Professor Li Gonghui
Director and doctoral advisor, Urology Department of Sir Run Run Shaw Hospital (SRRSH),
Zhejiang University School of Medicine National committee member of Chinese Urological Association, Chinese Medical Association
National committee member of Urology Branch of Chinese Medical Doctor Association
Group leader of CUA Infection and Inflammation Study Group
Committee member of CUA Robotics Study Group
Vice-chairman of Urological Association, Zhejiang Medical Association

Q1. What are the current trends in the diagnosis and treatment of urinary tract infection (UTI) in China?

Empirical antibiotic therapies may be changed/adjusted based on the spectrum of pathogen. In recent years, the frequent use of antimicrobials has caused a change in the spectrum of UTI pathogens in China. It has also led to the emergence of antimicrobial resistance – which is becoming increasingly common in clinical settings. Although the most common pathogen for UTI remains Escherichia coli, the prevalence of other pathogens (e.g., Klebsiella pneumoniae, Enterococcus faecium, and Enterococcus faecalis) is also gradually increasing. In addition, the prevalence of extended-spectrum β-lactamase (ESBL)-producing E. coli is also increasing. Thus, prior to the confirmation of pathogen via urine culture and drug sensitivity test, empirical treatment should be given based on the local spectrum of UTI pathogens .

The use of antimicrobial agents is increasingly standardised. With the rising cases of antimicrobial resistance, the reasonable use of antimicrobial agent is increasingly emphasised. Various guidelines on diagnosis and treatment are established. The use of antibiotics will be increasingly standardised in the future for accurate and reasonable use to prevent unnecessary use.

Development of biomarkers for UTI. Atypical presentation of UTI is common. The combination of clinical symptoms and laboratory test results are essential to diagnose UTI. Midstream urine culture is the gold standard for UTI diagnosis. However, false positives are common with this method and is time consuming. Thus, research is underway to identify new and reliable biomarkers for rapid diagnosis. Below are two examples:

1. Xanthine oxidase (XO) – Human XO is mainly found in the liver. Research by Ciragil et al. showed that XO activity increases in patients with UTI. XO activity significantly increased with a bacterial count of >10⁵/mL in the urine. The sensitivity and specificity of urine XO activity for UTI diagnosis are both 100%. As such, urine XO may be a new potential biomarker for the diagnosis of UTI.
2. Myeloperoxidase (MPO) is a good biomarker for inflammation. Research has shown that MPO protein and activity increase in renal diseases. Ciragil et al. [9] also found that MPO activity increased significantly in the urine of patients with confirmed UTI. MPO activity has 87% sensitivity and 100% specificity for UTI diagnosis.

Development of rapid diagnostics for pathogens and ESBLs. The biomarkers mentioned above are only effective for determining if UTI is present but cannot identify the causative pathogen. Thus, it is not so useful in guiding empirical antibiotic selection. This identification may be achievable in the future through sequencing of bacterial 16S ribosomal DNA from the arena (urine sediment) and pathogen specificity ELISA kits for urine.

Q2. What special attention should we pay to the diagnosis and treatment of complicated UTI?

Complicated UTI refers to UTI cases that are accompanied by other diseases that may lead to infections or treatment failure. For instance, the presence of structural or functional abnormality in the genitourinary tract or other underlying diseases.

There are two standards for the diagnosis of complicated UTI: 1. Positive urine culture and 2. At least one of the following factors: indwelling urinary catheter, stent or intermittent bladder catheterisation, more than 100ml of residual urine, obstructive urinary tract diseases such as bladder outlet obstruction, neurogenic bladder, stones and any tumours, vesicoureteral reflux or other dysfunction, urinary diversion, urothelium damaged by chemotherapy or radiotherapy, perioperative and postoperative UTIs, renal insufficiency, renal transplantation, diabetes, and immunodeficiency.

The following should be considered in the diagnosis and treatment of UTI:

1. Risk factors and accompanying symptoms should be considered for diagnosis. Common symptoms of lower UTI are frequency, urgency and urodynia. Nephralgiaand fever are more commonly observed in upper UTI. However, diverse clinical symptoms may be present. Attention should be paid to the patient’s imaging examination, such as ultrasound, abdominal X-ray, urography, and CT scan to identify structural or functional abnormality in the urogenital tract or other diseases prone to causing infections.
2. Select the antimicrobial agent based on the result of urine culture and drug sensitivity test. Special attention should be paid to the local UTI pathogen spectrum and antimicrobial resistance patterns in complicated UTI for empirical therapy, as well as an assessment of underlying diseases. Before the drug sensitivity test results, patients with complicated UTI are often treated with empirical therapy or using non-standard antimicrobial. This exacerbates drug resistance. Currently, a characteristic of the bacteria spectrum of complicated UTI in China is that the proportion of coli has decreased, while the proportion of ESBL strains has increased. Another characteristic is that the proportion of Enterococcus infection has increased. Understanding of possible pathogenic bacterial spectrum and local drug resistance situation is necessary for empirical treatment. Assessment of the severity of underlying urinary system diseases (including assessment of renal function) is also necessary. Empirical therapy requires timely adjustments based on clinical reactions and urine culture results. Treatment will continue 3-5 days after fever subsides or after the comorbidity (such as urinary catheter or stones) has been cleared.
3. Control of the complication factors and treatment of comorbidity. If the patient has a urinary tract obstruction disease such as stones, tumours, constriction, congenital malformation, or neurogenic bladder that causes or exacerbates UTI, surgical treatment should be performed to remove the risk factor. Standardised treatment and good control of blood sugar are also crucial for patients with diabetes.
4. Prevention of urosepsis during a surgery to treat urinary tract obstruction. The infection should be treated and controlled before surgery. Avoid long surgery time and excessive pressure in the renal pelvis. Changes of white blood cell count should be monitored at the early stages after surgery. Urosepsis should be identified and treated promptly.
5. Improve patient education and behavioural therapy for patients to minimise the possibility of reinfection. Patients with diabetes should be reminded to strictly control their blood sugar. The frequency of catheter replacement and urethral orifice cleaning and care should be explained to patients who require long-term indwelling catheters. Drink plenty of water and urinate after sexual activity to flush out the bacteria. Patients should acquire the habit of wiping from front to back after defecating to avoid contaminating the urethral orifice.

Q3. As one of the commonly used drugs for UTI, what role does quinolone play in the treatment of UTI and what are some of the challenges faced?

Clinically, we will select antimicrobial agents based on the pharmacokinetics of the drug and the site of infection.

Drugs such as nitrofurantoin and fosfomycin trometamol have high urinary concentration. However, they have lower concentration in the blood, so they are only used in treating lower UTI and cannot be used for upper UTI.

Levofloxacin and β-lactam antibiotics have high concentration in both blood and urine. They can be used to treat both upper and lower UTIs.

There are two primary targets of quinolones: inhibition of DNA gyrase and topoisomerase IV, leading to inhibition of bacterial DNA synthesis, thus achieving bactericidal effect.

They differ according to the order of invention, namely, first, second, third, and fourth-generation. Currently, third-generation fluoroquinolones (including ofloxacin, enoxacin, and ciprofloxacin) are the most commonly used in China. These antibiotics are significantly stronger against Gram-negative bacteria than the previous two generations. They also have antibacterial effect on some Gram-positive bacteria and anaerobic bacteria as well as Mycoplasma chlamydia. Fourth-generation quinolones (moxifloxacin and gatifloxacin) have even stronger antibacterial effect. However, they are not recommended for UTI treatment as their urinary concentration is relatively low.

Third-generation quinolones that are commonly used in clinical settings include ciprofloxacin and levofloxacin. These are oral medications that are well absorbed, widely distributed in the body, excreted through the kidney partially in their original form with high urinary concentration – making them suitable for UTI treatment. Currently, although the proportion of other pathogens is increasing, the most commonly observed UTI causative pathogen is still E. coli. Thus, quinolones with strong antibacterial effect on Gram-negative bacteria and high urinary concentration remain the most commonly used empirical treatment for UTI. The newly marketed quinolone, sitafloxacin, is also characterised by renal metabolism and high urinary concentration. In vitro tests also showed strong antibacterial activity against pathogens such as ESBL-producing E. coli, thus adding a new option to clinical treatment.

The widespread application of quinolones in clinical settings and drug residue from widespread use in livestock and poultry breeding has gradually caused drug resistance rates to increase. More studies have reported that bacterial quinolone resistance is increasingly worrying and may already be unsuitable as an empirical treatment choice for hospitalised infected patients. (One such report stated that out of the 213 strains (49.31%) of pathogens detected from a total of 432 UTI cases, there were 159 strains (74.65%) of Gram-negative bacteria – consisting of mainly E. coli and K. pneumoniae. There were 54 strains (25.35%) of Gram-positive bacteria, consisting of mainly E. faecium and E. faecalis. Of the Gram-negative bacteria, E. coli has higher drug resistance rates towards ciprofloxacin and levofloxacin at 84.23% and 83.26%, respectively. The drug resistance rates of K. pneumoniae are 25.00% and 30.00% for ciprofloxacin and levofloxacin, respectively. Among the Gram-positive bacteria, E. faecium has higher drug resistance rates towards ciprofloxacin and levofloxacin at 80.77% and 76.92%, respectively. The drug resistance rates of E. faecalis are 54.55% and 63.64% for ciprofloxacin and levofloxacin, respectively. The drug resistance rate of ESBL-producing E. coli is 93.22% for both ciprofloxacin and levofloxacin. The drug resistance rates of non-ESBL-producing E. coli are 78.00% and 76.00% for ciprofloxacin and levofloxacin, respectively.)

References:

1. Chinese expert consensus on diagnosis and treatment (2015 edition) – complex urinary tract infection, urinary tract infection diagnosis and treatment, Chinese expert consensus editorial team, Chinese Journal of Urology, 2015,36(4):241-244.
2. DOI:10.3760/cma.j.issn.1000-6702.2015.04.001
3. http://rs.yiigle.com/CN112330201504/130153.htm
4. Sun Limin, Distribution of pathogens in midstream urine culture and analysis of quinolone drug resistance, “Primary medicine forum”, 2020,24(22),3217-3218 DOI:10.19435/j.1672-1721.2020.22.066
5. Zhou Kun, Recent research on the clinical application of quinolone antimicrobial agents, “Anti-infective Pharmacology”, 2020,17( 06),782-785 DOI:10.13493/j.issn.1672-7878.2020.06-002