Urinary tract infections (UTIs) are commonly encountered in clinical practice, yet their treatment is not as straightforward as many assume. Professor Wenjie Yang from the Department of Infectious Diseases at Tianjin City First Central Hospital begins with epidemiology, etiology, and resistance trends of UTIs, and emphasizes the principles and precautions of treating UTIs with oral antimicrobial agents. This discussion is highly beneficial for guiding clinical practice, and we share the insights below.
Epidemiology of Urinary Tract Infections:
UTIs require patients to exhibit urinary tract irritation and/or systemic symptoms such as fever, along with the presence of pathogens in urine cultures. Based on clinical presentation, site of infection, severity, and risk factors, UTIs are categorized into complicated UTIs (cUTIs) and uncomplicated UTIs. Uncomplicated UTIs include uncomplicated cystitis, pyelonephritis, and recurrent UTIs; cUTIs include all other UTIs not defined as uncomplicated, such as those in males, patients with urinary tract anatomical or functional abnormalities, catheterized individuals, those with kidney disease, immunocompromised conditions (e.g., diabetes), and patients undergoing radiotherapy or chemotherapy.
A global report from 2019 indicates that there were 404.6 million cases of UTIs worldwide, with 236,790 deaths; women had a 3.6 times higher incidence rate than men. From 1990 to 2019, the number of deaths from UTIs increased by 2.4 times, and the age-standardized mortality rate rose from 2.77 per 100,000 in 1990 to 3.13 per 100,000 in 2019. The incidence of UTIs increases with age, particularly among individuals over 60. Additionally, research shows that UTIs rank second to third in community-acquired infections; they account for 35%-45% of hospital-acquired infections; catheter-associated UTIs are the second leading cause of bloodstream infections; about 50% of women will experience a UTI in their lifetime, with 30% suffering from recurrent UTIs, and 2.4% of all women experiencing frequent UTIs; in the United States, the annual cost of medical care and lost productivity due to UTIs is approximately $3.5 billion.
Data from China’s CARSS surveillance network from 2014 to 2023 shows that Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp. are the most commonly isolated pathogens in urinary tract infections (UTIs) in China, followed by Pseudomonas aeruginosa. Specifically, E. coli is the primary pathogen for uncomplicated cystitis, with other common pathogens including Enterococcus, Staphylococcus, K. pneumoniae, and Proteus mirabilis. For complicated cystitis, E. coli also predominates, with Klebsiella spp., Enterococcus spp., P. aeruginosa, other Enterobacteriaceae, and Proteus spp. also commonly identified.
Pathogen Resistance Trends in UTIs:
A multicenter study on the antimicrobial activity of E. coli from urinary sources suggests that the use of cephalosporins and fluoroquinolones should be restricted in empirical treatment of community-acquired UTIs in China. CARSS surveillance data indicates that from 2014 to 2023, the resistance rates of K. pneumoniae from urinary sources in China to levofloxacin, ceftriaxone, and nitrofurantoin all exceeded 30%. Resistance rates of Enterococcus faecalis and E. faecium to levofloxacin were over 30%, but lower for nitrofurantoin and ampicillin. E. faecium showed high resistance rates to levofloxacin, ampicillin, and nitrofurantoin above 30%. Research identifies risk factors for UTIs caused by ESBL-producing Enterobacteriaceae including male gender, old age, history of UTIs, hospitalization, use of antimicrobial agents, underlying diseases, catheterization, international travel, and freshwater swimming. Risk factors for Enterococcus UTIs include being male, aged between 55 and 75, community-acquired infections, urinary retention, hospital-acquired infections, and urinary tract tumors.
Oral Antimicrobial Treatment for UTIs:
The application of antimicrobial agents for UTIs should consider several factors including local epidemiological data, antimicrobial spectrum and in vitro activity, pharmacokinetic/pharmacodynamic (PK/PD) characteristics, safety, as well as accessibility, compliance, and cost-effectiveness. The choice of administration route for UTI treatment should follow these principles: For lower urinary tract infections, select drugs with high urinary concentration and recommend oral administration; for upper urinary tract infections, which may involve bloodstream infection, consider drug concentration in kidney, urine, and blood, recommending intravenous administration initially followed by oral drugs as the condition stabilizes and provided that the pathogen is sensitive to oral agents, hemodynamics are stable, the source of infection is controlled, and gastrointestinal function is normal.
For acute uncomplicated pyelonephritis with mild systemic symptoms and no signs of sepsis, initial oral treatment can be considered. However, for complicated urinary tract infections (UTIs), which often involve complex and resistant pathogens, intravenous formulations should be selected to cover ESBL-producing Enterobacteriaceae. In cases where local resistance to fluoroquinolones is less than 10%, and the patient, a mildly symptomatic female in an outpatient setting, has not used fluoroquinolones in the past six months, oral levofloxacin or ciprofloxacin can be considered. If the patient shows signs of sepsis or more severe systemic symptoms, intravenous antimicrobial therapy should be initiated promptly.
When prescribing antimicrobials, attention should be paid to the CLSI guidelines on antimicrobial sensitivity interpretation for Enterococci and urinary isolated Enterobacteriaceae. For urinary isolates of Enterobacteriaceae, it is important to consider: (1) specific susceptibility breakpoints based on the site of infection and treatment regimen; (2) alternative testing for cefazolin, which uses breakpoints of 16 mg/L for uncomplicated UTIs and 2 mg/L for complicated UTIs to predict sensitivity to oral agents like cefaclor, cefadroxil, cefpodoxime proxetil, cefprozil, and cephalexin—cefazolin-resistant strains should not be assumed resistant to cefadroxil, cefpodoxime, or cephalexin; (3) ampicillin results can predict amoxicillin susceptibility; (4) tetracycline sensitivity can predict doxycycline and minocycline sensitivity, while those intermediate or resistant to tetracycline may still be sensitive to doxycycline and minocycline; however, doxycycline is not recommended for treating UTIs; (5) fosfomycin is only recommended for urinary isolates of E. coli, not other Enterobacteriaceae.
For Enterococci isolated in urine cultures, the CLSI interpretations are as follows: (1) Penicillin-sensitive non-β-lactamase producing Enterococci can predict sensitivity to ampicillin, amoxicillin, ampicillin-sulbactam, amoxicillin-clavulanate, and piperacillin-tazobactam; (2) ampicillin sensitivity can predict amoxicillin sensitivity and sensitivity to non-β-lactamase producing Enterococci for amoxicillin-clavulanate, ampicillin-sulbactam, and piperacillin-tazobactam; (3) β-lactamase production in Enterococci is very rare; (4) oral ampicillin is only appropriate for treating uncomplicated UTIs, prescribed as 0.5g every 6 hours, or alternatively, amoxicillin 0.25g every 8 hours or 0.5g every 12 hours; (5) fosfomycin is only recommended for urinary isolates of E. faecium.
Initially, it is crucial to assess the risk of infection with multidrug-resistant Enterobacteriaceae and Enterococci. Oral cephalosporins are limited to empirical treatment of patients without risk of multidrug-resistant Enterobacteriaceae and for infections with Enterococci. Specific dosing for acute uncomplicated cystitis includes cefuroxime axetil 1g/day for 5 days, cephalexin 500mg every 6 hours for 5 days, cefdinir 300mg every 12 hours for 5 days, and other similar regimens. These treatments are alternatives for acute uncomplicated cystitis and empirical treatment of uncomplicated pyelonephritis. Despite resistance monitoring showing fluoroquinolone resistance, these agents, being concentration-dependent with high urinary concentrations, are still viable for treating cystitis. Fosfomycin demonstrates effective treatment activity against multidrug-resistant Enterobacteriaceae and Gram-positive bacteria, with oral formulations achieving urine concentrations comparable to intravenous administration, making it effective for UTIs. Sitravatin is an oral fluoroquinolone excreted via the urinary route (70%-80%) and is effective against Enterococci and ciprofloxacin-resistant E. coli, making it a treatment option for UTIs caused by Enterococci and multidrug-resistant Enterobacteriaceae.
Regarding sequential oral therapy for urosepsis, a retrospective study by the U.S. Veterans Affairs hospitals from 2016 to 2022, comparing fluoroquinolones, sulfonamides, and cephalosporins, showed that sulfonamides and fluoroquinolones were more effective than beta-lactams with high bioavailability, and treatments lasting over 8 days had a lower recurrence rate than shorter treatments.
Prevention of recurrent UTIs includes continuous and intermittent prevention strategies, lasting from 1 to 12 months. Intermittent prevention is particularly used for sexually associated UTIs, with a single dose taken before or after sexual activity, proving both effective and safe. Additionally, the safety of oral antimicrobials during pregnancy should be considered. For cases where empirical treatment fails, in severe cases, or among populations at high risk of infection with multidrug-resistant organisms, urine cultures should be promptly conducted to identify the pathogen and its resistance profile, allowing for tailored treatment adjustments.
In summary, UTIs are common infectious diseases clinically, predominantly caused by E. coli, K. pneumoniae, and Enterococci. In China, the resistance situation among UTI isolates is severe, with widespread resistance to various antimicrobials. The choice of oral antimicrobial therapy for UTIs must consider the site of infection, local resistance trends, individual risk factors, in vitro susceptibility testing, pharmacokinetics and pharmacodynamics of the antimicrobials, as well as safety and compliance. Oral antimicrobials are suitable for treating lower urinary tract infections and for sequential treatment of more severe upper urinary tract infections, complicated UTIs, urosepsis, and for preventing recurrent UTIs.
Professor Wenjie Yang
Director of the Department of Infectious Diseases at Tianjin City First Central Hospital
Chief Physician and Master’s Supervisor
Recognized as a Tianjin City Expert with Outstanding Contributions in 2021
Member of the National Health Commission’s Committee on the Clinical Use of Antimicrobial Agents and Evaluation of Bacterial Resistance, Vice-Chairman of the Committee on Evidence-Based and Translational Research for Infectious Diseases at the Chinese Research Hospital Association, Standing Committee Member and Tianjin Chief of the Bacterial Infections and Resistance Prevention Branch of the Chinese Medical Association, Director of the Office for the Clinical Application and Management of Antimicrobial Drugs in Tianjin, and President of the Tianjin Infectious Diseases Physicians Association
Professor Yang specializes in the diagnosis and treatment of infectious diseases across various systems and organs, particularly in complex and severe infections, including multidrug-resistant bacterial infections, fungal infections, infections in the elderly and immunocompromised populations, as well as the differentiation of unexplained fevers and the diagnosis and treatment of complex and difficult internal medicine conditions.
