Summative Case #6

Pyelonephritis refers to a clinical syndrome characterized by flank pain, tenderness, and fevers. It is often accompanied by dysuria, urinary urgency, and urinary frequency, accompanied by evidence of acute infection in the kidney (Sobel & Brown, 2020).

There are two main pathways for bacteria to infect the urinary tract: (1) ascending and (2) hematogenous.

In the ascending route of infection, bacteria from the intestinal tract are the source. In women, bacteria from the rectum can colonize the vaginal introitus and periurethral tissue. The urethra can then become colonized with these uropathogens from the vagina given the close proximity. The bacteria can then enter the bladder. In some cases, bacteria are able to ascend into the ureters and kidneys from the bladder. The risk of this is especially high if the patient has vesicoureteral reflux.

In the hematogenous route of infection, organisms in the blood of a patient with bacteremia exit the vascular system and invade the renal parenchyma. This is most commonly seen with staphylococcus aureus bacteremia, which can frequently cause abscesses in the kidneys. The type of organism causing the infection can inform us of the most likely route of infection. Staphylococcus aureus and other gram-positive organisms rarely cause infection via the ascending route of infection, so it is important to consider a hematogenous source and evaluate as such. On the other hand, gram- negative organisms such as Escherichia coli rarely cause infection of the kidneys via the hematogenous route.

Impact of the Vulvovaginal Microbiome on UTI Risk

Rachel Weston is not alone in struggling with recurrent UTI during her postmenopausal years. The estrogen deficiency which occurs with menopause increases the risk of UTI in this population and many older women struggle with frequent recurrences of UTIs. Loss of estrogen changes the microbiome of the vagina by decreasing the prevalence of lactobacillus bacteria, which are protective. This facilitates colonization of the vaginal introitus with potential pathogenic bacteria from the intestinal tract. Additionally, estrogen deficiency reduces the contractility and emptying capacity of the bladder, which also makes it easier for bacteria to ascend into the bladder and cause infection (Sobel & Brown, 2020).

Extended-spectrum beta-lactamase (ESBL) is an enzyme produced by bacteria, which inactivates all beta-lactam antibiotics. This category includes penicillins, cephalosporins, and aztreonam. ESBL producing organisms are not categorically resistant to other non-beta-lactam antibiotics such as fluoroquinolones, trimethoprim-sulfamethoxazole, carbapenems, and gentamicin. However, they can possess other antibiotic-resistance mechanisms which confer resistance to agents outside of the beta-lactam class. ESBL-producing ability is generally a genetically mediated resistance mechanism. Genes which bestow the ability to produce ESBL can be carried by any gram-negative bacteria but are most prevalent in E. coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis.

UTIs with multidrug-resistant bacteria, like the ESBL E. coli in this case, have been increasing in prevalence over recent years in the United States. These bacteria can cause both uncomplicated UTI such as cystitis, which is limited to the bladder, and complicated UTI such as pyelonephritis, which involves the upper urinary tract.

Recurrent UTI is defined as ≥ 3 UTIs within the previous one year or ≥ 2 UTIs in six months. This is a common problem among women, particularly older women. Risk factors which predispose women to experiencing recurrent UTIs can be divided into host behavioral, anatomic, biologic, and genetic factors.

In most cases, women with recurrent UTI do not require imaging or urological evaluation. However, this is warranted if there is a concern for underlying structural or functional abnormalities of the urinary tract. For example, kidney stones and obstructive uropathy are an underlying pathology in some cases of recurrent urinary tract infection.

Behavioral Changes

Behavior or lifestyle modifications can sometimes be helpful in reducing UTI frequency for women who suffer from recurrent UTI. It is important to remember that many of these interventions lack well-designed studies to support their efficacy. Nonetheless, it is appropriate to consider some of these strategies as a way to minimize or reduce antibiotic exposures. Selecting which behavioral modification strategies to try should be done as part of a collaborative, shared decision-making conversation with the patient.

Liberal Fluid Intake

The flushing mechanism of urine flow during micturition is one of the ways that the human body protects the bladder from infection. Additionally, some characteristics of the urine, such as reduced osmolarity and lower pH, can be inhibitory for some types of bacteria. Based on these understandings, it is theoretically reasonable that by harnessing the body’s natural defense mechanisms by increasing the flushing mechanism of micturition and diluting the osmolarity of the urine, increased fluid intake may reduce the risk of UTI. Therefore, in women with recurrent UTIs without a contraindication (e.g. heart failure), liberal fluid intake with a daily target of two to three liters can be recommended as a strategy for UTI prevention.

Sexual Activity and Contraception

Use of spermicide for contraception, particularly with a diaphragm, is a strong risk factor for UTI in women. Sexual activity habits can also influence UTI risk. Frequency of sexual intercourse is a strong risk factor for recurrent UTIs. Additionally, engaging with a new sexual partner increases risk. These risk factors can be shared and discussed with patients, but the decision on whether or not the patient wants to make any changes to their sexual activities should be individualized and based on the patient’s unique context, values, and preferences. Women should be encouraged to urinate after sexual activity to help flush out any bacteria introduced into the urinary system.

Hygiene

Recurrent UTIs are not caused by poor hygiene. It is important for clinicians to be aware of this and share this understanding with patients. The presumption that recurrent UTIs are caused by poor hygiene is not supported by evidence and can be stigmatizing and demoralizing to patients. It also can result in patients spending inordinate time and energy trying to optimize their hygiene when it is already adequate, which does not improve the frequency of their UTIs.

Topical Estrogen

As discussed earlier in the case study, the estrogen deficiency experienced by postmenopausal women is one of the reasons that this group is at especially high risk of experiencing recurrent UTIs.

Vaginal estrogen application can be an effective intervention to reduce the frequency of UTIs in postmenopausal women. Estrogen helps to create conditions in the vaginal introitus which are conducive to enrichment with lactobacillus bacteria, the presence of which discourages pathogenic bacteria from the rectum from colonizing this area and subsequently ascending into the bladder. Oral estrogen replacement has not demonstrated this same efficacy. Vaginal estrogen is generally well tolerated, though potential adverse effects include vaginal bleeding, vaginal discomfort, and increased discharge. There is a theoretical risk of increased risk of estrogen-dependent cancer (e.g., breast cancer). Though this effect has not been demonstrated in studies, it is prudent to consult with an oncologist or gynecologist before starting vaginal estrogen in patients with a history of or who are at high-risk for estrogen-dependent tumors (Gupta, 2024).

Antibiotic and Antibiotic-Sparing Strategies for Frequent Recurrences

There is often a need for more aggressive management of recurrent UTIs if the interventions above have not effectively reduced the infection frequency. These interventions can generally be categorized as antibiotic-based and antibiotic-sparing. In general, it is best to start with an antibiotic-sparing strategy and move to an antibiotic-based strategy if that fails. Although antibiotic-based strategies are more effective, they have more potential adverse effects including toxicities from the antibiotics, Clostridioides difficile infection, and selective pressure for antibiotic resistance in the individual patient and the larger community of patients.

Antibiotic-Sparing Strategies

Methenamine and cranberry products are the two mainstays of antibiotic-sparing prevention of recurrent UTIs (Gupta, 2024).

Methenamine is a urinary antiseptic medication. Formulated as enteric coated salt, methenamine is well-absorbed through the gastrointestinal tract and is excreted through the kidneys, which allows it to concentrate in the urine. As long as the urine pH is acidic with a pH less than six, methenamine hydrolyzes into ammonia and formaldehyde in the urine. By essentially adding formaldehyde to the urine in the bladder, methenamine can be effective at creating an environment that is inhospitable to bacteria (Horton, 2020).

Methenamine is not effective in patients whose urine pH is generally greater than six because it does not hydrolyze into formaldehyde. It is also not effective in preventing UTIs in patients with indwelling catheterizations or who use frequent intermittent catheterization because the frequent or continuous elimination of urine does not allow enough time for conversion to formaldehyde. Additionally, it is contraindicated in patients with renal failure because as a renally cleared medication, there is risk of accumulation. Since methenamine hydrolyzes into ammonia as well as formaldehyde, it is also contraindicated in patients with liver failure (Horton, 2020).

As stated above, methenamine is not an antibiotic. It is an antiseptic. The difference is that antiseptics, like methenamine, do have a specific bacterial target but work within an environment to reduce the ability of bacteria to grow and survive. While useful for preventing UTIs in some patients, methenamine cannot be used as a treatment for acute cystitis or acute pyelonephritis. It is also important to avoid the coadministration of methenamine with sulfonamide antibiotics because of the risk of sulfonamide crystallization in the urine (Horton, 2020).

Although limited, there is in vitro and clinical evidence that cranberry products may reduce UTI frequency in some patients. The mechanism behind this effect is that components of the cranberry product, such as fructus and proanthocyanidins, inhibit the ability of pathogenic bacteria to adhere to the uroepithelial cells in the urinary tract. There are no standard doses and there is variability in the concentrations of active ingredients across formulations, but generally women should drink an 8-ounce (~240 mL) glass of cranberry juice once or twice daily or take 500mg-1000 mg of cranberry concentrate tablets daily (Horton, 2020).

Antibiotic-Based Strategies

Before proceeding with an antibiotic-based prevention strategy, it is important to consider the risk of antibiotic resistance and also to confirm the diagnosis of recurrent UTI. Antibiotic-based prevention is not ideal in women that have already had infections with bacteria with increased antibiotic resistance, particularly if recent pathogens have limited oral treatment options. By selecting for resistance to the agent used for prophylaxis, this strategy could quickly leave the patient with no oral antibiotic treatment options for future UTIs. Antibiotic-based prevention strategies should not be used in patients with ambiguous, vague symptoms that are not specific to UTI, even if these symptoms occur in the context of bacteriuria. An example of this is fatigue or mental status changes without fever or urinary-specific symptoms, even if there is growth of bacteria on the urine culture for this patient. The rationale for this is that without urinary symptoms, it is likely that the presence of bacteria on the urine culture represents asymptomatic bacteriuria occurring coincident with another unrelated clinical process, causing the mental status changes. In that case, the antibiotics offer no benefit but expose the patient and community to all of the risks of antibiotic use (Gupta, 2024).

If the patient is a good candidate for antibiotic-based UTI prevention, post-coital or continuous prophylaxis dosing options can be considered. Post-coital prophylaxis is ideal for women whose UTI episodes are strongly correlated with sexual activity. In this strategy, the woman takes a single dose of an antibiotic immediately after each instance of sexual intercourse. The decision of which antibiotic to use should be based on the patient’s history of usual UTI pathogens and their susceptibility with nitrofurantoin and trimethoprim-sulfamethoxazole being preferred when possible. See Table 4 for options and doses (Gupta, 2024).

If UTIs are not correlated with sexual activity, then continuous antibiotic prophylaxis is a better strategy for prevention. In this case, patients take an antibiotic every day to prevent UTI. The doses are generally lower than those for UTI treatment. Selection of an antibiotic to use for continuous prophylaxis should be based on allergies, drug tolerance, medication interactions, and the microbiology of the patient’s historical UTIs. Again, nitrofurantoin and trimethoprim-sulfamethoxazole are preferred agents whenever they are appropriate based on the above criteria. Fluoroquinolones should generally not be used for continuous prophylaxis because the higher risk of serious adverse reactions outweighs the potential benefits in most cases. See Table 5 for options and doses (Gupta, 2024).