Monday, August 27, 2018

Fosfomycin: The Forgotten Treasure





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).

Notable PK1,2
     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:


Potential Role
Fosfomycin In-vitro susceptibility
Clinical Cure Rate
ESBL cystitis3,4,5,10,16  
95.1-100%
93%
VRE cystitis* 6,7,8,9,10,16
86-98.7%
82%
CRE cysitis† 10,11,16
73.5-93%
-
Pseudomonal cystitis† 10,14
75-85%
-
Patients with multiple severe allergies or predisposing factors that limit other options13,14,15,17,18


E.coli: 94-100%
(non-ESBL/CRE)


91.1-96%
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.

Drug-Drug Interactions
Medications used to increase gastrointestinal motility (e.g. metoclopramide) may decrease oral absorption of fosfomycin, thus reducing its efficacy.

Help with Adding to Formulary

Susceptibility Testing
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.

Other Tips
     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.

Dosing Considerations1,2,10,12


Indication
Dose*
Uncomplicated UTI
3g PO x 1 dose
Complicated UTI
3g PO q48-72h x 3 doses
Prostatitis
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)


References
1.)   Product Information: MONUROL(R) sachet oral solution, fosfomycin tromethamine oral solution. Zambon Switzerland Ltd, Cadempino, Switzerland, 2007
2.)   Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; February 1, 2018.
3.)   Pullukcu H, Tasbakan M, Sipahi OR, et al. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents 2007; 29: 62-5.
4.)   Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch Intern Med 2008; 168: 1897-902.
5.)   Auer S, Wojna A, Hell M. Oral treatment options for ambulatory patients with urinary tract infections caused by extended-spectrum-beta-lactamase-producing Escherichia coli. Antimicrob Agents Chemother 2010; 54: 4006-8
6.)   Varughese C, Tichy E, Topal J. Oral fosfomycin in the treatment of vancomycin-resistant enterococcal urinary tract infections. Abstract #215. IDSA Annual Meeting; October 21, 2011 Boston, MA.
7.)   Shrestha NK, Chua JD, Tuohy MJ, et al. Antimicrobial susceptibility of vancomycin-resistant Enterococcus faecium: potential utility of fosfomycin. Scand J Infect Dis. 2003; 35: 12-4.
8.)   Allerberger F, Klare I. In-vitro activity of fosfomycin against vancomycin-resistant enterococci. J Antimicrob Chemother 1999; 43: 211-7.
9.)   Perri MB, Hershberger E, Ionescu M, et al. In vitro susceptibility of vancomycin-resistant enterococci (VRE) to fosfomycin. Diagn Microbiol Infect Dis 2002; 42: 269-71.
10.) Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother 2012 ;56:5744-8.
11.) Endimiani A, Patel G, Hujer KM, et al. In vitro activity of fosfomycin against blaKPC-containing Klebsiella pneumoniae isolates, including those nonsusceptible to tigecycline and/or colistin. Antimicrob Agents Chemother 2010; 54: 526–9.
12.) Los-Arcos I,  Pigrau C, Rodríguez-Pardo D, et al.  Long-term fosfomycin-tromethamine oral therapy for difficult-to-treat chronic bacterial prostatitis. Antimicrob Agents Chemother 2016 ; 60: 1854–58.
13.) Swiatlo E, Sells N, Chasta D et al. In Vitro Susceptibility of Common Urinary Tract Pathogens to Fosfomycin. Open Forum Infectious Diseases, Volume 1, Issue suppl_1, 1 December 2014, Pages S36
14.) Maraki S, Samonis G, Rafailidis P et al. Susceptibility of urinary tract bacteria to fosfomycin. Antimicrob Agents Chemother. 2009 Oct;53(10):4508-10
15.) Karlowsky JA, Denisuik AJ, Lagacé-Wiens PR et al. In Vitro activity of fosfomycin against Escherichia coli isolated from patients with urinary tract infections in Canada as part of the CANWARD surveillance study. Antimicrob Agents Chemother. 2014;58(2):1252-6
16.) Vardakas KZ, Legakis NJ, Triarides N, Falagas ME. Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents. 2016 Apr;47(4):269-85.
17.) Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract
infection. Clin Ther. 1999; 21: 1864-72
18.) Bozkurt O, Kara C, Akarsu S et al. Comparison efficacy of single dose fosfomycin with ciprofloxacin in the treatment of urinary tract infection in symptomatic women. Turk Uroloji Dergisi 2008; 34: 360–2.
19.) Huttner A, Kowalczyk A, Turjeman A et al. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018 May 1;319(17):1781-1789
20.) Komp Lindgren P, Klockars O, Malmberg C et al. Pharmacodynamic studies of nitrofurantoin against common uropathogens.J Antimicrob Chemother. 2015 Apr;70(4):1076-82


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