Krista Gens, PharmD, BCPS-AQ ID

Fosfomycin (Monurol) is an antibiotic that uses a unique mechanism of action to establish its bactericidal activity. It inactivates the enzyme, enolpyruvyl transferase, irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, one of the first steps in bacterial cell wall synthesis. It also reduces the adherence of bacteria to uroepithelial cells.

There is generally no cross-resistance between fosfomycin and other classes of antibacterial agents, such as beta-lactams and aminoglycosides.

 Fosfomycin has a broad spectrum of in vitro activity covering gram-positive pathogens, including methicillin resistant 

, and gram-negative pathogens, including 

, extended-spectrum beta-lactamase (ESBL) pathogens, and carbapenem-resistant 

 Although a relatively old and “forgotten”

 antibiotic (discovered in 1969 and FDA-approved in 1996), fosfomycin can be safe and potentially useful in an era of increasing prevalence of multi-drug—resistant bacteria.

The poor bioavailability of oral fosfomycin (37%) limits its use in patients who are critically ill. Intravenous (IV) fosfomycin is approved for use outside the United States and can be imported to the United States from Europe on a compassionate-use basis under the aegis of the emergency investigational new drug application process. A small number of case studies from the United States have reported the use of IV fosfomycin as an adjunctive agent in successful treatment of blood and disseminated infections due to extensively drug-resistant 

 In a recent multi-center, phase 2, placebo-controlled trial, fosfomycin was used in an experimental inhalation system, along with amikacin, as an adjunct agent to standard IV antibiotics to treat gram-negative bacterial ventilator-associated pneumonia.

 The remainder of this article will focus on the use of oral fosfomycin for both FDA-approved and unapproved indications.

Oral fosfomycin is FDA approved at a single 3-g dose to treat uncomplicated urinary tract infection (UTI) (ie, acute cystitis) in women due to susceptible strains of 

 Fosfomycin is listed as one of the first-line treatment options, along with trimethoprim-sulfamethoxazole and nitrofurantoin, in the Infectious Diseases Society of America (IDSA) guidelines for uncomplicated cystitis.

 Fosfomycin has been shown to be effective for uncomplicated UTIs as a single dose (see 

 Additionally, it is recommended for the treatment of uncomplicated cystitis in elderly individuals.

 Primarily because of increasing bacterial resistance to other agents, the use of fosfomycin in the United States is starting to increase for both FDA-approved and non—FDA-approved indications.

Every 48-to-72 hours dosing in complicated UTIs

Only 1 clinically appreciable drug interaction (metoclopramide)

Development of resistance with increased use, including while on therapy for 

Broad spectrum of activity (may cover most organisms associated with UTIs) including resistant pathogens such as ESBLs, some CRE, VRE, and MRSA

Not recommended to use in pyelonephritis, and limited data in prostatitis

Potential for treatment failure regardless of in vitro susceptibilities

UTI = urinary tract infection; ESBL = extended spectrum beta-lactamases; CRE = carbapenem-resistant enterobacteriaceae; VRE = vancomycin-resistant enterococci; MRSA = methicillin-resistant staphylococcus

Although not an FDA-approved indication, fosfomycin is used to treat complicated UTIs, excluding pyelonephritis, perinephric abscess, or UTI associated with bacteremia. It is important for providers to realize that the dosing of fosfomycin in these instances is different for complicated infections. For complicated UTIs, fosfomycin is commonly given in 3-g doses every 48 to 72 hours for 6 to 21 days. Three doses are usually sufficient, but the total duration is guided by clinical improvement.

There are data available supporting the use of fosfomycin for complicated UTIs. According to the results of a recent single-center, retrospective study from the Henry Ford Health System, outpatient therapy with fosfomycin (including as a step-down agent) was noninferior to IV ertapenem (Invanz) for outpatient treatment of ESBL UTI, mostly attributed to ESBL 

 Fosfomycin and amoxicillin-clavulanate were shown to be equally effective for cystitis caused by susceptible isolates with cure rates of 93%.

 However, another retrospective analysis on the use of fosfomycin to treat complicated UTIs due to multidrug-resistant organisms demonstrated a notable discordance between in vitro susceptibility (overall 86%) and microbiological cure (overall 59%). The largest discordance occurred for carbapenem-resistant 

 (92% in vitro susceptibility vs 46% microbiological cure rate). Microbiological failure was more common in patients who underwent solid organ transplant and in patients with ureteral stents.

is relatively common, and resistance can emerge while on therapy, regardless of in

 It is important for providers to note that even patients with susceptible organisms may fail fosfomycin therapy.

Another complicated UTI for which fosfomycin cannot be used is pyelonephritis. The IDSA guidelines do not recommend fosfomycin use to treat pyelonephritis due to less than optimal serum and renal tissue concentrations after oral dosing.

 Ode and colleagues studied fosfomycin in patients with fosfomycin and found a success rate of just 44% and considerably lower concentrations in the renal tissues compared with the urine.

 Therefore, fosfomycin should be avoided if there are concerns about upper urinary tract (ie, kidney) involvement.

Prostatitis is another disease state in which oral fosfomycin has been used. Fosfomycin achieves reasonable intraprostatic tissue levels

 and is active against extended-spectrum beta-lactamase—producing organisms.

 For these reasons, the consensus guidelines by the Prostatitis Expert Guidance Group in the United Kingdom state that fosfomycin can be considered in patients with chronic bacterial prostatitis due to multi-drug-resistant gram-negative infections, based on susceptibility results and discussion with local microbiologists.

 However, studies have been small or consist of case studies, and there is limited clinical experience and outcome data.

Fosfomycin may be an attractive option to treat UTIs for many reasons. First, it achieves urinary concentrations well above typical minimum inhibitory concentrations (~1000-4000 mcg/mL) and is able to sustain them for long periods of time (>100 mcg/mL at 48 hours and greater than the minimum inhibitory concentration of 

 Thus, it is an attractive single-dose regimen for uncomplicated UTIs.

 Second, there is no hepatic or renal adjustment.

 Third, there is only 1 clinically relevant drug interaction with metoclopramide that decreases absorption of fosfomycin listed in the package insert.

 Interestingly, fosfomycin may actually decrease the nephrotoxicity and ototoxicity of aminoglycosides and cisplatin if administered together.

 Fourth, due to relatively low use and an unshared mechanism of action, resistance to fosfomycin remains relatively low even among some multi-drug—resistant organisms.

 Some studies even suggest that fosfomycin may still cover up to 97% of ESBL-producing 

 Fifth, patients with multiple allergies could use fosfomycin when treatment options become severely limited. Finally, from a patient perspective, oral outpatient treatment may be favorable for quality of life and avoiding the risk of catheter-related infections or thrombosis in patients who would otherwise require IV antibiotics due to organisms resistant to other oral options.

Fosfomycin use does not come without drawbacks, in addition to the previously mentioned diseases states where it cannot be used. As previously mentioned, patients may fail therapy even if their organism is sensitive.

 In addition, fosfomycin has an average wholesale price of $79 per dose, which is substantially costlier than most other oral options, especially if treating complicated UTIs where longer treatments may be needed. Insurance coverage can be variable, so patients may pay out of pocket. Subsequently, given its cost and limited use, many retail pharmacies do not stock it. Therefore, patients may have difficulty getting their prescriptions filled. In addition, increasing use of fosfomycin has been shown to increase resistance. The results of a study conducted in Spain showed increasing rates of fosfomycin resistance from 2005 to 2009 in both ESBL-producing and non-ESBL—producing 

 In the time span of the study, resistance rates among non-ESBL—producing 

 increased from 1.5% in 2005 to 2.9% in 2009. Similarly, the rates of fosfomycin resistance in ESBL-producing 

 increased from 4.4% in 2005 to 11.4% in 2011. The authors, in part, linked the increasing resistance rates to increasing use of fosfomycin to treat UTIs.

 There are not many antibiotics left to treat drug-resistant pathogens, and therefore increased resistance to fosfomycin is very worrisome.

In addition, most microbiology labs are not able to test susceptibilities for fosfomycin, so most providers will not be able to immediately confirm that the isolate is sensitive and may end up using it without knowing if it is effective in vitro. Fosfomycin can also be difficult to use in clouded clinical pictures. If there is any suspicion that a UTI involves the upper urinary tract, fosfomycin should be avoided. Finally, patients must be counseled as to how to properly take the fosfomycin to avoid decreasing efficacy. Fosfomycin comes as powder in a sachet. The sachet must be opened and the contents mixed in liquid before consumed. Patients must also be told not to mix it with hot water.

Fosfomycin can be an attractive option to treat UTIs due to its broad spectrum and general ease of use, but it should be used with caution. In line with the basic principles of antimicrobial stewardship, other treatment options should be considered first when choosing empiric treatment based upon local susceptibility patterns to preserve fosfomycin’s spectrum of activity against multi-drug—resistant pathogens. Fosfomycin should be reserved for use in uncomplicated UTIs and the appropriate complicated UTIs, with multi-drug–resistant pathogens, when the risk outweighs the benefit of using alternative agents. Use of fosfomycin can also be considered in patients with multiple allergies that preclude other options. Providers and patients must be aware of the considerable cost, potential lack of availability, appropriate dosing for uncomplicated versus complicated UTIs, and recommendations for administration to maximize the potential for positive outcomes. Providers also must be aware of the potential for treatment failure despite in vitro susceptibility.

Michael Wankum, PharmD, BCPS, is a clinical pharmacy specialist in infectious diseases at North Healthcare. Christina Koutsari, PharmD, PhD, is a PGY2 infectious diseases pharmacy resident at Abbott Northwestern Hospital in Minneapolis. Krista Gens, PharmD, BCPS-AQ ID, is an infectious diseases clinical pharmacy coordinator and a PGY2 infectious diseases pharmacy residency program coordinator at Abbott Northwestern Hospital in Minneapolis.

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Articles

Fosfomycin (Monurol) is an antibiotic that uses a unique mechanism of action to establish its bactericidal activity.