Key takeaways:
- Fosfomycin (CONTEPO) has been approved to treat complicated urinary tract infections (cUTIs) in adults, including acute pyelonephritis.
- The drug targets bacterial cell walls earlier than β-lactam antibiotics and shows no known cross-resistance to other antibiotic classes.
- In the ZEUS trial, fosfomycin demonstrated noninferior efficacy to piperacillin/tazobactam, achieving a 63.5% overall success rate.
- Common adverse reactions included elevated transaminases, hypokalemia, and neutropenia, with overall favorable tolerability.
- Fosfomycin joins other newly approved antibiotics such as gepotidacin, addressing growing resistance and unmet treatment needs in UTI care.
The FDA has approved fosfomycin (Contepo; Meitheal Pharmaceuticals, Inc) as an injection to treat complicated urinary tract infections (cUTIs) such as acute pyelonephritis in patients aged at least 18 years.1
With no known cross-resistance to other antibiotic classes, fosfomycin has shown efficacy against the Escherichia coli and Klebsiella pneumoniae strains linked to cUTIs. It is an injectable epoxide that targets bacteria’s cell wall at an earlier stage compared with β-lactam antibiotics.
"The rise of multidrug-resistant pathogens poses a significant threat to our ability to combat infectious diseases, underscoring the continued need for novel therapies that target resistant organisms in patients having cUTIs," said Keith S. Kaye, MD, MPH, chief of the Division of Allergy, Immunology, and Infectious Diseases at Robert Wood Johnson Medical School.
ZEUS trial demonstrates safety and efficacy
The phase 2 and 3 ZEUS trial (NCT05021835) highlighted positive safety and efficacy results for fosfomycin in patients hospitalized with cUTIs such as acute pyelonephritis. Noninferiority was noted when compared with piperacillin or tazobactam for overall success, defined as clinical cure and microbiological eradication.
This end point was measured during the test-of-cure visit in the microbiological modified intent-to-treat population. Overall success rates included 63.5% for fosfomycin and 55.6% for piperacillin and tazobactam combined, indicating a treatment difference of 7.9%.
A positive safety profile was also reported. Common adverse reactions were those reported in more than 2% of patients taking fosfomycin and included the following:
- Transaminase elevations in 10.3%
- Hypokalemia in 9.9%
- Neutropenia in 6.4%
- Nausea in 4.3%
- Diarrhea, vomiting, and hypocalcemia in 3.9% each
- Hypernatremia in 3.4%
- Headache in 2.6%
- Hypophosphatemia in 2.1%
Mechanism and indications for use
Fosfomycin is in a class of antibiotics known as phosphonics. These drugs prevent cell wall precursors from forming through binding and inhibiting phosphoenolpyruvate transferase. This also prevents cell wall synthesis and eradicates bacteria.
Activity has been proven against gram-negative bacteria and other antimicrobial-resistant pathogens. Investigators noted fosfomycin should only be used in patients with proven or strongly suspected infections caused by susceptible bacteria.
“With an estimated 3 million cases of cUTIs treated in the hospital setting annually, there is a critical need for a safe and effective treatment option. Contepo’s safety, efficacy, and novel mechanism of action make it a favorable new treatment option,” said Keith Robinson, MD, MS, FCCP, chief medical officer of Meitheal Pharmaceuticals.
Broader progress in UTI treatment approvals
Fosfomycin is just one of multiple drugs that received FDA approval for UTI treatment in 2025. Another example is gepotidacin, which received approval for uncomplicated UTIs in March.2 The importance of this approval was highlighted by Ryan Haumschild, PharmD, MS, MBA, CPEL, vice president of pharmacy at Emory Healthcare, in an interview with Contemporary OB/GYN.
The safety and efficacy of gepotidacin were confirmed in the phase 3 EAGLE-2 (NCT04020341) and EAGLE-3 (NCT04187144) trials. A therapeutic success rate of 58.5% was reported, indicating significant superiority to the standardized treatment nitrofurantoin, which had a success rate of 43.6%. This highlights a safer option for patients experiencing adverse effects from other antibiotics.
"How can we use this new option that might have a different [adverse] effect profile and leverage that for specific patient populations, [so that] we can decrease resistance?" said Haumschild.
