Antibiotics Deconstructed: IV Fosfomycin

Antibiotics Deconstructed is a new series examining newly approved, repurposed, and novel therapeutics.

Historical Context

IV fosfomycin has been used internationally since the early 1970s, particularly in Europe, but remained unavailable in the United States primarily due to regulatory and commercial barriers rather than scientific ones.^1-3 The drug is off-patent and inexpensive in global markets, which historically made it unattractive for sponsors to invest in the costly FDA approval pathway.⁴

The FDA requires a sponsor-submitted NDA supported by FDA-acceptable trials and inspected manufacturing facilities, and no company undertook that effort for decades.^2,5 Meanwhile, European health systems allowed legacy antibiotics to enter practice based on national approvals and early comparative trials that predated modern noninferiority frameworks.6 The U.S. also had ready access to carbapenems, fluoroquinolones, and broad beta-lactams, delaying perceived clinical need. ⁷

Multiple FDA delays in the 2010s–early 2020s were related to manufacturing site deficiencies and inspection barriers, including pandemic-era travel restrictions, not to efficacy or safety failures.^5,8 Approval in 2025–2026 reflects resistance pressure, stewardship demand for carbapenem-sparing agents, and a sponsor finally willing to absorb regulatory cost, rather than any sudden discovery of benefit.^2,9

Mechanism of Action

Fosfomycin inhibits MurA (UDP-N-acetylglucosamine enolpyruvyl transferase), blocking the first committed step in bacterial peptidoglycan synthesis, a mechanism unique among currently marketed antibiotics.^10-11 This lack of cross-resistance explains its retained activity against many ESBL-producing and MDR Enterobacterales.^11-12 IV fosfomycin achieves high serum levels and excellent renal parenchymal and urinary concentrations, making it particularly effective for complicated UTIs and pyelonephritis. ^13-14

By contrast, oral fosfomycin tromethamine achieves very high urinary concentrations but poor and inconsistent systemic tissue levels, which is why PO therapy is restricted to uncomplicated cystitis.^15-16 IV fosfomycin penetrates inflamed tissues reasonably well (including kidney, lung, bone, and CSF), but non-GU use generally relies on combination therapy to mitigate resistance selection at higher bacterial inocula.^11,17 Resistance can emerge rapidly in vitro via transport mutations or FosA-mediated inactivation, particularly in hospital-acquired infections when used as monotherapy outside the urinary tract.^11,18 Clinically, this has driven European practice toward short courses, high-dose regimens, and combination use in HAIs and MDR infections.^17,19

Data Review

Globally, IV fosfomycin entered practice following European clinical trials in the 1970s–1980s that demonstrated efficacy in complicated UTIs, pyelonephritis, sepsis, and pneumonia, albeit with smaller sample sizes and less rigorous endpoints by modern standards.^1,6,20 Over subsequent decades, its role was reinforced by PK/PD studies, observational cohorts, and multicenter experiences—particularly in Spain, Italy, and Germany—well before US involvement.^11,17,21 Modern systematic reviews before 2020 encompassed thousands of patients, showing acceptable clinical cure rates and relatively low on-therapy resistance emergence when used appropriately.^22,23

The ZEUS trial was not conceptually novel but rather translated this experience into an FDA-acceptable randomized noninferiority design for cUTI and acute pyelonephritis.²⁴ ZEUS demonstrated comparable overall success and high clinical cure rates versus piperacillin-tazobactam, establishing regulatory legitimacy.^24,25 The FOSFOMIC/FOREST-style Spanish bacteremic UTI trials showed reasonable efficacy but highlighted tolerability issues and reinforced the importance of patient selection and combination strategies.^26-27 Together, these trials validated decades of international practice rather than replacing it.

Availability

IV fosfomycin is now available in the US as Contepo following FDA approval in late 2025, with commercial rollout extending into 2026.^2,5 Globally, fosfomycin disodium has long been manufactured in Europe and parts of Asia, but US supply depends on FDA-inspected facilities and compliant GMP documentation, which historically caused delays.^5,8 The last decade’s antibiotic supply chain disruptions—including pandemic-related shutdowns and API sourcing constraints—were a major factor in repeated approval setbacks.^8,28 Current production is centralized rather than diversified, which may initially limit availability to larger health systems and academic centers.⁵ Unlike oral fosfomycin, IV supply is hospital-restricted and tied closely to stewardship oversight.² Over time, availability is expected to stabilize, but it is unlikely to become as commoditized in the U.S. as it is in Europe due to regulatory overhead and lower margins.^4,9

Cost

IV fosfomycin is substantially more expensive in the US than in Europe due to branded status, regulatory costs, and limited competition.^4,29 For insured patients, PPO coverage typically places it on higher specialty tiers with prior authorization, while CMS reimbursement for inpatient use is bundled and absorbed by hospitals rather than patients directly.³⁰ Out-of-pocket costs without insurance are expected to be high, limiting ambulatory or extended outpatient use.²⁹ Compared with generic carbapenems (eg, meropenem) or piperacillin-tazobactam, IV fosfomycin is often more expensive on a per-day basis in the U.S., though this may be offset in selected cases by carbapenem-sparing value. ^31,32 It is markedly costlier than older beta-lactams and fluoroquinolones, which remain generically inexpensive but increasingly compromised by resistance.³³ From a stewardship and health-system perspective, its value proposition lies less in raw acquisition cost and more in preserving last-line agents and managing MDR infections where alternatives are limited. ^9,31

References

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