What information is available on IV fosfomycin for the treatment of complicated urinary tract infections?
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Introduction
Complicated urinary tract infections (UTIs) are currently defined by the Infectious Diseases Society of America (IDSA) as infections that extend beyond the bladder in men or women, and include pyelonephritis, febrile or bacteremic UTI, catheter-associated UTI, and prostatitis.1 In women between 18 and 49 years of age, the estimated incidence of pyelonephritis in the United States (US) is 28 cases per 10,000 people.2 About 7% of cases require hospital admission. Risk factors for complicated UTIs include patients with indwelling catheters, immunosuppression, urinary tract abnormalities, and antibiotic exposure.3 For both complicated and uncomplicated UTIs, the most common causative agent is uropathogenic Escherichia coli.2,3 The next most common pathogens for complicated UTIs, in order of prevalence, are Enterococcus spp., Klebsiella pneumoniae, Candida spp., Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and group B Streptococcus.
For the treatment of complicated UTIs, the 2025 IDSA guideline recommends options for antimicrobials as empiric therapy based on a patient’s severity of illness (ie, presence or absence of sepsis), risk factors for resistant organisms, other patient-specific factors (eg, risk of allergic reaction, contraindications, drug-drug interactions), and, if the patient is septic, consultation of the antibiogram.1 Intravenous (IV) beta-lactam antibiotics, such as piperacillin-tazobactam and third- or fourth-generation cephalosporins, and fluoroquinolones are recommended as preferred options. Carbapenems, another class of beta-lactam antibiotics, are preferred in patients with sepsis. Novel beta-lactam-beta-lactamase inhibitors, cefiderocol, plazomicin, and older aminoglycosides are recommended as alternatives. For patients with complicated UTI without sepsis, oral therapy may be appropriate. The preferred oral antibiotics in these cases include third-generation cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole.
A concern with any type of infection and treatment is the emergence and spread of antimicrobial resistance (AMR).4 Based on a systematic analysis, 1.27 million deaths were attributable to bacterial AMR globally in 2019.5 The common causative UTI pathogens, E. coli and K. pneumoniae, were among the 6 leading pathogens for deaths associated with resistance. E. coli and K. pneumoniae are also both part of the Enterobacteriaceae family, which can acquire plasmids encoding extended-spectrum beta-lactamases (ESBLs).3 Beta-lactamases can inactivate beta-lactam antibiotics, such as penicillins and cephalosporins, which can then lead to resistance to these antibiotics.6 Given the concern of AMR, including ESBLs, there is a need for additional antibiotics with differing mechanisms. In October 2025, the US Food and Drug Administration (FDA) approved an IV formulation of fosfomycin (Contepo®) for the treatment of complicated UTIs, including acute pyelonephritis, caused by susceptible isolates of E. coli and K. pneumoniae in adults ≥18 years.7 The purpose of this frequently asked question (FAQ) review is to provide summary information on IV fosfomycin, including clinical efficacy data on its use for the treatment of complicated UTIs.
Drug Overview
Fosfomycin was first approved for use in the US as an oral product (Monurol®) in 1996 for the treatment of uncomplicated UTIs (acute cystitis) in women due to susceptible strains of E. coli and Enterococcus faecalis.8 The brand name of oral fosfomycin has since been discontinued; however, generic formulations are available.9 Oral fosfomycin is not indicated for the treatment of pyelonephritis.10 Since oral fosfomycin may not achieve adequate levels in renal parenchyma and blood, it is generally not an appropriate choice for complicated UTIs.1 The IV formulation of fosfomycin was FDA approved in October 2025 for the treatment of complicated UTIs, including acute pyelonephritis, based on its demonstrated efficacy in a multinational, double-blind, randomized clinical trial (RCT).7 An overview of IV fosfomycin, including its FDA-approved indication and dosing, is provided in Table 1.
table 1
| Table 1. Summary of FDA-approved prescribing information for IV fosfomycin.7 | ||||
|---|---|---|---|---|
| Indication | Limitations of Use | Dose/frequencya | Preparation for administration | Duration of treatment |
| Treatment of complicated UTIs, including acute pyelonephritis, caused by susceptible isolates of E. coli and K. pneumoniae in patients ≥18 years of age | To reduce development of drug-resistant bacteria and maintain effectiveness, only use to treat infections that are proven or strongly suspected to be caused by susceptible bacteria When culture and susceptibility information are available, they should be considered; in the absence of such data, local epidemiology and susceptibility patterns may contribute to empiric selection | 6 grams every 8 hours via IV infusion over 1 hour | Supplied as a dry powder in a single-dose vial; must be constituted and further diluted prior to infusion After reconstitution and dilution, stable for 16 hours at 20-25°C at concentrations of 15 to 30 mg/mL in Sterile Water for Injection, USP | 14 days |
| Abbreviations: CrCl=creatinine clearance; IV=intravenous; USP=United States Pharmacopeia; UTIs=urinary tract infections. aFor patients ≥18 years of age and older with estimated CrCl >50 mL/min; dosage adjustments recommended in patients with renal impairment. |
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Mechanism of Action
Fosfomycin is an epoxide antibacterial; it works by disrupting bacterial cell wall synthesis through covalently binding and inhibiting phosphoenolpyruvate transferase (MurA), thereby blocking synthesis of peptidoglycan and bacterial cell walls.7,11 MurA catalyzes a reaction that is part of the initial steps of bacterial peptidoglycan biosynthesis.11 Currently, fosfomycin is the only antibiotic used in practice that targets these steps. Against Enterobacterales, fosfomycin is bactericidal.7 Fosfomycin resistance may occur due to chromosomal mutations leading to alterations of bacterial transport systems or modification of the fosfomycin binding site in MurA. Enzymatic inactivation of fosfomycin may also occur; the enzymes involved in resistance include fosfomycin-hydrolyzing enzymes (FosA, FosB, FoxX) and fosfomycin kinases (FomA, FomB, and FosC). A summary on the pharmacokinetics of IV fosfomycin, as well as oral fosfomycin for comparison, is provided in Table 2.
table 2
| Table 2. Pharmacokinetics of fosfomycin after single dose.7,10 | ||
|---|---|---|
| Oral | IV | |
| Oral bioavailability | Fasting: 37% Fed: 30% | N/A |
| Cmax, mean (SD) | Fasting: 26.1 (9.1) mcg/mL With high-fat meal: 17.6 (4.4) mcg/mL | 228 (43) mcg/mL |
| Volume of distribution, mean (SD) | 136.1 (44.1) La | 27 (5.2) L |
| Protein binding | Not bound to plasma proteins | |
| Half-life, mean (SD) | 5.7 (2.8) hours | 2.8 (0.6) hours |
| Excretion | Excreted unchanged Urine: 38% Feces: 18% | Excreted unchanged Urine: 70% at 12 hours; 74-80% at 48 hours |
| Abbreviations: Cmax=maximum serum concentration; IV=intravenous; SD=standard deviation. aVolume of distribution at steady state. |
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Safety Considerations
The use of IV fosfomycin is contraindicated in patients with any known hypersensitivity to the drug or any of its excipients.7 Within each vial of fosfomycin for IV use, there is 1980 mg of sodium. This high sodium content may result in changes in serum electrolytes, including increased sodium levels and decreased levels of potassium, calcium, and phosphorus. During IV fosfomycin treatment, a low-sodium diet is recommended. Fosfomycin IV has also been shown to prolong the QT interval and increase alanine aminotransferase and aspartate aminotransferase levels during clinical trials. Hypersensitivity reactions (eg, rash, urticaria, anaphylaxis), neutropenia (including agranulocytosis), and Clostridioides difficile-associated diarrhea have all been reported with use of IV fosfomycin. Common adverse reactions (incidence ≥2%) of IV fosfomycin include elevations in transaminase levels, hypokalemia, neutropenia, nausea, vomiting, diarrhea, hypocalcemia, hypernatremia, headache, and hypophosphatemia. In terms of drug interactions, concomitant use of IV fosfomycin and other known drugs that prolong the QT interval should be avoided due to the potential increased risk of ventricular arrhythmia. Examples of drugs that prolong the QT interval include class IA or III antiarrhythmic medications, tricyclic antidepressants, macrolides, and antipsychotics. Fosfomycin is present in human breast milk. Due to the potential for adverse reactions in a breastfed infant, patients should not breastfeed during treatment with fosfomycin and for 24 hours after the last dose.
Literature summary
The efficacy and safety of IV fosfomycin for complicated UTIs are largely supported by a phase 2/3 randomized controlled noninferiority trial (ZEUS).12 The efficacy of IV fosfomycin has also been assessed in an RCT for the treatment of multidrug-resistant (MDR) E. coli bacteremic UTIs and in a systematic review (SR) and meta-analysis (MA) of IV fosfomycin for a variety of infection types.13,14 A summary of each of these studies is available in Table 3.
In ZEUS, 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI, including acute pyelonephritis, were randomized 1:1 to receive either IV fosfomycin or IV piperacillin-tazobactam for a fixed 7-day course; switch to oral therapy was prohibited.12 The most common pathogens at baseline were E. coli and K. pneumoniae. Fosfomycin IV met noninferiority when compared to piperacillin-tazobactam for the primary endpoint of overall success, a composite of clinical cure (ie, the complete resolution or significant improvement of signs and symptoms such that no further antimicrobial therapy is warranted) plus microbiologic eradication (baseline pathogen reduced to <104 CFU/mL on urine culture, and if applicable, negative on repeat blood culture) in the microbiologic modified intention-to-treat population (mITT). The authors of ZEUS concluded that IV fosfomycin is effective for the treatment of complicated UTIs, including acute pyelonephritis, and that IV fosfomycin offers a new IV therapeutic option with a differentiated mechanism for patients with serious gram-negative infections, including those with ESBL-E.
In another RCT conducted at 22 Spanish hospitals, IV fosfomycin was compared with ceftriaxone or meropenem for the treatment of bacteremic UTIs due to MDR E. coli in 143 adults.13 This study used a dose and frequency of 4 grams of IV fosfomycin every 6 hours, differing from the FDA-approved dose and frequency of 6 grams IV every 8 hours. After 4 days of IV treatment, patients were allowed to switch to oral therapy. For the primary endpoint of clinical and microbiological cure at 5 to 7 days after finalization of treatment (test of cure [TOC]), fosfomycin did not demonstrate noninferiority to the active comparators in the mITT population (ie, patients who met study criteria and received at least 1 dose of study drug). The authors stated that this finding is likely due to an increased rate of AE-related discontinuations in the fosfomycin group. Despite not meeting non-inferiority in the mITT population, clinical cure rates for fosfomycin were similar to those for ceftriaxone or meropenem in the clinical evaluable population (ie, all patients evaluated at TOC or had a previous failure). The adverse events that led to drug discontinuation in the fosfomycin group were heart failure, alithiasic cholecystitis, and persistent fever. All patients treated with IV fosfomycin who developed heart failure were ≥80 years of age, had chronic heart failure, and/or had chronic kidney insufficiency. The sodium content of the IV formulation of fosfomycin may have contributed to heart insufficiency; therefore, its use should be avoided in patients ≥80 years old and in patients with chronic heart or kidney insufficiency. The authors concluded that the data suggest IV fosfomycin is effective and may be considered in select patients.
In an SR/MA conducted in 2016, the use of IV fosfomycin for various types of infections was assessed.14 Of the 128 studies included in the SR, most originated from France, Germany, Austria, Japan, or Spain. Fosfomycin IV was primarily used for sepsis/bacteremia, UTIs, respiratory tract infections, bone and joint infections, and central nervous system infections. The most common causative pathogens were Staphylococcus spp., followed by E. coli and Pseudomonas spp. There were 10 comparative studies (including 7 RCTs) used for the MA. Comparisons in the MA included studies that used fosfomycin IV as either monotherapy or in combination with another antimicrobial. The MA did not find a difference in clinical efficacy between fosfomycin and comparators in general, or when used as monotherapy or combination therapy. This study did not include a subgroup analysis of outcomes based on the type of infection. The authors concluded that IV fosfomycin may serve as an antibiotic option for challenging infections; however, more well-designed RCTs are desired.
table 3
| Table 3. Clinical studies evaluating IV fosfomycin.12-14 | ||||
|---|---|---|---|---|
| Study design | Subjects | Interventions and Comparators | Results | Conclusions |
| MA | ||||
| Grabein et al 201714 SR and MA of controlled trials and observational studies assessing use of IV fosfomycin for infections in adults and pediatric patients | N=128 studies for SR (17 comparative studies, 111 non-comparative) N=10 studies for MA (7 RCTs, 3 observational studies) Most common infection types in SR: bacteremia/sepsis (27%) RTIs (17%; mostly pneumonia) UTIs (12%), bone/joint infections (13%; mostly osteomyelitis) Most common pathogens in SR: Staphylococcus spp. (41%) E. coli (16%), Pseudomonas spp. (13%) Streptococcus spp. (7%) Klebsiella spp. (6%) | Fosfomycin IV at varying dosages Fosfomycin IV plus sulbactam-cefoperazonea, cefotaxime, colistin, gentamicin, cefmetazolea, penicillin, doripenema, or cefuzonama at varying dosages Sulbencillina, sulbactam-cefoperazonea, cefotaxime, colistin, ampicillin, ampicillin plus gentamicin, ceftriaxone, fosfomycin plus flomoxefa, or cefapirina at varying dosages | Efficacy (based on MA) Clinical efficacy Fosfomycin vs comparators: OR, 1.44; 95% CI, 0.96 to 2.15 Fosfomycin vs comparators as monotherapy: OR, 1.41; 95% CI, 0.83 to 2.39 Fosfomycin vs comparators as combination therapy: OR, 1.48; 95%, 0.81 to 2.71 Microbiological efficacy Fosfomycin vs comparators: OR, 1.28; 95% CI, 0.82 to 2.01 Pooled estimate of development of fosfomycin resistance during monotherapy: 3.4% (95% CI, 1.8% to 5.1%) Safety (based on SR) Rate of AEs with fosfomycin: 18% Common AEs with fosfomycin: GI disorders (including nausea, vomiting, diarrhea, and dysgeusia): 5.24% Abnormal laboratory findings (including elevated hepatic enzymes): 3.85% Hypokalemia: 2.92% | No difference in clinical or microbiological efficacy between fosfomycin and other antibiotics observed in MA; fosfomycin showed favorable safety outcomes |
| RCT | ||||
| Sojo-Dorado et al 202213 MC, OL, NI, RCT conducted in Spain Duration: 10 to 14 days | N=143 adults with bacteremic UTIs due to MDR E. coli Median age (IQR): 72 (62 to 81) years Women: 51% Of isolates from 68 of 81 patients with ceftriaxone-resistant E. coli, 94.1% were ESBL producers | Fosfomycin disodium 4 grams every 6 hours IV over 60 minutes Comparators: Ceftriaxone 1 gram every 24 hours over 2 to 4 minutes, or Meropenem 1 gram every 8 hours IV over 15 to 30 minutes, if ceftriaxone resistant After 4 days of IV treatment, a switch to oral was allowed to an in vitro active oral drug: patients randomized to IV fosfomycin would receive oral fosfomycin; patients assigned comparator would receive oral cefuroxime axetil, ciprofloxacin, amoxicillin-clavulanate, or trimethoprim-sulfamethoxazole at standard dosing | Primary Clinical and microbiological cure at TOC in mITT populationb Fosfomycin 48/70 (68.6%) Comparator 57/73 (78.0%) Risk difference: -9.4 (95% CI, -21.5 to ∞; p1-sided=0.1) Secondary Clinical cure at TOC in CEP Fosfomycin 59/61 (96.7%) Comparator 64/71 (90.1%) Risk difference: 6.6 (-0.2 to ∞) Microbiological cure at TOC in MEP Fosfomycin 48/58 (82.8%) Comparator 59/69 (85.5%) Risk difference: -2.7 (95% CI, -13.3 to ∞) Safety Rate of AEs: Fosfomycin 62.9% Comparator 56.2% Serious AEs: Fosfomycin 18.6% Comparator 13.7% Discontinuation due to AEs: Fosfomycin 8.5% Comparator 0% AEs leading to discontinuation in the fosfomycin group: Heart failure (5.7%) Alithiasic cholecystitis (1.4%) Persistent fever (1.4%) | Fosfomycin IV exceeded the NI threshold for the primary endpoint and therefore did not meet noninferiority to the comparator group (ceftriaxone or meropenem) for the treatment of bacteremia UTIs due to MDR E. coli |
| Kaye et al 201912 ZEUS Phase 2/3, MC, DB, RCT Duration: 7 days (up to 14 days for patients with bacteremia) | N=465 hospitalized adults with suspected or microbiologically confirmed complicated UTI, including acute pyelonephritis Mean age (SD): Fosfomycin 49.9 (20.9) years Piperacillin-tazobactam 51.3 (20.7) Most common baseline pathogens: E. coli: Fosfomycin 72.3% Piperacillin-tazobactam 74.7% K. pneumoniae: Fosfomycin 14.7% Piperacillin-tazobactam 14.0% SIRS at baseline: Fosfomycin 33.7% Piperacillin-tazobactam 29.2% Bacteremia at baseline: Fosfomycin 10.3% Piperacillin-tazobactam 7.3% Mean duration of IV therapy: 7.1 days | Fosfomycin 6 grams every 8 hours Piperacillin-tazobactam 4.5 grams every 8 hours Dosage adjustments for fosfomycin were made for patients with CrCl <50 and ≥20 mL/min; patients with CrCl <20 mL/min were excluded from study Oral step-down therapy was prohibited for both treatment groups | Primary Overall success (complete resolution or significant improvement of signs and symptoms plus microbiologic eradication) at TOC in m-MITT populationc Fosfomycin 119/184 (64.7%) Piperacillin-tazobactam 97/178 (54.5%) Treatment difference: 10.2 (95% CI, -0.4 to 20.8) Secondary Clinical cure at TOC in m-MITT population Fosfomycin 167/184 (90.8%) Piperacillin-tazobactam 163/178 (91.6%) Treatment difference: -0.8 (95% CI, -7.2 to 5.6) Microbiological eradication at TOC in m-MITT population Fosfomycin 121/184 (65.8%) Piperacillin-tazobactam 100/178 (56.2%) Treatment difference: 9.6 (95% CI, -1.0 to 20.1) Exploratory Clinical cure at TOC in m-MITT population for ESBL pathogens Fosfomycin 52/56 (93%) Piperacillin-tazobactam 51/55 (93%) Microbiologic eradication at TOC in m-MITT population for ESBL pathogens Fosfomycin 32/58 (55%) Piperacillin-tazobactam 27/57 (47%) Safety Rate of AEs: Fosfomycin 42.5% Piperacillin-tazobactam 32.0% Serious AEs: Fosfomycin 2.1% Piperacillin-tazobactam 2.6% Common AEs with fosfomycin: GI disorders (including nausea, vomiting, diarrhea): 10.7% Elevated ALT: 8.6% Elevated AST: 7.3% Hypokalemia: 6.4% | Fosfomycin IV was noninferior to piperacillin-tazobactam for the treatment of complicated UTIs, including acute pyelonephritis |
| Abbreviations: AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CEP=clinically evaluable population; CI=confidence interval; CrCl=creatinine clearance; DB=double-blind; ESBL=extended-spectrum beta-lactamase; GI=gastrointestinal; IQR=interquartile range; IV=intravenous; MA=meta-analysis; MC=multicenter; MDR=multidrug resistant; MEP=microbiologically evaluable population; mITT=modified intention-to-treat; m-MITT=microbiologic modified intention-to-treat; NI=noninferiority; OL=open-label; OR=odds ratio; RCT=randomized controlled trial; RTI=respiratory tract infection; SD=standard deviation; SIRS=systemic inflammatory response syndrome; SR=systematic review; TOC=test of cure; US=United States; UTI=urinary tract infection. aNot available in the US. bNI margin: -7%. cNI margin: -15%. |
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Conclusion
Fosfomycin has a unique mechanism of action; its IV formulation has demonstrated efficacy for treating complicated UTIs, including pyelonephritis, in the RCT ZEUS. Additional studies also suggest a potential benefit; however, safety concerns, such as the sodium content in the IV formulation, should be taken into consideration. Fosfomycin IV offers an additional option for treating complicated UTIs, including infections that may be resistant to other antimicrobial agents. Additional studies will help better define IV fosfomycin’s place in therapy.
References
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- Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol. 2019;11:1756287219832172. doi:10.1177/1756287219832172
- Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284. doi:10.1038/nrmicro3432
- US Centers for Disease Control and Prevention. Antimicrobial resistance facts and stats. CDC.gov website. Updated February 4, 2025. Accessed November 25, 2025. https://cdc.gov/antimicrobial-resistance/data-research/facts-stats/index.html
- Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0
- Bhuiya S, Kaushik S, Logheeswaran J, et al. Emergence of recurrent urinary tract infection: dissecting the mechanism of antimicrobial resistance, host-pathogen interaction, and hormonal imbalance. Microb Pathog. 2025;206:107698.
- Contepo. Prescribing information. Meitheal Pharmaceuticals Inc.; 2025.
- US Food and Drug Administration. FDA review: Monurol. US Food and Drug Administration website. Published December 19, 1996. Accessed November 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/050717Orig1s000rev.pdf
- US Food and Drug Administration. Orange Book: Approved drug products with therapeutic equivalence evaluations. US Food and Drug Administration website. Updated November 2025. Accessed November 26, 2025. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
- Fosfomycin tromethamine granules for oral solution. Prescribing information. Amneal Pharmaceuticals LLC.; 2023.
- Kim DH, Lees WJ. Molecular pharmacology of the antibiotic fosfomycin, an inhibitor of peptidoglycan biosynthesis. Biochemistry. 2025;64(8):1720-1727. doi:10.1021/acs.biochem.4c00522
- Kaye KS, Rice LB, Dane AL, et al. Fosfomycin for injection (ZTI-01) versus piperacillin-tazobactam for the treatment of complicated urinary tract infection including acute pyelonephritis: ZEUS, a phase 2/3 randomized trial. Clin Infect Dis. 2019;69(12):2045-2056. doi:10.1093/cid/ciz181
- Sojo-Dorado J, López-Hernández I, Rosso-Fernandez C, et al. Effectiveness of fosfomycin for the treatment of multidrug-resistant Escherichia coli bacteremic urinary tract infections: a randomized clinical trial. JAMA Netw Open. 2022;5(1):e2137277. doi:10.1001/jamanetworkopen.2021.37277
- Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect. 2017;23(6):363-372. doi:10.1016/j.cmi.2016.12.005
Prepared by:
Jacqueline Wasynczuk, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy
December 2025
The information presented is current as November 20, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.