A Renaissance for Old Drugs: Fosfomycin and Colistin

Fosfomycin
Who would have thought that a drug that has been around since 1969 [2] could become eligible for QIDP status in 2015? Well, Zavante Therapeutics recently garnered the coveted QIDP designation for fosfomycin IV. This formulation has been available in Europe for a quite some time but not in the US where only the PO version is available.

Fosfomycin has some truly unique features but it is its activity against MDR pathogens that makes it so interesting nowadays. While the oral form is only approved for uncomplicated cystitis, fosfomycin IV has much greater use potential. It is a cell wall-active bactericidal antibiotic with excellent tissue distribution which also has an impressive broad spectrum. Active against MRSA and against enterococci of the faecalis and faecium variety, it also covers most gram-negative rods including non-lactose fermenters. Importantly, it has reliable activity against ESBLs and even KPC. In contrast, P. aeruginosa, acinetobacter and anaerobes are either resistant or not consistently susceptible.[1]

The side effect profile seems rather benign and manageable. As a di-sodium compound and drug which requires daily doses of 12-16 gram, the salt load needs to be considered, esp. for patients with CHF. However, similar issues exist for ticarcillin and carbenicillin, and ID practitioners have learnt to manage this quite well.

Of note, there are efforts underway to develop a dry-powder formulation of fosfomycin for inhalational use, as single agent and in combination with aminoglycosides.

It seems that the days of fosfomycin as a cystitis-only drug are numbered.

Colistin
Since the advent of MDR-enterobacteriaceae, CPEs and ESBLs, treatment choices are few, and what was available is not pretty: tigecycline (Tygacil) is nice to have for acinetobacter infections, but efficacy at approved doses is borderline and tolerability is just …well, borderline too. Penems obviously are getting much use in ESBL infections, to the point that concerns are mounting about overuse and loss of efficacy.

And then there is colistin, administered as a prodrug called colistimethate. It is an old drug (discovered in 1947!) and was approved in an era when clinical testing was less rigorous and submission dossiers looked more like a 100-page doctoral thesis or a White Paper memorandum.

Colistin is approved for gram-negative infections, esp. P. aeruginosa and Acinetobacter, hence its attractiveness. It has considerable toxicities, similar to aminoglycosides: nephro- and neurotoxicity occur fairly often. By analogy, one would think that therapeutic drug monitoring would optimize exposure at an effective and least toxic level. However, I assume hospital pharmacists are getting called about more basic things, like the proper starting dose.

Dosing for this drug seems to be based on empiricism and not much else. There is approved dosing in units and in mg/kg, with adjustment for active drug, renal function, etc, etc.  No wonder that almost the entire colistin chapter in Mandell’s latest edition is about dosing, advocating a more rational approach to dosing based on exposure, half-life and protein-binding [3].

In summary, these two drugs (and thiamphenicol which was discussed in an earlier blog) may be alternatives for ceftazidime/avibactam (Avycaz) for MDR infections.

It is good to see that small companies are actively pursuing the development of some long-neglected drugs.  Avanti Zavante !

 

References:
[1] A Michalopoulos  Internat J Infect Dis 15 (2011): e732
[2] M Santesmases, Dynamis 2011; 31: 407 (account of the research work done by CEPA/Merck)
[3] K Kaye in Mandell PPID 2014

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