We have all been there, a patient with so many complicating factors that it’s difficult to choose the least worst option to treat a urinary tract infection. For example: a patient with a CrCl ~22 ml/min, a prolonged QTc, sulfa allergy (described as immediate death), and amoxicillin allergy (also somehow described as immediate death) who absolutely refuses to try a cephalosporin. How is it this difficult to treat a simple urinary tract infection?!?!?!
There is one antibiotic that has your back, fosfomycin (Monurol®). (And to get this out of the way, I fully endorse challenging penicillin allergies with appropriate agents, as long as the provider, the care team, and the patient are on board with the plan.)
What is Fosfomycin1,2
Fosfomycin is a bactericidal phosphoric acid derivative antibiotic that disrupts cell wall synthesis by inhibiting pyruvyl transferase. Fosfomycin is only available as a 3g oral sachet in the United States, though it is available as an intravenous product elsewhere.
Spectrum of Activity
Fosfomycin has activity against a broad range of gram-positive and gram-negative aerobic microorganisms commonly associated urinary tract infections. These include E.coli, Klebsiella spp. Enterococcus spp. (including vancomycin resistant Enterococcus spp [VRE]), Enterobacter spp., Citrobacter spp. Pseudomonas spp., and Serratia spp. Additionally, and discussed in more detail below, fosfomycin commonly retains activity against extended spectrum beta-lactamase (ESBL) producing organisms and carbapenem-resistant enterobacteriaceae (CRE).
● Absorption- Fosfomycin’s oral bioavailability is approximately 30-37%. Due to the limited systemic absorption, use in pyelonephritis, peri-nephric abscess, or any systemic infection is contraindicated.
● Distribution- Due to limited systemic absorption, it is expected that oral fosfomycin has minimal tissue distribution.
Adverse Effects of Significance 2
Fosfomycin is generally very well tolerated. The most common adverse effects include diarrhea, nausea, and headache, which happen to be common adverse effects of most drugs.
Fosfomycin in Pregnancy 1
Adverse events have not been observed in animal reproduction studies. Several studies have used a single dose of fosfomycin for the treatment of asymptomatic bacteriuria in pregnant women with no adverse fetal effects reported. Fosfomycin is classified as a pregnancy category B drug.
Preparation and Administration 1,2
The contents of each 3g sachet should be poured into 3-4 ounces (½ cup) of cold water and stirred until completely dissolved. Hot water should not be used. The solution should be administered by mouth immediately after it is prepared.
Potential Roles of Fosfomycin
Fosfomycin is a first line option for uncomplicated cystitis per the current IDSA guidelines for the treatment of uncomplicated cystitis. However, we have no shortage of agents for uncomplicated cystitis, many of which are less expensive, narrower in spectrum, and more readily available at a typical community pharmacy than fosfomycin. Where fosfomycin really presents a unique option is in the following situations:
Fosfomycin In-vitro susceptibility
Clinical Cure Rate
VRE cystitis*† 6,7,8,9,10,16
CRE cysitis† 10,11,16
Pseudomonal cystitis† 10,14
Patients with multiple severe allergies or predisposing factors that limit other options13,14,15,17,18
Patients at high risk for noncompliance 13,14,15,17,18
*One study showed 77% in-vitro susceptibility with an additional 21% intermediate †Due to the lack of acknowledged fosfomycin breakpoints for bacteria other than E. coli and E. faecalis, results were interpreted according to criteria for E.coli and E. faecalis (i.e. susceptible at a MIC ≤64 g/ml)
Despite promising in-vitro data for the treatment of CRE and Pseudmonal cysitits there is limited clinical data for use against these pathogens. Patients should be carefully selected when using fosfomycin in these situations.
Medications used to increase gastrointestinal motility (e.g. metoclopramide) may decrease oral absorption of fosfomycin, thus reducing its efficacy.
Help with Adding to Formulary
Most microbiology laboratories do not routinely perform susceptibility testing for fosfomycin. Send outs usually take some time, and in my experience I rarely receive the results before the patient has finished their course of fosfomycin. Meaning the results weren’t useful in that we already clinically knew if the treatment had worked or not. For this reason I generally don’t recommend send out fosfomycin susceptibilities, even when using fosfomycin for a pathogen for which it has variable activity.
● Team up with your inpatient colleagues- They have just as much incentive to want fosfomycin available. Fosfomycin can prevent admissions solely for IV antibiotic therapy to treat MDR-pathogens for which no other oral options are available, this is important to us from an ED perspective. From an inpatient perspective fosfomycin may help facilitate the discharge of a patient receiving IV antibiotics for MDR-pathogens. It’s a great way to build relationships and having multiple areas of the institution pushing for fosfomycin make it difficult to say no.
● Reach out to local pharmacies- Ask them to stock fosfomycin so you have a go to place for patients to get it. Preferably something close to the ED.
● Work with case management- Many insurances require a prior authorization to cover fosfomycin. Pharmacies in my area charge about $90 per dose without insurance making it cost prohibitive for many patients. I’ve found case management to be extremely helpful in these instances.
3g PO x 1 dose
3g PO q48-72h x 3 doses
3g q48-72h x 21 days
*There are no renal or hepatic doses adjustments for oral fosfomycin.
One Punch Knockout Too Good To Be True?
Huttner et al. recently published a study comparing clinical and microbiologic efficacy of nitrofurantoin 100mg po three times daily and fosfomycin 3g as a single dose in women with uncomplicated cystitis.19 They found clinical resolution through day 28 was achieved in 70% of patients receiving nitrofurantoin vs 58% receiving fosfomycin ([95% CI, 4%-21%]; P = 0.004). This calls into question if a single 3g dose of fosfomycin is adequate for the treatment of uncomplicated cystitis. Until there is a study to specifically answer this question, we will have to practice in a grey area. Here are some things to consider:
● MacroTID???- nitrofurantoin 100mg po twice daily is endorsed by the IDSA rather then the three times daily used in this study. Since the pharmacokinetic/pharmacodynamic index that best correlated to the antibacterial activity of nitrofurantoin against E.coli was T>MIC, increasing the frequency of nitrofurantoin dosing may make it an unfair comparison.20
● Most patients with MDR pathogens have complicated cystitis- in reserving fosfomycin primarily for MDR pathogens we will therefore primarily be using 3 dose regimens
● One dose of fosfomycin > zero doses of anything else- for non-compliant patients giving a single dose in the ED may be the only reasonable option
If you read nothing else:
● Fosfomycin is an often forgotten oral antibiotic available for the treatment of lower urinary tract infections.
● Fosfomycin retains activity against many MDR-pathogens such as ESBL, VRE, CRE, and Pseudomonas spp. making it an attractive oral option for cystitis caused by these pathogens.
● Despite being a first line recommendation for uncomplicated cystitis per IDSA guidelines, fosfomycin may not be ideal for the majority of these situations. It is more broad in spectrum of activity, is more expensive, and is less commonly stocked in retail pharmacies then many other options for uncomplicated cystitis.
● Consider fosfomycin in patients with current or recent history of MDR lower urinary tract infections, in patients with multiple drug allergies/predisposing factors that make other options not feasible, and/or in patients at high risk for noncompliance.
● Fosfomycin can prevent admissions solely for IV antibiotic therapy to treat MDR-pathogens for which no other oral options are available.
● Dosing of fosfomycin is unique in that uncomplicated UTIs may be treated with a single dose, though recent data has called this into question. Complicated UTIs should be treated with 3 doses.
Tony Mixon, PharmD, BCPS
Emergency Medicine/Infectious Disease Clinical Pharmacist
Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD), Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD), and Scott Dietrich, PharmD (@PCC_PharmD)
1.) Product Information: MONUROL(R) sachet oral solution, fosfomycin tromethamine oral solution. Zambon Switzerland Ltd, Cadempino, Switzerland, 2007
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