IV Fosfomycin To The Rescue – And To a Place Near You

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A recent letter to the Editor by Simkins et al. is worth reviewing [1]. The authors describe the complicated course of a patient who suffered graft rejection after liver transplantation, received broad-spectrum antibiotics during prolonged hospitalization and eventually had a bloodstream infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) which was resistant to colistin and tigecycline. The organism, however, was fosfomycin-sensitive. The team obtained IV fosfomycin from a European source which cleared the infection once treatment was initiated.

However, here is the rub: it took 10 (ten!) days to get IV fosfomycin to the bedside, as the drug is not approved in the US and had to be imported. In such cases, an emergency IND is required which involves paperwork and contact with the FDA. This process has been streamlined in 2015 and should not be too burdensome anymore [2]. Nonetheless, shipment of drugs not approved in the US can easily get stuck in customs – as in this case, for 3 days – creating all kinds of bureaucratic issues which take an inordinate amount of time and effort to get resolved [3].

This should give pause for reflection. These days we are clamoring for new drugs with activity against CRE. We could have the foresight to stockpile fosfomycin at CDC or another location to make access faster and easier. Fosfomycin PO is already approved in the US as a UTI agent, however, fosfomycin IV is not, for reasons unclear. Probably there was no sponsor for this old drug.

It sounds too good to be true: here is an antibiotic which has not been used much and has retained excellent activity against some of the most difficult-to-treat pathogens. Fosfomycin has a remarkably broad spectrum of activity, very favorable PK, a cidal mode of action, no significant DDI, and a decent safety profile. Importantly, several recent publications have remarked on fosfomycin’s good activity against CRE [4].

There is no need for lengthy Phase 3 trials, no need to study PK/PD, ADME and dose finding, or to conduct studies in hepatic and renal impairment, for QTc effects etc, etc as all this data is already available. Fosfomycin has a novel cell wall targeting MoA (murA inhibition), represents a molecular class distinctly different from other antibacterials, does not result in cross-resistance with other antibiotics, and has moderate risk for clinical resistance development. Approved and used in Europe for many years, it is a well-known entity listed in several pharmacopoeias. It is not an ‘investigational’ drug under development for which little more is known other than preclinical data.

A good review of the microbiology, PK and clinical data situation has been published by Michalopoulos [5].

Antibiotics like fosfomycin should be available expeditiously and with minimal paperwork. They should be accessible from within the USA. An international pharmacy could be set up in close cooperation with FDA or CDC to provide this and similar drugs which are already approved in other jurisdictions.

Physicians should not have to deal with customs issues; our gate keepers, i.e., FDA and US CBP (Customs and Border Protection), should take on the responsibility for a smooth delay-free shipment process for an emergency IND drug shipment. The current situation is unnecessarily difficult and really should be streamlined.

[1] J Simkins. Intravenous Fosfomycin Treatment for Carbapenem-Resistant Klebsiella pneumoniae in the United States.  Ann Pharmacother 2015; 49:1177
[2] FDA Guidance for Industry. Individual Patient Expanded Access Applications: Form FDA 3926. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM432717.pdf
[3] https://help.cbp.gov/app/answers/detail/a_id/320/~/purchasing-medications-from-a-supplier-outside-the-u.s.
[4] K Linsenmeyer. Activity of Fosfomycin against Extended-Spectrum-b-Lactamase Producing Uropathogens in Patients in the Community and Hospitalized Patients. Antimicrob Agents Chemother 60:1134, 2016
[5] A Michalopoulos.  The revival of fosfomycin. Internat J Infect Dis 15 (2011): e732

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