Editor’s Note: The Infectious Diseases Society of America (IDSA) has recently released its Clinical Practice Guidelines for the Treatment and Management of Complicated Urinary Tract Infections (cUTI)—the first IDSA guideline dedicated specifically to cUTI. The updated guideline revises the definition of cUTI and proposes a four-step framework to support individualized empiric treatment decisions.For empiric therapy in cUTI, the guideline recommends third- or fourth-generation cephalosporins, carbapenems, piperacillin–tazobactam, or fluoroquinolones as first-line options, regardless of the presence of sepsis. Newer antimicrobial agents—including β-lactam/β-lactamase inhibitor (BL/BLI) combinations and the novel siderophore cephalosporin cefiderocol—are introduced as alternative options, particularly for patients with treatment failure or infections caused by resistant organisms. In addition, the guideline reviews evidence supporting step-down oral therapy with fluoroquinolones and shorter treatment durations.
To promote rational antimicrobial use in cUTI, Infectious Disease Frontline invited Professor Ludong Qiao from Beijing Tongren Hospital, Capital Medical University, to summarize key guideline updates and recent research developments.
Rising Burden of Urinary Tract Infections and Antimicrobial Resistance
Urinary tract infections (UTIs), including uncomplicated UTI (uUTI) and complicated UTI (cUTI), are among the most common community- and hospital-acquired infections, predominantly caused by Gram-negative bacteria. A 2022 global analysis estimated 404.61 million UTI cases worldwide in 2019, with 236,790 associated deaths. Data from the 2018 U.S. National Inpatient Sample (NIS) indicated that nearly one-quarter of UTI cases were classified as cUTI.
As populations age, the clinical and economic burden of UTIs continues to grow, alongside a marked increase in antimicrobial resistance—often exceeding the resistance thresholds that informed older empiric treatment guidelines. Meanwhile, multiple clinical trials evaluating novel antibiotics for UTIs have been published, underscoring the need to reassess treatment strategies.
Simplified Definition of cUTI: Focus on Infection Extent
A clear disease definition is fundamental to effective diagnosis, treatment, and research. Earlier IDSA guidelines classified UTIs based on the presence of complicating host or anatomical factors, distinguishing uUTI from cUTI. While conceptually straightforward, this approach resulted in heterogeneous patient populations, variable treatment response, and higher recurrence rates.
The updated IDSA guideline simplifies classification by focusing primarily on anatomical extent of infection:
- Infection confined to the bladder → uUTI
- Infection extending beyond the bladder (e.g., fever, bacteremia, catheter-associated infection, or pyelonephritis) → cUTI
Importantly, patients with diabetes, immunosuppression, or underlying urinary tract abnormalities are no longer automatically categorized as cUTI.
Male prostatitis is classified as cUTI; however, due to the unique pharmacokinetic and pharmacodynamic properties of prostatic tissue, the guideline does not apply to prostatitis.
Empiric Therapy: A Four-Step Individualized Decision Framework
Surveillance data from U.S. emergency departments show that resistance among urinary pathogens now exceeds thresholds used in the 2010 IDSA guideline. For example, resistance rates among outpatient isolates (2018–2020) reached:
- 22.4% for trimethoprim–sulfamethoxazole
- 21.6% for fluoroquinolones
Given substantial geographic and patient-level variability in resistance patterns, the expert panel concluded that no single empiric regimen is universally optimal. Instead, the guideline recommends a four-step individualized decision process:
Four-Step Framework
- Assess disease severity to prioritize urgency and antimicrobial spectrum
- Evaluate patient-specific risk factors for resistant organisms
- Consider comorbidities and safety factors to minimize adverse events
- For septic patients, consult local antibiograms to optimize empiric coverage
Novel Antimicrobials: Expanding Options for Resistant cUTI
Before applying the four-step framework, the guideline outlines potential empiric therapy options for cUTI, including both intravenous and oral regimens.
Recommended Empiric Treatment Options
Clinical Scenario
First-Line Options
Alternative Options
Sepsis (with or without shock)
3rd/4th-generation cephalosporins, carbapenems, piperacillin–tazobactam, fluoroquinolones
Novel BL/BLI combinations, cefiderocol, plazomicin, or older aminoglycosides
Non-septic (IV therapy)
3rd/4th-generation cephalosporins, piperacillin–tazobactam, fluoroquinolones
Carbapenems, novel BL/BLI agents, cefiderocol, plazomicin
Non-septic (oral therapy)
Fluoroquinolones or trimethoprim–sulfamethoxazole
Amoxicillin–clavulanate or oral cephalosporins
The guideline emphasizes early initiation of empiric therapy in severe infections, while incorporating resistance risk, antimicrobial spectrum, and local susceptibility data.
Cefiderocol: A Key Weapon Against Carbapenem-Resistant Pathogens
UTI pathogens exploit virulence factors such as adhesins, siderophores, and toxins to colonize and invade the urinary tract. Cefiderocol, a novel siderophore cephalosporin, contains a catechol side chain that chelates iron and utilizes bacterial iron transport systems to gain intracellular access—enhancing antimicrobial activity and helping overcome resistance mechanisms.
Resistance Landscape (CHINET 2025, China)
Carbapenem resistance remains high among urinary pathogens:
- Carbapenem-resistant Klebsiella pneumoniae (CRKP): 24.6%
- Carbapenem-resistant Pseudomonas aeruginosa (CRPA): 24.9%
- Carbapenem-resistant Acinetobacter baumannii (CRAB): 76.5%
- Carbapenem-resistant Enterobacterales (CRE): 10.8%
Cefiderocol demonstrates strong in vitro activity against:
- CRKP
- CRPA
- CRAB
- CRE producing KPC, NDM, VIM, IMP, and OXA-48 enzymes
These properties make cefiderocol a valuable therapeutic option for multidrug-resistant cUTI.
Clinical Evidence Supporting Cefiderocol
APEKS-cUTI Trial
A multicenter randomized controlled trial demonstrated that cefiderocol was non-inferior to imipenem–cilastatin in treating cUTI.
Composite clinical and microbiological response rates:
- Cefiderocol: 73%
- Imipenem–cilastatin: 55% (Adjusted difference: 18.58%, 95% CI: 8.23–28.92%)
PROVE Real-World Study
Real-world evidence further supports cefiderocol’s efficacy and safety. At IDWeek 2025, subgroup analyses revealed that early empiric use was associated with improved outcomes compared with salvage therapy:
- Clinical cure rate: 73.7% vs. 54.3%
- 30-day all-cause mortality: 14.0% vs. 30.0%
Step-Down Therapy and Shortened Treatment Duration
Emerging data suggest that early transition from intravenous to oral therapy and shorter antibiotic courses may be feasible in selected patients.
The guideline conditionally recommends:
- Switching to oral therapy once clinical improvement occurs and an effective oral option is available
- Limiting fluoroquinolone therapy to ≤7 days in responsive cUTI cases, with or without bacteremia
However, these recommendations are based on low-quality evidence, much of which predates the current era of widespread fluoroquinolone resistance. Evidence supporting shortened regimens or oral β-lactam therapy remains limited.
Therefore, treatment duration and step-down decisions should be individualized, and further research is needed—particularly on optimal treatment duration and oral step-down strategies for newer agents such as BL/BLI combinations and cefiderocol.
Professor Ludong Qiao
