- Multiple active agents may be appropriate for MDR gram-negative (MDR-GN) localized or systemic UTI with risk factors for treatment failure, depending on local epidemiology, patient comorbidities, and specific resistance mechanisms (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

- Rapid molecular diagnostics are essential to distinguish between carbapenemase types (e.g., KPC vs NDM), which directly determines therapeutic selection (Tamma PD, et al. 2024).

- Carbapenem-based regimens or ceftazidime–avibactam lose activity against MBL-producing Enterobacterales (e.g., New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM), and imipenemase (IMP) (Heil & McCreary, 2025; Tamma PD, et al. 2024).

- PK/PD optimization—using extended infusions and renal-adjusted dosing—ensures sustained concentrations above the MIC, maximizing efficacy (Rizk NA, et al. 2017).

- Targeted therapy with aztreonam–avibactam supports stewardship goals by minimizing unnecessary broad-spectrum exposure once resistance mechanisms are defined (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

- Early diagnostic-driven adjustment of therapy can reduce time to appropriate treatment and improve clinical outcomes in high-risk cUTI (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

Introduction

The management of UTIs has undergone significant evolution in recent years, driven by rising antimicrobial resistance, advances in rapid diagnostics, and a refined understanding of disease classification. This literature review synthesizes current evidence on UTI management, emphasizing the 2025 EAU Guidelines, molecular diagnostic integration, PK/PD optimization, and antimicrobial stewardship principles essential for contemporary clinical practice (Bonkat G, et al. 2025).

Updated Classification of UTIs

The Localized vs Systemic Paradigm

The 2025 EAU Guidelines on Urological Infections introduced a conceptual shift, abandoning the long-standing "complicated vs uncomplicated" dichotomy in favor of a clinically grounded division into "localized" and "systemic" infections. The prior terminology had become increasingly ambiguous, often conflating anatomical risk factors with clinical severity (Bonkat G, et al. 2025).

The EAU now defines localized UTI as an infection confined to the bladder, presenting with symptoms such as dysuria, frequency, or urgency without systemic features. In contrast, systemic UTI refers to infections accompanied by signs of systemic illness, including fever, hypotension, rigors, or costovertebral angle tenderness, with or without local symptoms. This classification emphasizes clinical presentation rather than the patient's demographic or comorbid profile, allowing for clearer diagnostic and therapeutic decision-making. It aligns treatment intensity with disease severity—distinguishing mild cystitis suitable for outpatient oral therapy from systemic infections (such as pyelonephritis or prostatitis) that require hospital-based, IV management (Bonkat G, et al. 2025).

Risk Factors for Treatment Failure

Alongside this redefinition, the EAU guidelines highlight the identification and management of risk factors for treatment failure as a central component of UTI care. Both localized and systemic infections may be complicated by host or structural factors that predispose to a more severe or recurrent course. The updated risk framework—summarized in Table 2 of the 2025 guidelines—includes:

Urinary tract abnormalities

Obstruction

Calculi

Indwelling catheters

Recent antibiotic use

Resistant pathogens

Immunocompromise

Advanced age or frailty

Recognizing these variables early enables clinicians to adapt therapy appropriately—selecting broader-spectrum empiric agents, extending treatment duration, or pursuing imaging and source control when necessary. Unlike the former model, which categorically labeled all such cases as "complicated," the new EAU approach separates disease severity from host-related risk, promoting individualized management and more precise antimicrobial stewardship (Bonkat G, et al. 2025).

Role of Rapid and Molecular Diagnostics

Diagnostic Technologies in MDR-GN Infections

The increasing prevalence of MDR-GN pathogens has driven the integration of rapid and molecular diagnostic technologies into clinical management. Conventional urine culture and phenotypic AST typically require 48–72 hours, during which patients receive empirical treatment, often with broad-spectrum antibiotics.

In contrast, multiplex PCR platforms and resistance gene panels can identify both the causative organism and key resistance determinants—such as blaNDM, blaKPC, blaOXA-48, and blaCTX-M—directly from urine or positive blood cultures within a few hours. These assays, now used in many tertiary centers, allow clinicians to detect ESBL and carbapenemase producers early in the diagnostic process, even before bacterial growth is evident. This capacity for rapid identification of MDR-GN mechanisms is particularly valuable in high-risk or septic patients, where early optimization of therapy can markedly improve outcomes and reduce unnecessary exposure to last-line agents (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

Integration of Rapid Diagnostics into Clinical Decision-Making

Early molecular diagnostic results directly inform timely modification of antimicrobial therapy, bridging the gap before complete phenotypic AST data become available. Modern diagnostic workflows now combine rapid identification (via Matrix-Assisted Laser Desorption/Ionization–Time of Flight (MALDI-TOF) or multiplex PCR) with early resistance gene detection to support case-based therapeutic algorithms. At presentation, empiric therapy is guided by clinical severity, source of infection, and patient-specific risk factors—particularly prior antibiotic exposure, recent hospitalization, or known colonization with MDR organisms (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

Once rapid diagnostic results are available—often within hours—therapy can be rapidly adjusted:

Detection of blaCTX-M triggers escalation from a third-generation cephalosporin to a carbapenem.

Identification of blaNDM or blaOXA-48 prompts early consideration of combination regimens involving aztreonam–avibactam, cefiderocol, or colistin, depending on local susceptibility data.

Absence of resistance markers supports confident de-escalation to narrower-spectrum agents.

For patients with prior antibiotic exposure—who are at higher risk of harboring resistant Gram-negative organisms—rapid molecular testing plays an essential role in avoiding delays to effective therapy. Empirical regimens in these individuals should cover probable resistance mechanisms based on prior culture data or epidemiological risk, with prompt refinement once molecular results are available. For example, in a patient with recurrent ESBL E. coli UTI previously treated with fluoroquinolones, an initial empiric regimen including a carbapenem may be justified, but if early PCR confirms absence of ESBL or carbapenemase genes, therapy can be narrowed safely within 24 hours (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

When integrated into diagnostic–stewardship workflows, molecular platforms enable real-time precision therapy, allowing empiric regimens to be rationalized within the first 24 hours, long before traditional cultures would have informed such adjustments. This rapid turnaround shortens time to effective therapy, reduces mortality in MDR-GN sepsis, and supports hospital-level antimicrobial governance by curbing indiscriminate carbapenem use (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

Antimicrobial Stewardship Principles

Prevention of Unnecessary Broad-Spectrum Use

Antimicrobial stewardship has become central to modern infection management, particularly in the MDR-GN era (Tamma PD, et al. 2024; Bonkat G, et al. 2025). The increasing availability of rapid molecular and microbiological diagnostics now allows stewardship interventions to occur far earlier in the clinical course. When rapid PCR or MALDI-TOF results confirm the absence of key resistance determinants—such as blaCTX-M, blaKPC, or blaNDM—clinicians can confidently de-escalate from broad-spectrum empiric therapy (e.g., carbapenems or piperacillin–tazobactam) to narrower agents such as ceftriaxone, amoxicillin–clavulanate, or trimethoprim–sulfamethoxazole, provided susceptibility is consistent (Tamma PD, et al. 2024).

Similarly, rapid identification of a non–ESBL–producing E. coli or Klebsiella from urine or blood culture permits step-down to oral therapy, reducing both hospital stay and ecological impact. In catheter-associated or healthcare-associated infections, early pathogen identification can also prevent unnecessary use of agents active against Pseudomonas or Enterococcus when these organisms are not implicated (Bonkat G, et al. 2025; Gawrys GW, et al. 2018). These targeted adjustments not only lower antimicrobial resistance pressure but also minimize toxicity, cost, and disruption of the patient's microbiome (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

Treatment of MDR Pathogens

Management of MBL-Producing Enterobacterales

Treatment of MBL-producing Enterobacterales, such as NDM, VIM, and IMP producers, remains one of the most challenging areas of antimicrobial therapy. Traditional β-lactamase inhibitors (e.g., avibactam, vaborbactam, relebactam) lack activity against MBL enzymes, prompting the development of novel combination strategies (Tamma PD, et al. 2024; Wise MG, et al. 2023).

Aztreonam–avibactam has emerged as a promising dedicated option because aztreonam is intrinsically stable to MBL hydrolysis, while avibactam protects it from co-produced ESBL or AmpC enzymes frequently present in MBL-producers (Cornely OA, et al. 2020; Wise MG, et al. 2023; Tamma PD, et al. 2024). Clinical and microbiological data from phase 3 trials and real-world cohorts demonstrate high in vitro activity (> 95% susceptibility) and favorable clinical cure rates (approximately 80%–90%) in bloodstream and localized or systemic UTIs with risk factors for treatment failure caused by NDM- or VIM-producing Enterobacterales.

In the absence of commercially available aztreonam–avibactam (pending full regulatory approval in some regions), many centers employ ceftazidime–avibactam combined with aztreonam as a practical, synergistic alternative. This regimen has shown comparable outcomes, with in vitro synergy restoring susceptibility in > 90% of MBL-producing isolates, including E. coli and Klebsiella pneumoniae (Falcone M, et al. 2021; Tamma PD, et al. 2024). Both strategies offer reliable, carbapenem-sparing options with substantially improved tolerability compared to older salvage regimens.

Limited Role of Older Agents

Older agents—colistin, tigecycline, and aminoglycosides—retain limited but clinically constrained roles. Colistin's narrow therapeutic window, poor urinary tract penetration, and nephrotoxicity (up to 40%–50% incidence) limit its use, particularly in diabetic or renally impaired patients (Li J, et al. 2006; Tamma PD, et al. 2024). Tigecycline achieves subtherapeutic urinary concentrations, rendering it unsuitable for urinary infections and problematic for bacteremia due to low serum levels (Yahav D, et al 2011).

Aminoglycosides such as amikacin or plazomicin may retain in vitro activity against select isolates but are associated with ototoxicity and nephrotoxicity, both of which are accentuated in diabetic patients with baseline renal compromise. In such populations, TDM is essential if aminoglycosides are used as adjuncts (Wagenlehner FME, et al. 2019). Clinical experience consistently shows higher mortality and relapse rates when colistin- or tigecycline-based regimens are used as monotherapy compared with β-lactam–β-lactamase inhibitor combinations (van Duin D, et al. 2018). Consequently, aztreonam–avibactam or ceftazidime–avibactam plus aztreonam represent the current evidence-based standards for treating MBL-producing Enterobacterales, balancing potent microbiologic efficacy with improved safety profiles and reduced renal risk in vulnerable groups (Tamma PD, et al. 2024).

PK/PD Optimization

Principles of PK/PD in UTI Management

PK/PD optimization is central to effective UTI management, particularly in the era of rising resistance and limited therapeutic options (Gupta K, et al. 2011; Bonkat G, et al. 2025). Because most antimicrobials are excreted renally, achieving high urinary concentrations is usually straightforward; however, ensuring adequate drug exposure at the specific infection site—whether bladder, renal parenchyma, or prostate—requires tailored dosing strategies (Bonkat G, et al. 2025; Charalabopoulos K, et al. 2003).

For lower-tract infections such as cystitis, high urinary concentrations rather than systemic levels determine efficacy. Short courses of highly urinary-excreted agents like nitrofurantoin, pivmecillinam, or fosfomycin achieve optimal bactericidal activity. Conversely, in upper tract or systemic infections (pyelonephritis, bacteremic UTI), adequate plasma and tissue penetration is essential, favoring agents such as fluoroquinolones, cephalosporins, or carbapenems (Cattrall JWS, et al. 2019; Bonkat G, et al. 2025).

In prostatic infections, where the blood–prostate barrier restricts drug diffusion, lipophilic weak bases (e.g., fluoroquinolones, trimethoprim, macrolides) achieve superior intraprostatic concentrations. In contrast, hydrophilic β-lactams penetrate poorly unless the gland is acutely inflamed (Charalabopoulos K, et al. 2003).

Calculating and Applying PK Parameters

Optimizing antibiotics for UTIs requires matching each drug's PK/PD driver to the pathogen's MIC and the infection site (Bonkat G, et al., 2025):

Time-dependent β-lactams: Efficacy tracks with the fraction of the dosing interval that free drug stays above the MIC (fT > MIC). Extended or continuous infusions and shorter intervals can raise fT > MIC in pyelonephritis or bacteremic UTI (Craig WA, 1998; Roberts JA, et al. 2014).

Concentration-dependent agents (e.g., aminoglycosides): Efficacy hinges on achieving a high peak concentration (Cmax/MIC). Loading doses or higher early exposures can be critical in severe disease (Abdul-Aziz MH, et al. 2024).

Fluoroquinolones: Best predicted by AUC/MIC ratio—the area under the concentration–time curve over 24 hours divided by the minimum inhibitory concentration, where achieving adequate area under the concentration-time curve relative to MIC predicts clinical success (Forrest A, et al. 1993).

As soon as early identification and, when available, rapid resistance markers plus local MIC expectations are known, the regimen should be tailored to hit the right exposure target at the relevant site (urine vs renal parenchyma vs prostate) Bonkat G, et al. 2025). In systemic presentations, guidelines emphasize escalating promptly based on illness severity and then refining with culture data—starting with a regimen likely to achieve target exposures in sepsis, then de-escalating once susceptibilities and clinical response allow Rhodes A, et al. 2021).

Host Factors Influencing PK/PD

Host factors profoundly influence PK/PD performance and must be considered when designing therapy.

Renal impairment reduces drug clearance and increases toxicity risk for renally eliminated antibiotics such as aminoglycosides, vancomycin, and β-lactams (Roberts JA, et al. 2014). Conversely, augmented renal clearance in septic or critically ill patients can lower antibiotic exposure, necessitating higher or extended-infusion dosing (Udy AA, et al. 2018). Notably, nitrofurantoin is contraindicated at eGFR < 30 mL/min/1.73 m² because of poor urinary recovery and higher adverse effects, risking treatment failure in cystitis (Bonkat G, et al. 2025).

In diabetic or obese patients, altered volume of distribution and tissue perfusion may result in subtherapeutic concentrations in renal and prostatic tissues (Pai MP & Bearden DT, 2007). In catheterized or neurogenic bladder patients, biofilm formation and impaired drainage can further compromise local drug activity, underscoring the importance of source control (Bonkat G, et al. 2025).

Dosing Modification in High-Risk Groups

Dosing modification and monitoring are crucial in high-risk patient groups where standard antibiotic regimens may fail to achieve PK/PD targets or increase toxicity risk.

In diabetic patients, reduced renal reserve, microvascular changes, and frequent comorbidities (e.g., nephropathy or peripheral vascular disease) alter drug clearance and tissue penetration. Agents such as aminoglycosides and colistin require particular caution due to narrow therapeutic windows and markedly higher nephrotoxicity rates (Tsuji BT, et al. 2019; Roberts JA, et al. 2014). Adjusted or once-daily aminoglycoside dosing with serum level monitoring is recommended, for amikacin, target peaks ~50–80 mg/L with low troughs (e.g., < 2 mg/L), and for gentamicin/tobramycin, peaks ~6–10 mg/L with troughs < 2 mg/L to balance efficacy and renal safety (Coste A, et al. 2020; Roberts JA, et al. 2014). For β-lactams, dose/infusion adjustments based on dynamic eGFR (and augmented renal clearance in sepsis) are often required, especially during sepsis when renal function can fluctuate rapidly (Udy AA, et al. 2014; Roberts JA, et al. 2014).

In obese patients, increased adipose tissue and altered plasma protein binding expand the apparent volume of distribution, often necessitating higher loading doses or weight-based dosing (e.g., aminoglycosides dosed on adjusted body weight, β-lactams on total body weight for loading followed by adjusted maintenance) (Pai & Bearden, 2007). Lipophilic antibiotics such as fluoroquinolones and macrolides generally penetrate adipose and prostatic tissue well, while hydrophilic agents (β-lactams, glycopeptides) may underexpose unless infusion strategies or higher doses are used (Roberts JA, et al. 2014).

TDM, when available, should be routine for agents with narrow PK/PD margins: Aminoglycosides, vancomycin, and colistin should be monitored for both peak efficacy and trough toxicity; β-lactam TDM is increasingly used in critically ill or renally unstable patients to maintain fT > MIC (Abdul-Aziz MH, et al. 2020; Tsuji BT, et al. 2019). Tight renal function surveillance—at least daily creatinine measurement during IV therapy—is critical to avoid accumulation. By combining dynamic renal monitoring, individualized weight-based dosing, and TDM-guided adjustments, clinicians can achieve optimal antimicrobial exposure while minimizing toxicity (Roberts JA, et al. 2014).

Supportive Measures and Source Control

Urological Evaluation and Imaging

Supportive measures play a vital role in optimizing outcomes for patients with localized or systemic UTIs with risk factors for treatment failure or recurrent disease, complementing antimicrobial therapy. Early urological referral is recommended when there is suspicion of anatomic or functional abnormality, obstruction, urolithiasis, or recurrent infection despite appropriate antimicrobial therapy. According to the 2025 EAU Guidelines, structural evaluation should be considered in men, patients with recurrent pyelonephritis, or those with atypical presentations, as failure to identify a reversible cause increases the risk of relapse and resistance development (Bonkat G, et al. 2025).

Bladder ultrasound serves as a first-line, non-invasive tool to assess for postvoid residual urine, hydronephrosis, or stones that may perpetuate infection. In more complex cases, contrast-enhanced CT or MRI may be indicated to detect abscesses, obstruction, or emphysematous changes. Identifying and addressing these sources of infection are critical components of source control, particularly in systemic or relapsing cases (Bonkat G, et al. 2025).

Follow-Up and Prevention Strategies

Following treatment, post-therapy urine cultures are not routinely required in asymptomatic individuals but are indicated in those with persistent or recurrent symptoms, diabetes, or structural abnormalities. For recurrence prevention, strategies include:

Optimizing hydration.

Minimizing catheter dwell time.

Correcting voiding dysfunction.

In women, consider non-antibiotic prophylaxis such as vaginal estrogen therapy, D-mannose, or cranberry formulations, which have modest evidence for reducing recurrence frequency.

In select high-risk patients with repeated infections, urological follow-up and patient education on hydration, bladder emptying, and early symptom recognition are essential. Together, these supportive interventions form the foundation for preventing relapse and reducing antimicrobial exposure in recurrent or localized/systemic UTI with risk factors management (Bonkat G, et al. 2025).

Integrated Clinical Framework

Summary of Evidence-Based Approach

Optimal management of UTIs in the contemporary era requires integration of 3 essential streams at the bedside:

1. Molecular and rapid diagnostic data use multiplex PCR (identification from urine/positive blood culture plus ESBL/carbapenemase markers) to stratify early: absence of key genes supports narrowing; presence of blaCTX-M favors early carbapenem consideration; MBL genes prompt aztreonam-based strategies (pending local access) while awaiting full AST (Tamma PD, et al. 2024; Bonkat G, et al. 2025).

2. Clinical risk factors layer patient factors—severity (sepsis vs no sepsis), prior cultures/exposures, devices/obstruction, stones, immunocompromise—because these predict resistant uropathogens and treatment failure and should steer the initial breadth of therapy and the need for imaging/source control (Bonkat G, et al. 2025).

3. PK/PD-aligned dosing fits the drug to the site and PK/PD target: For systemic UTI/pyelonephritis, prioritize regimens that achieve tissue exposure (e.g., prolonged-infusion β-lactams for fT > MIC, AUC/MIC targets for fluoroquinolones); For cystitis, prefer narrow agents with high urinary concentrations. As soon as cultures finalize, de-escalate to a targeted effective agent and plan an IV-to-oral switch when clinically improving and an oral option meets exposure requirements (Bonkat G, et al. 2025).

Throughout clinical decision-making, anchor terminology and treatment decisions in the 2025 EAU localized vs systemic framework to align treatment intensity with presentation while addressing modifiable risk factors separately (Bonkat G, et al. 2025). This integrated approach ensures that diagnostic advances, antimicrobial stewardship principles, and PK/PD optimization converge to deliver personalized, evidence-based care that maximizes efficacy while minimizing resistance development and toxicity; for MBL-producing Enterobacterales, preferred options include ceftazidime–avibactam plus aztreonam or aztreonam–avibactam (where available), supported by guidance and outcome data (Tamma PD, et al. 2024; Falcone M, et al. 2021).

Conclusion

The management of UTIs has evolved substantially, driven by improved disease classification, molecular diagnostic capabilities, and a refined understanding of antimicrobial pharmacology. The 2025 EAU Guidelines' localized vs systemic paradigm provides a more transparent framework for treatment intensity, while rapid diagnostics enable early precision therapy and timely de-escalation. PK/PD optimization ensures adequate drug exposure at infection sites while accounting for host factors, and comprehensive antimicrobial stewardship preserves the efficacy of available agents. When combined with appropriate supportive measures and source control, this integrated, evidence-based approach offers the foundation for optimal outcomes in an era of increasing antimicrobial resistance (Tamma PD, et al. 2024; Bonkat G, et al. 2025).