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Cystitis is a very common infection of the lower urinary tract. Women are typically affected, and more than 30 percent will experience at least one episode of cystitis in their lifetime. The diagnosis of this condition and its management are widely known and applied in the outpatient healthcare setting. However, recurrent cystitis, associated with a significant morbidity, is more challenging since their diagnostic evaluation, management and prevention differ significantly between disciplines. Several treatment and prevention options are offered to women with recurrent cystitis. Antibiotic prevention and treatment options should not be first-line, given the importance to limit resistance development and efficacy of alternatives in most situations. The proposed chapter is a narrative review on the current state-of-the-art for the diagnostic evaluation, management and prevention of recurrent cystitis, and aims to discuss other issues and aspects that could be addressed for an optimal management of this condition.
Farhat Hached Hospital, University of Sousse, Sousse, Tunisia
Sana Rouis
Ibn Jazzar Hospital, University of Sousse, Kairouan, Tunisia
Amel Omezzine Letaief
Farhat Hached Hospital, University of Sousse, Sousse, Tunisia
*Address all correspondence to: skander.es@gmail.com
1. Introduction
Urinary tract infections (UTI) are the most common adult bacterial infection in the world [1, 2]. UTI are twice more likely to occur in women than men over all age groups. A third of women are diagnosed with a UTI before the age of 24 years and half develop at least one episode by 35 years of age. Up to 70% of women will suffer from a UTI during their lifetime, and of those, 30% will have recurrent UTIs. Older women are more likely to get a UTI and suffer from recurrence [3, 4]. Interestingly, the majority of women experiencing recurrence do so despite culture directed antibiotic treatment, having no obvious abnormalities in the urinary tract, so-called uncomplicated UTI.
The differentiation between complicated and uncomplicated UTI has clinical importance for evaluation and type of treatment. In general, uncomplicated UTI is present in immunocompetent patients with no anatomical or functional abnormalities in their urinary tract system and host. Multi-Drug Resistant bacteria was added in the recent interdisciplinary guideline as a factor of complicated UTI [5]. The majority of guidelines reported on otherwise healthy non-pregnant women with uncomplicated rUTI or recurrent cystitis (RC).
RC poses significant clinical challenges, has a major impact on quality of life and represents a substantial social cost. This cost is usually shared between the patient as an out-of-pocket payment, and a co-payment or indemnity with an affiliated health insurance. This also depends on the complexity of the case that would require further investigation, treatment and prophylaxis [6]. According to a recent cost analysis in the United States, doctor visit and diagnosis tools for the RC can cost up to USD 700, the full course of acute antibiotics USD 22 on average for simple RC, or USD 3590 for multi-drug resistant RC. However, prophylaxis can cost on average USD 110 [6].
We present in this review an update on RC features of diagnosis, management and prevention in women who have no obvious causal factor for complications.
Contemporary studies and Guidelines define RC in healthy women as: three episodes of acute symptomatic cystitis in the previous 12 months or two episodes within the 6 months. Proof of a positive urine culture, with strain identification and susceptibility pattern, was also frequently incorporated in the definition. At least 2 culture-proven episodes are suggested. The usually accepted threshold of 105 CFU/mL could be lower (103 CFU/mL) in RC [7, 8]. Equal or more than 102 CFU/mL was also associated with a high Positive Predictive Value, in E. coli symptomatic acute cystitis and RC [9]. The differentiation between reinfection (different microorganism, more likely >2 week-interval) and persistent infection (same microorganism and < 2 weeks) is not incorporated in definition of RC. However, it’s important for clinician to consider reclassifying patient, treated for uncomplicated cystitis, which recur within 2 weeks, as complicated and require further investigation.
2.1 Etiology/pathogenesis
RCs may be caused by one of two mechanisms: repeated ascending infections or chronic/persistent infection in the bladder.
The source of repeated ascending infections, the same as acute UTI, occurs by the endogenous rectal flora via a perineal–urethral route. Bacteria migrate from the gastrointestinal tract into the bladder. Recent researches demonstrate a complex relationship between intestinal, vaginal and urinary microbiome [10].
The second mechanism, persistent infection in the bladder, explains that 48–80% of UTIs observed were due to a relapse with an E. coli strain identical to the primary infecting strain [8]. Moreover, antibiotics applied to the perineal area have been shown to be ineffective in reducing the risk of rUTI. The most plausible hypothesis is the survival of bacteria in bladder through the progression of transient intracellular bacterial communities (IBC) into persistent quiescent intracellular reservoirs. In UroPathogenic Escherichia coli (UPEC), of the adhesion molecules, type 1 fimbriae are more associated with IBC formation whereas P fimbriae have a close association with pyelonephritis. As shown in animal models, some species of E. coli possess the ability to create a state of quiescent infection in the bladder that may be responsible for multiple recurrences [11, 12].
More specifically, polymorphisms between individuals may include differences in blood groups and cell-mediated immunity [9]. The genetic background of susceptibility to rUTI is not fully understood, but remains an important area of investigation. Further investigation in this area may help lead to early identification of adults predisposed to rUTI and prediction of recurrence rates.
2.2 Risk factors
Understanding the risk factors associated with RC can help physicians to tailor prophylactic strategies to effectively reduce the potential for recurrence. Risk factors for RC can be divided into those related to premenopausal women, and those related to postmenopausal women (Table 1). The level of evidence for individual proposed risk factors in both groups varies, and myths about risk and erroneous risk-avoidance behaviors persist among both patients and physicians. However, treatment of asymptomatic bacteriuria in patients with RC has been shown to increase the risk of subsequent symptomatic UTI episodes and is therefore not recommended for these patients [11, 13].
Premenopause: Risk factors in premenopausal women include sexual intercourse, the use of spermicides that may alter vaginal pH and thus affect its flora, changes in bacterial flora, history of UTIs during childhood or family history of UTIs. A greater predisposition for vaginal colonization by uropathogens appears to result from genetic predisposition, potentially due to the increased ability of bacteria to adhere to the epithelium due to an increased expression of E. coli receptors on epithelial cells. Lack of postcoital urination, vaginal douches, restrictive underwear, and the hygiene and circumcision status of male partners have been proposed as risk factors, but lack an evidence base.
Postmenopause: A history of UTIs during premenopause increases postmenopausal risk of recurrence. Vulvovaginal atrophy is also a risk factor in this group due to the relationship between reduced estrogen and glycogen production and decreased Lactobacilli colonization. In addition, factors such as urinary incontinence, anterior vaginal wall prolapse, increased postvoid residual urine volume, and intermittent or permanent urinary catheterization predispose to complicated UTIs. Women aged >70 years have additional risk factors due to institutionalization with increased rates of catheterization, incontinence, prolapse surgery and decreased functional status.
Nomogram for predicting recurrence risk: A recently published study modeled recurrence risk based on two Italian populations from different centers. Using these data, a nomogram was produced to predict the likelihood of 12-month recurrence based on the most important risk factors identified [14].
The diagnosis of RC is based on clinical information and history that allow clinician to confirm and ensure proper reasoning of the diagnosis and management.
First of all, it is necessary to collect all relevant information, together with possibly mentioned in previous records, about the medical history (previous UTI episodes in the last years, antibiotics received for UTI or other infections, any chronic condition, including but not limited to immunosuppressive treatment, renal insufficiency, neurogenic bladder, pregnancy, menopause, current sexual intercourse and previous or existing sexually transmitted infections) [15, 16]. Some factors need to be taken into account, despite not having been largely described in the literature, such as anxiety and emotional disorders, that seem to interfere with complete voiding [17].
Furthermore, anamnesis should be conducted to put the episode of cystitis in its context, including the symptoms that are observed (dysuria, hematuria, nocturia, urgency) as these can predict the positivity of urine cultures, increasing the probability of having a UTI, however there is not a symptom that rules in exclusively the diagnosis of RC [18]. Anamnesis, as well as the physical examination (general, neurological, renal, vaginal), are also important to remove suspicions of other diagnostics, structural abnormality or altered associated comorbidities [16]. Intuitively, it is possible to confirm the diagnosis of recurrent bacterial cystitis based on the definition mentioned above [8].
3.1.2 Urinalysis and urine culture
The prescription of urine dipstick and urine culture varies across guidelines, which may differentiate the entity ‘culture proven episodes of acute bacterial cystitis and associated symptoms’ [5]. Most recent guidelines except the UK National Institute for Clinical Healthcare and Excellence (NICE) emphasized the importance of urine cultures for the initial diagnosis of RC [19, 20].
In general, both urine examination and urine culture contribute to the diagnosis of RC [5]. In fact, the urine culture often clarifies doubts regarding urine analysis results accuracy. On the other hand, urine analysis can rapidly facilitate the diagnosis and help the clinician, in relatively frequent occurring, with false positive and contaminated urine culture. Combining results of both tests can improve the authenticity of the diagnosis [21]. For the diagnosis of each acute RC episode, guidelines were variable. While it has been shown useful in some recommendations to prescribe dipstick and culture for each acute episode, the EAU and AAFP indicated that repeated urine culture is usually not required if typical symptoms are present and patients are appropriately responding to antibiotics. They should also be performed at least once when the patient is symptomatic [16].
In the case of persistence of symptoms of UTI following a confirmed diagnosis of RC and appropriate use of antimicrobials, some situations are to be considered [22]:
If the urine culture was positive, and it becomes negative, it may be normal to have ongoing symptoms due to the hypersensitivity of the bladder, especially after a severe UTI episode, and it can be associated with a dysfunction of the pelvic muscle floor. Therefore, the treatment is focused on prevention and hygienic lifestyle (i.e., heading 5. prevention).
If the urine culture was initially negative or not performed, and/or other symptoms are associated such as microhaematuria ± micropyuria, other investigations should be performed in order to rule out other diagnostics (i.e., heading 3.a.iii further investigations).
It is widely known that RC culture analyses isolate negative gram rods largely dominated by E. coli, followed by Staphylococcus saprophyticus, Proteus mirabilis, and Klebsiella pneumoniae [11].
3.1.3 Further investigations
RC does not require extensive investigations apart from the urine analysis [8]. Cystoscopy and imaging should only be performed without delay in atypical cases, for example, if renal calculi, outflow obstruction, interstitial cystitis or urothelial cancer is suspected [15]. Furthermore, cystoscopy should be recommended also in women that are suspected to suffer from trigonitis. The term “trigonitis” was first introduced in the literature in 1905 as cystitis trigoni [23]. In fact, the reason behind the distinct trigonal endoscopic findings in trigonitis and its underlying pathophysiology is poorly understood. Cystoscpic evaluation is sufficient for the diagnosis and subsequent management of these patients [24]. Endoscopic findings in trigonitis reveal inflammatory lesions such as cystitis cystica, cystitis glandularis, and occasionally small tiny stones within the triangular boundaries of the trigone. Numerous therapeutic strategies have been reported to treat symptomatic trigonitis, including antibiotic therapy, intravesical instillation of different agents, electrofulguration and laser coagulation [25, 26, 27].
Further investigation and referral to specialists are indicated in these situations [19].
The SOGC and AWMF guidelines recommend cystoscopy and upper tract imaging in patients with hematuria and persistent urine culture of bacteria other than E coli (expert opinion; insufficient evidence) [8].
RC leads to a regular consumption of antimicrobials. The choice of antimicrobial therapy is guided by three parameters: efficacity, tolerability, and ecological impact on the gut microbiota [28]. On the other hand, cystitis can be treated with non-antimicrobial treatments of proven efficacy.
4.1 Antimicrobial treatment and stewardship
Without treatment, recurrent cystitis occurring in women with no risk factors of complication is often self-limiting over time and rarely associated with serious complications [29]. However, antimicrobial treatment usually improves symptoms and eliminates bacteria within a few days [30]. Hence, patients with RC should be treated during symptomatic episodes, with an Antimicrobial.
Oral treatment with Fosfomycin-trometamol, Pivmecillinam and nitrofurantoin should be considered for first line treatment, when available. Alternative antimicrobials including trimethoprim alone or combined with a Sulphonamide (Co-trimoxazole) or trimethoprim should only be considered as drugs of first choice in areas with known resistance rates for E. coli of <20% [15].
In fact, due to the increasing prevalence of multiresistant bacteria, it is capital to avoid antimicrobial overprescribing. Especially, it is important to save antimicrobials that induce the emergence of antimicrobial resistance, such as the so-called “critically important antimicrobials” [31].
4.1.1 Antimicrobial resistance
Antimicrobial resistance is now one of the most major threats to patient safety worldwide [32]. Resistance to amoxicillin is now 79.8% among urinary isolates of E. coli in some countries in Africa, and high levels of resistance to many commonly prescribed antimicrobials have been identified worldwide [33]. More than 20% of E. coli strains causing uncomplicated cystitis are now resistant to these agents in several regions of the United States and other countries [34]. The prevalence of resistance to nitrofurantoin among E. coli strains is <5%. However, uropathogens non-E. coli are often resistant to it. On the other hand, the overuse of fluoroquinolones, antimicrobials that induce the emergence of antimicrobial resistance created resistance to these drugs in UPEC. This resistance is particularly marked in developed countries (55–85% of resistance), compared with developing countries (5–30% of resistance) [35].
Three-day dosing regimens are recommended because of their association with better adherence, lower cost, and lower frequency of adverse reactions, compared to 7–10 day regimens [36]. Several studies confirmed the efficacy of the dosage regimens of 3 days of trimethoprim (TMP), trimethoprim-sulfamethoxazole (TMP-SMX), or a fluoroquinolone for taking management of acute uncomplicated cystitis [36]. By comparison, three-day beta-lactam regimens are less effective than ≥5 days of treatment [36]. Nitrofurantoin is a safe and effective agent but should be administered for a minimum of 7 days. The equivalence of the efficacy of a five-day treatment at nitrofurantoin and a 3-day course of TMP-SMX has been demonstrated [37]. Among other reasonable empirical choices in terms of uncomplicated cystitis, there is also the administration of a single dose of Fosfomycin [36]. The single-dose regimens are less effective than schemas dosages of three to 7 days, even with fluoroquinolones [36, 38]. However, fluoroquinolones can become a reasonable first-line treatment for women in whom the presence of resistance to antimicrobials or an allergy or intolerance to more conventional treatment is confirmed or suspected, as well as for women living in areas where resistance to TMP-SMX is <20% [36].
4.1.2 Side-effects of antimicrobials
Antimicrobial associated collateral damage is critical, producing long-term side effects in the individual patient as well as society as a whole. Several studies have shown that fluoroquinolones and cephalosporins are more likely than other classes of antimicrobials to alter fecal microbiota, and cause Clostridium difficile infection and other damage. In fact, fluoroquinolones should not be used to treat acute uncomplicated cystitis because the disabling and serious adverse effects result in an unfavorable risk-benefit ratio [15, 39]. On the other hand, pivmecillinam has an unknown safety profile and potential carnitine deficiency with prolonged use, especially in prophylaxis [40].
4.1.3 Current guidelines for the management of cystitis
The literature search showed that there are several available guidelines affording recommendations for the management of recurrent cystitis. All guidelines recommended short (< 7 days) courses of antimicrobials for treatment of acute episodes in those with recurrent cystitis, rather than prolonged courses [8].
The guidelines of the European Association of Urology (EAU) provided an updated table recapitulating the first-line treatments and alternatives together with the daily dose and the duration of the therapy for recurrent cystitis [15] (Table 2). The EAU guidelines strongly recommend not to use aminopenicillins or fluoroquinolones to treat uncomplicated cystitis. However, fluoroquinolone can be prescribed when the use of other antibiotics recommended for the treatment of these infections is considered inappropriate [15].
Antimicrobial
Daily dose
Therapy duration
First line women
Fosfomycin-trometamol
3 g SD
1
Nitrofurantoin macrocristal
50–100 mg q.i.d.
5
Nitrofurantoin monohydrate/macrocrystal
100 mg b.i.d.
5
Nitrofurantoin microcrystal ER
100 mg b.i.d.
5
Pivmecillinam
200 mg t.i.d
3–5
Alternatives
Cephalosporins (eg, cefadroxil)
500 mg b.i.d.
3
If the local resistance pattern for E. coli is <20%
Trimethoprim
200 mg b.i.d
5
Trimethoprim-sulfamethoxazole
160–180 mg b.i.d
3
Table 2.
First-line treatments and alternatives together with the daily dose and the duration of the therapy for cystitis recommended by the EAU [15].
b.i.d. = bis in die (twice a day); EAU = European Association of Urology; q.i.d. = quarter in die (four times a day); SD = single dose.
The Table 3 showed a comparison of the different guidelines: AUA/CUA/SUFU, SOGC and AAFP [8]. Symptomatic management with analgesia in patients with suspected cystitis is supported by the AUA/CUA/SUFU (while awaiting results of urine culture) and SSGO (delay antibiotics for 48 hours and administer analgesia in non-pregnant women aged <65 years with uncomplicated cystitis). Likewise, the NICE guidelines advise on symptomatic management for all patients, but recommended immediate antimicrobials for non-pregnant women, either immediately or deferred if stable or worsening symptoms after 48 h.
Expectant management of recurrent cystitis with analgesia
Antibiotics are recommended but can consider symptomatic therapy in consultation with patient
Likely underutilized, can attempt whilst awaiting cultures
—
Immediate antibiotics leads to better clinical outcomes and delaying antibiotics whilst awaiting cultures is not recommended
Recommend a short course of antibiotic treatments (no longer than 7 days)
Recommend short courses in uncomplicated cystitis nitrofurantoin and fosfomycin-trometamol as first-line antibiotics
Moderate recommendation, evidence level B nitrofurantoin and fosfomycin-trometamol as first-line antibiotics cotrimoxazole among the first-line antibiotics, with the condition “ dependent on the local antibiogram ”
Recommended antibiotics for a duration of up to 7 days
- Recommend a short course of antibiotics
Recommend self-initiated acute treatment for compliant patients
Strong recommendation
Moderate recommendation
Moderate recommendation
Offer for those who decline prophylactic antibiotics
Table 3.
Comparison of guidelines’ key recommendations on the diagnosis and initial management of recurrent cystitis [8].
European Association of Urology.
American Urology Association/Canadian Urology Association/ Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction.
Society of Obstetricians and Gynecologists of Canada.
American Academy of Family Physicians.
Both the AUA/CUA/SUFU and EAU guidelines advocate nitrofurantoin and fosfomycin-trometamol as first-line antimicrobials for the treatment of symptomatic cystitis. The AUA/CUA/SUFU guidelines also include cotrimoxazole among the first-line antimicrobials, with the condition “dependent on the local antibiogram for the treatment of symptomatic cystitis in women”, without specifying whether this refers to the patient’s antibiogram or the local resistance model [41]. Of the old antimicrobials, the EAU guidelines also include pivmecillinam, an effective molecule according to systematic reviews and meta-analyses [15, 42].
In patients with good compliance, self-diagnosis and self-treatment with a short course regimen of an antimicrobial agent should be considered [15, 42]. The choice of antimicrobials is the same as for sporadic acute uncomplicated cystitis. It is important to notice that patients with recurrent cystitis, developing acute urinary tract infection while receiving antibiotic prophylaxis, should be treated with an alternative Antimicrobial according to the antibiogram.
4.2 Non-antibiotic treatment
We are encountering a real rise in rates of resistance to antimicrobials to undesirable levels worldwide; and untreatable cystitis presents a real concern. This problem is exacerbated by the overuse of antimicrobials. To control this crisis in antimicrobial resistance, nonantimicrobial approaches may be a very interesting alternative to reduce symptoms in acute uncomplicated cystitis without recurring to antimicrobial use [43].
4.2.1 Nonsteroidal anti-inflammatories (NSAIDs)
No studies evaluating NSAIDs as a curative and prophylactic agent for RC have been conducted. However, two randomized controlled trials have evaluated the use of the NSAID (Ibuprofen) for the treatment of acute uncomplicated cystitis in women with interesting results [44, 45].
4.2.2 Chinese herbal medicine (CHM)
The biological plausibility of CHM for recurrent cystitis is supported by in vitro research suggesting that some commonly used Chinese herbs may confer significant diuretic, antibiotic, immune enhancing, antipyretic, anti-inflammatory and, pain-relieving activities for the treatment of recurrent cystitis [46]. Individual herbs such as Huang Lian (Coptis Chinensis Franch) have large spectrum antibacterial activity but also display specific action against E. coli [47]. There is growing evidence that some herbal medicines can disable bacterial efflux pumps, and may serve as an important adjuvant treatment to conventional antibiotics [48].
In a recent Meta-analysis comparing the overall effectiveness of treatments during acute phases of infection and rates of recurrence, CHM had a higher rate of effectiveness for acute cystitis (RR 1.21, 95% CI 1.11 to 33) and reduced recurrent cystitis rates (RR 0.28, 95% CI 0.09 to 0.82). Active CHM treatments were more effective in reducing infection incidence (RR 0.40, 95% CI 0.21 to 0.77) [49]. However, the evidence in the premenopausal women is limited. For these reasons, the use of CHM cannot be recommended until larger, and well-conducted randomized trials are performed.
4.2.3 Follow-up
Post-treatment urine cultures in asymptomatic patients are not indicated (Figure 1).
Figure 1.
Algorithm of management of recurrent cystitis.
RC occurring during the first 2 weeks after treatment of an acute episode suggests a possible relapse and should be managed with pre-treatment urine culture, determination of antimicrobial susceptibility, and treatment with fluoroquinolone for 7 days [15, 28, 38]. Clinical monitoring only is required, and a urine culture should still be performed in case of clinical failure [15, 28].
Antibiotics are usually effective in the management of acute infections and are the primary means of prophylaxis for patients who experience RC. However, their value is diminished by the emergence of increasing drug-resistant bacteria. Therefore, it is important to develop alternative prevention strategies.
5.1 Hygienic and dietary measures
Given the stepwise passage of intestinal germs the perineum, then towards the bladder by migrating through the urethra, it is accepted that a simple daily washing of the vulva limits proliferation. Washing before and after sexual intercourse (for both partners) and post-coital micturition can reduce the occurrence of post-coital cystitis [50]. According to the same study, daily changes of underwear also have a significant impact on the accumulation of bacteria in the vulvar region. An interesting British study on post-void wiping habits shows that the directions of the toilet paper have a significant impact on the risk of developing a UTI [51]. It is strongly recommended to wipe from front to back, which is not the case in most countries. This is not the case in almost 50% of this panel of women.
Hydration: The flow of urine mechanically slows down the migration of bacteria to the bladder. It is therefore necessary to diuresis (2 L/day) by sufficient and regular water intake in accordance with the recommendations of the European Food Safety Authority (EFSA) [52], as well as good voiding habits (C-III) [53]. It has been shown that effective flushing of the urinary tract through urine is essential to reduce the uropathic load, provided that bladder emptying is regular and complete provided that regular and complete emptying of the bladder is achieved [54].
Micturition habits: It is essential that micturition is regular. Some micturition habits are unsuitable because they are insufficient (<5 micturitions/d) often because some women hold back. A simple micturition calendar could then be set up over a few days to visualize the micturition calendar the rhythm of micturition and thus to regularize it. In some cases, a voiding reprogramming can be considered. This consists of imposing regular micturition at fixed times initially, then adapted to the diuresis and needs. The regulation of intestinal transit is recommended by professional agreement as a prophylactic measure in the recommendations of the French Agency for Health Products Safety (Afssaps) [55].
Contraception: Women suffering from RC who use a contraceptive method containing a spermicide should be offered an alternative form of contraception.
These conservative measures may be advised, although the evidence is inconclusive.
5.2 Non-antimicrobial prophylaxis
The rationale behind non antimicrobial therapy results from two main drawbacks of the antimicrobial prophylaxis: (i) the emergence of resistant strains in the urine and (ii) the failure to fully eradicate microorganisms with antimicrobial therapy in RC.
5.2.1 Cranberries
Cranberry (in Latin, vaccinium macrocarpon) has attracted a great interest in medical research. The effects of proanthocyanidins (PACs), active constituents inhibiting the adhesion of E. coli to uroepithelial cells, have been studied or mentionedin a multitude of publications. It appears that their efficacy, even if controversial, have been shown to be effective in recurrence of cystitis in 20–50% of cases [56]. Cranberry was been shown to be associated to a significant antibiotic consumption decrease. In fact, compliance seems to be better in capsule or powder form (capsules) than in juice. The minimum effective daily dose would be 36 mg of PACs [56, 57]. The duration of action of the active ingredient is proportional to the ingested dose. Thus, 36 mg of PACs twice a day would be preferable for a more prolonged anti-adhesion effect [58]. Cranberry has no significant contraindications. However, there are some undesirable effects, particularly at high doses [57]. The most frequent observed side effects include: episodes of nausea and gastro-esophageal reflux, infrequent, with cranberry juice; mild laxative effects; increased risk of stones with long-term intake in capsule. It should be noted that the consumption of cranberries is contraindicated in the case of treatment with warfarin. A recent Cochrane review of 10 studies with a total of 1049 participants found some evidence that cranberry juice and its derivatives may reduce the number of symptomatic UTIs over a 12-month period, particularly in women who experience RC [59]. Furthermore, there are no definitive data on the amount and the duration of administration for the intervention to reach its maximum effectiveness. Recent data from guidelines showed that experts and panels continue to recommend cranberries for the prophylaxis of RC (Grade C) [60].
5.2.2 D-mannose
Normally present in the human metabolism, D-mannose is involved in the glycolysis of proteins. This simple monosaccharide, naturally found in various plants, and fruits/berries, have the potential to inhibit bacterial adhesion to uroepithelial. Research suggests that free D-mannose in urine saturate E. coli FimH structures, and subsequently block E. coli adhesion to urinary tract epithelial cells. This so-called competitive inhibition is considered as one of the potential mechanisms for preventing UTI development. In fact, type 1 pili mediate binding, invasion, and biofilm formation of UPEC in the host urothelium during urinary tract infection via the adhesinFimH. Although type 1 fimbriae were extensively studied in E.coli, type 1 pili have been documented in several other uropathogens commonly involved in RC, for example, Klebsiella pneumoniae. Furthermore, D-mannose does not present an antibiotic-like activity, considering that it does not induce FimH variants that can modify bacterial adhesiveness.
The overall picture of clinical studies with D-mannose in the prophylaxis of RC is favorable. In an open-label clinical trial conducted on 308 women, 3 groups of women over 6 months were compared against the control group, D-mannose (2 g powder/d) provided the same result as daily nitrofuratoin (50 mg/d) [61]. Thus, the risk of recurrence of UTI was reduced by 45%. In addition, the antibiotic caused more adverse events (29%: diarrhea, nausea, skin rush, headache, vaginal burning), whereas D-mannose induced only a few episodes of diarrhea in 8% of cases. However, not many scientific papers advise a daily prophylactic dose of 2 to 3 g of D-mannose. No side effects have been reported [37, 62]. NICE warns takers of cranberry products or D-mannose for the sugar content of these products, which should be considered as part of the person’s daily sugar intake [19]. Yet, the quality of studies interested on D-mannose leaves something to be desired; they are mostly confounded with other active ingredients, have small numbers of participants, are open label or uncontrolled.
5.2.3 Vaginal estrogen
Overall, commonly prescribed forms of vaginal estrogen with contemporary dosing schedules can prevent UTIs in postmenopausal women with RC. As a result, the AUA guidelines recommend in peri- and post-menopausal women with RC, clinicians should recommend vaginal estrogen therapy to reduce the risk of future UTIs if there is no contraindication to estrogen therapy (Moderate Recommendation; Evidence Level: Grade B) [8]. However, according to all current guidelines, clinicians should not recommend systemic estrogen to reduce the risk of RC in postmenopausal women.
Data from two small randomized controlled trials indicate that in postmenopausal women with recurrent UTI, the administration of vaginal estrogen results in fewer UTIs [63, 64]. However, there is no sufficient data to recommend one type or form of vaginal estrogen. Creams are less expensive than rings and tables, and may be more effective but they may also be more difficult to apply for some women and may have some side effects (itching, burning, occasional spotting) [62, 63].
5.2.4 Methenamine hippurate
Methenamine Hippurate is a urinary antiseptic agent that is converted to formaldehyde in an acidic urine environment which is directly toxic to bacteria. A randomized control trial in 2022 demonstrated Methenamine Hippurate was non-inferior to prophylactic antibiotics for reducing the incidence of symptomatic UTIs over a 12-month period. Continuous methenamine prophylaxis avoids the risks of long-term prophylactic antibiotic treatment including the development of antibiotic resistance. NHS guidelines recommends that Methenamine might be appropriate for women with a history of RC, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in various studies [65].
5.2.5 Glycosaminoglycan (GAG) therapy
Exogenous GAGs especially in the combination of HA + CS were investigated for efficacy in preventing RC. Various studies demonstrated intravesical GAGs reduced the recurrence of UTIs caused by E. coli and showed clinical benefit up to 36 months after treatment. A randomized double-blind controlled trial of HA + CS + CaCl (four instillations at weekly intervals then five instillations at monthly intervals) monitored for 12 months and patients treated with GAGs therapy had fewer RC and a longer interval free from recurrence [66]. However, the high cost of this treatment still represents a limit, especially with intravesical instillations.
5.2.6 Probiotics
Instillation of Lactobacillus in the vagina is considered to stop the ascent of uropathogens into the bladder. A randomized trial compared high-dose cranberry with Lactobacillus and vitamin A to placebo, and provided low-strength evidence that fewer patients had UTI recurrences with treatment (9.1% versus 33.3%, p = 0.0053) [67]. The available studies suggest that probiotics may be beneficial and most authors consider this approach to be promising, but further research is required before probiotics can be recommended for use in the prevention of UTIs.
5.2.7 Immunoprophylaxis: vaccines
Injectable and oral vaccines have been developed in the last decades and shown to be effective and not associated with any observable adverse effects in pregnant women and their offspring [68]. In order to eliminate some of the adverse reactions of the parenteral vaccine, four mucosal vaccines have been developed in the form of a vaginal suppository or oral tablet form; however, the benefits of the vaccine appeared to wane following the last dose [69]. The safety of the only parenteral vaccine currently under development (FimCH) has been proven safe in a Phase I clinical trial. A recent meta-analysis showed that OM-89 (Uro-Vaxom®) showed the greatest reduction in UTI recurrence with a maximum effect shown at 3 months compared with 6 months (RR = 0.67, 95% CI 0.57–0.78). Recent guidelines recommend the use of OM-89 oral vaccine as prophylaxis for RC (Moderate to strong recommendation) [8, 68].
5.2.8 Acupuncture
Two small trials have evaluated the role of acupuncture, compared to placebo acupuncture or no treatment, in the prophylaxis of RC. Over a six-month period, both studies showed that acupuncture could play a significant role in the prevention of RC. They concluded that acupuncture appeared to be a valid alternative to the antibiotic strategy [70].
5.3 Antimicrobial prophylaxis
5.3.1 Prophylactic antibiotics
There are many antimicrobial options for the prevention of RC. A Cochrane review of 19 trials indicated that antibiotics were more effective than placebo in reducing the number of clinical and microbiological recurrences in premenopausal and postmenopausal women with RC [38, 42]. Studies comparing intermittent (post coital) with continuous strategies revealed equal effectiveness. NICE has licensed Nitrofurantoin and Trimethoprim for the prophylaxis of RC. However, all antibiotics have potential risks that should be discussed with patients prior to prescribing for short-, medium-, or long-term prophylaxis. The most tested schedule of antibiotic prophylaxis (TMP, TMP-SMX, nitrofurantoin, cephalexin) was daily dosing. However, Fosfomycin used prophylactically is dosed every 10 days. The duration of antibiotic prophylaxis in the literature ranged from 6 to 12 months. In clinical practice, the duration of prophylaxis can be variable, from 3 to 6 months to 1 year, with periodic assessment and monitoring. Some women stay on continuous or post-coital prophylaxis for years to maintain the benefit without adverse events. However, it should be noted that continuing prophylaxis for years is not evidence-based. The choice of antibiotic should be based on community resistance patterns, adverse events and local costs.
The three main management strategies generally considered are continuous antimicrobial prophylaxis, post-coital prophylaxis and self-treatment patient [38, 42].
5.3.2 Continuous antimicrobial prophylaxis
Continuous prophylaxis can be administered daily at bedtime. Some authors suggest prophylaxis every second night or three nights a week. One study showed that weekly prophylaxis was more effective than monthly prophylaxis. No studies have compared daily and weekly prophylaxis [71]. No recommendation can be made as to the optimal prophylaxis.
5.3.3 Post coital antimicrobial prophylaxis
A causal relationship between infections and sexual intercourse may be suspected when the interval is consistently between 24 and 48 hours [38]. Two studies suggest that in sexually active women experiencing a UTI associated with sexual intercourse the post-coital approach may be a better option [72]. In fact, antibiotic prophylaxis taken before or after sexual intercourse has been shown to be effective and safe. This use of antibiotics is associated with a significant reduction in recurrence rates. Additionally, intermittent dosing is associated with decreased risk of adverse events including gastrointestinal symptoms and vaginitis.
5.3.4 Choice of agents of prophylaxis
For women with RC who are not pregnant, consider a trial of antibiotic prophylaxis only if behavioral and personal hygiene measures, and vaginal estrogen (in postmenopausal women) are not effective or not appropriate [8].
For women with RC; ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis if behavioral and personal hygiene measures alone are not effective or not appropriate, with specialist advice.
Review antibiotic prophylaxis for RC at least every 6 months, with the review to include: assessing the success of prophylaxis; discussion of continuing, stopping or changing prophylaxis (taking into account the person’s preferences for antibiotic use and the risk of antimicrobial resistance) (Table 4, Figure 2).
This chapter is a narrative review of the current state-of-the-art for the diagnostic evaluation, management and prevention of recurrent bacterial cystitis, and aims to discuss other issues and aspects that could be addressed for the optimal management of this condition.
After a well-conducted anamnesis, the diagnosis of RC should be confirmed. Thus, most recent guidelines emphasized the importance of urine cultures for the initial diagnosis of RC [19, 20]. RC does not require extensive investigations apart from urine analysis and urine culture [8]. Cystoscopy and upper tract imaging are recommended in patients with hematuria and persistent urine culture of bacteria other than E. coli [8]. For the management of RC, antimicrobial treatment usually improves symptoms and eliminates bacteria within a few days. Oral treatment with Fosfomycin-trometamol, Pivmecillinam and nitrofurantoin should be considered for first-line treatment, when available. Alternative antimicrobials including trimethoprim alone or combined with a Sulphonamide (Co-trimoxazole) should only be considered as drugs of first choice in areas with known resistance rates for E. coli [15].
Although prophylactic antibiotics remain the preferred preventive treatment in rUTIs, the emergence of antimicrobial resistance worldwide has made the development of non-antibiotic strategies a priority. In this review, we discussed vaccines, D-mannose, Vaginal estrogen, Methenamine Hippurate, Glycosaminoglycan (GAG) therapy, probiotics, bacteriophages, and acupuncture, highlighting the challenges each of these approaches face. Lactobacillus-containing products and cranberry products in conjunction with propolis have shown the most robust results to date and appear to be the most promising new alternative to currently used antibiotics. On another side, proper bladder management is crucial. Women suffering from RC should improve the voiding patterns before or after intercourse and the frequency of urination, ensure good hydration and change contraception based on spermicide. They also should be advised to follow some hygienic measures e.g. avoid the use of hot tubs and tight clothing, although evidence is inconclusive.
A better understanding of UTIs mechanisms will help direct future research on the topic. The nonantibiotic alternatives for rUTI seem promising, but research needs to focus better on the nonantibiotic treatment and prophylaxis of recurrent UTI. Double-blind, placebo-controlled, randomized studies are required to provide high-level evidence of efficacy for all the agents discussed above. A combination of these agents might be the most efficient process to reduce the rate of recurrent UTI without turning to antimicrobial use. Studies of combination therapies in specific patients (such as premenopausal women, postmenopausal women, and men) are also needed to target these treatments optimally. Research into the underlying molecular mechanisms of bacterial adherence and invasion seems most promising and could lead to the identification of novel targets for drug development. These strategies aim to reduce the crisis of antimicrobial resistance and pave the road for a new era in the management of recurrent UTIs.
Canadian Urological Association (CUA) and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU)
COMEGO
Mexican College of Gynecology and Obstetrics Specialists
EAU
European Society of Urology
NICE
National Institute of Clinical Healthcare and Excellence
RC
Recurrent cystitis
rUTI
Recurrent Urinary Tract Infection
SOGC
Society of Obstetricians and Gynecologists of Canada
SSGO
swiss Society of Gynecology and Obstetrics (SSGO)
SEIMC
Spanish Society of Clinical Microbiology and Infectious Diseases
TMP
trimethoprim
TMP-SMX
trimethoprim-sulfamethoxazole
UPEC
Uropathogenic E. coli
UTI
Urinary Tract Infection
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Written By
Skander Essafi, Maha Abid, Sana Rouis and Amel Omezzine Letaief
Submitted: 07 January 2023Reviewed: 03 April 2023Published: 21 July 2023
Open access peer-reviewed chapter
