OTC, there is a concern that some women may use it to treat the pain associated with a UTI without seeking further medical care. Therefore, pharmacists should also counsel patients to seek appropriate treatment when necessary.¹⁸ Table 1 lists the common drug therapies used to treat cases of acute uncomplicated cystitis.

Treatment of Acute Pyelonephritis
The IDSA recommends an oral 14-day course of a fluoroquinolone in cases of acute pyelonephritis involving young, nonpregnant women. Treatment courses as short as five to seven days can be used in mild-to-moderate cases of acute pyelonephritis.⁵ Cultures and sensitivities should be obtained because of potential complications of pyelonephritis. Once bacteria have been identified based on culture and sensitivity and the uropathogen is not resistant to TMP-SMX, TMP-SMX can be used as an alternative to a fluoroquinolone. In addition, amoxicillin or amoxicillin-clavulanic acid can be used to treat pyelonephritis, especially in pregnant women. For serious cases of pyelonephritis, hospitalization is recommended with an IV course of a fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside.⁵ As the patient improves (as measured by resolution of fever), IV therapy can be changed to postoperative. An oral regimen that is active against the offending organism is recommended and usually includes TMP-SMX, fluoroquinolones, or amoxicillin or amoxicillin-clavulanic acid (in cases of gram-positive infections).⁵ To fully assess which antibiotics are best to use based on pathogens isolated, local antimicrobial susceptibilities should be performed periodically and evaluated.⁵

UTIs During Pregnancy
Many women may experience a UTI during their pregnancy due to alterations in hormones and pressure changes that arise in the bladder from the enlarging ureters and urethra.¹¹ Dilation of the lower urinary tract is due to smooth muscle contraction caused by progesterone and mechanical obstruction caused by the uterus. This can lead to urinary stasis, decreased peristalsis, and increased bladder capacity, potentially contributing to UTI development.¹² In 20% to 40% of cases, UTIs during pregnancy are a progression of asymptomatic bacteriuria (ASB), which occurs in 2% to 7% of pregnant women. ^9,11 Normally, ASB does not require treatment; however, in pregnant women, there is a 15% chance that it will progress to acute cystitis and a 45% possibility that it will progress to pyelonephritis.¹¹ UTIs are the most common bacterial infection to occur in pregnant women.¹⁹ In comparison to a UTI in a nonpregnant woman, a UTI in a pregnant woman is more likely to be complicated and cause pyelonephritis. This can lead to complications during pregnancy in both the mother and the fetus. Pregnant women may experience premature delivery, infants with low birth weight, intrauterine growth retardation, preeclampsia, anemia, thrombocytopenia, and transient renal insufficiency.^19,20

Due to the risks that have been associated with UTIs in pregnant women, it is recommended that treatment be more aggressive than in nonpregnant women and should begin as soon as possible. According to the American College of Obstetricians and Gynecologists, screening of ASB is recommended in all pregnant women.¹² Urine cultures are recommended early in pregnancy in order to detect ASB. If discovered, antibiotic treatment is given for three to seven days. Early detection and treatment of ASB can prevent the development of a UTI by 80% to 90%.⁵ A repeat culture is obtained two weeks after treatment is completed to ensure the infection has been eradicated.⁷ Cultures are then obtained monthly until delivery to ensure that another infection has not developed.⁹

The safest antibiotics to use during pregnancy for the treatment of ASB are nitrofurantoin, amoxicillin, amoxicillin with clavulanate, and cephalosporins.¹¹ The development of resistance to amoxicillin is common among uropathogens and should be monitored. In the U.S., up to 33% of the uropathogens that cause UTIs are resistant to amoxicillin.²¹ Therefore, amoxicillin should be used only if susceptibility results are known. Tetracyclines and fluoroquinolones are contraindicated during pregnancy and should be avoided throughout all the developmental trimesters.⁹ TMP-SMX can only be used safely during the second trimester. Use of TMP-SMX is discouraged during the first trimester due to possible teratogenic effects to the fetus, since trimethoprim is a folic acid antagonist.⁹ During the third trimester, use of TMP-SMX could displace bilirubin from its binding sites, resulting in kernicturus (bilirubin encephalopathy).⁹

When two or more courses of antibiotic therapy fail to suppress ASB, then suppressive therapy can be used for the remainder of the pregnancy. Nitrofurantoin 50 to 100 mg once at bedtime is a common option for suppressive therapy; cephalexin 250 to 500 mg once at bedtime is a recommended alternative.⁹ These prophylactic therapies can also be used in women who have recurrent UTIs during pregnancy. ⁹ Of note, nitrofurantoin is contraindicated at term (third trimester) due to a risk of hemolytic disease in infants who have a G6PD deficiency. This risk is low, however, and many physicians will still use it after weighing the risks versus the benefits of its use.⁹ In addition, nitrofurantoin is not recommended for the treatment of pyelonephritis due to its inadequate tissue penetration.

If a pregnant woman presents with acute cystitis, then the infection is generally considered complicated. ⁹ Treatment for acute cystitis in pregnant women is listed in Table 2 . Beta-lactams are appropriate and usually work more efficiently when used for more than three days.⁹

Pyelonephritis during pregnancy requires hospitalization and treatment with IV antibiotics. Initial preferred agents include ampicillin plus gentamycin or cephalosporins. If there is no response within 72 hours, drug resistance is likely, and cultures should be obtained and the therapy changed appropriately.¹² If symptoms do not resolve despite culture-specific therapy, an ultrasound is advised to rule out other possible diagnoses, such as renal abscess, nephrolithiasis, or structural abnormality. The two most common causes of initial treatment failure are drug resistance and nephrolithiasis.¹³ Parenteral therapy can be switched to a two-week course of oral therapy once the patient is afebrile. Suppressive therapy should then be used for the remainder of the pregnancy.¹²

Prevention of UTIs
A UTI can be an uncomfortable infection to experience based on its clinical signs and symptoms. Although not well studied, several preventive measures have been suggested by health care providers (Table 3).²² Many of these methods have not been proven to be clinically effective. However, if an individual is susceptible to UTIs, these methods may be worth trying, since they do not pose harm to patients.

Recurrent Infections
Women who experience recurrent infections are advised to use preventive treatments ( Table 3). As noted previously, many women with a UTI will develop a recurrent infection within six months of the initial infection.¹¹ If an individual experiences two or more symptomatic UTIs within six months or three or more UTIs within one year, then antimicrobial prophylaxis may be indicated.¹¹

Three types of prophylactic regimens are available--continuous use, postcoital therapy, and self-treatment. Continuous use usually consists of six months or more of daily therapy. Studies have shown that there is a 95% reduction in recurrent infections when continuous prophylaxis with TMP-SMX, trimethoprim alone, nitrofurantoin, ciprofloxacin, or norfloxacin is used.¹⁷ Postcoital therapy is indicated for individuals who notice that their UTI may be associated with sexual intercourse. In these cases, antibiotics can be used as prophylaxis with each act of sexual intercourse; spermicides, diaphragms, or feminine hygiene products should also be avoided.¹¹ In most cases, TMP-SMX, nitrofurantoin, or a fluoroquinolone is used for prophylaxis. As noted previously, TMP-SMX should be used with caution because of resistant uropathogens that have already been identified. In addition, many health care providers choose not to use fluoroquinolones owing to the fear of emerging resistance and the need to save this medication for more complicated cases. Therefore, nitrofurantoin may be the most advantageous option for prophylaxis due to the low rate of resistance (<5%) to the more common uropathogens. ¹⁷ Nitrofurantoin is less active than the fluoroquinolones and TMP-SMX against aerobic gram-negative rods, with the exception of E coli.¹⁷ It is also inactive against Proteus and Pseudomonas species and therefore should not be used against these uropathogens.¹⁷ Self-treatment has also been studied and was proven effective in some women who can accurately diagnose their recurrent infection based on signs and symptoms. In these instances, women can be instructed to start a three-day course of an antibiotic at symptom onset and report to a physician if symptoms do not resolve within 48 to 72 hours of treatment completion.¹⁷

Conclusion
Most UTI cases are uncomplicated and can be easily treated if detected early. Due to the emerging resistance to antibiotics such as TMP-SMX and amoxicillin, choosing an appropriate antibiotic is key to early treatment and prevention of further complications from UTIs. Pregnant women should be routinely screened for ASB in order to prevent UTI-related complications during pregnancy. For women who experience recurrent infections, preventive and suppressive therapy may be beneficial in deterring future infections.

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