Challenges of Treating Urinary Tract Infections in Post-Menopausal Women.
Many new recommendations for the antimicrobial treatment of urinary tract infections were published in 2016 with the underlying purpose to reduce growing antimicrobial resistance. In May 2016, the United States Food and Drug Administration (FDA) (2016b) advised that the serious side effects associated with fluoroquinolones generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options. The FDA found that fluoroquinolones are associated with disabling and potentially permanent serious side effects that can involve the tendons, muscles, joints, nerves, and central nervous system (CNS). Then on July 26, 2016, the FDA went one step further and approved changes to the label to address these serious safety issues (FDA, 2016a).
The World Health Organization (WHO), the United Nations (UN), and other organizations have also acknowledged the growing antibiotic crisis, and in September 2016, jointly approved a wideranging declaration to address the rising number of drug-resistant infections that have the potential to kill millions, likening it to a "slow tsunami" (Kaiser Family Foundation, 2016). These recommendations challenge all healthcare providers to re-evaluate antibiotic prescribing practices.
Historical Overview of Urinary Tract Infection Treatment Practices
How have we arrived at this point in history that the FDA, WHO, and UN are concerned enough about antibiotic treatment and resistance to issue a warning and a declaration? Nicolle (2016), in her conference report, "The Paradigm Shift to Non-Treatment of Asymptomatic Bacteriuria," gives a historical background of our changing perspectives on asymptomatic bacteriuria (ABU) over the years.
In a retrospective review of autopsies between 1933 and 1957, Freedman (1967) found that persons dying of renal failure were noted on autopsy to have chronic pyelonephritis. Further review of these patient's histories found that less than 30% had a history of ever having a urinary tract infection in their lifetime. This led to the concern that asymptomatic urinary tract infections cause renal failure, and ultimately, death. In the mid-1950s, the first quantitative urine cultures were developed to differentiate true bacteriuria from contaminated voided specimens by comparing voided specimens to catheterized specimens. Using this new technology, Kass (1962) differentiated between true bacteriuria with a catheter versus contaminated specimens. From their research, they found that 30% to 40% of women with repeated high qualitative counts also had pyuria (>5 white blood cells/high power field). It was found that pyuria was not present in specimens from women with lower quantitative counts.
Later in the 1960s, studies demonstrated that pregnant women with ABU were at increased risk to develop pyelonephritis, premature labor, intrauterine growth retardation, and increased neonatal death (Whalley, 1967). In response to this, healthcare providers began treating pregnant women with positive urine cultures and found that treatment of ABU in pregnancy prevented pyelonephritis in women and improved neonatal outcomes. Thus, a new paradigm began with evidence that bacteriuria is common and dangerous. Bacteria could actually play a role in disease and should be treated aggressively. However, long-term studies over the following years showed that treatment of ABU did not change outcomes except in pregnant women.
In 2005, the Infectious Diseases Society of America developed guidelines for the diagnosis and treatment of ABU in adults. Pregnant women and patients undergoing traumatic urologic interventions should be screened and treated for ABU. ABU has not been shown to be harmful in all other adult populations, and in fact, may cause harm if treated. These populations include premenopausal, non-pregnant women; women with diabetes mellitus; older adults; institutionalized persons; those with spinal cord injury; and catheterized patients while the catheter remains in situ (Nicolle et al., 2005).
Despite these recommendations, overuse of antibiotics to treat ABU is a common practice and has been recognized to be a major health issues (increased antimicrobial resistance, disabling side effects, and Clostridium difficile infections) and economic issues (higher healthcare costs and reduced reimbursement for nosocomial symptomatic urinary tract infections in hospitalized patients) (Cai et al., 2015; Hansson, Jodal, Lincoln, & Svanborg-Eden, 1989; Harding, Zhanel, Nicolle, & Cheang, 2002; Piacenti & Leuthner, 2013; Srigley et al., 2013).
Asymptomatic Urinary Tract Infections
ABUs were once thought to be dangerous but are no longer considered dangerous. Research suggests that ABU may prevent a symptomatic urinary tract infection, and treatment of ABU can lead to a future symptomatic urinary tract infection. It is easy to misinterpret symptoms of atrophic vaginitis as a urinary tract infection. It is also psychologically difficult not to treat with antibiotics when a rapid screening test is positive for urinary tract infection for fear a complication might develop. A good history is of utmost importance in diagnosing a urinary tract infection.
ABU, also called asymptomatic urinary tract infection, is a common finding in healthy women. ABU occurs in greater than 8% of postmenopausal women (age 50 to 70 years), 27% of women with diabetes mellitus, 16% of older adult women in the community, and 50% of older adult women in long-term care (Nicolle et al., 2005; Nicolle, Zhanel, & Harding, 2006). Bacteria sampled from the genitourinary tract can either be pathogens causing symptoms or mere colonizers when no symptoms are present.
Post-menopausal women are at a higher risk than men of the same age for symptomatic and ABU. Post-menopausal women experience a reduction of estrogen, which can increase the pH of the vagina and urethral tissues, leading to an environment unfriendly for lactobacillus, normal colonizing bacteria, and friendly for bacterial colonization with uro-pathogens (Perrotta, Aznar, Mejia, Albert, & Ng, 2008).
Loss of estrogen also gives rise to symptoms of vaginal dryness, itching, dyspareunia, urinary urgency, and urinary incontinence, which can imitate the symptoms of a urinary tract infection, leading to concern that a urinary tract infection is the cause of the symptoms. On office evaluation, the rapid urinalysis is positive for leukocyte esterase without a positive result on nitrite or blood. A positive leukocyte esterase suggests infection or inflammation. A urinalysis is a screening test for the absence of a urine infection; thus, an assumption is made that the leukocytes in the urine sample are from the bladder. The woman is then either treated for presumed infection, or is treated and the urine specimen sent for culture and sensitivity to guide treatment or rule in or rule out a urinary tract infection. In the above scenario, atrophic vaginitis is an inflammatory condition of the vagina that can cause elevation of leucocytes leading to positive leukocyte esterase on rapid screening urinalysis secondary to contamination. With symptoms present and a positive leukocyte esterase result, the concern for a urinary tract infection as the cause of the woman's symptoms is likely. Unless a urine culture is obtained to rule out infection as the cause of her symptoms, this patient has a high chance of being treated for a urinary tract infection.
An uncontaminated specimen is most important in the reliability of the rapid screening tests but almost impossible to collect. Several studies have documented that even with education of nurses explaining a "clean catch midstream" technique to women and instruction on "clean catch midstream" with a tampon in place, specimens were still contaminated (Lifshitz & Kramer, 2000). If the urine culture is found to be positive in the above situation, the patient may have ABU with atrophic vaginitis.
Knottnerus, Geerlings, Moll van Charante, and ter Riet (2013) researched a step-by-step procedure to evaluate for the presence of a urinary tract infection. A history is of utmost importance. These authors recommend asking three key questions when taking a history. Does the woman think she has a urinary tract infection? If yes, does she have pain with micturition? If yes, is there vaginal irritation? If the answer to this is no, then the symptoms are not vaginal. The strongest indicator that a bladder infection is present with the above scenario is a positive history of urinary tract infection symptoms and a positive nitrate and/or blood present on the rapid urinalysis screen. If the urine culture is negative in this instance, a hematuria evaluation should be completed.
Increased awareness of antibiotic resistance as the result of inappropriate treatment of positive rapid urine tests prompts prescribers to consider other differential diagnoses, such as atrophic vaginitis combined with ABU. A rapid urinalysis is best to screen out a urinary infection as the cause of the symptoms when the test result shows negative leukocyte esterase and nitrites. However, rapid urinalysis is often used to screen in a urinary tract infection when the patient has confusing symptoms. Multiple studies have shown that at least 30% and up to 60% of patients with ABU are unnecessarily treated with antibiotics, which can lead to resistance and symptomatic urinary tract infections (Hartley et al., 2016).
There are no known complications to not treating ABU, even in women with diabetes mellitus (Harding et al., 2002; Nicolle et al., 2006). Research suggests that women with positive urine cultures without urinary tract symptoms can have spontaneous clearing of the infection in follow up without antibiotic treatment (Knottnerus et al., 2013). Placebo arms of randomized trials have shown that 25% to 80% of women with a symptomatic urinary tract infection have resolution of their symptoms within one week. Hence, the body has the capability of resolving ABU and even symptomatic urinary tract infections without intervention (Ferry, Holm, Stenlund, Lundholm, & Monsen, 2004, 2007; Richards, Toop, Chambers, & Fletcher, 2005). Women may be receptive to delaying treatment to avoid antibiotic exposure (Knottnerus et al., 2013; Leydon, Turner, Smith, & Little, 2010).
According to Cai (2012), some evidence suggests that treatment of ABU may lead to the development of a symptomatic urinary tract infection, and over time, can lead to antibiotic resistance. Darouiche and Hull (2012) considered emerging evidence that ABU may actually play a protective role in the prevention of a symptomatic urinary tract infection. A paradigm shift is slowly developing that ABU is no longer harmful and may be beneficial for some women.
Psychology of Prescribing Antibiotics
To understand the motivators for prescribing unnecessary antibiotics for ABU, Eyer, Lang, Aujesky, and Marschall (2016) undertook a qualitative study in a tertiary care hospital in Switzerland. These authors sought to understand the psychological mechanisms underlying antibiotic misuse and define barriers for implementation of the 2005 Infections Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults (Nicolle et al., 2005). Twenty-one physicians were interviewed in a case-based, semistructured interview with open-ended questions. The study revealed that the most common reason for treating an ABU was the decision to collect a urine specimen for a culture when urinary tract infection symptoms were not present. The treatment error occurred several days later when the culture report became available, and the patient was treated without taking the full clinical picture into account.
According to Eyer et al. (2016), the most common psychological factor leading to the treatment of ABU was fear of complications developing from not treating the infection and the hope of improving the patient's condition. Several clinical studies have shown that a simple education program for the hospital house staff can decrease unnecessary antimicrobial use in hospitalized patients with ABU from a pre-education level of treatment of over 60% to as low as 10% with post-education. This was accomplished without affecting patient outcomes. The studies involved a formal education program either once or several times during the education period that lasted for as little as three months to as long as one year. Most education programs included a handout or pocket card with algorithms to help house staff make the correct decision of when to test for a urinary tract infection. A simple education program such as this for outpatient providers may also reduce the treatment of ABU (see Tables 1 and 2) (Chowdhury et al., 2012; Hartley et al., 2016; Irfan et al., 2015; Kelley et al., 2014).
Education of providers on the treatment of ABU can reduce overprescribing of antibiotics, resulting in a reduction of bacterial resistance. It can also improve care for post-menopausal women by not exposing them unnecessarily to the risks of antibiotic treatment.
Symptomatic Urinary Tract Infections
Urinary tract infections are the most common bacterial infection in general and in women, and cost upwards of $2.6 billion annually in the United States (Foxman, 2002). More than 8.1 million visits to healthcare providers occur each year to evaluate and treat urinary tract infections (Schappert & Rechtsteiner, 2008). Forty percent to 50% of women have at least one urinary tract infection during their life, and 20% to 30% will have a recurrence (Hooton, Besser, Foxman, Fritsche, & Nicolle, 2004; Kunin, 1994). Diagnosis of a urinary tract infection is best made through a good history of the presenting symptoms or problem. Many factors place women at a greater risk than men for urinary tract infections. Some factors can be mitigated through prevention plans to reduce the occurrence and re-occurrence of urinary tract infections.
Factors that Place Post-Menopausal Women at Risk for Urinary Tract Infections
Urinary tract infections are more common in women due to a shorter urethra that allows uropathogens easier access to the bladder. The first step in a urinary tract infection is colonization of the peri-urethral tissue by uro-pathogens. In menopausal women, decline of estrogen in the vagina and peri-urethra area leads to a downward shift of the normal protective lactobacillus bacteria to an upward shift of uro-pathogens such as E. coli. Other potential contributors include uncontrolled diabetes mellitus, chronic urinary incontinence, history of urinary tract infection before menopause, genetic contributors, atrophic vaginitis, the presence of a bladder prolapse (cystocele), a postvoid urinary residual over 100 mL, and in the older adult woman, catheterization and physical/mental decline (Schaeffer, Matulewiez, & Klumpp, 2016).
Urinary incontinence is consistently associated with urinary tract infections in post-menopausal women. However, it is unclear how incontinence leads to urinary infections. A bladder prolapse can interfere in the ability of the bladder to empty completely, leading to post-void residual with resultant inability to flush uro-pathogens from the bladder, urinary urgency, and urge incontinence.
The next step necessary for urinary infection is bacteria adherence to the urethra and bladder lining, which can be affected by spermicides, loss of estrogen, and genetics. The last step in a bladder infection is proliferation of the bacteria by antimicrobial resistance and bacterial virulence (Schaeffer et al., 2016).
Diagnosis of Urinary Tract Infection in Post-Menopausal Women
Diagnosis of an uncomplicated simple urinary tract infection in women is made via a combination of symptoms and positive laboratory tests. A simple uncomplicated urinary tract infection can be diagnosed by the presence of two of the three symptoms: urinary frequency, urgency, and dysuria without vaginal symptoms. This has a greater than 90% chance of a correct diagnosis. No confirmatory rapid urine testing is necessary. This test provides little additional information when the history is strongly suggestive of a urinary tract infection because a negative leukocyte esterase and nitrites do not reliably rule out an infection (Bent, Nallamothu, Simel, Fihn, & Saint, 2002). To avoid the pitfalls of treating an asymptomatic urinary tract infection, a urine culture should only be obtained when symptoms are present in a patient with a complicated history, guiding treatment of a symptomatic urinary infection with positive nitrites and/or red and white blood cells on urine dipstick (Bent et al., 2002).
When diagnosing and planning treatment for a urinary tract infection in post-menopausal women, it is critical to not only evaluate signs and symptoms and quantify laboratory findings, but to also take into account if this woman has a positive history of a urinary tract infection at an early age and a positive family history of urinary tract infection; she may have genetic components contributing to her urinary tract infections. It is also important to evaluate if she has a history that might suggest if the urinary tract infection is complicated. The definition of complicated urinary tract infection is a history of functional, metabolic, or anatomical conditions, such as obstruction, stones, diabetes mellitus, neurogenic bladder, renal insufficiency, and/or immunosuppression; this will change how you approach management and treatment (Hooton, 2012).
A woman without a past history of urinary tract infection who gives a history of two urinary tract infections within a few months should be questioned about presence of a vaginal bulge that would suggest vaginal prolapse. Vaginal prolapse of the anterior wall of the vagina (cystocele) along with the uterus or apex (in a woman with a prior hysterectomy) can cause kinking of the urethra and lead to urinary residuals and urinary tract infections (Wong, Mei, Wieslander, & Tarnay, 2017). If she gives symptoms of a vaginal bulge, a post-void urinary residual should be obtained. If the residual is 100 mL or greater, a physical examination is indicated (Schaeffer et al., 2016). She should be offered a trial of a vaginal pessary to evaluate if this intervention can manage the urinary residuals and urinary tract infections.
Treatment of Urinary Tract Infection--Simple/ Uncomplicated
Shorter courses of antibiotics are as effective as longer courses, reducing exposure of the patient to antibiotics and the potential for collateral damage. The 2010 International Clinical Practice Guidelines for Treatment of Acute Uncomplicated Cystitis and Pyelonephritis encourage use of nitrofurantoin, trimethoprim-sulfamethoxazole, and fosfomycin trimetamol in women as first-line agents. Also encouraged are the use of fluoroquinolones for "important uses" secondary to new evidence showing increased collateral damage, as noted in the July 16, 2016, FDA drug safety communication (see Table 2) (Gupta et al., 2011).
The Challenge of Recurrent Urinary Tract Infection in Post-Menopausal Women
Risk factors for uncomplicated urinary infection differ in post-menopausal women versus younger women (see Table 3). In prospective studies, sexual activity in post-menopausal women is not associated with recurrent urinary tract infections. The strongest and most consistent risk factor for post-menopausal women is a history of a urinary infection at a young age, which suggests a genetic influence. Hu et al. (2004) found three urologic factors that were strongly associated with recurrent urinary tract infections in post-menopausal women: urinary incontinence, presence of a cystocele, and post-void residual urine. These factors along with a history of a urinary tract infection before menopause were most strongly associated with recurrent urinary tract infections in postmenopausal women (Foxman et al., 2001; Raz et al., 2000). A urinary tract infection before menopause likely represents a genetic influence. One genetic influence is through a mechanism of "non-secretor" status. This non-secretor status is thought to be from a gene (FUT2) that interacts with a blood type gene and determines the ability to secrete or not secrete blood type antigens into body fluids and tissues. Not having the ability to secrete these antigens allows binding sites for specific E. coli on vaginal and uro-epithelial cells. The genetic factor also includes an increased inflammatory response (Lomberg et al., 1986; Stapleton, Hooton, Fennell, Roberts, & Stamm, 1995)
A second genetic influence is the interleukin (IL)-8 receptor (IL-8R or CXCRI). IL-8 is an inflammatory cytokine that promotes neutrophil migration across the infected uro-epithelium. This is thought to cause children to develop pyelonephritis and to continue this proneness of pyelonephritis into adulthood (Godaly et al., 1998; Godaly, Proudfoot, Offord, Svanborg, & Agace, 1997; Lundstedt et al., 2007).
Recurrent Urinary Tract Infection: Management Options
Management of urinary tract infections involves repeated exposure to antibiotics, which can lead to bacterial resistance and side effects. Prevention strategies that do not include antibiotics should be considered.
Although voiding pre- and post-coitus, wiping technique, wearing tight undergarments, chronic deferring of voiding, and vaginal douching have not shown any impact in preventing urinary tract infections, they could be considered on a caseby-case basis (Scholes et al., 2000). Evaluation of diarrhea and fecal incontinence could suggest a fecal impaction, which can lead to voiding dysfunction and possible incomplete bladder emptying leading to recurrent urinary tract infections.
Assessing fluid intake and urinary incontinence patterns with a bladder diary can evaluate hydration and help guide management of urinary incontinence with bladder training or timed voiding. Increasing fluid intake is encouraged to prevent and treat a urinary tract infection. Beetz (2003) noted that many studies done during the 1960s and 1970s show some effect, but many questions were unanswered, and further research has not answered these questions (Schaeffer et al., 2016).
Women who have urinary incontinence often limit their fluid intake to manage their urinary incontinence. Symptoms of dizziness and confusion without the presence of the usual symptoms of a urinary tract infection should not be assumed to be a urinary tract infection despite the presence of bacteriuria. Many women who arrive at the emergency room with dizziness and confusion who respond to IV antibiotics may actually be benefiting from the IV hydration and not the IV antibiotic (Elstad, Maserejian, McKinlay, & Tennstedt, 2011; Knottnerus et al., 2013).
Vaginal estrogen use in postmenopausal women has been shown to be an effective non-antibiotic prevention measure, either in the form of estrogen cream, tablet, or ring, and is thought to work by promoting the growth of lactobacilli in the vaginal and peri-urethral area (Eriksen, 1999; Raz & Stamm, 1993). There has been patient confusion in the past on the safety of vaginal estrogen secondary to the package inserts that give safety warnings for oral estrogen. Women's healthcare providers have spent countless hours explaining these safety warnings to their female patients. In March 2016, the Committee on Gynecologic Practice gave opinion on the safety of vaginal estrogen in women with a history of estrogen-dependent breast cancer with urogenital symptoms. "Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms" (Farrell, 2016, p. e93). Vaginal estrogens for the treatment of vaginal dryness are safe and effective in women with breast cancer, especially at dosages of estradiol less than 25 g twice weekly (Dalleur, Boland, & Spinewine, 2012).
Cranberry products have been used for centuries to prevent and treat urinary tract infections. It is believed that cranberry products may prevent urinary tract infections because they contain proanthocyanins (PAC), which are thought to prevent bacteria (mostly E. coli) from adhering to uroepithelial cells that line the wall of the bladder. Without adhesion, the bacteria cannot infect the mucosal surface (Howell & Foxman, 2002). Most research completed on cranberry products has suffered from high dropouts for numerous reasons and substantial heterogeneity across trials that make it difficult to draw conclusions about the effectiveness of cranberry products in preventing urinary tract infections (Canadian Agency for Drugs and Technologies in Health, 2016; Jepson, Williams, & Craig, 2012). A recent study on long-term care residents (LTCRs) noted that a dose of PAC 9 mg twice a day (BID) for 12 months reduced the incidence of clinically defined urinary tract infections by 26% in high-risk patients. However, it was not found to be cost-effective for low-risk patients (Caljouw et al., 2014; van den Hout, Caljouw, Putter, Cools, & Gussekloo, 2014). Another 2016 study of LTCRs with a dose of PAC 72 mg BID for 12 months did not reduce the incidence of bacteriuria and pyuria over one year (Juthani-Mehta et al., 2016). In moving forward, studies should focus on the necessary dose of PAC to prevent urinary tract infections (Chughtai, Thomas, & Howell, 2016; Wang et al., 2012). Currently, it is difficult to advise patients on a dose of PAC to use and to find a cranberry product that clearly labels the contained dose of PAC (Sanchez-Patan et al., 2012). Wang and colleagues (2012) suggest a dose of 36 mg of PAC BID may be a place to start.
The precise way in which Lactobacillus promote their beneficial effects is still unknown. However, specific Lactobacillus strains seem to interfere with adherence, growth, and colonization of uro-pathogens (Falagas, Betsi, Tokas, & Athanasiou, 2006). The route that Lactobacillus are administered, either vaginal or oral, may affect outcomes. Four randomized controlled studies evaluated Lactobacillus-containing vaginal suppository and indicated some level of efficacy; however, these products are not currently available in the United States (Baerheim, Larsen, & Digranes, 1994; Reid, Bruce, & Taylor, 1992; Stapleton et al., 2011; Uehara et al., 2006). A phase II clinical trial with Lactobacillus crispatus vaginal suppositories for the prevention of recurrent urinary tract infections in women is currently being done and will end in 2018 (Wada et al., 2016).
Two hundred fifty-two postmenopausal women with an average of seven urinary tract infections in the preceding year were randomized in a non-inferiority trial to either receive Lactobacillus rhamnosus (GR-1) and Lactobacillus reuteri (RC-14) orally daily or trimethoprim-sulfamethoxazole daily (TMP-SMX) at a dose of 400 to 480 mg (single strength). After 12 months of prophylaxis, the number of UTIs were reduced to 2.9 (TMP-SMX) and 3.3 (Lactobacillus). It was concluded that the Lactobacillus treatment was not inferior to the TMP-SMX treatment. However, unlike TMP-SMX, Lactobacillus do not increase antibiotic resistance (Beerepoot et al., 2012).
Methenamine hippurate/madelate, a drug developed 60 years ago, offers an option to reduce the use of antibiotics in patients with recurrent urinary tract infections. It was not recommended after a review of the available research in 2012, but with increasing antibacterial resistance and collateral damage with antibiotic use, it is now being considered as a prevention management option (Lo, Hammer, Zegarra, & Cho, 2014). The action of methanamine creates an environment that is inhospitable to bacteria. Methenamine converts to formaldehyde when it comes in contact with acidic urine. Formaldehyde destroys both gram-positive and gram-negative bacteria without collateral damage and bacterial resistance (Musher & Griffith, 1974). To promote the effectiveness of the drug, the acid content of urine is increased by co-administrating with 1,000 mg vitamin C. The usual prophylaxis dose of hippurate is 1 gram BID and for mandelate is 1 gram four times a day. Methenamine hippurate/madelate has been shown to be safe for long-term use and without adverse effects.
In vitro and in vivo animal studies have shown that d-mannose can inhibit the adhesion of bacteria to uro-epithelial cells (Michaels, Chmiel, Plotkin, & Schaeffer, 1983). A study of 308 women with recurrent urinary tract infections was randomized to three groups to receive 2 grams of D-mannose powder daily in 7 ounces of water, continuous daily antibiotic prophylaxis with nitrofurantoin 50 mg, or no prophylaxis. The rate of recurrent urinary tract infections in the D-mannose group was 15%, compared to 20% in the nitrofurantoin group, and 60% in the group without prophylaxis (Kranjcec, Papes, & Altarac, 2014).
Another recently published pilot study showed that using D-mannose 1.5 grams twice a day for three days and then once a day for 10 days reduced the symptoms of an acute urinary tract infection. The women were then randomized to receive either continued prophylaxis with D-mannose 1.5 grams or no prophylaxis. The recurrence rate of another urinary tract infection for the following six months was 4.5% in the D-mannose group and 33% in the no prophylaxis group (Domenici et al., 2016). Initial research on D-mannose for non-antibiotic prevention and treatment provides promising options with minimal drawbacks that plague antibiotic treatment. Vaginal estrogen and D-mannose either in combination or separately could be offered to post-menopausal women with a history of early onset urinary tract infections that would suggest a genetic influence. These two safe interventions may provide the protection against bacterial adherence and increase Lactobacillus that can reduce uro-pathogens in the peri-urethral area and together reduce the incidence of recurrent urinary tract infections in postmenopausal women.
Daily, suppression, or continuous antimicrobial prophylaxis is effective in reducing the risk of recurrent urinary tract infections in women (see Table 4) (Rudenko & Dorofeyev, 2005). Prophylaxis has been advocated for women who experience two or more symptomatic urinary tract infections over a six-month period (Nicolle & Ronald, 1987) or three or more over a 12-month period (Ronald & Conway, 1988). Each woman, after education of the risks and benefits, has to decide whether or not she is willing to take on the risks of daily antibiotics for the benefits she perceives she will have. General risks include vaginal and oral candidiasis, gastrointestinal symptoms (including the potential for Clostridium difficile), and developing a resistance to the antibiotic being used as the prophylaxis. Community-acquired Clostridium difficile infection (CA-CDI) is becoming more prevalent. In North America, 20% to 30% of Clostridium difficile infections are community-acquired. The highest risk factor for developing Clostridium difficile infection is antibiotic exposure in the four weeks prior. Multiple antibiotic exposures increase the risk. Antibiotics that show the highest risk are clindamycin, fluoroquinolones, and cephalosporin. Use of gastric acid suppression medication can also increase the risk by disruption of the microbiota (Bloomfield & Riley, 2016).
If the woman notes a relationship between vaginal sexual activity and a urinary tract infection, she can first try post-coital prophylaxis, which carries lesser antibiotic exposure risk (Stapleton, Latham, Johnson, & Stamm, 1990). Women who prefer to minimize their intake of antimicrobials may wish to try self-diagnosis and self-treatment with a short-course TMP-SMX 160/800 BID for three days or nitrofurantoin BID for five days (Gupta, Hooton, Roberts, & Stamm, 2001; Schaeffer & Stuppy, 1999). Self-start antibiotic treatment can either be tried alone or with a prophylaxis plan. Fluoroquinolones should be reserved for complicated urinary tract infection, and when resistance to nitrofurantoin and TMP-SMX is found per recent FDA warnings. The choice of self-start antibiotic depends on if daily prophylaxis is also part of the treatment plan and local resistance patterns of trimethoprim-sulfamethoxazole. Urinary tract infections can be accurately self-diagnosed by women up to 95% of the time and short-course antimicrobial therapy is highly effective in curing the infections (Gupta et al., 2011; Schaeffer & Stuppy, 1999). Women using self-start have more symptomatic urinary tract infections than women on continuous or post-coital prophylaxis, but their symptoms resolve quickly, and the overall quantity of antimicrobials used is less with self-diagnosis and self-treatment. With a self-start plan, a woman can start a prescription treatment at the first sign of a urinary tract infection.
In a meta-analysis, no conclusions could be made regarding the best antibiotic choice or the optimal duration of prophylaxis (the maximal duration tested was one year), schedule, or doses. Most authorities advocate a six-month trial of antibiotics administered at bedtime, followed by observation for further infection. The timing (morning versus bedtime) has never been studied, but bedtime dosing is frequently noted in research studies. The theory is the antibiotic will have more time in the bladder due to less frequent voiding in the nighttime. The choice of six months is based upon observations that urinary tract infections seem to cluster in some women (Stamm, McKevitt, Roberts, & White, 1991). However, it appears that most women return to the previous pattern of recurrent infections once prophylaxis is stopped (Schaeffer et al., 2016). Therefore, some women may require longer prophylaxis. Although most women rarely need urological work up prior to starting a prevention plan, a urological work up is recommended in women who do not respond to a treatment plan, such as daily pro phylaxis, or who revert to infection patterns after stopping prophylaxis treatment (Schaeffer et al., 2016).
Prophylaxis treatment should be restricted to women who have clear documented recurrent urinary infections, a good relationship with a medical provider, and are motivated and compliant with medical instructions. A standing order for urine culture could be made available for women whose symptoms have not resolved within two days of self-start treatment.
Recent review of the safety and tolerability of nitrofurantoin for daily prophylaxis has been favorable. It was noted to have less resistance patterns and less effect on intestinal flora, but with more risk of adverse events, usually seen as gastrointestinal side effects (Muller, Verhaegh, Harbarth, Mouton, & Huttner, 2016). The FDA states that nitrofurantoin is contraindicated for use among patients with a creatinine clearance of less than 60 mL/min/ 1.73[m.sup.2]. There may not be adequate concentration of the drug in the urine to affect resolution of the bacterial infection. However, this decision is based on little data (Oplinger & Andrews, 2013). Recent data suggest that nitrofurantoin can be safely administered to patients with creatinine clearance of at least 40 mL/min/1.73[m.sup.2] and with equal cure rates to those with higher creatinine clearance (Singh et al., 2015). However, there are concerns regarding the use of daily nitrofurantoin in patients with creatinine clearance less than 50 mL/min/1.72[m.sup.2] because they may have more risk of pulmonary complications (cough and dyspnea) (Geerts et al., 2013; Hainer & White, 1981; Israel, Brashear, Sharma, Yum, & Glover, 1973).
Non-Antibiotic Options for Treatment Of Symptomatic UTI
Twenty percent to 50% of women with symptoms of a urinary tract infection either have symptom improvement or recover in one week without using antibiotics (Christiaens et al., 2002; Ferry et al., 2007).
Two-thirds of women with uncomplicated urinary tract infection treated symptomatically with ibuprofen 400 to 600 mg three times a day for three days recovered without use of antibiotics in three separate randomized clinical studies against ciprofloxacin, mecillinam, and fosfomycin. Some women may accept more symptoms initially in trade for avoiding the use of antibiotics and should be offered this as a treatment option (Bleidorn, Gagyor, Kochen, Wegscheider, & Hummers-Pradier, 2010; Gagyor et al., 2015; Vik et al., 2014).
On the Forefront
Acupuncture has been used in the treatment and prevention of many clinical conditions. Two trials by the same group of investigators showed some effect in reducing the symptoms of urinary tract infections in women with a history of recurrent urinary tract infection. This interesting treatment option warrants further exploration (Alraek & Baerheim, 2001; Aune, Alraek, LiHua, & Baerheim, 1998).
Various bacterial extracts have been used in research studies for the management of recurrent UTIs. An effective bacterial extract must be able to stimulate the host's immune system to produce antibodies and cytokines (Naber, Cho, Matsumoto, & Schaeffer, 2009). However, the exact mechanisms of protection and immunological basis remain unclear.
Vaccinating with whole or lysed fractions of inactivated pathogens can be an effective method to generate protective immunity. Several successful vaccines against human pathogens have been developed using this method, including Bordetella pertussis (whooping cough), Vibrio cholerae (cholera), and Salmonella Typhi (typhus) that contain killed whole bacteria. Four vaccines have been developed for urinary tract infection with limited success.
Urovac[R] (Solco Basel AG, Birsfelden, Switzerland and Protein Express, Cincinnati, Ohio, USA) is a vaginal vaccine currently available in Europe for management of recurrent urinary tract infections. It contains heat-killed uro-pathogens delivered via a vaginal suppository and has had some success in three different trials (Hopkins, Elkahwaji, Beierle, Leverson, & Uehling, 2007; Uehling, Hopkins, Balish, Xing, & Heisey, 1997; Uehling, Hopkins, Elkahwaji, Schmidt, & Leverson, 2003).
Oral Immune Stimulants
OM-89/Uro-Vaxom[R] (OM Pharma, Myerlin, Switzerland) has been approved for use in Switzerland since 1988, and it is marketed and sold in almost 40 countries worldwide, excluding the United States and Canada. OM-89 is a daily oral capsule. In five research studies, female participants were given 90 days of treatment with OM-89 versus placebo and showed OM-89 to be significantly more effective than placebo in preventing recurrent urinary tract infection. Although OM-89 appears to reduce the incidence of recurrent urinary tract infection, with limited toxicity issues, the required daily administration may create problems with patient compliance.
Urvakol[R] (Institute of Microbiology, Prague, Czech Republic) and Urostim[R] (National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria) is administered daily as oral tablets containing mixtures of inactivated uropathogens. Both formulations contain strains of E. coli, P. mirabilis, and E. faecalis; Urvakol also includes a strain of Pseudomonas aeruginosa, whereas Urostim contains K. pneumoniae. Data from animal and patient studies demonstrate that Urvakol and Urostim have immune-stimulating activity as measured by cytokine production and the presence of vaccine-specific antibodies in the serum, urine, and saliva of patients after immunization. No large-scale placebo controlled clinical trials have been completed at this date and neither is currently available in th United States (Brumbaugh & Mobley, 2012).
The concept of bacterial interference, both passive and active, embodies the use of bacteria of low virulence to compete with and protect against colonization and infection by disease-causing organisms. Passive bacterial interference is achieved when naturally present commensal bacteria help defend against host infection by pathogenic organisms. It is possible that the primary mechanism for bacterial interference is competition with other bacteria for nutrients. Genetically engineered a-virulent E. coli was found in a preliminary study in patients with spinal cord injury and showed a 50-fold reduction in symptomatic urinary tract infection in those who were successfully colonized with the a-virulent strain (Darouiche et al., 2011).
Oral Hyaluronic Acid, Chondroitin Sulfate, Curcumin, and Quercetin
A prospective evaluation of 145 post-menopausal women were consecutively recruited from the database of three different investigators. All women had mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections. Women were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin and the third group was treated with HA, CS, curcumin, and quercetin, and local estrogens. After one year of treatment, the reduction of urinary tract infections was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments (Torella et al., 2016).
Nseir, Taha, Nemarny, and Mograbi (2013) showed an association between low serum levels of 25-hydroxy vitamin D and the risk of recurrent urinary tract infection. The mechanism(s) that link vitamin D deficiency with recurrent urinary tract infection are unknown, but one theory has been postulated. Infections in the urinary tract induce epithelial cells to produce cathelicidin to fight the infection. Vitamin D can stimulate cathelicidin production, which may help fight microbial invasion. However, more studies are needed to investigate the mechanisms involved in the pathogenesis of vitamin D deficiency and predisposition to urinary tract infections.
Glycosaminoglycan HA and CS are thought to protect the bladder urothelium. Damage to the urothelium may increase bacterial adherence and infection risk. Eight studies have been completed so far with glycosaminoglycan HA and +/- CS delivered intravesically (Ciani et al., 2016; Cicione et al., 2014; Constantinides et al., 2004; Damiano et al., 2011; De Vita, Antell, & Giordano, 2013; Gugliotta et al., 2015; Torella et al., 2013; Z^bkowski, Jurkiewicz, & Saracyn, 2015). All studies noted "significant" reduction in the rate of urinary tract infections after the intravesical instillation treatment. A meta-analysis by De Vita et al. (2013) concluded that "Intra-vesical HA and HA-CS in combination significantly reduced cystitis recurrence, mean UTI recurrence time, and PUF total score. Study limitations include the small number of patients and possible bias. Further studies are needed to validate this promising treatment modality" (p. 545).
Antibiotic resistance is a growing problem that will require diligence from all healthcare providers to reduce this global health and safety issue. A careful history of the presenting problem and use of non-antibiotic prevention management techniques in the treatment of symptomatic and recurrent urinary tract infections can go far in reducing this global health and safety issue. Educating patients and healthcare providers on the responsible use of antibiotics can reduce antibiotic resistance in post-menopausal women.
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Jan Baker, MS, APRN, is a Family Nurse Practitioner, University of Utah, Department of Obstetrics and Gynecology, Division of Urogynecology, Salt Lake City, UT.
Table 1. Example of Pocket Card Front (Evaluation) Does the patient have any of the following without alternate explanation? * Urgency, frequency, dysuria. * Suprapubic pain/tenderness. * Flank pain or tenderness. * New onset delirium. * Fever >38[degrees]C/Rigors. * Acute hematuria. * Increased spasticity or autonomic dysreflexia in spinal cord injury patient. * Concern for sepsis. * Pregnant. * Possible urologic surgery. Yes Send urinary analysis and urine culture and sensitivity. Document indications for culture Start empiric therapy. No Do not send culture on following patients without symptoms: * Premenopausal women. * Non-pregnant women. * Older community-dwelling women. * Frail elderly institutionalized women. * Catheterized women. Table 2. Example of Pocket Card Back (Treatment) Preferred Length of Treatment Treatment Trimethoprim- BID x 3 days sulfamethoxazole DS Nitrofurantoin 100 mg BID x 5 days Trimethoprim 100 mg BID x 3 days Secondary Length of Treatemnt Treatment Fosfomycin One dose tromethamine (Monurol[R]) 3 gm Ciprofloxacin (Cipro[R]) BID 3 days 250 mg Cephalexin (Keflex[R]) QID 7 days 250 mg Cephalexin (Keflex) BID 7 days 500 gm A full 7-to 10-day antibiotic course should be used in patients with diabetes mellitus, symptom duration greater than 7 days, age over 65 years, or past history of pyelonephritis or urinary tract infections with resistant organisms. Notes: BID = 2 times a day, QID = 4 times a day. Sources: American College of Obstetricians and Gynecologists, 2008; Chowdhury et al., 2012; Hartley et al., 2016; Irfan et al., 2015; Kelley et al., 2014. Table 3. Risk Factors for Urinary Tract Infections in Pre-Menopausal and Post-Menopausal Women Pre-Menopausal History or urinary tract infection Frequent or recent sexual activity Diaphragm contraception use Use of spermicidal agents Increasing parity Diabetes mellitus type 1 and type 2 Obesity Sickle cell trait Anatomic congenital abnormalities Urinary tract calculi Neurologic disorder requiring Indwelling or intermittent cathing Urinary incontinence Post-Menopausal Vaginal atrophy Lifetime history of urinary tract infection Incomplete bladder emptying Poor perineal hygiene Vaginal prolapse (cystocele) Diabetes mellitus type 1 and type 2 Urinary incontinence Sources: Foxman et al., 2001; Hu et al., 2004; Raz et al., 2000; Schaeffer, Matulewiez, & Klumpp, 2016. Table 4. Prophylaxis Antimicrobials Trimethoprim-sulfamethoxazole 40 mg/200 mg Trimethoprim-sulfamethoxazole 40 mg/200 mg (3x weekly) Trimethoprim 100 mg Nitrofurantoin 50 mg Nitrofurantoin 100 mg Cefaclor 250 mg Cephalexin 250 mg Norfloxacin 200 mg Ciprofloxacin 125 mg Fosfomycin 3 gm every day for 3 months Sources: Adapted from Hooton & Gupta, 2016; Schaeffer, Matulewiez, & Klumpp, 2016.
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|Title Annotation:||Special Series on Gerontological Urology|
|Date:||Jan 1, 2018|
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