Urinary tract infections (UTIs) are among the most frequently encountered bacterial infections in elderly patients and constitute a major cause of morbidity, hospital admissions, and antimicrobial use worldwide [1–3]. Advancing age is associated with multiple predisposing factors for UTI, including impaired immune response, post-void residual urine, hormonal changes, urinary incontinence, catheterization, and comorbid conditions such as diabetes mellitus and chronic kidney disease [4–7]. Elderly patients often present with atypical or subtle symptoms, leading to delayed diagnosis and increased risk of recurrence and complications [8,9].

The management of UTIs in older adults is further complicated by age-related changes in pharmacokinetics and pharmacodynamics, polypharmacy, and heightened susceptibility to drug-related adverse effects [10–12]. Inappropriate antibiotic selection in this population contributes to treatment failure, recurrence, and the growing problem of antimicrobial resistance [13–15]. Rising resistance among common uropathogens, particularly Escherichia coli and Klebsiella species, has reduced the effectiveness of several traditionally used oral antibiotics [16–18].

Fosfomycin trometamol and nitrofurantoin have re-emerged as important oral treatment options for lower UTIs and are recommended as first-line agents in multiple international guidelines [19–21]. Fosfomycin acts by inhibiting bacterial cell wall synthesis and achieves high urinary concentrations after a single oral dose, offering the advantage of simplified dosing and improved adherence [22,23]. Nitrofurantoin exerts bactericidal activity through multiple enzymatic pathways and has maintained low resistance rates despite decades of clinical use [24,25].

Several clinical trials and observational studies have compared fosfomycin and nitrofurantoin in adult populations, reporting variable outcomes in terms of clinical cure, microbiological eradication, and recurrence [26–28]. Evidence suggests that while fosfomycin provides effective short-term symptom relief, nitrofurantoin may offer more sustained clinical and bacteriological cure, particularly at longer follow-up intervals [29,30]. However, elderly patients remain underrepresented in these studies, and age-specific data are limited [31–33].

Given the increasing burden of UTIs in the geriatric population and the need for evidence-based antibiotic stewardship, a focused evaluation of fosfomycin and nitrofurantoin in elderly patients is essential. This systematic review and meta-analysis aims to compare their efficacy, recurrence rates, and safety profiles in older adults, thereby providing clinically relevant evidence to guide optimal management of UTIs in this vulnerable population [34–36].

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 January, 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.

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.

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.

Figure 2: Bar graph depicting microbiological cure rates following treatment with fosfomycin and nitrofurantoin in elderly patients with urinary tract infection. Nitrofurantoin demonstrates a higher rate of bacteriological eradication compared with fosfomycin.

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.

Figure 3: Line graph illustrating recurrence rates of urinary tract infection in elderly patients treated with fosfomycin and nitrofurantoin. Recurrence was higher following fosfomycin therapy compared with nitrofurantoin.

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.

Figure 4: Stacked bar chart showing the incidence of adverse events in elderly patients treated with fosfomycin and nitrofurantoin for urinary tract infection. Both agents were generally well tolerated, with mild gastrointestinal adverse events being the most commonly reported. Serious adverse events were rare and comparable between the two groups.

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 5: Forest plot showing odds ratios for clinical cure comparing nitrofurantoin versus fosfomycin in patients with urinary tract infection. The pooled estimate indicates a higher likelihood of clinical cure with nitrofurantoin. Horizontal lines represent 95% confidence intervals.

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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