Urinary tract infections (UTIs) are among the most common bacterial infections affecting the elderly population and represent a significant cause of morbidity, healthcare utilization, and antimicrobial consumption worldwide [1]. Advancing age is associated with multiple physiological, anatomical, and functional changes in the urinary tract, including reduced immune response, impaired bladder emptying, hormonal alterations, and increased prevalence of comorbid conditions such as diabetes mellitus, chronic kidney disease, and neurogenic bladder [2,3]. These factors predispose elderly individuals to higher rates of UTI, atypical clinical presentations, recurrent infections, and complications compared with younger adults [4].

Management of UTIs in elderly patients poses unique therapeutic challenges. Polypharmacy, altered pharmacokinetics, age-related decline in renal function, and increased susceptibility to drug-related adverse events complicate antibiotic selection in this population [5]. In addition, the global rise in antimicrobial resistance, particularly among uropathogens such as Escherichia coli, Klebsiella pneumoniae, and Enterococcus species, has reduced the effectiveness of commonly used oral antibiotics, necessitating renewed interest in older antimicrobial agents with favorable resistance profiles [6,7].

Fosfomycin trometamol and nitrofurantoin have re-emerged as important first-line oral agents for the treatment of uncomplicated lower UTIs. Fosfomycin exerts its bactericidal effect by inhibiting the initial step of bacterial cell wall synthesis and demonstrates broad-spectrum activity against both Gram-negative and Gram-positive uropathogens, including extended-spectrum beta-lactamase (ESBL)-producing strains [8]. Its pharmacokinetic profile allows for high urinary concentrations after a single oral dose, making it an attractive option for outpatient therapy and improving patient compliance, particularly in elderly individuals [9].

Nitrofurantoin, a nitrofuran derivative, acts by interfering with multiple bacterial enzyme systems and has maintained low resistance rates over decades of use [10]. It is commonly administered over a 5–7 day course and is recommended by several international guidelines for the treatment of uncomplicated cystitis [11]. However, concerns regarding reduced efficacy in patients with impaired renal function and the risk of pulmonary, hepatic, and neurological adverse effects—especially with prolonged or repeated use—are particularly relevant in the geriatric population [12,13].

Several randomized controlled trials and observational studies have compared fosfomycin and nitrofurantoin in adult populations with uncomplicated UTIs, with mixed results regarding clinical and microbiological cure rates [14–16]. While some studies report comparable short-term efficacy, others suggest superior sustained clinical resolution with multi-day nitrofurantoin regimens compared with single-dose fosfomycin therapy [17]. Importantly, most of these studies predominantly enrolled younger or middle-aged adults, with limited representation or subgroup analysis of elderly patients, thereby restricting the generalizability of findings to older age groups [18].

Given the growing burden of UTIs in elderly patients and the increasing emphasis on antimicrobial stewardship, a critical appraisal of existing evidence comparing fosfomycin and nitrofurantoin in this population is warranted. This systematic review and meta-analysis aims to evaluate and synthesize available data on the efficacy and safety of fosfomycin and nitrofurantoin in elderly patients with UTIs, with a focus on clinical cure, microbiological eradication, recurrence rates, and adverse outcomes. By addressing current evidence gaps, this study seeks to inform rational antibiotic selection and optimize therapeutic outcomes in geriatric patients with urinary tract infections.

This review followed PRISMA recommendations.

Eligibility criteria

• Population: Adults with lower urinary tract infection; we prioritized studies reporting outcomes for elderly patients (≥65 years). Due to paucity of elderly-stratified RCTs, adult RCTs and observational studies were included; elderly subgroup data or cohorts focusing on older adults were extracted when available.
• Interventions/comparators: Oral fosfomycin (any regimen) vs nitrofurantoin (any regimen), or studies reporting either agent with extractable outcome data.
• Outcomes: Primary — clinical cure at ~28 days (or nearest reported time point). Secondary — microbiological cure, recurrence (30–90 days), adverse events, serious adverse events, discontinuation.
• Study designs: RCTs, non-randomized comparative trials, cohort studies, and large case series with relevant outcomes.
• Exclusions: Studies limited to pediatric populations, topical/urodynamic prophylaxis only, or lacking outcome data.

Search strategy

We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and Web of Science from inception to June, 2025 using terms combining: (“fosfomycin” OR “fosfomycin trometamol”) AND (“nitrofurantoin” OR “nitrofurantoin macrocrystals” OR “nitrofurantoin monohydrate”) AND (“urinary tract infection” OR “cystitis” OR “UTI” OR “lower urinary tract infection”) AND (elder* OR old* OR “>=65” OR “older adults”). Additional searches included clinicaltrials.gov for ongoing trials and backward citation searching of included articles and prior meta-analyses.

Study selection and data extraction

Two reviewers screened titles/abstracts and full texts. Data extracted: study design, setting, sample size, patient age (mean, ≥65 subgroup if available), intervention details (dose, duration), comparator, clinical and microbiologic outcomes, follow-up duration, adverse events, and risk-of-bias domains.

Risk of bias assessment

We used Cochrane RoB2 for RCTs and ROBINS-I for non-randomized studies. Discrepancies resolved by consensus.

Data synthesis

Given heterogeneity in populations (age distribution, complicated vs uncomplicated UTI), interventions (single vs multiple-dose fosfomycin), and outcomes, we performed a narrative synthesis. A formal pooled meta-analysis was planned where ≥3 sufficiently homogeneous studies provided comparable outcome data. However, elderly-specific data were sparse; therefore, the primary synthesis is descriptive with focused discussion on the implications for elderly patients.

Overview of Included Studies

A total of 18 studies fulfilled the eligibility criteria and were included in the systematic review. Of these, 6 were randomized controlled trials (RCTs), 8 observational cohort studies, and 4 systematic reviews/meta-analyses that provided extractable comparative data. Only 3 studies reported outcomes specifically in elderly patients (≥65 years), while the remaining studies included mixed adult populations with mean ages ranging from 30 to 62 years. Due to heterogeneity in study design, patient characteristics, dosing regimens, and outcome definitions, a quantitative pooled meta-analysis restricted to elderly patients was not feasible; therefore, results are presented as a structured qualitative synthesis with tabulated comparisons.

Study Characteristics

Table 1 summarizes the key characteristics of the studies included in the review.

Table 1. Characteristics of Studies Included in the Systematic Review

Clinical Cure Rates

Clinical cure, defined as complete resolution of urinary symptoms at follow-up, was the most consistently reported outcome. Across comparative trials, nitrofurantoin demonstrated higher sustained clinical cure rates, particularly at 28 days of follow-up.

Table 2. Clinical Cure Rates Reported in Comparative Studies

Overall, while fosfomycin achieved satisfactory early symptom relief, nitrofurantoin showed greater durability of clinical response, particularly in studies with longer follow-up.

Microbiological Cure

Microbiological cure, defined as eradication of the causative organism on follow-up urine culture, was reported in fewer studies. Nitrofurantoin consistently showed higher microbiological eradication rates at later time points.

Table 3. Microbiological Cure Rates

Single-dose fosfomycin was associated with higher rates of persistent bacteriuria and relapse, especially among elderly patients with comorbidities.

Recurrence of UTI

Recurrence within 30–90 days was more frequently reported in patients treated with fosfomycin.

Table 4. UTI Recurrence Rates

Elderly patients exhibited higher recurrence rates overall, regardless of treatment, but recurrence was consistently lower in the nitrofurantoin group.

Adverse Events

Both drugs were generally well tolerated. Gastrointestinal adverse effects were more common with fosfomycin, while nitrofurantoin was associated with mild nausea and rare drug discontinuation.

Table 5. Adverse Events Profile

In elderly patients, no significant increase in serious adverse events was observed with either drug when used for short-course therapy.

Summary of Key Findings

• Nitrofurantoin demonstrated higher sustained clinical and microbiological cure rates than single-dose fosfomycin.
• Fosfomycin showed good short-term efficacy but higher recurrence rates, especially in elderly patients.
• Both agents were generally safe in elderly patients when used appropriately.
• Lack of elderly-specific randomized data remains a major limitation.

Figure 1: Bar graph depicting comparative clinical cure rates of fosfomycin and nitrofurantoin in elderly patients with urinary tract infection. Nitrofurantoin shows superior clinical cure compared to fosfomycin.

Figure 2: Bar graph showing recurrence rates of urinary tract infection in elderly patients following treatment with fosfomycin and nitrofurantoin. Fosfomycin is associated with a higher recurrence rate compared to nitrofurantoin.

The present systematic review synthesizes available evidence comparing the efficacy and safety of fosfomycin and nitrofurantoin for the treatment of urinary tract infections in elderly patients. The findings indicate that while both agents remain valuable oral options for lower UTIs, nitrofurantoin demonstrates superior sustained clinical and microbiological outcomes, particularly when assessed at longer follow-up intervals. However, the overall evidence base specific to elderly patients remains limited, and most conclusions are extrapolated from studies conducted predominantly in younger adult populations.

UTIs are disproportionately prevalent among elderly individuals due to age-related physiological changes, impaired host defenses, increased post-void residual urine, and higher rates of comorbid conditions such as diabetes mellitus and chronic kidney disease [1,2]. These factors contribute not only to increased incidence but also to higher recurrence rates and treatment failures, emphasizing the importance of selecting antibiotics with durable efficacy and favorable safety profiles in this population [3]. In this context, older antimicrobial agents such as fosfomycin and nitrofurantoin have regained prominence owing to their retained activity against common uropathogens and relatively low resistance rates [4].

The reviewed studies suggest that nitrofurantoin provides higher sustained clinical cure rates compared with single-dose fosfomycin, especially when outcomes are evaluated at 28 days or beyond [5]. This observation is consistent with findings from large randomized trials demonstrating lower rates of persistent symptoms and bacteriological failure with multi-day nitrofurantoin therapy [6]. The superior durability of response with nitrofurantoin may be attributable to prolonged urinary exposure and continued suppression of residual bacterial populations, which is particularly relevant in elderly patients who may have impaired bladder emptying or structural urinary abnormalities [7].

Fosfomycin, on the other hand, offers the advantage of single-dose administration, which may improve adherence in elderly patients and reduce the risk of dosing errors [8]. Its broad antimicrobial spectrum, including activity against extended-spectrum beta-lactamase–producing organisms, further enhances its appeal in an era of rising antimicrobial resistance [9]. Nevertheless, several studies included in this review report higher recurrence and persistent bacteriuria rates with single-dose fosfomycin, suggesting that while initial symptom relief is often achieved, sustained eradication may be less reliable, particularly in older patients with comorbidities or complicated infections [10,11].

Microbiological outcomes followed a similar trend, with nitrofurantoin demonstrating higher eradication rates at follow-up cultures compared with fosfomycin in most comparative studies [6,12]. Persistent bacteriuria is of particular concern in elderly patients, as it may predispose to recurrent symptomatic infections, bacteremia, and increased healthcare utilization [13]. These findings raise important questions regarding the adequacy of single-dose fosfomycin in elderly populations and suggest that alternative dosing strategies or longer treatment courses may be necessary in selected patients [14].

Safety considerations are especially critical in geriatric patients. Nitrofurantoin has historically been associated with pulmonary, hepatic, and neurological toxicity, particularly with long-term or prophylactic use [15]. However, short-course therapy, as used in the included studies, was generally well tolerated, with adverse events largely limited to mild gastrointestinal symptoms [16]. Fosfomycin demonstrated a favorable safety profile overall, although gastrointestinal adverse effects were reported more frequently [17]. Importantly, no significant increase in serious adverse events was observed in elderly patients treated with either agent for short durations, supporting their continued use when appropriately prescribed [18].

Despite these findings, the review highlights a major gap in the literature: the lack of randomized controlled trials specifically designed for elderly populations. Most studies either excluded older patients with comorbidities or failed to report age-stratified outcomes, limiting the generalizability of results [19]. Given that elderly patients often present with atypical symptoms, altered pharmacokinetics, and higher risk of complicated UTIs, direct evidence in this population is urgently needed [20].

In summary, available evidence suggests that nitrofurantoin offers more durable clinical and microbiological efficacy than single-dose fosfomycin for the treatment of lower UTIs, a finding that appears particularly relevant in elderly patients prone to recurrence. Fosfomycin remains a useful alternative, especially where adherence is a concern or resistance limits other options. However, individualized treatment decisions should consider renal function, comorbidities, infection severity, and local antimicrobial resistance patterns. Future well-designed trials focusing on elderly and frail populations are essential to optimize antibiotic selection and improve outcomes in this growing patient group.

Both fosfomycin and nitrofurantoin are effective oral options for treating urinary tract infections in elderly patients. However, available evidence suggests that nitrofurantoin provides more sustained clinical and microbiological cure, whereas fosfomycin, despite its single-dose convenience, is associated with higher recurrence rates. Treatment choice in elderly patients should be individualized based on renal function, comorbidities, antimicrobial resistance patterns, and patient adherence. Further elderly-focused randomized studies are needed to strengthen evidence-based recommendations.

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