Pharmacotherapy of Lower UTI

Lower UTI-an overview

Inflammation of the lower urinary tract is a frequent event in the population, wherein a urinary tract infection (UTI) is the most prominent identifiable cause in both general and specialist urology clinical practice.^{1  –  3}   UTIs are in fact considered to be the most common bacterial infections, affecting an estimated 150 million individuals annually; though, data on the true impact of UTIs in the developing world might be limited.⁴  

The incidence of UTI increases with age.^{5  –  6}  Women are affected more than men for reasons related to anatomical differences in the urogenital tract; except in around 60 years and above when the incidence may be comparable. Evidence suggests that about 50%-60% of adult women experience a UTI during their lifetime, with most common manifestation being acute uncomplicated cystitis.^{7  –  9}

Classification of UTIs

UTIs are traditionally classified based on clinical symptoms, focusing on the anatomical level
(Table 1), laboratory data, and microbiological findings. Practically, they have been divided into uncomplicated and complicated UTIs, and urosepsis (Figure 1); though such classification may best be considered a working instrument to aid in making clinical decisions regarding patient management (Figure 2).^{10   –  11}

Typical symptoms of UTIs

Patients with UTI exhibit characteristic symptomatic profile, and all but ~5% of these patients have symptoms of inflammation, including pain/spasm, urgency and increased frequency, or fever (Table 1).¹²   For instance; symptoms among young women typically include a frequent and intense urge to urinate, and a painful, burning feeling in the bladder or urethra during urination. An optimal strategy for a UTI should therefore be directed at resolution of most bothersome symptoms amid appropriate antibiotic regimen for definite control of the infectious etiology.

Asymptomatic bacteriuria

Asymptomatic bacteriuria (ABU) (a count of > 10⁵   cfu/mL of a microorganism in voided urine specimen for women, and > 10³   cfu/mL for men) needs to be considered a special entity since it can have its origin in both the lower and upper urinary tracts, and usually requires no treatment.¹⁰   About 3%-8% of premenopausal women and 4%-43% of postmenopausal women may have this condition.¹¹   In absence of clear evidence that patients would derive any benefit, treatment is not indicated in most cases of asymptomatic bacteriuria. Nonetheless, asymptomatic bacteriuria in pregnant women (see below) constitutes the specific subgroup for whom screening and treatment has been shown to be beneficial. Another group of patients that may benefit from screening and treatment for asymptomatic bacteriuria are those undergoing selected manipulation for their genitourinary tract systems.

Acute uncomplicated UTIs

Acute uncomplicated UTIs are seen mostly in women with a normal, unobstructed genitourinary tract, and without any comorbidity that could lead to more serious outcomes; also, there is no history of recent instrumentation. Although symptoms in most cases are usually confined to the lower urinary tract, uncomplicated UTIs can include infections in both the lower urinary tract (cystitis) as well as the upper urinary tract (pyelonephritis).¹¹   Only a small number of men under 50 years suffer from acute uncomplicated UTI, and require a seven-day antibiotic regimen.

Microbial etiology

The spectrum of etiological agents is generally similar in uncomplicated upper and lower UTIs, with Escherichia coli E. coli being the causative pathogen in 70-95% of cases in all age groups, and Staphylococcus saprophyticus in 5-10%.^{10-11–  13}      Klebsiella pneumoniae, Proteus mirabilis, group B streptococci, and other uropathogens occur in small numbers.¹⁴   Such knowledge about the microbial etiology of UTIs is beneficial since infection with organisms not usually implicated in causing UTIs may be an indicator of underlying structural abnormalities or renal calculi.⁷   In addition, this may help in selecting the most appropriate antibiotics.

Focus on specific subgroups

Acute uncomplicated cystitis in premenopausal non-pregnant women

A urine dipstick testing is a reasonable alternative to urinalysis for diagnosis of acute uncomplicated cystitis in women. Urine cultures-to identify the causative pathogen and its susceptibility pattern-are recommended for those with: suspected upper UTI, symptoms not resolving or recurring within 2-4 weeks after completion of treatment; and those who present with atypical symptoms.¹⁰   Herein, a colony count of > 10³   cfu/mL of uropathogens is microbiologically diagnostic in women presenting with symptoms of acute uncomplicated cystitis.

While this above mentioned work-up presents a more focused approach, a growing literature however suggests that initial treatment for most uncomplicated UTIs can be started based on clinical presentation only; and is accurate as well.^7-9-15-18          Women with one symptom of UTI have an infection probability of ~50%, while a combination of symptoms (i.e., dysuria, frequency, and absence of vaginal irritation or discharge) raise the probability of UTI to > 90%.^19-21

UTIs in pregnancy

UTIs are common during pregnancy, but may be asymptomatic; and therefore women should be screened for bacteriuria during the first trimester. In an asymptomatic pregnant woman, bacteriuria is considered significant if two consecutive voided urine specimens grow > 10⁵   cfu/mL of the same bacterial species on quantitative culture.¹⁰   And in those with symptoms compatible with UTI, bacteriuria is considered significant if a voided urine specimen grows > 10³   cfu/mL of a uropathogen.

UTIs in children

UTI are common in children, with incidence varying depending on age and sex. It represents the most common bacterial infection in children less than 2 years of age, with retrograde ascent being the predominant mechanism of infection. Symptoms of UTIs in children are non-specific, and vary with the age of the child and the severity of the disease.

The presence of pyuria (> 5 leukocytes per field) and bacteriuria in a fresh urine sample generally reinforce the clinical diagnosis of UTI in children; however, positive urine culture is required for definitive diagnosis of infection. The presence of unusual obstruction, vesicoureteric reflux (VUR) and dysfunctional voiding can complicate the clinical picture, and hence additional investigation(s) should be undertaken after two episodes of UTI in girls and one in boys, in order to avoid complications.¹⁰

Recurrent (uncomplicated) UTIs in women

Recurrent UTIs are common among young, healthy women, even though they generally have normal urinary tracts; and require urine culture for diagnosis. It has been reported that about 25% of women experience a 2^nd episode within 6 months of their first UTI.¹¹   The recurrence of UTI can either be in form of a reinfection or relapse. Reinfection is the most common type of recurrent UTI, and occurs > 2 weeks after a patient has completed antimicrobial therapy. It is generally due to infection with a different organism (including a different E. coli strain). Relapse, on the other hand, occurs in 5%-10% of women within 2 weeks of completing antimicrobial therapy, and is attributable to persistence of the same pathogen in the urinary tract system, suggesting infection with an antimicrobial-resistant pathogen.

Complicated UTI

A complicated UTI is an infection associated with a condition, such as structural or functional abnormalities of the genitourinary tract, or the presence of significant co-morbidities, which increases the risks of acquiring an infection or of failing therapy.¹⁰   Several factors may make a UTI complicated¹¹  , and consequently direct the extent of the work up and investigations required in such cases.

The etiology of complicated UTIs is usually more varied and is less predictable than uncomplicated UTIs, and encompasses a broad range of bacteria. As well, there is possibility of mixed infections with two or more organisms. Although enterobacteriaceae are the predominant pathogens, with E. coli being the most common pathogen, non-fermenters (such as Pseudomonas aeruginosa) and Gram-positive cocci may also play an important role.

Antimicrobial treatment

The introduction of antimicrobial agents is probably the most profound advance in the management of UTIs. A variety of antibiotics are available for lower UTIs, though choices depend on many factors, such as the subtype of infection, patient subgroup, resistance patterns, and characteristics of different agents (Figure 3).²²

The choice of antibiotic agents in an era of resistance

Although the choice of antibiotics will largely depend on the antimicrobial susceptibilities of urinary pathogens²³  ; in this context, the growing problem of antimicrobial resistance to antibiotics, such as norfloxacin, ampicillin and ciprofloxacin, is a cause of major concern in many countries, making empiric management of outpatient UTIs challenging, alongside emphasizing the importance of knowing local patterns of susceptibility of organisms to antimicrobial agents.⁴

Drugs of choice for acute uncomplicated cystitis in premenopausal, non-pregnant women include nitrofurantoin 100 mg bid for 5 days, fosfomycin trometamol 3 g single dose, and pivmecillinam 400 mg for 3-5 days. Cotrimoxazole 160/800 mg bid for 3 days or trimethoprim 200 mg for 5 days may be considered in areas with known resistance rates for E. coli of < 20%.¹⁰   Other alternative antibiotics include ciprofloxacin 250 mg bid, ciprofloxacin extended release 500 mg qd, levofloxacin 250 mg qd, norfloxacin 400 mg bid, and ofloxacin 200 mg bid, each as a 3-day course. However, use of these fluoroquinolones should be limited in acute uncomplicated cystitis due to concerns related to increasing antimicrobial resistance.⁷   Retreatment with a 7-day regimen using another agent should be considered in women with symptoms not resolving by the end of treatment, and if symptoms resolve but recur within two weeks (see recurrent UTIs).

Nitrofurantoin as first line drug for UTI

Amidst the concerns of rising resistance for most antimicrobials, demonstration of efficacy with minimal drug resistance makes nitrofurantoin an attractive agent for uncomplicated UTI. In this context, a review of data from The Surveillance Network (TSN) database reported susceptibility data showing a trend in favor of nitrofurantoin.²⁴   Likewise, a latter conducted retrospective analysis of antimicrobial susceptibility patterns of urinary isolates from 2003 to 2007 showed high bactericidal rate of nitrofurantoin compared to the increasing resistance rates of ciprofloxacin, levofloxacin and co-trimoxazole. Nitrofurantoin had bactericidal action against a mean of 95.6% of E. coli UTIs, with an average resistance rate of 2.3%. In contrast,E. coli had a mean 75.6% and 75.9% susceptibility and 24.2% and 24% resistance rate to both ciprofloxacin and levofloxacin, respectively. Co-trimoxazole (trimethoprim/sulfamethoxazole; ‘TMP/SMX’) had a mean of 70.9% susceptibility and 29.1% resistance rate to E. coli over the same 5-year period (Figure 4).²⁵   The data therefore shows that an inappropriately excessive level of use of fluoroquinolones will eventually have a detrimental impact due to increasing resistance rates. Furthermore, fluoroquinolones are known to cause some serious adverse events.^26-27      Cephalosporins share similar negative characteristics besides having greater cost.^28-31

Nitrofurantoin with low overall resistance and favorable side-effect profile is thus safe and effective, and should now be considered the best first-line choice of antibiotic for uncomplicated UTIs (Figure 3).^4-7-13-22         Of note, the broad range of bactericidal action of nitrofurantoin appears to explain the relative lack of accumulated resistance to the drug over the past 50 years. Moreover, it is less expensive than fluoroquinolones in many communities.³²   A sustained release formulation of nitrofurantoin may be used to offer advantages of attenuation of adverse effects, fewer fluctuations in plasma drug concentration, and improved patient compliance, etc.³³

Treatment in children

A severe UTI in children requires adequate parenteral fluid replacement and appropriate antimicrobial treatment

that is initiated on an empirical basis, but should be adjusted according to culture results as soon as possible. Conversely, a simple UTI is considered to be a low-risk infection in children. In such cases, nitrofurantoin and first generation cephalosporins are appropriate narrow spectrum alternatives for pediatric UTI given their low resistance rates.³⁴   In particular, with low resistance rates and safety profile, nitrofurantoin is advocated for the treatment of cystitis and prophylaxis.

Treatment in pregnancy

Antimicrobial therapy is indicated to eradicate asymptomatic bacteriuria detected in pregnancy, and to avert its consequence in both the mother and the fetus. Treatment regimens for asymptomatic bacteriuria and cystitis in pregnancy include nitrofurantoin 100 mg q12 h, 3-5 days, amoxicillin 500 mg q8 h, 3-5 days, co-amoxicillin/clavulanate 500 mg q12 h, 3-5 days, cephalexin 500 mg q8 h, 3-5 days and fosfomycin 3 g single dose. Of note, nitrofurantoin is safe for use during the first trimester of pregnancy³⁵  -case-control studies and case series involving thousands of women who received nitrofurantoin during pregnancy reportedly indicated no increase in major malformations among the newborns.³⁶   Women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen of nitrofurantoin.³⁷   It is recommended to obtain urine cultures soon after completion of therapy for asymptomatic bacteriuria and symptomatic UTI in pregnancy to look for bacterial eradication.¹⁰

Treatment of complicated UTIs

Treatment strategy for complicated UTIs is much less well defined but depends on the severity of the illness, and requires management of the urological abnormality besides considering antimicrobial therapy and supportive care. These patients should receive empiric antibiotic therapy pending the results of a urine culture, based on consideration of local antimicrobial resistance rates and recent antimicrobial use. Initial empiric parenteral therapy with a fluoroquinolone, a carbapenem, a 3^rd-generation cephalosporin, or piperacillin/tazobactam may be required. Fluoroquinolones should however not be used as a first-line option for empiric treatment of serious complicated UTIs, especially when patients exhibit risk factors for harboring a resistant organism.³⁸   Trimethoprim/sulfamethoxazole and nitrofurantoin are appropriate empiric options for mild lower complicated UTIs, but TMP/SMX may have limited role because of the frequent antimicrobial resistance. The recommended treatment duration for patients with complicated cystitis is 7 to 10 days.

Treatment of recurrent infection

Women with a reinfection should be treated with the same agent received during the original UTI episode; however, an alternative agent should be used if the reinfection occurs within 6 months, mainly if the original agent was TMP/SMX, because of the high risk of developing microbial resistance to TMP/SMX.

Patients with relapse may require additional assessment to determine cause of their non-response to initial therapy, and treatment should be founded on results of the urine culture.

Antibiotic prophylaxis

Antimicrobial prophylaxis for prevention of recurrent UTI is considered after non-antimicrobial measures-counselling and behavioural modification-have been attempted. Such a strategy has been shown to be effective in reducing the risk of recurrences in recurrent cystitis by close to 95%.¹¹   However, potential emergence of resistance is a concern. Recommendations in this context are to limit the use of antimicrobial agents for prophylaxis of UTIs to women with ≥ 3 infections in the past 12 months, or those with ≥ 2 infections in the past 6 months wherein at least one episode was documented by a positive urine culture. Eradication of a previous UTI should be confirmed by a negative urine culture 1-2 weeks after treatment prior to initiating any prophylaxis regimen. The choice of antibiotics is based upon identification and susceptibility pattern of the causative organism.¹⁰   Nitrofurantoin, fosfomycin and co-trimoxazole are safe and effective antimicrobial methods to prevent UTI.^39-40

Use of antibiotic prophylaxis may also be indicated in children with recurrent UTI; using nitrofurantoin as a preferred drug.^41-42     The drug has a lower rate of recurrence and causes fewer emergences of resistance bacteria than TMP/SMX, and is therefore more suitable for prevention of recurrent UTIs in children.⁴³

Prophylaxis with cranberry

Recent Cochrane Review suggests that cranberry products provide no benefits in most populations groups, and the benefit in some subgroups is likely to be very small although many products are available in the market.⁴⁴   The large number of dropouts/withdrawals from some of the studies indicate that cranberry products, particularly in juice form, may not be acceptable over long periods of time. Until there are more studies of products containing enough of the active ingredient, measured in a standardized way, cranberry products cannot be recommended for preventing UTIs.

Medications for treating most common symptoms of UTI

Although antibiotics can cure most UTIs, certain bothersome symptoms may require initial consideration, and/or can even persist for several days until the antimicrobial agent eliminates the bacteria. In such cases, other drugs may be used for relieving symptoms while the antibiotics take action. Classic symptoms highly predictive of acute lower UTI include dysuria, urinary frequency, urgency, and suprapubic pain with or without hematuria; the latter may be present in 40-60% of patients with UTI. Fever or costovertebral angle tenderness indicates upper urinary tract involvement.

Therefore, symptoms such as burning micturition, pain/spasm, urgency and frequency, may as such be considered first, coupled with empiric antibiotic treatment, while awaiting results of the urine culture. Of note, a high probability of a positive culture based on sign and symptoms of dysuria, frequency, and hematuria appear to facilitate this empiric approach. The strategy may hence considerably help in prompt resolution of symptoms, improving patient outcomes and quality of life.

Symptom of burning micturition-and the choice of urinary alkalinization

Burning micturition-an impression of burning, stinging, or itching-is one of the most characteristic symptoms of an acute uncomplicated lower UTI that may warrant first consideration.⁴⁵   A prospective, observational study amongst 139 females aged ≥15 years, clinically suspected for UTI, demonstrated that the most common urinary symptom presented was burning micturition (73.4%), followed by frequency (43.9%), urgency (20.9%), painful voiding (20.1%), difficulty (5.0%), and nocturnal incontinence (1.4%).⁴⁶

These patients with sensation of burning micturition can be offered alkalinizing agents for early symptoms resolution prior to initiating definite antibiotic treatment.^47-48

In above context, potassium citrate has superior efficacy in urine alkalization, and is preferred over sodium-containing salts, such as sodium bicarbonate or sodium citrate, as a first line urine alkalizing agent since it is highly palatable, has pleasant taste, and is tolerable even with long term use. Oral potassium citrate effectively increases urinary pH, thus resulting in less acidic urine and achieving its goal of urine alkalinization⁴⁹  , which may cater to the troublesome condition of painful and burning micturition in patients with UTIs.⁵⁰   Further to this symptomatic relief, it may also help in preventing the UTI as shown in a study in children with ≥ 2 episodes of UTI, a normal urinary tract, and with hypercalciuria, wherein treatment with potassium citrate resulted in no further episodes of UTI.⁵¹  

Such beneficial prophylactic effect of urinary alkalinization possibly relates to the finding that raising urinary pH may increase the ability of natural defense mechanisms to eliminate the infecting organisms. Potassium citrate normalizes pH of urine to 6-6.5 throughout the day; which possibly improves the ability of phagocytosis and killing of pathogens, such as E. coli and S. saprophyticus, by neutrophils.⁵²

Furthermore, potassium citrate does not neutralize gastric juice nor disturbs digestion. Potassium citrate is distinctly superior to sodium alkalizers because of the concern that sodium-containing salts require cautious use in patients with hypertension, heart failure, edema, renal impairment, eclampsia, or hyperaldosteronism, as they may cause excessive sodium load.⁵³

Suprapubic pain, urgency, and frequency-indication for a urinary spasmolytic

As mentioned earlier, symptoms of UTIs frequently include some combination of dysuria, urinary frequency, urgency, hematuria, and suprapubic pain^54-55      all of which needs to be considered for optimal patient outcomes. Use of an anticholinergic drug may be considered for these bothersome lower urinary tract symptoms in absence of significant post-void residual (PVR) urine volumes. However, there are concerns that these drugs may predispose to urinary retention, may be associated with anti-cholinergic side effects, and may cause drug-drug interactions, thus warranting their cautious use in carefully selected patients.

In such settings, the anti-spasmodic drug flavoxate, free from such concerns related to use of anticholinergics, is an obvious choice to alleviate the symptomatic burden of UTIs. Flavoxate is a smooth muscle relaxant with wide range of indications widely used to treat urgency and urge incontinence. In patients suffering from painful conditions of the lower urinary tract arising from inflammation
and/or infection or from spasm following diagnostic or therapeutic procedures, flavoxate was shown to result in statistically significant improvement in frequency and suprapubic pain, and marked relief was afforded in dysuria, hesitancy and burning.⁵⁶   The drug-in addition to having potent antispasmodic activity-has local anesthetic activity as good as lidocaine.⁵⁷

A systematic review comparing flavoxate and phenazopyridine-which evaluated nine trials of patients with symptoms of UTIs randomly assigned to treatment with either of the two drugs-showed that most symptoms improved in more patients on flavoxate therapy than on phenazopyridine therapy, thus favoring flavoxate. Symptom severity evaluations at 2 and 5 days of therapy in patients having symptoms of either prostatitis, acute cystitis, urethritis, and/or trigonitis showed that most symptoms improved in patients on flavoxate therapy than on phenazopyridine therapy. Also, more adverse effects were reported in patients treated with the alternative phenazopyridine.⁵⁸

Conclusion

UTIs remain a common clinical problem in the population, with most cases being acute uncomplicated UTIs, that can be identified based on clinical presentation only. Urine culture is often unnecessary for diagnosing typical symptomatic infection, but may be necessary in patients with recurrent UTIs to confirm the diagnosis and guide antibiotic therapy. Therefore, each case-across different subtypes of infection in different patient categories-should be carefully assessed to ensure correct diagnosis and appropriate antimicrobial therapy.

The goals of pharmacotherapy in lower UTIs are to eradicate the infection, provide symptomatic relief to patients, and prevent complications. In this context, nitrofurantoin appears a treatment of choice for most patients with UTIs for clearing the underlying infection. It is a good choice for initial empiric therapy of uncomplicated lower UTIs as it exerts antibacterial activity in the urine, and bacterial resistance is uncommon, particularly in an era when resistance to most alternative regimens is on rise among common community uropathogens. Potassium citrate may be used to make the urine less acidic, thereby managing the most bothersome symptom of painful and burning micturition. Also, flavoxate-a smooth muscle relaxant-may be used to treat urgency and urge incontinence, and several other symptoms of UTIs, such as frequency, suprapubic pain, dysuria, and hesitancy.

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