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Issue: August 2018
ByDonald Kaye, MD, MACP
August 23, 2018
6 min read
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Fosfomycin for uncomplicated cystitis in women: Less for more?

Issue: August 2018
ByDonald Kaye, MD, MACP
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Fosfomycin, along with nitrofurantoin and trimethoprim/sulfamethoxazole, are recommended by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases as first-line therapy for acute uncomplicated cystitis in women. Pivmecillinam is also recommended but is not available in the United States. Fluoroquinolones are considered effective but have a propensity for collateral damage and should be reserved for other important uses.

History, pharmacology and antimicrobial activity

Fosfomycin, marketed as Monurol (Allergan) in the United States, is an old drug that first became available commercially in the early 1970s. The drug acts by inhibiting an enzyme-catalyzed reaction in the first step of the synthesis of the bacterial cell wall. Because the mechanism of action is unique, there is no cross-resistance with other classes of antibiotics. At present, there is no generic version of fosfomycin available in the U.S.

Donald Kaye

The agent is available only in oral formulations in the U.S, approved by the FDA for the “treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.” It has been used for many years in some other countries, where it is also available for use intravenously. Although it was approved by the FDA in 1969, it has not been used widely in the U.S.

Fosfomycin has a wide spectrum of activity against aerobic gram-positive and gram-negative bacteria, including Staphylococcus aureus (methicillin sensitive and resistant), enterococci (including vancomycin resistant) and many gram-negative bacilli, including those positive for extended-spectrum beta-lactamase (ESBL), as well as carbapenem-resistant Enterobacteriaceae (CRE). According to the literature, Staphylococcus saprophyticus and Pseudomonas aeruginosa are variably susceptible to fosfomycin.

As a confounding issue, the Clinical & Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing state that a prescribed amount of glucose 6-phosphate (G-6-P) must be present for testing susceptibilities to fosfomycin because minimum inhibitory concentrations (MICs) are much higher without the presence of G-6-P. Apparently, urine does not contain G-6-P, so the MIC in urine may be much higher than in vitro tests may indicate. In any case, most U.S. microbiology labs are not able to test for susceptibilities to fosfomycin.

Fosfomycin is well-tolerated with few side effects. A single dose of fosfomycin tromethamine containing 3 g of fosfomycin is dissolved in 3 to 4 oz of water. The fosfomycin tromethamine is rapidly absorbed and converted to fosfomycin. Fosfomycin is excreted in the urine and feces. Antibacterial levels have been reported to be present in the urine for 24 hours or longer. Because of its activity against resistant bacteria, it has been used off label for complicated lower UTIs caused by resistant organisms, sometimes with repeated doses (eg, every 2-3 days).

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Except for the inconvenience of having to dissolve the powder in water, fosfomycin would appear to be an ideal drug for its approved and recommended use as a first-line treatment for uncomplicated cystitis in women. However, for several reasons discussed below, I propose that, currently, fosfomycin may not be not a reasonable first-line therapy for many, if not most, with uncomplicated cystitis in the U.S.

Effectiveness of fosfomycin for uncomplicated lower UTIs

As stated in the guidelines, fosfomycin “appears to have inferior efficacy compared with standard short-course regimens,” according to data submitted to the FDA and summarized in The Medical Letter on Drugs and Therapeutics. The agent’s inferior efficacy was a result of less eradication of bacteriuria.

Most of the literature comparing a single dose of fosfomycin to nitrofurantoin, trimethoprim/sulfamethoxazole or quinolones for longer periods of time shows equivalence in terms of clinical response but, in general, a lower rate of eradication of bacteriuria for fosfomycin. Asymptomatic bacteriuria is of little or no consequence in nonpregnant adult women, and the lower rate of response can be ignored. In fact, follow-up urine cultures are not recommended in those with clinical cure. However, it does raise a question about whether and for how long the urine levels are actually antibacterial, remembering that urine lacks G-6-P.

Clinical response is paramount, because the primary reason for treatment is to relieve symptoms. For this reason, a recent large study by Huttner and colleagues published in JAMA is disturbing, because it found that clinical resolution of uncomplicated cystitis was significantly better with 5 days of nitrofurantoin than with single-dose fosfomycin. Not surprisingly, eradication of bacteriuria with nitrofurantoin was also better.

In this study, the rate of the lack of clinical response as defined by the investigators at 14 days was 30% with a single dose fosfomycin and 23% with 100 mg nitrofurantoin three times a day for 5 days (P = .03). At 28 days, clinical failure rates were 39% and 27%, respectively (P = .004). Perhaps more importantly, the clinical response with E. coli infection was significantly worse with fosfomycin than with nitrofurantoin despite less than 1% resistance to fosfomycin (50% cure rate with fosfomycin vs. 78% cure rate with nitrofurantoin [P < .001]). Several observations are necessary: 1) the guideline-recommended dose of nitrofurantoin is 100 mg twice daily, not three times daily; 2) clinical failure at 14 days is more representative of failure to respond than 28 days because of the possibility of reinfections; and 3) these are unusually high failure rates for both agents compared with the literature.

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Clearly, these results need to be replicated, but the study serves as a word of caution about the effectiveness of single-dose fosfomycin.

Cost of fosfomycin

The prices of drugs vary greatly depending on pharmacy and formulary prices, but one way of comparing them is visiting GoodRx.com (https://www.goodrx.com). GoodRx provides free coupons and lists the prices at various pharmacies in the U.S. The results are somewhat astounding. The lowest GoodRx price for the most common version of one dose of fosfomycin is around $85.35, 15% off the average retail price of $101.50. The lowest GoodRx price for 14 capsules of the most common version of nitrofurantoin mono/macro is around $19.81, 58% off the average retail price of $47.81. The lowest GoodRx price for 20 tablets of the most common version of sulfamethoxazole/trimethoprim is around $3.99, 75% off the average retail price of $16.14. The lowest GoodRx price for 20 tablets of the most common version of ciprofloxacin is around $4, 90% off the average retail price of $40.20. Thus, the average retail price of one dose of fosfomycin in the U.S. is more than twice the average retail price of more than enough of any of the other drugs used to treat uncomplicated cystitis.

Fosfomycin is also not on many formularies, as opposed to the other agents recommended for uncomplicated cystitis; therefore, the prospect of a reduced cost is not available to many with drug plans.

Availability of fosfomycin in the US

Fosfomycin is not available in many U.S. pharmacies and must be ordered. Prescriptions frequently take 24 hours or more to fill. Cystitis is an uncomfortable infection, and the prospect of having to wait for 24 hours or more to start therapy is not pleasant for many patients.

Usefulness for infection caused by MDR bacteria

Fosfomycin is active against many antimicrobial-resistant, gram-negative bacilli (GNB), including those positive for ESBL, as well as CRE. Therefore, the oral fosfomycin available in the U.S. is useful for off-label treatment of complicated cystitis, especially when caused by antimicrobial-resistant GNB. However, it may have to be used with repeated doses.

Summary and conclusions

Because of its broad spectrum of activity against the bacteria that cause UTIs and its relative lack of toxicity, fosfomycin would seem to be an ideal drug for treatment of cystitis. However, fosfomycin in a single dose, as recommended by guidelines and approved by the FDA, is probably less effective for uncomplicated cystitis than the other recommended agents. Currently, it is certainly more expensive and less available in the U.S. than the other agents. All of this adds up to making it a questionable first choice for therapy of uncomplicated cystitis at present. Fosfomycin is “less for more” — probably less effective, less available, and more expensive.

  • For more information:
  • Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.

Disclosure: Kaye reports no relevant financial disclosures.

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