Professor Xu Tao

Chief Physician, Professor (Associate Professor), Doctoral Supervisor

Director, Department of Urology, Peking University People’s Hospital

Deputy Director, Peking University Applied Lithotripsy Institute

Deputy Chairman, Beijing Medical Association Urology Branch, and Leader of Basic and Translational Group

Member of the Urology Branch and Vice-chairman of the Laser Group of the Chinese Medical Association

Member of the Standing Committee of the Urology Specialists Branch and Member of the Oncology Group of the Chinese Medical Association

Member of the Urogenital Tumour of Male Genital System Specialist Committee and Member of the Bladder Cancer Group of the China Anti-Cancer Association

Vice President of the Urology Branch of the China Association of [Medical] Equipment

There is a lack of concrete etiological data on complicated urinary tract infections (cUTI), but its clinical prevalence is clearly on the rise and the condition has become increasingly complex. To better understand the etiological distribution, diagnosis, treatment and prevention of cUTI, we invited Professor Xu Tao from the Department of Urology, Peking University People’s Hospital, to give us an overview of the treatment strategies for cUTI.

Q1: cUTI is characterised by high heterogeneity and it becomes increasingly complex every year.

cUTI is broadly and inconsistently defined in domestic and international guidelines. A wide range of underlying conditions are included in the definition, resulting in significant heterogeneity in complex urinary tract infections. For example, the 2020 EAU guidelines mainly define cUTI as urinary tract infections combined with medical conditions that increase the risk of complications (combined with systemic problems, such as diabetes, immunocompromisation, or with anatomical problems of the urinary tract, such as urinary tract obstruction, or  with functional problems of the urinary tract, such as neurogenic bladder) making the infection difficult to cure.¹ cUTI is mainly defined and diagnosed in domestic Chinese Guidelines for the Diagnosis and Treatment of Urological and Male Diseases (2019 version) as: 1. positive urine culture, and 2. combined with at least one complicating factor, including medical and surgical problems.²

cUTI is becoming increasingly complex with the increasing use of clinical urological interventions including  antibiotics , and the diversification of clinical treatments such as chemotherapy and radiotherapy.

Q2: cUTI is predominantly co-infections with high detection rate of drug-resistant bacteria

The 2021 CHINET China Antimicrobial Surveillance Network showed that Escherichia coli, Enterococcus faecalis and Klebsiella pneumoniae were the main causative agents of urinary tract infections in China.³ For simple urinary tract infections, E. coli is the main causative organism; for cUTI, E. coli accounts for less than half of the cases, and most of them are combined with other flora infections, and the detection rate of enterococci and Pseudomonas aeruginosa has increased in recent years.

People at high risk of drug resistance are  clinically assessed through 2 main methods: 1. those for whom it is difficult to control the infection after frequent and long-term antibiotics use;  and 2. those with complicating factors, such as long-term indwelling catheters and ureteral stents which bacteria adhere to and form a biofilm and develop high drug resistance.⁴ These include, for example, those with diseases such as neurogenic bladder and urinary stones, especially cases involving infected or obstructive stones.

Q3: Stratified management of cUTI focuses on the stratification of comorbidities. Quinolones can be the preferred regimen for initial empirical antimicrobial treatment.

Stratified management of patients with complex urinary tract infections focuses on assessment of the complexity and severity of co-morbidities for each individual, based on the specific impact of co-morbidities in the development of the infection. For example, in a patient with ureteral stones causing ureteral obstruction and consequently an abscessed kidney, the patient presents with an acute systemic infection, possibly with high fever or even toxic shock. For such patients, the clinical priority must be to remove the obstruction and subsequently consider antimicrobial therapy. For patients with well-managed diabetes with co-infection, antimicrobial therapy is the preferred treatment.

Patients with cUTI often present with more severe or  more complex problems. In the absence of acquired drug sensitivity, clinicians must provide initial empirical treatment based on the likely pathogen spectrum and drug resistance in the locality, as well as the patient’s condition and the characteristics of the antimicrobial agent. It is recommended to choose drugs with high urine concentration – quinolones, such as levofloxacin and Sitafloxacin.⁵ Sitafloxacin is a new type of quinolone with broad-spectrum⁶ and high sensitivity⁷. It is effective against G+, G- and atypical pathogens, and has relatively good antibacterial activity against drug-resistant bacteria. It has obvious advantages in the treatment of difficult-to-treat and complicated infectious diseases. It also provides a favourable therapeutic option in the clinical treatment of cUTI. In addition, cephalosporins (second or third generation) and fosfomycin aminotriol (which can be used for non-febrile, lower urinary tract infections) are also commonly used antimicrobial drugs in clinical practice for initial empirical treatment.

Q4: Long-term low-dose antimicrobial use as a treatment option to prevent recurrence of UTI must be addressed with clinical caution

Low-dose long-term drug regimens date back to the 1990s. For patients with recurrent infections (more than two occurrences within six months), long courses of low-dose antibacterial therapy with drugs that have fewer side effects,  such as compounded sulfamethoxazole and furantoin⁸  were selected, and the dosing regimens were all based on urine culture and drug sensitivity results. However, there is a lack of high quality clinical evidence for such regimens. This is because if the patient has other cofactors, such as a long-term indwelling urinary catheter, the presence of prostatic hyperplasia, or chronic urinary retention, the treatment should prioritise the primary disease. In addition, for more serious or complicated infections, a lower dose is hardly effective in eradicating the root cause of the disease.

Therefore, long courses of low-dose treatment regimens in clinical practice should be approached with caution, as they may otherwise induce changes in the flora and even cause the development of drug-resistant flora. However, my personal experience suggests that such an application should be strictly limited to simple infections. Another similar prophylactic treatment is for sexually-transmitted infections, where a single oral dose is recommended before and after sexual intercourse.

Preventive management of patients at high risk of cUTI is more challenging  because of the multifactorial and highly heterogeneous concerns : inadequate standardisation of antibiotic use and problems that are difficult to resolve, such as primary diseases (diabetes) and comorbidities (long-term recurrent urinary stones, infectious stones). It is therefore difficult to obtain high quality evidence to make recommendations, and current guidelines  present the problem relatively broadly. The search for more uniform and valuable recommendations or implementable options that can be applied to all patients is still ongoing.

References

1. Bonkat G, R. Bartoletti R, Bruyère F, et al.  EAU Guidelines on Urological Infections 2020.
2. Huang J, Wang JY, Kong TZ, et al. Chinese guidelines for the diagnosis and treatment of urological and male diseases (2019 edition). Beijing: Science Press, 2020: 410-418.
3. CHINET China Bacterial Drug Resistance Surveillance 2021 http://www.chinets.com/Data/AntibioticDrugFast
4. Zhang JM, Zhang X, Luo HM, et al. Observation of bacterial biofilm in ureteral stents and distribution of pathogenic bacteria and drug resistance[J]. Chinese Tissue Engineering Research, 2020, 24(16): 2556-2560.
5. Wu XJ, Fan YX, Zhang J, et al. Pharmacokinetics and pharmacokinetics/pharmacodynamics of oral cetefloxacin in healthy Chinese subjects[J]. Chinese Journal of Infection and Chemotherapy, 2018, 14(4): 352-359.
6. China Instruction Manual for Cetefloxacin (Version Date: 17/5/2021)
7. Wu S, Yang Y, Yan G, et al.  Comparative activities of sitafloxacin against recent clinical isolates in hospitals across China[J]. Eur J Clin Microbiol Infect Dis. 2021 Nov;40(11):2271-2283.
8. Ge JB, Xu YJ. Internal medicine (8th ed.) [M]. Beijing: People’s Health Press, 2013:496-502.