Fosfomycin retains strong activity against most ESBL-producing Escherichia coli, with susceptibility rates consistently around 95–96% across studies in multiple countries. That makes it one of a shrinking number of oral antibiotics still useful for urinary tract infections caused by these resistant bacteria. The picture is more nuanced for Klebsiella pneumoniae, where fosfomycin susceptibility drops considerably, and the reliability of lab testing itself becomes a problem. Understanding where fosfomycin fits in the ESBL landscape requires looking at several angles: which organisms respond, which clinical scenarios have real evidence behind them, and where the drug’s limitations lie.
Why Fosfomycin Sidesteps ESBL Resistance
ESBL enzymes break down certain beta-lactam antibiotics, rendering drugs like cephalosporins and many penicillins useless. Fosfomycin works through a completely different mechanism. It blocks MurA, the enzyme responsible for the very first step in building the bacterial cell wall’s peptidoglycan layer. Because fosfomycin’s target has nothing to do with the beta-lactam binding sites that ESBLs attack, producing an ESBL enzyme gives bacteria no advantage against fosfomycin.1PubMed Central. Fosfomycin: Mechanism and Resistance The drug is bactericidal, meaning it kills bacteria rather than just slowing their growth, and it reaches very high concentrations in urine after a single oral dose. That combination of unrelated mechanism and favorable urine levels explains why it keeps working against ESBL-producing strains that have become resistant to many other options.
Susceptibility in the Lab Depends Heavily on the Species
The headline numbers for E. coli are reassuring. A large study comparing ESBL and non-ESBL E. coli isolates from urinary tract infections found susceptibility rates of about 96% in both groups, meaning the presence of ESBL genes made essentially no difference to fosfomycin activity.2Microbiology Spectrum. Antimicrobial susceptibilities of clinical bacterial isolates from urinary tract infections to fosfomycin and comparator antibiotics determined by agar dilution method and automated micro broth dilution A Netherlands-based study of ESBL-producing urinary isolates likewise reported that roughly 96% of E. coli fell within the susceptible range.3Journal of Antimicrobial Chemotherapy. Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods Data from Taiwan echoed the pattern, finding about 95.5% susceptibility among ESBL-producing E. coli urinary isolates.4PubMed. Antimicrobial susceptibilities of urinary extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae to fosfomycin and nitrofurantoin in a teaching hospital in Taiwan
Klebsiella pneumoniae is a different story. That same Netherlands study found only about 88% susceptibility among ESBL-producing K. pneumoniae, which sounds decent but is a meaningful drop from the E. coli numbers.5Journal of Antimicrobial Chemotherapy. Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods The Taiwan data showed an even steeper decline, with only about 58% of ESBL-producing K. pneumoniae susceptible.6PubMed. Antimicrobial susceptibilities of urinary extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae to fosfomycin and nitrofurantoin in a teaching hospital in Taiwan And in the study using agar dilution, ESBL-producing K. pneumoniae susceptibility was only about 37%.7Microbiology Spectrum. Antimicrobial susceptibilities of clinical bacterial isolates from urinary tract infections to fosfomycin and comparator antibiotics determined by agar dilution method and automated micro broth dilution The takeaway is clear: fosfomycin is a reliable choice against ESBL-producing E. coli but a gamble against ESBL-producing Klebsiella without susceptibility testing to back it up.
The Lab Testing Problem for Klebsiella
Even when clinicians order fosfomycin susceptibility testing, the results for Klebsiella may not be trustworthy. The gold-standard method for testing fosfomycin is agar dilution, a labor-intensive procedure that most routine clinical labs do not perform. More common automated systems and gradient diffusion strips show excellent agreement with agar dilution for E. coli but perform poorly for K. pneumoniae. A South African study found that disk diffusion and gradient diffusion had about 98% agreement with agar dilution for E. coli but only 47% agreement for K. pneumoniae.8PubMed Central. Fosfomycin susceptibility testing and resistance mechanisms in Enterobacterales in South Africa
The problem is partly structural. Both CLSI (the U.S. standard-setting body) and EUCAST (the European equivalent) have published fosfomycin breakpoints primarily for E. coli. When labs apply those breakpoints to Klebsiella or Pseudomonas, they are extrapolating beyond the validated range.9Journal of Clinical Microbiology. Performance of Four Fosfomycin Susceptibility Testing Methods against an International Collection of Clinical Pseudomonas aeruginosa Isolates The Netherlands study highlighted that switching between CLSI and EUCAST breakpoints significantly changed error rates for certain automated platforms, with one system misclassifying a substantial fraction of resistant E. coli as susceptible under CLSI rules.10Journal of Antimicrobial Chemotherapy. Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods For clinicians, the practical implication is that a fosfomycin-susceptible report for E. coli on your lab slip is fairly reliable, but a similar report for Klebsiella deserves some skepticism unless agar dilution was used.
Clinical Evidence for Uncomplicated Lower Urinary Tract Infections
The strongest clinical evidence for oral fosfomycin against ESBL-producing bacteria involves uncomplicated lower UTIs, meaning bladder infections without kidney involvement. A review of available studies found clinical success in more than 78% of patients treated with fosfomycin for lower UTIs caused by ESBL-producing E. coli, leading the authors to describe it as an effective outpatient option for these infections, excluding pyelonephritis.11American Journal of Therapeutics. Potential Role of Fosfomycin in the Treatment of Community-Acquired Lower Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli
A real-world comparison of multidose fosfomycin versus nitrofurantoin for ESBL-producing lower UTIs found that fosfomycin was noninferior: about 92% of fosfomycin-treated patients met the composite outcome of clinical and microbiological success, compared with about 83% in the nitrofurantoin group.12Infectious Diseases in Clinical Practice. Real-World Outcomes With Multidose Fosfomycin Compared to Nitrofurantoin for Lower Urinary Tract Infections Due to Extended-Spectrum β-Lactamase–Producing Enterobacterales Nitrofurantoin is another oral drug with preserved activity against many ESBL producers, so this head-to-head comparison is particularly relevant for the two main oral options clinicians can reach for. The standard dosing for an uncomplicated UTI is a single 3-gram sachet of fosfomycin trometamol, though the multidose regimen used in that study reflects growing clinical practice for ESBL infections where clinicians want additional assurance.
Complicated UTIs and Pyelonephritis
Once an infection extends beyond the bladder, oral fosfomycin reaches its limits. For pyelonephritis and complicated UTIs, intravenous fosfomycin has been studied as an alternative to broader-spectrum IV antibiotics. The ZEUS trial, a phase 2/3 randomized study, compared IV fosfomycin to piperacillin-tazobactam in complicated UTI and acute pyelonephritis. The drug met its noninferiority endpoint, with high clinical cure rates among patients harboring resistant organisms including ESBL producers.13Clinical Infectious Diseases. 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 A review of the ZEUS data and related evidence concluded that the strongest case for IV fosfomycin is in ESBL-producing, non-bacteremic complicated UTI or pyelonephritis in hemodynamically stable patients.14PubMed. Intravenous Fosfomycin in Complicated Urinary Tract Infection
A prospective cohort study from the FOSFOMIC project compared IV fosfomycin to standard-of-care antibiotics for complicated E. coli urinary infections. Clinical cure rates were comparable, around 65% in both groups. The fosfomycin group showed numerically lower mortality, though the difference was not statistically significant. One trade-off was more frequent non-severe side effects with fosfomycin, affecting about 23% of patients compared with roughly 8% in the comparator group. Fosfomycin performed comparably in the pyelonephritis subgroup and was not inferior even in cases with bloodstream involvement.15PubMed. Effectiveness and tolerability of intravenous fosfomycin in treating complicated urinary tract infections caused by Escherichia coli: a prospective cohort study from the FOSFOMIC project It is worth noting that IV fosfomycin is not yet widely available in every country; in the United States, its development path has centered on the complicated UTI indication.
Beyond UTIs and the Role of Combination Therapy
For severe systemic infections caused by ESBL-producing or carbapenem-resistant organisms, fosfomycin is rarely used alone. Instead, it serves as a partner drug in combination regimens. A comprehensive review found growing clinical evidence supporting IV fosfomycin as a well-tolerated component of combination therapy for severe infections in critically ill patients, including those caused by ESBL-producing and carbapenemase-producing bacteria.16PubMed Central. Fosfomycin Use in Treating Severe Difficult-to-Treat Gram-Negative Infections—A Comprehensive Review The rationale for combination use is twofold: fosfomycin can enhance the activity of partner drugs, and the risk of resistance emerging during treatment is lower when two drugs with different mechanisms are used together.
Lab studies bear this out. Against ESBL-producing K. pneumoniae, fosfomycin combined with imipenem showed synergy in nearly 79% of isolates tested. Against ESBL-producing E. coli, the same combination was synergistic in 55% of isolates.17PubMed. Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates In vitro testing of fosfomycin with newer beta-lactam/beta-lactamase inhibitor combinations against metallo-beta-lactamase-producing K. pneumoniae and Pseudomonas aeruginosa found positive interactions in at least half of isolates for most pairings tested, with particularly strong synergy seen between fosfomycin and ceftazidime-avibactam.18PubMed Central. In Vitro Evaluation of Fosfomycin Combinations Against Metallo-β-Lactamase-Producing Klebsiella pneumoniae and Pseudomonas aeruginosa Clinical Isolates This combination approach also positions fosfomycin as a carbapenem-sparing option, a priority in antimicrobial stewardship, since overusing carbapenems drives further resistance.19PubMed Central. Fosfomycin in antimicrobial stewardship programs
The Resistance Concern
Fosfomycin resistance rates among E. coli remain low overall, but there are warning signs. A large surveillance study from Portugal found that only about 0.5% of nearly 20,000 E. coli isolates were fosfomycin-resistant. Among those resistant isolates that carried a plasmid-mediated resistance gene, two-thirds also produced an ESBL, suggesting that the same mobile genetic elements carrying ESBL genes can co-carry fosfomycin resistance.20PubMed. Occurrence of plasmid-mediated fosfomycin resistance (fos genes) among Escherichia coli isolates, Portugal The most worrying resistance mechanism is a family of plasmid-borne genes called fosA variants, which produce enzymes that chemically inactivate fosfomycin. These genes originally sit on Klebsiella chromosomes, which partly explains why Klebsiella is intrinsically less susceptible, but they can jump to E. coli on mobile plasmids. One such variant, fosA6, was identified in an ESBL-producing E. coli strain at a U.S. hospital, carried on a self-transferable plasmid alongside a CTX-M-type ESBL gene.21Journal of Antimicrobial Chemotherapy. Glutathione-S-transferase FosA6 of Klebsiella pneumoniae origin conferring fosfomycin resistance in ESBL-producing Escherichia coli Another variant, fosA8, was similarly found on a transferable plasmid in a CTX-M-15-producing E. coli from a urine sample.22Antimicrobial Agents and Chemotherapy. Identification of FosA8, a Plasmid-Encoded Fosfomycin Resistance Determinant from Escherichia coli, and Its Origin in Leclercia adecarboxylata
The coupling of ESBL and fosfomycin resistance genes on the same plasmids is an uncomfortable finding. It means that heavy use of cephalosporins, which selects for ESBL producers, could indirectly co-select for fosfomycin resistance at the same time. For now, the clinical impact is small since fosfomycin resistance in E. coli remains rare, but this co-selection mechanism is exactly the kind of evolutionary shortcut that can erode an antibiotic’s usefulness faster than expected.
There is also a more immediate concern about resistance emerging during treatment. In pharmacodynamic models, fosfomycin dosing regimens up to 24 grams per day led to the emergence of resistant bacterial subpopulations within 30 to 40 hours.23PubMed Central. Fosfomycin: Pharmacological, Clinical and Future Perspectives This tendency toward rapid mutational resistance when the drug is used alone is a major reason why IV fosfomycin is typically paired with a second agent for serious infections rather than given as monotherapy.
Safety and Practical Considerations
For the oral formulation used in uncomplicated UTIs, fosfomycin has an enviable safety profile. Gastrointestinal symptoms like diarrhea and nausea are the most common side effects, and the single-dose regimen limits their duration.24PubMed. Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria The oral form is also considered safe in pregnancy. Studies have shown that a single dose of fosfomycin trometamol achieved bacteriological results comparable to multi-day courses of cefuroxime axetil or amoxicillin-clavulanic acid in pregnant women with asymptomatic bacteriuria or lower UTIs.25PubMed. Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria That makes it one of the very few targeted oral options for ESBL UTIs during pregnancy.
The IV formulation is a different matter. Each gram of fosfomycin contains about 330 mg of sodium, and since typical IV doses run around 12 grams per day, the sodium load can be substantial. One publication found that 6% of patients receiving IV fosfomycin experienced cardiovascular side effects related to sodium overload, and low potassium was the single most common adverse event at 26%.26PubMed Central. Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database For patients with heart failure or a tendency toward fluid retention, this sodium burden is a real clinical consideration. Electrolyte monitoring, particularly potassium, is standard practice during IV fosfomycin courses.
The drug’s pharmacokinetic profile helps explain both its strengths and limits. Fosfomycin is a small, water-loving molecule with virtually no protein binding, so it is cleared almost entirely by the kidneys. That means urine concentrations are extremely high, which is ideal for treating UTIs. It also distributes reasonably well into tissues, including inflamed tissues and abscess fluid.27PubMed Central. Deciphering pharmacokinetics and pharmacodynamics of fosfomycin However, the flip side of renal clearance is that dosing needs adjustment in patients with impaired kidney function, and oral bioavailability is limited enough that the oral form is really only suited for lower urinary tract targets where urine drug levels are what counts.
Biofilm Activity
One less commonly discussed advantage of fosfomycin is its activity against biofilms, the sticky bacterial communities that form on urinary catheters and other surfaces. An in vitro study found that fosfomycin disrupted biofilms in about 67% of E. coli isolates, 74% of Klebsiella species, and 88% of Pseudomonas species at concentrations below the standard minimum inhibitory concentration.28PubMed Central. In vitro effect of fosfomycin on multi-drug resistant gram-negative bacteria causing urinary tract infections Biofilms are a major reason catheter-associated UTIs are so difficult to treat: bacteria embedded in biofilm are often hundreds of times more tolerant of antibiotics than free-floating cells. Whether fosfomycin’s biofilm-disrupting ability translates into better clinical outcomes in catheter-associated infections is an area that still needs more study, but the lab data offer at least a mechanistic rationale for its use in that setting.
Cost and the Carbapenem-Sparing Argument
Before fosfomycin became a hot topic in infectious disease circles, ESBL-producing UTIs were often treated with carbapenems, the most powerful class of beta-lactam antibiotics. Carbapenems work, but they are IV-only drugs requiring healthcare facility visits or home infusion setups, and their overuse accelerates the spread of carbapenem-resistant organisms, which are among the most dangerous bacteria in existence. A small comparative study found that fosfomycin trometamol achieved clinical and microbiological success rates comparable to carbapenems for complicated lower UTIs caused by ESBL-producing E. coli, with significantly lower drug acquisition costs.29PubMed. Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection The savings go beyond the drug price tag: keeping a patient on oral fosfomycin avoids the infrastructure costs of IV administration and reduces the selection pressure that breeds carbapenem resistance across the healthcare system.
Resistance Flowing Between Animals and Humans
A dimension of fosfomycin resistance that rarely reaches the patient-facing conversation is the role of animal agriculture. Surveillance of livestock in one study found that fosfomycin-resistant E. coli colonized about 11% of pigs, 9% of cattle, and 7% of chickens. Among those resistant isolates, 96% carried the fosA3 gene and 93% co-carried a CTX-M-type ESBL gene.30Journal of Applied Microbiology. Dissemination of plasmid‐mediated fosfomycin resistance fosA3 among multidrug‐resistant Escherichia coli from livestock and other animals This tight linkage between fosfomycin resistance and ESBL production in animal isolates mirrors what has been seen in human strains and suggests a shared reservoir. The resistance genes travel on the same mobile DNA elements, so antibiotic use in farming that selects for ESBL producers simultaneously enriches for fosfomycin resistance.
Companion animals are part of this picture, too. A study of fosfomycin-resistant bacteria from dogs and cats found that most strains were multidrug-resistant and co-carried ESBL genes alongside fosfomycin resistance determinants.31PubMed Central. Fosfomycin Resistance in Bacteria Isolated from Companion Animals (Dogs and Cats) The conclusion from both studies is that the extended use of other antibiotic classes, particularly those that select for ESBL-producing organisms, may be indirectly driving fosfomycin resistance upward in animal populations. Whether and how quickly this animal reservoir will erode fosfomycin’s effectiveness in human medicine remains an open question, but it underscores that preserving this drug’s utility is not just a matter of careful prescribing in human healthcare. It is a One Health problem.