Urological Infections Epidemiology, aetiology and pathophysiology Part 1

Urological Infections

Epidemiology, aetiology and pathophysiology

Part 1

Comprehensive Review Article

Prof. Dr. Semir. A. Salim. Al Samarrai

 Classification:

Different classification systems of UTI exist. Most widely used are those developed by the Centres for Disease Control and Prevention (CDC) [1], Infectious Diseases Society of America (IDSA) [2], European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [3] as well as the U.S. Food and Drug Administration (FDA) [4,5]. Current UTI guidelines frequently use the concept of uncomplicated and complicated UTI with a number of modifications (Figure 1).

Figure 1: Concept of uncomplicated and complicated UTI

 

 

 

 

 

The following classification of UTIs is adopted in the EAU Urological Infections Guidelines:

 

 

 

 

 

 

 

 

• Antimicrobial Stewardship

Although the benefits to patients of antibiotic use are clear, overuse and misuse have contributed to the growing problem of resistance amongst uropathogenic bacteria, which is a serious threat to public health [6,7]. In acute care hospitals, 20-50% of prescribed antibiotics are either unnecessary or inappropriate [8]. In response, a worldwide initiative seeks to incorporate Antimicrobial Stewardship programs in healthcare [9]. Antimicrobial Stewardship aims to optimise clinical outcomes and ensure cost-effective therapy whilst minimising unintended consequences of antimicrobial use such as healthcare associated infections including Clostridium difficile, toxicity, selection of virulent organisms and emergence of resistant bacterial strains [10].

  Asymptomatic bacteriuria in adults:

• Background

Urinary growth of bacteria in an asymptomatic individual (asymptomatic bacteriuria – ABU) is common, and corresponds to a commensal colonisation [11]. Clinical studies have shown that ABU may protect against superinfecting symptomatic UTI, thus treatment of ABU should be performed only in cases of proven benefit for the patient to avoid the risk of selecting antimicrobial resistance and eradicating a potentially protective ABU strain [12,13].

• Epidemiology, aetiology and pathophysiology

Asymptomatic bacteriuria occurs in an estimated 1-5% of healthy pre-menopausal females. Increasing to 4-19% in otherwise healthy elderly females and men, 0.7-27% in patients with diabetes, 2-10% in pregnant women, 15-50% in institutionalised elderly populations, and in 23-89% in patients with spinal cord injuries [14]. Asymptomatic bacteriuria in younger men is uncommon, but when detected, chronic bacterial prostatitis must be considered. The spectrum of bacteria in ABU is similar to species found in uncomplicated or complicated UTIs, depending on the presence of risk factors.

• Diagnostic evaluation

Asymptomatic bacteriuria in an individual without urinary tract symptoms is defined by a mid-stream sample of urine showing bacterial growth > 105 cfu/mL in two consecutive samples in women [15] and in one single sample in men [16]. In a single catheterised sample, bacterial growth may be as low as 102 cfu/mL to be considered representing true bacteriuria in both men and women [14,17]. Cystoscopy and/or imaging of the upper urinary tract is not mandatory if the medical history is otherwise without remark. If persistent growth of urease producing bacteria, i.e. Proteus mirabilis is detected, stone formation in the urinary tract must be excluded [18]. In men, a digital rectal examination (DRE) has to be performed to investigate the possibility of prostate diseases.

Disease management:

• Patients without identified risk factors

Asymptomatic bacteriuria does not cause renal disease or damage [19]. Only one prospective, non-randomised study investigated the effect of treatment of ABU in adult, non-diabetic, non-pregnant women [20], and found no difference in the rate of symptomatic UTIs. Furthermore, as the treatment of ABU has been proven to be unnecessary in most high-risk patient subgroups, there is panel consensus that the results of these subgroups can also be applied to patients without identified risk factors. Therefore, screening and treatment of ABU is not recommended in patients without risk factors.

• Patients with ABU and recurrent UTI, otherwise healthy

One RCT investigated the effect of asymptomatic bacteriuria (ABU) treatment in female patients with recurrent symptomatic UTI without identified risk factors [13] and demonstrated that treatment of ABU increases the risk for a subsequent symptomatic UTI episode, compared to non-treated patients (RR 0.28, 95% CI 0.21 to 0.38; n=673). This protective effect of spontaneously developed ABU can be used as part of prevention in female patients with recurrent symptomatic UTI; therefore, treatment of ABU is not recommended.

Pregnant women:

• Is treatment of ABU beneficial in pregnant women?

Twelve RCTs comparing antibiotic treatments of ABU with placebo controls or no treatment [21-32], with different antibiotic doses and regimens were identified, ten published before 1988 and one in 2015. Eleven RCTs (n=2,002) reported on the rate of symptomatic UTIs [21,23-31,33]. Antibiotic treatment significantly reduced the number of symptomatic UTIs compared to placebo or no treatment (average RR 0.22, 95% CI 0.12 to 0.40).

Six RCTs reported on the resolution of bacteriuria [21-23,25,28,30]. Antibiotic treatment was effective in the resolution of bacteriuria compared to placebo (average RR 2.99, 95% CI 1.65 to 5.39; n=716). Eight RCTs reported on the rate of low birthweights [21,23-26,29,32,33]. Antibiotic treatment was associated with lower rates of low birthweight compared to placebo or no treatment (average RR 0.58, 95% CI 0.36 to 0.94; n=1,689). Four RCTs reported on the rate of preterm deliveries [29,30,32,33]. Antibiotic treatment was associated with lower rates of preterm delivery compared to placebo or no treatment (average RR 0.34, 95% CI 0.18 to 0.66; n=854).

Based on the beneficial maternal and foetal effects of antibiotic treatment pregnant women should be screened and treated for ABU. However, the panel of EAU Guidelines edition 2022 would like to emphasize that most available studies have low methodological quality and are from the 60s to 80s. Diagnostic and treatment protocols and accessibility to medical services have dramatically changed since then; therefore, the quality of evidence for this recommendation is low. In a newer study of higher methodological quality, the beneficial effects of antibiotic treatment are not as evident [33]. Therefore, it is advisable to consult national recommendations for pregnant women.

• Which treatment duration should be applied to treat ABU in pregnancy?

 Sixteen RCTs comparing the efficacy of different antibiotic treatments in pregnant women with ABU were identified [34-49]. There was significant heterogeneity amongst the studies. Studies compared different antibiotic regimens or the same antibiotic regimens with different durations. The duration of treatment ranged from single dose to continuous treatment (until delivery). For practical purposes the grouping strategy used by the previously published Cochrane review by Widmer et al., was adopted with some modifications [50]. The following treatment groups were used for comparison:

1. single dose (single day);
2. short course (2-7 days);
3. long course (8-14 days);
4. continuous (until delivery).

Nine studies compared single dose to short course treatment [35,39,40,44-49], one study compared single dose to long course treatment [43] and one study compared long course to continuous treatment [36]. As long term and continuous antibiotic treatment is not used in current practice, only studies comparing single dose to standard short course treatment are presented.

• Single dose vs. short course treatment Three RCTs reported on the rate of symptomatic UTIs [39,48,49], with no significant difference between the two durations (average RR 1.07, 95% CI 0.47 to 2.47; n=891). Nine RCTs reported on the rate of ABU resolution [35,39,40,44-49], with no significant difference between the two durations (average RR 0.97, 95% CI 0.89 to 1.07; n=1,268). Six RCTs reported on the rate of side effects [35,39,44,45,47,48]. Single dose treatment was associated with significantly less side effects compared to short course treatment (average RR 0.40, 95% CI 0.22 to 0.72; n=458). Three RCTs reported on the rate of preterm deliveries [39,41,49], with no significant difference between the two durations (average RR 1.16, 95% CI 0.75 to 1.78; n=814). One RCT reported on the rate of low birthweights [49]. There were significantly more babies with low birthweight in the single dose duration compared to short course treatment (average RR 1.65, 95% CI 1.06 to 2.57; n=714). According to the data analysis, single dose treatment was associated with a significantly lower rate of side effects but a significantly higher rate of low birthweight. Therefore, standard short course treatment should be applied to treat ABU in pregnancy; however, it should be emphasised that the overall quality of the scientific evidence underpinning this recommendation is low.

Patients with identified risk-factors:

• Diabetes mellitus

Diabetes mellitus, even when well regulated, is reported to correlate to a higher frequency of ABU [51]. One RCT demonstrated that eradicating ABU did not reduce the risk of symptomatic UTI and infectious complications in patients with diabetes mellitus. The time to first symptomatic episode was also similar in both groups. Furthermore, untreated ABU did not correlate to diabetic nephropathy [52]. Screening and treatment of ABU in well-controlled diabetes mellitus is therefore not recommended. However, poorly regulated diabetes is a risk factor for symptomatic UTI and infectious complications.

• ABU in post-menopausal women

Elderly women have an increased incidence of ABU [53]. Four RCTs compared antibiotic treatment of ABU with placebo controls or no treatment, in a post-menopausal female population, with different antibiotic doses and regimens [54-57]. Women in these studies were mostly nursing home residents, which may bias the results of this analysis. Three RCTs reported on the rate of symptomatic UTIs (average RR 0.71, 95% CI 0.49 to 1.05; n=208) and the resolution of bacteriuria (average RR 1.28, 95% CI 0.50 to 3.24; n=203) [39,48,49], with no significant benefit of antibiotic treatment. Therefore, ABU in post-menopausal women does not require treatment, and should be managed as for pre-menopausal women.

• Elderly institutionalised patients

 The rate of ABU is 15-50% in elderly institutionalised patients [58]. Differential diagnosis of ABU from symptomatic UTI is difficult in the multi-diseased and mentally deteriorated patient, and is probably a cause of unnecessary antibiotic treatment [59,60]. Seven RCTs compared antibiotic treatment of ABU with placebo controls or no treatment in elderly patients, with different antibiotic doses and regimens [54-5,61-63]. Three RCTs reported on the rate of symptomatic UTIs [54,59,61]. Antibiotic treatment was not significantly beneficial in reducing the rate of symptomatic UTIs compared to placebo or no treatment (average RR 0.68, 95% CI 0.46 to 1.00; n=210). Six RCTs reported on the resolution of bacteriuria [54,56,57,61-63]. There was no benefit of antibiotic treatment compared to placebo in the resolution of ABU (average RR 1.33, 95% CI 0.63 to 2.79; n=328). One RCT compared the rates of incontinence in this patient group before and after the eradication of ABU, and found no effect of antibiotic treatment [64]. Therefore, screening and treatment of ABU is not recommended in this patient group.

• Patients with renal transplants

Two RCTs and two retrospective studies compared the effect of antibiotic treatment to no treatment in renal transplant patients [65-68]. Meta-analysis of the two RCTs did not find antibiotic treatment beneficial in terms of reducing symptomatic UTIs (RR 0.86, 95% CI 0.51 to 1.45; n=200). The two retrospective studies reached the same conclusion. Furthermore, there were no significant differences in the rate of ABU clearance, graft loss or change in renal function during long-term follow-up up to 24 months [65-68]. Therefore, treatment of ABU is not recommended in renal transplant recipients.

• Patients with dysfunctional and/or reconstructed lower urinary tracts

Patients with lower urinary tract dysfunction (LUTD) (e.g. neurogenic bladder patients secondary to multiple sclerosis, spinal cord injury patients, patients with incomplete bladder emptying, patients with neo-bladder and ileo-cystoplasty, patients using clean intermittent catheterisation (CIC), and patients with ileal conduits, orthotopic bladder replacement and continent reservoirs) frequently become colonised [69,70]. Studies have shown no benefit in ABU treatment in these patient groups [71,72]. Furthermore, in LUTD patients who do not spontaneously develop ABU, deliberate colonisation with an ABU strain (Escherichia coli 83972) has shown a protective effect against symptomatic recurrences [71,72]. Screening and treatment of ABU in these patient groups is therefore, not recommended. If these patient groups develop recurrent symptomatic UTI the potential protective effect of a spontaneously developed ABU against lower UTI must be considered before any treatment.

• Patients with catheters in the urinary tract

Patients with indwelling or suprapubic catheters and nephrostomy tubes invariably become carriers of ABU, with antibiotic treatment showing no benefit [73]. This is also applicable for patients with ABU and indwelling ureteral stents [74]. Routine treatment of catheter-associated bacteriuria is not recommended.

• Patients with ABU subjected to catheter placements/exchanges

In patients subjected to uncomplicated placement/exchanges of indwelling urethral catheters ABU is not considered a risk factor and should not be screened or treated [75]. In patients subjected to placement/ exchanges of nephrostomy tubes and indwelling ureteral stents, ABU is considered a risk factor for infectious complications [76]; therefore, screening and treatment prior to the procedure is recommended.

• Immuno-compromised and severely diseased patients, patients with candiduria

These patient groups have to be considered individually and the benefit of screening and treatment of ABU should be reviewed in each case. Patients with asymptomatic candiduria may, although not necessarily, have an underlying disorder or defect. Treatment of asymptomatic candiduria is not recommended [77].

• Prior to urological surgery

 In diagnostic and therapeutic procedures not entering the urinary tract, ABU is generally not considered as a risk factor, and screening and treatment are not considered necessary. On the other hand, in procedures entering the urinary tract and breaching the mucosa, particularly in endoscopic urological surgery, bacteriuria is a definite risk factor. Two RCTs [78,79] and two prospective non-randomised studies [80,81] compared the effect of antibiotic treatment to no treatment before transurethral prostate or bladder tumour resections. Antibiotic treatment significantly reduced the number of post-operative symptomatic UTIs compared to no treatment in the meta-analysis of the two RCTs (average RR 0.20, 95% CI 0.05 to 0.86; n=167). The rates of post-operative fever and septicaemia were also significantly lower in case of antibiotic treatment compared to no treatment in the two RCTs. One RCT including patients with spinal cord injury undergoing elective endoscopic urological surgeries found no significant difference in the rate of post-operative UTIs between single-dose or three to five days short term pre-operative antibiotic treatment of ABU [82]. A urine culture must therefore be taken prior to such interventions and in case of ABU, pre-operative treatment is recommended.

• Prior to orthopaedic surgery

One RCT (n=471) and one multicentre cohort study (n=303) comparing the treatment of ABU with no treatment prior to orthopaedic surgery (hip arthroplasty/hemiarthroplasty or total knee arthroplasty) were identified [83,84]. Neither of the studies showed a beneficial effect of antibiotic treatment in terms of prosthetic joint infection (3.8% vs. 0% and 3.9% vs. 4.7%, respectively). The cohort study reported no significant difference in the rate of post-operative symptomatic UTI (0.65% vs. 2.7%) [84]. Therefore, treatment of bacteriuria is not recommended prior to arthroplasty surgery.

• Pharmacological management

If the decision is taken to eradicate ABU, the same choice of antibiotics and treatment duration as in symptomatic uncomplicated or complicated UTI can be given, depending on gender, medical background and presence of complicating factors. Treatment should be tailored and not empirical.

Uncomplicated cystitis:

• Introduction

 Uncomplicated cystitis is defined as acute, sporadic or recurrent cystitis limited to non-pregnant women with no known relevant anatomical and functional abnormalities within the urinary tract or comorbidities.

• Epidemiology, aetiology and pathophysiolog

Almost half of all women will experience at least one episode of cystitis during their lifetime. Nearly one in three women will have had at least one episode of cystitis by the age of 24 years [85]. Risk factors include sexual intercourse, use of spermicides, a new sexual partner, a mother with a history of UTI and a history of UTI during childhood. The majority of cases of uncomplicated cystitis are caused by E. coli.

Diagnostic evaluation:

• Clinical diagnosis

The diagnosis of uncomplicated cystitis can be made with a high probability based on a focused history of lower urinary tract symptoms (dysuria, frequency and urgency) and the absence of vaginal discharge [86,87]. In elderly women genitourinary symptoms are not necessarily related to cystitis [88,89].

• Differential diagnosis

Uncomplicated cystitis should be differentiated from ABU, which is considered not to be infection but rather a commensal colonisation, which should not be treated and therefore not screened for, except if it is considered a risk factor in clearly defined situations.

• Laboratory diagnosis

In patients presenting with typical symptoms of an uncomplicated cystitis urine analysis (i.e. urine culture, dip stick testing, etc.) leads only to a minimal increase in diagnostic accuracy [90]. However, if the diagnosis is unclear dipstick analysis can increase the likelihood of an uncomplicated cystitis diagnosis [91,92]. Taking a urine culture is recommended in patients with atypical symptoms, as well as those who fail to respond to appropriate antimicrobial therapy [93,94].

Disease management:

Antimicrobial therapy is recommended because clinical success is significantly more likely in women treated with antimicrobials compared with placebo [95]. In female patients with mild-to-moderate symptoms, symptomatic therapy (e.g. Ibuprofen), as an alternative to antimicrobial treatment, may be considered in consultation with individual patients [96-99]. The choice of antimicrobial therapy should be guided by:

• spectrum and susceptibility patterns of the aetiological pathogens;
• efficacy for the particular indication in clinical studies;
• tolerability and adverse reactions;
• adverse ecological effects;
• costs;
• availability.

According to these principles and the available susceptibility patterns in Europe, oral treatment with fosfomycin trometamol 3 g single dose, pivmecillinam 400 mg three times a day for three to five days, and nitrofurantoin (e.g. nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for five days), should be considered for firstline treatment, when available [100-103]. Alternative antimicrobials include trimethoprim alone or combined with a sulphonamide. Co-trimoxazole (160/800 mg twice daily for three days) or trimethoprim (200 mg twice daily for five days) should only be considered as drugs of first choice in areas with known resistance rates for E. coli of < 20% [104,105]. Aminopenicillins are no longer suitable for empirical therapy because of worldwide high E. coli resistance. Aminopenicillins in combination with a beta-lactamase inhibitor such as ampicillin/sulbactam or amoxicillin/clavulanic acid and oral cephalosporins are not recommended for empirical therapy due to ecological collateral damage, but may be used in selected cases [106,107].

• Cystitis in pregnancy

Short courses of antimicrobial therapy can also be considered for treatment of cystitis in pregnancy [108], but not all antimicrobials are suitable during pregnancy. In general, penicillins, cephalosporins, fosfomycin, nitrofurantoin (not in case of glucose-6-phosphate dehydrogenase deficiency and during the end of pregnancy), trimethoprim (not in the first trimenon) and sulphonamides (not in the last trimenon), can be considered.

• Cystitis in men

Cystitis in men without involvement of the prostate is uncommon and should be classed as a complicated infection. Therefore, treatment with antimicrobials penetrating into the prostate tissue is needed in males with symptoms of UTI. A treatment duration of at least seven days is recommended, preferably with trimethoprim sulfamethoxazole or a fluoroquinolone if in accordance with susceptibility testing [109].

• Renal insufficiency

In patients with renal insufficiency the choice of antimicrobials may be influenced by decreased renal excretion; however, most antimicrobials, have a wide therapeutic index. No adjustment of dose is necessary until glomerular filtration rate (GFR) is < 20 mL/min, with the exception of antimicrobials with nephrotoxic potential, e.g. aminoglycosides. The combination of loop diuretics (e.g. furosemide) and a cephalosporin is nephrotoxic. Nitrofurantoin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73m2 as accumulation of the drug leads to increased side effects as well as reduced urinary tract recovery, with the risk of treatment failure [110].

Table 1: Suggested regimens for antimicrobial therapy in uncomplicated cystitis

 

 

 

 

 

 

 

 

• Follow-up

Routine post-treatment urinalysis or urine cultures in asymptomatic patients are not indicated [14]. In women whose symptoms do not resolve by end of treatment, and in those whose symptoms resolve but recur within two weeks, urine culture and antimicrobial susceptibility testing should be performed [111]. For therapy in this situation, one should assume that the infecting organism is not susceptible to the agent originally used. Retreatment with a seven-day regimen using another agent should be considered [111].

Recurrent UTIs:

• Introduction

 Recurrent UTIs (rUTIs) are recurrences of uncomplicated and/or complicated UTIs, with a frequency of at least three UTIs/year or two UTIs in the last six months. Although rUTIs include both lower tract infection (cystitis) and upper tract infection (pyelonephritis), repeated pyelonephritis should prompt consideration of a complicated aetiology.

• Diagnostic evaluation

 Recurrent UTIs are common. Risk factors are outlined in (Table 2). Diagnosis of rUTI should be confirmed by urine culture. An extensive routine workup including cystoscopy, imaging, etc., is not routinely recommended as the diagnostic yield is low [112]. However, it should be performed without delay in atypical cases, for example, if renal calculi, outflow obstruction, interstitial cystitis or urothelial cancer is suspected.

Table 2: Age-related associations of rUTI in women

 

 

 

 

• Disease management and follow-up

Prevention of rUTIs includes counselling regarding avoidance of risk factors, non-antimicrobial measures and antimicrobial prophylaxis [111]. These interventions should be attempted in this order. Any urological risk factor must be identified and treated. Significant residual urine should be treated optimally, including by clean intermittent catheterisation (CIC) when judged to be appropriate.

• Behavioural modifications

 Women with rUTI should be counselled on avoidance of risks (eg, insufficient hydration, habitual and postcoital delayed urination, wiping from back to front after defecation, douching and wearing occlusive underwear) before initiation of long-term prophylactic drug treatment, although there is limited evidence available regarding these approaches [113, 114]. An open-label RCT found that additional fluid intake of 1.5 L in pre-menopausal women with rUTI who were low-volume drinkers (< 1.5 L a day) reduced the number of cystitis episodes and antibiotic usage over a twelve-month period [115].

Non-antimicrobial prophylaxis:

• Hormonal replacement

Based on the results of four meta-analyses topical oestrogen admission (either as a creme or a pessary) shows a trend towards rUTI prevention [116-119]. All studies reported that application was superior compared to placebo but was inferior compared to antibiotics. Due to its pharmacokinetics vaginal admission has no systematic side effects, however local irritation and minor bleeding can occur. The use of oral oestrogens was not effective for rUTI prophylaxis compared to placebo, furthermore it was associated with an unfavourable systematic side effect profile. A single prospective, non-comparative study of 30 pre-menopausal women with rUTI on oral contraceptives reported a beneficial effect of topical oestrogen admission [120].

• Immunoactive prophylaxis

Several meta-analyses and systematic reviews based on nine RCTs showed that oral immunotherapy with OM-89 is an effective and safe method for the prevention of rUTIs compared to placebo at short-term follow-up (< six months) [117, 121,122]. A vaginal suppository containing ten strains of heat-killed uropathogenic bacteria significantly reduced the risk of rUTI compared to placebo in a meta-analysis of three small RCTs [121-123]. The preventive effect was more pronounced with booster treatment.

• Prophylaxis with probiotics (Lactobacillus spp.)

Four meta-analyses with differing results and ten relevant systematic reviews were identified [117,124-136]. Two meta-analyses reported significant positive effects for rUTI prevention with effective probiotics compared to placebo [128,130]. The contradictory results of the four meta-analyses are a result of the analysis of different Lactobacillus strains and different administration regimes, treatment durations, and patient populations. Most studies concluded that not all Lactobacillus strains are effective for vaginal flora restoration and rUTI prevention.

The highest efficacy was shown with L. rhamnosus GR-1, L. reuteri B-54, L. reuteri RC-14, L. casei shirota, and L. crispatus CTV-05 [117,126,128,130]. Although meta-analyses including all known Lactobacilli strains did not show a significant treatment benefit [117,126,128,130], sensitivity analysis excluding studies using ineffective strains resulted in a positive treatment effect [128]. Of the ten systematic reviews seven concluded that prophylaxis with vaginal probiotics has a beneficial clinical impact for the prevention of rUI [118,119, 124,127,129,131-134,136].

• Prophylaxis with cranberry

Six meta-analyses and several systematic reviews including 82 clinical trials were identified [117,137-141]. A Cochrane review and meta-analysis found that when compared with placebo, water or no treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall or in women with recurrent UTIs [137]. However, five subsequent meta-analyses concluded that consumption of cranberry-containing products may protect against UTIs in certain patient populations [117,138-141]. The differing outcomes across the meta-analyses can be contributed to the clinical and methodological heterogeneity of the included studies [142].

• Prophylaxis with D-mannose

A meta-analysis including one RCT, one randomised cross-over trial and one prospective cohort study analysed data on 390 patients and found that D-mannose was effective for rUTI prevention compared to placebo with comparable efficacy to antibiotic prophylaxis [143]. Another systematic review, concluded that D-mannose had a significant effect on UTI, but that further studies were needed to confirm these findings [124].

• Endovesical instillation

Endovesical instillations of hyaluronic acid (HA) and chondroitin sulphate (CS) have been used for glycosaminoglycan (GAG) layer replenishment in the treatment of interstitial cystitis, overactive bladder, radiation cystitis, and for prevention of rUTI [144]. A meta-analysis (n=143) based on two RCTs and two non-RCTs found significantly decreased UTI rates per patient/year and significantly longer mean UTI recurrence times for HA and HA-CS therapy compared to control treatment [145]. In addition, subgroup analysis of the two RCTs using HA-CS reported a significantly decreased UTI rate per patient/year, significantly longer mean UTI recurrence time and a significantly better pelvic pain and urgency/frequency (PUF) total score. However, 24-hour urinary frequency was not significantly improved after therapy [145]. Another meta-analysis (n=800) including two RCTs and six non-RCTs found that when compared to control treatment HA, with or without CS, was associated with a significantly lower mean UTI rate per patient/ year and a significantly longer time to UTI recurrence [146]. Furthermore, HA-CS therapy was associated with significantly greater mean reductions in PUF total and symptom scores and the percentage of patients with UTI recurrence during follow-up was also lower [146]. As randomised controlled studies are available only for HA plus CS, the quality of evidence is higher for the combination than for HA alone.

• Methenamine hippurate

A Cochrane review from 2012 based on thirteen studies, with high levels of heterogeneity, concluded that methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis [147]. However, a meta-analysis from 2021 based on six studies found that although studies showed a trend towards a benefit for methenamine hippurate in prevention of rUTIs there was no statistically significant difference between the efficacy of methenamine hippurate and any comparators [148]. Due to these contradictory results, no recommendation on the use of methenamine can be made.

Antimicrobials for preventing rUTI:

• Continuous low-dose antimicrobial prophylaxis and post-coital prophylaxis

Four meta-analyses and numerous systematic reviews and guidelines were identified [119,149-159]. All available meta-analyses conclude that antibiotic prophylaxis is the most effective approach against UTI recurrences compared with placebo or no treatment [149-151]. Antimicrobials may be given as continuous low-dose prophylaxis for longer periods, or as post-coital prophylaxis. There is no significant difference in the efficacy of the two approaches. There is no consensus about the optimal duration of continuous antimicrobial prophylaxis, with studies reporting treatment duration of three to twelve months. After discontinuation of the drug, UTIs tend to re-occur, especially among those who have had three or more infections annually. It is mandatory to offer both continuous low-dose antimicrobial and post-coital prophylaxis after counselling, and when behavioural modifications and non-antimicrobial measures have been unsuccessful. Differences in outcomes between antibiotics did not reach statistical significance. The choice of agent should be based on the local resistance patterns. Regimens include nitrofurantoin 50 mg or 100 mg once daily, fosfomycin trometamol 3 g every ten days, trimethoprim 100 mg once daily and during pregnancy cephalexin 125 mg or 250 mg or cefaclor 250 mg once daily [111,160]. Post-coital prophylaxis should be considered in pregnant women with a history of frequent UTIs before onset of pregnancy, to reduce their risk of UTI [161].

• Uncomplicated pyelonephritis

Uncomplicated pyelonephritis is defined as pyelonephritis limited to non-pregnant, pre-menopausal women with no known relevant urological abnormalities or comorbidities.

Diagnostic evaluation:

• Clinical diagnosis

 Pyelonephritis is suggested by fever (> 38°C), chills, flank pain, nausea, vomiting, or costovertebral angle tenderness, with or without the typical symptoms of cystitis [162]. Pregnant women with acute pyelonephritis need special attention, as this kind of infection may not only have an adverse effect on the mother with anaemia, renal and respiratory insufficiency, but also on the unborn child with more frequent pre-term labour and birth [163].

• Differential diagnosis

 It is vital to differentiate as soon as possible between uncomplicated and complicated mostly obstructive pyelonephritis, as the latter can rapidly lead to urosepsis. This differential diagnosis should be made by the appropriate imaging technique.

• Laboratory diagnosis

 Urinalysis including the assessment of white and red blood cells and nitrite, is recommended for routine diagnosis [164]. In addition, urine culture and antimicrobial susceptibility testing should be performed in all cases of pyelonephritis.

• Imaging diagnosis

 Evaluation of the upper urinary tract with ultrasound (US) should be performed to rule out urinary tract obstruction or renal stone disease in patients with a history of urolithiasis, renal function disturbances or a high urine pH [165]. Additional investigations, such as a contrast enhanced computed tomography (CT) scan, or excretory urography should be considered if the patient remains febrile after 72 hours of treatment, or immediately if there is deterioration in clinical status [165]. For diagnosis of complicating factors in pregnant women, US or magnetic resonance imaging (MRI) should be used preferentially to avoid radiation risk to the foetus [165].

Disease management:

• Outpatient treatment

 Fluoroquinolones and cephalosporines are the only antimicrobial agents that can be recommended for oral empirical treatment of uncomplicated pyelonephritis [166]. However, oral cephalosporines achieve significantly lower blood and urinary concentrations than intravenous cephalosporines. Other agents such as nitrofurantoin, oral fosfomycin, and pivmecillinam should be avoided as there is insufficient data regarding their efficacy [167]. In the setting of fluoroquinolone hypersensitivity or known resistance, other acceptable choices include trimethoprim-sulfamethoxazole (160/800 mg) or an oral beta-lactam, if the uropathogen is known to be susceptible. If such agents are used in the absence of antimicrobial susceptibility results, an initial intravenous dose of a long-acting parenteral antimicrobial (e.g. ceftriaxone) should be administered. A short outpatient antibiotic course of treatment, for acute pyelonephritis, has been shown to be equivalent to longer durations of therapy in terms of clinical and microbiological success. However, this is associated with a higher recurrence rate of infection within four to six weeks and needs to be tailored to local policies and resistance patterns [168].

• Inpatient treatment

 Patients with uncomplicated pyelonephritis requiring hospitalisation should be treated initially with an intravenous antimicrobial regimen e.g. a fluoroquinolone, an aminoglycoside (with or without ampicillin), or an extended-spectrum cephalosporin or penicillin [169]. Ceftolozane/tazobactam achieved a clinical response rate of over 90% in patients with uncomplicated pyelonephritis [170,171]. It also demonstrated significantly higher composite cure rates than levofloxacin among levofloxacin-resistant pathogens [172]. Ceftazidimeavibactam combination has been shown to be effective for treating ceftazidime-resistant Enterobacterales and Pseudomonas aeruginosa UTIs [173]. Novel antimicrobial agents include imipenem/cilastatin, cefiderocol, meropenem-vaborbactam and plazomicin. Imipenem/cilastatin has been investigated in a phase 2 randomised trial and showed good clinical response rates [174]. Cefatazidime-avibactam and doripenem showed similar efficacy against ceftazidime non-susceptible pathogens and may offer an alternative to carbapenems in this setting [175]. Meropenem vaborbactam has been shown to be non-inferior to piperacillin-tazobactam in a phase 3 RCT [176]. It was also effective for treating carbapenem-resistant Enterobacterales with cure rates of 65% compared to best available treatment [177]. Once daily plazomicin was non-inferior to meropenem for the treatment of cUTIs and acute pyelonephritis caused by Enterobacterales, including multidrug-resistant strains [178]. Cefiderocol was noninferior to imipenem/cilastatin for the treatment of complicated UTI in people with multidrug-resistant Gramnegative infections in a phase 2 RCT [179]. Carbapenems and novel broad spectrum antimicrobial agents should only be considered in patients with early culture results indicating the presence of multi-drug resistant organisms. The choice between these agents should be based on local resistance patterns and optimised on the basis of drug susceptibility results. In patients presenting with signs of urosepsis empiric antimicrobial coverage for ESBL-producing organisms is warranted [180]. Patients initially treated with parenteral therapy who improve clinically and can tolerate oral fluids may transition to oral antimicrobial therapy [181].

Table 3: Suggested regimens for empirical oral antimicrobial therapy in uncomplicated pyelonephritis

 

 

 

 

 

Table 4:  Suggested regimens for empirical parenteral antimicrobial therapy in uncomplicated pyelonephritis

 

 

 

 

 

 

 

 

In pregnant women with pyelonephritis, outpatient management with appropriate parenteral antimicrobials may also be considered, provided symptoms are mild and close follow-up is feasible [182,183]. In more severe cases of pyelonephritis, hospitalisation and supportive care are usually required. After clinical improvement parenteral therapy can also be switched to oral therapy for a total treatment duration of seven to ten days. In men with febrile UTI, pyelonephritis, or recurrent infection, or whenever a complicating factor is suspected a minimum treatment duration of two weeks is recommended, preferably with a fluoroquinolone since prostatic involvement is frequent [184].

Complicated UTIs:

• Introduction

 A complicated UTI (cUTI) occurs in an individual in whom factors related to the host (e.g. underlying diabetes or immunosuppression) or specific anatomical or functional abnormalities related to the urinary tract (e.g. obstruction, incomplete voiding due to detrusor muscle dysfunction) are believed to result in an infection that will be more difficult to eradicate than an uncomplicated infection [185-187]. New insights into the management of cUTIs also suggest to consider infections caused by multi-drug resistant uropathogens [188]. The underlying factors that are generally accepted to result in a cUTI are outlined in (Table 5). The designation of cUTI encompasses a wide variety of underlying conditions that result in a remarkably heterogeneous patient population. Therefore, it is readily apparent that a universal approach to the evaluation and treatment of cUTIs is not sufficient, although there are general principles of management that can be applied to the majority of patients with cUTIs. The following recommendations are based on the Stichting Werkgroep Antibioticabeleid (SWAB) Guidelines from the Dutch Working Party on Antibiotic Policy [189].

Table 5: Common factors associated with complicated UTIs

Diagnostic evaluation:

• Clinical presentation

 Isolated multi-drug resistant organisms A cUTI is associated with clinical symptoms (e.g. dysuria, urgency, frequency, flank pain, costovertebral angle tenderness, suprapubic pain and fever), although in some clinical situations the symptoms may be atypical for example, in neuropathic bladder disturbances, CA-UTI or patients who have undergone radical cystectomy with urinary diversion. In addition, all patients with nephrostomy may have an atypical clinical presentation. Clinical presentation can vary from severe obstructive acute pyelonephritis with imminent urosepsis to a postoperative CA-UTI, which might disappear spontaneously as soon as the catheter is removed. Clinicians must also recognise that symptoms, especially lower urinary tract symptoms (LUTS), are not only caused by UTIs but also by other urological disorders, such as, for example, benign prostatic hyperplasia and autonomic dysfunction in patients with spinal lesions and neurogenic bladders. Concomitant medical conditions, such as diabetes mellitus and renal failure, which can be related to urological abnormalities, are often also present in a cUTI.

• Urine culture

 Laboratory urine culture is the recommended method to determine the presence or absence of clinically significant bacteriuria in patients suspected of having a cUTI.

• Microbiology (spectrum and antimicrobial resistance)

 A broad range of micro-organisms cause cUTIs. The spectrum is much larger than in uncomplicated UTIs and the bacteria are more likely to be resistant (especially in treatment-related cUTI) than those isolated in uncomplicated UTIs [190,191]. E. coli, Proteus spp., Klebsiella spp., Pseudomonas spp., Serratia spp. and Enterococcus spp. are the most common species found in cultures. Enterobacterales predominate (60-75%), with E. coli as the most common pathogen; particularly if the UTI is a first infection. Otherwise, the bacterial spectrum may vary over time and from one hospital to another [192].

• General principles of cUTI treatment

Appropriate management of the urological abnormality or the underlying complicating factor is mandatory. Optimal antimicrobial therapy for cUTI depends on the severity of illness at presentation, as well as local resistance patterns and specific host factors (such as allergies). In addition, urine culture and susceptibility testing should be performed, and initial empirical therapy should be tailored and followed by (oral) administration of an appropriate antimicrobial agent on the basis of the isolated uropathogen.

• Choice of antimicrobials

 Considering the current resistance percentages of amoxicillin, co-amoxiclav, trimethoprim and trimethoprim sulphamethoxazole, it can be concluded that these agents are not suitable for the empirical treatment of pyelonephritis in a normal host and, therefore, also not for treatment of all cUTIs [193]. The same applies to ciprofloxacin and other fluoroquinolones in urological patients [193]. Patients with a UTI with systemic symptoms requiring hospitalisation should be initially treated with an intravenous antimicrobial regimen, such as an aminoglycoside with or without amoxicillin, or a second or third generation cephalosporin, or an extended-spectrum penicillin with or without an aminoglycoside [189]. The choice between these agents should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results [167]. These recommendations are not only suitable for pyelonephritis, but for all other cUTIs. Alternative regimens for the treatment of cUTIs, particularly those caused by multidrug-resistant pathogens have been studied. Ceftolozane/tazobactam 1.5 g every eight hours demonstrated high clinical cure rates for cUTIs caused by ESBL-producing Enterobacterales in a pooled analysis of phase 3 clinical trials [194]. Cefiderocol (2 g) three times daily was non-inferior to imipenem-cilastatin (1 g) three times daily for the treatment of cUTI in patients with multidrug-resistant Gram-negative infections [179]. Imipenem/cilastatin plus relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI in a phase 2 RCT [174]. Ceftazidime/avibactam has been shown to be as effective as carbapenems for the treatment of cUTI in a systematic review reporting a baseline of 25% for ESBL-producing Enterobacterales, but more severe adverse events were reported in the ceftazidime/avibactam group [195]. Once-daily plazomicin was shown to be non-inferior to meropenem for the treatment of cUTIs caused by Enterobacterales, including multidrugresistant strains [178]. In view of the high degree of resistance, particularly among patients admitted to the department of urology, fluoroquinolones are not automatically suitable as empirical antimicrobial therapy, especially when the patient has used ciprofloxacin in the last six months [196]. Fluoroquinolones can only be recommended as empirical treatment when the patient is not seriously ill and it is considered safe to start initial oral treatment or if the patient has had an anaphylactic reaction to beta-lactam antimicrobials. Intravenous levofloxacin 750 mg once daily for five days has been shown to be non-inferior to a seven-to-fourteen-day regimen of levofloxacin 500 mg once daily starting intravenously and switched to an oral regimen (based on mitigation of clinical symptoms) [197].

• Duration of antimicrobial therapy

Treatment for seven [198] to fourteen days (for men fourteen days when prostatitis cannot be excluded) [199], is generally recommended, but the duration should be closely related to the treatment of the underlying abnormality. When the patient is hemodynamically stable and afebrile for at least 48 hours, a shorter treatment duration (e.g. seven days) may be considered in patients where a short-course treatment is desired due to relative-contraindications to the administered antibiotic [197].

Catheter-associated UTIs:

• Introduction

Catheter-associated UTI refers to UTIs occurring in a person whose urinary tract is currently catheterised or has been catheterised within the past 48 hours. The urinary catheter literature is problematic as many published studies use the term CA-bacteriuria without providing information on what proportion are CA-ABU and CA-UTI, and some studies use the term CA-UTI when referring to CA-ABU or CA-bacteriuria [190].

• Epidemiology, aetiology and pathophysiology

 Catheter-associated UTIs are the leading cause of secondary healthcare-associated bacteraemia. Approximately 20% of hospital-acquired bacteraemias arise from the urinary tract, and the mortality associated with this condition is approximately 10% [200]. A multistate point-prevalence survey of 11,282 patients across 183 hospitals reported that UTI accounted for 12.9% of healthcare acquired infections [201]. The incidence of bacteriuria associated with indwelling catheterisation is 3-8% per day [202-206]. The duration of catheterisation is the most important risk factor for the development of a CA-UTI [207,208]. A systematic review and meta-analysis reported an average CA-UTI incidence of 13.79/1000 hospitalised patients with a prevalence of 9.33% [209]. This study also demonstrated that patients at high risk for CA-UTI were female, had a prolonged duration of catheterisation, had diabetes and had longer hospital and intensive care unit (ICU) stays [209]. Urinary catheterisation perturbs host defence mechanisms and provides easier access of uropathogens to the bladder. Indwelling urinary catheters facilitate colonisation with uropathogens by providing a surface for the attachment of host cell binding receptors recognised by bacterial adhesins, thus enhancing microbial adhesion. In addition, the uroepithelial mucosa is damaged, exposing new binding sites for bacterial adhesins, and residual urine in the bladder is increased through pooling below the catheter bulb [210]. Catheter-associated UTIs are often polymicrobial and caused by multiple-drug resistant uropathogens. Diagnostic evaluation:

• Clinical diagnosis

Signs and systemic symptoms compatible with CA-UTI include new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause, flank pain, costovertebral angle tenderness, acute haematuria, pelvic discomfort and in those whose catheters have been removed dysuria, urgent or frequent urination and suprapubic pain or tenderness [189]. In the catheterised patient, the presence or absence of odorous or cloudy urine alone should not be used to differentiate CA-ABU from CA-UTI [189,190].

• Laboratory diagnosis

 Microbiologically, CA-UTI is defined by microbial growth of > 103 cfu/mL of one or more bacterial species in a single catheter urine specimen or in a mid-stream voided urine specimen from a patient whose urethral, suprapubic, or condom catheter has been removed within the previous 48 hours [190]. In catheterised patients, pyuria is not diagnostic for CA-UTI. The presence, absence, or degree of pyuria should not be used to differentiate CA-ABU from CA-UTI. Pyuria accompanying CA-ABU should not be interpreted as an indication for antimicrobial treatment. The absence of pyuria in a symptomatic patient suggests a diagnosis other than CA-UTI [190].

Disease management:

• Limiting catheterisation and appropriate catheter discontinuation

Indwelling catheters should be placed only when they are clinically indicated; for example, for management of urinary retention or where strict monitoring of fluid balance is required. Catheter restriction protocols are an important part of multi-modal interventions to reduce CA-UTI rates. Nurse-driven protocols in hospitals as well as community based multi-modal targeted infection programs have been proven to reduce CA-UTI rates [211,212]. Adjunctive devices such as electronic reminder systems have also been shown to assist in prompt catheter removal in hospital settings (including non-ICU). A systematic review of nineteen different interventions to reduce UTI (including catheter discontinuation and limiting catheterisation), in nursing home patients reported successful CA-UTI reduction and reduced catheter usage [213]. Another report of over 2,800 patients on a surgical oncology unit found that increasing catheter bundle compliance resulted in a significant reduction in CA-UTI rates [214].

• Urethral cleaning and chlorhexidine bathing

A network meta-analysis of 33 studies (6,490 patients) found no difference in the incidence of CA-UTI comparing the different urethral cleaning methods vs. disinfection [215]. The efficacy of chlorhexidine baths (either using 2% chlorhexidine-impregnated cloths or 4% chlorhexidine-based soap) in reducing CA-UTI is debatable. In a RCT of 10,783 ICU patients, no difference in CA-UTI rates were reported between chlorhexidine and control bathing groups [216]. However, a systematic review of fifteen studies involving only ICU patients reported that daily chlorhexidine bathing was associated with a significant reduction in CA-UTI (RR 0.68) [217].

• Alternatives to indwelling urethral catheterization

 Alternatives include intermittent urethral catheterisation (IC) or suprapubic catheterisation. In a systematic review of patients undergoing gynaecological surgery, indwelling catheters were associated with higher rates of symptomatic UTIs compared to IC [218]. A further meta-analysis of postpartum women reported no difference in the incidence of UTI after labour between continuous catheterisation and IC [218]. A prospective cohort study of nursing home residents found that residents with a suprapubic catheter had fewer CA-UTIs and where hospitalised less, but were more likely to be colonised with multidrug-resistant organisms [219]. A Cochrane review found insufficient evidence to assess the value of different policies for replacing long-term urinary catheters on patient outcomes [75]. Another Cochrane review investigating the role of urethral (indwelling or intermittent) vs. suprapubic catheterisation in the short-term found inconclusive evidence of an effect on UTI rates [220]. For patients with neurogenic bladders, a further systematic review found no randomised or quasi-randomised controlled trials and therefore no conclusions regarding the use of the different types of catheters could be made [221]. Therefore, based on the available literature, while there are some limited studies showing a benefit of IC or suprapubic catheterisation over urethral catheterisation for CA-UTI rates, there is insufficient evidence to recommend those approaches routinely [222].

• Impregnated or coated catheters

 Hydrophilic coated catheters have been found to be beneficial for reducing CA-UTI rates. A meta-analysis of seven studies investigating RCTs comparing hydrophilic coated to PVC (standard) catheters for IC found a statistically lower risk ratio (0.84) for the frequency of UTI in the hydrophilic catheter group [223]. A systematic review and practice policy statements on UTI prevention in patients with spina bifida recommended the use of single-use and hydrophilic catheters for IC [224]. Silver-alloy-impregnated catheters have not been associated with reduced CA-UTI rates. A small RCT of 54 ICU patients showed no significant difference in UTI rates between the silver-alloy impregnated group and the standard silicone foley catheter group [225]. In a cohort study of patients undergoing suprapubic catheter placement at the time of pelvic organ prolapsed surgery, a 5% difference in UTI rate at six weeks was noted, although this was not significant [226]. A systematic review of 26 trials (12,422 patients) reported that silver alloy-coated catheters were not associated with a statistically significant reduction in CA-UTI and were considerably more expensive [227]. However, the same study found that nitrofurazone-impregnated catheters reduce the risk of symptomatic CA-UTI; however, this was borderline significant (RR 0.84, 95% CI 0.71 to 0.99) [227]. A more recent RCT (214 patients) evaluating the use of nitrofurazone-infused catheters post-renal transplant found no benefit for their use [228]. Additionally, another RCT showed no benefit for the use of silveralloy-coated indwelling catheters for reduction of UTI in 489 patients with spinal cord injury [229]. From a microbiological perspective, there may be a difference in organisms causing CA-UTI from urethral and suprapubic catheters and therefore urine culture results are important to guide therapy [222].

• Antibiotic prophylaxis for catheter removal or insertion

 The question of whether antibiotic prophylaxis reduces the rate of symptomatic UTI in adults following indwelling bladder catheter removal has been the subject of multiple RCTs. A review and meta-analysis identified seven RCTs with 1,520 participants. Meta-analysis showed overall benefit for use of prophylaxis RR (95%CI) = 0.45 (0.28-0.72); ARR 5.8% (from 10.5% to 4.7%) with a number needed to treat (NNT) of 17 [198]. Results for individual trials were inconsistent with five trials including the possibility of no benefit [198]. In an affectional RCT with 172 participants undergoing laparoscopic radical prostatectomy randomised to seven days of ciprofloxacin (n=80) or no treatment (n=80) at the time of catheter removal, which occurred at a mean of nine days post-operatively, there was no difference in infective complications recorded at up to four weeks after catheter removal. More isolates obtained from the prophylaxis group (11) were resistant to ciprofloxacin compared to the no treatment group (3) [199]. With regards to catheter insertion, a systematic review and meta-analysis showed that prophylactic antibiotics reduced the rate of bacteriuria and other signs of infection, such as pyuria, fever and gram-negative isolates in patients’ urine, in surgical patients who undergo bladder drainage for at least 24 hours post-operatively [230].

• Antibiotic prophylaxis for intermittent self-catheterisation (ISC)

 An RCT investigating the effect of antibiotic prophylaxis in patients performing ISC showed that the frequency of symptomatic antibiotic-treated UTI was reduced by 48% using prophylaxis in a cohort of 404 patients performing ISC [231]. However, resistance against the antibiotics used for UTI treatment was more frequent in urinary isolates from the prophylaxis group than in those from the control group at nine to twelve months. While the literature shows some benefit for reduction of CA-UTI by utilising antibiotics, the routine use of antibiotics for such a common procedure in the healthcare setting would result in an increased usage of antimicrobials. As highlighted in some of the RCTs this strategy is associated with increased antimicrobial resistance. Antibiotic use is the main driving force in the development of antimicrobial resistance. Current antimicrobial stewardship principles would not favour the routine use of antibiotic prophylaxis for either catheter changes or ISC even when UTIs could be prevented [222].

• Antimicrobial treatment for suspected CA-UTI

 A urine specimen for culture should be obtained prior to initiating antimicrobial therapy for presumed CA-UTI due to the wide spectrum of potential infecting organisms and the increased likelihood of antimicrobial resistance. The urine culture should be obtained from the freshly placed catheter prior to the initiation of antimicrobial therapy [190]. Based on the global prevalence on infections in urology (GPIU) study, the causative micro-organisms in CA-UTI are comparable with the causative micro-organisms in other cUTIs; therefore, symptomatic CA-UTIs should be treated according to the recommendations for cUTI [232]. Seven days is the recommended duration of antimicrobial treatment for patients with CA-UTI who have prompt resolution of symptoms, and fourteen days of treatment is recommended for those with a delayed response, regardless of whether the patient remains catheterised or not [190]. A five-day regimen of levofloxacin may be considered in patients with CA-UTI who are not severely ill. Data are insufficient to make such a recommendation about other fluoroquinolones. With the rise in fluoroquinolone resistance, alternative antimicrobial agents should be selected where possible to start empirical therapy based on local microbiological information. A five-day antibiotic regimen with catheter exchange has been shown in one study to be non-inferior to a ten-day regimen with catheter retention on the basis of clinical cure [233]. A three-day antimicrobial regimen may be considered for women aged < 65 years who develop CA-UTI without upper urinary tract symptoms after an indwelling catheter has been removed. If an indwelling catheter has been in place for two weeks at the onset of CA-UTI and is still indicated, the catheter should be replaced to hasten resolution of symptoms and to reduce the risk of subsequent CA-bacteriuria and CA-UTI. If use of the catheter can be discontinued, a culture of a voided mid-stream urine specimen should be obtained prior to the initiation of antimicrobial therapy to help guide treatment [190]. Long-term indwelling catheters should not be changed routinely. Follow appropriate practices for catheter insertion and care [234].

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Author Correspondence:

Prof. Dr. Semir A. Salim. Al Samarrai

Medical Director of Professor Al Samarrai Medical Center.

Dubai Healthcare City, Al-Razi Building 64, Block D, 2^nd Floor, Suite 2018

E-mail: semiralsamarrai@hotmail.com

Tel: +97144233669