Combination Therapy for Carbapenem-resistant Gram-negative Bacteria

Alexandre P Zavascki; Jurgen B Bulitta; Cornelia B Landersdorfer


Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. 

In This Article


Fosfomycin, a phosphonic acid derivative, is another old broad-spectrum antibiotic that has become attractive as an alternative agent against CR GNB, particularly against Enterobacteriaceae.[17,152–155] Fosfomycin demonstrates considerable in vitro activity against many of these organisms.[156–160] It is an extremely low molecular weight antibiotic, which is chemically unrelated to any other anti-bacterial agent.[152,153] It also has a unique mechanism of action through inhibition of a specific component of peptidoglycan synthesis by blocking the formation of N-acetylmuramic acid.[152,153] This drug is available for oral use as fosfomycin tromethamine and as fosfomycin disodium for parenteral use. The latter form is available only in a few countries, mostly in Europe, where it has been increasingly used as an adjuvant treatment against CR GNB.[17]

Fosfomycin tromethamine is only used for the treatment of non-complicated urinary tract infections, because it rapidly reaches high urinary concentrations (1000–4000 mg/l), far above the MIC of most Enterobacteriaceae (≤64 mg/l), after the administration of the usual 3 g single dose.[161] However, most attention has been given to the intravenous use of fosfomycin, considering its favorable PK and safety profile, and its use as an adjuvant treatment against many CR Enterobacteriaceae has been increasingly reported.[162] It is less frequently used against P. aeruginosa, especially because of higher MICs and a higher potential for development of resistance during therapy in this organism.[88,163–169]

Fosfomycin has a negligible protein binding and high serum concentrations are reached following intravenous administration, with Cmax ranging from approximately 200 to 600 mg/l, depending on the dose and duration of infusion (bolus to 60 min), according to most recent PK studies.[161] Good distribution into many tissues and body fluids, including cerebral spinal fluid and lung, has also been reported.[161] However, despite these attractive PK characteristics, there are still many gaps in the knowledge of PK and PK/PD of fosfomycin that must be overcome to recommend this drug based on more complete scientific data. Its use, either as the main or adjuvant treatment against CR GNB, mostly relies on empirical experience.

The PK/PD index associated with microbiological activity of fosfomycin is still not elucidated and both concentration- and time-dependent activity have been suggested.[161] Thus, although well tolerated even in 'high' dosage regimens (20–24 g/day, divided in 3 or 4 doses), these doses are still empiric and no further recommendation can be made at this time. Dosage regimens have not been optimized based on clinical data comparing distinct dosage regimes or on PK/PD, as discussed earlier.

Finally, rapid emergence of resistance during therapy has been described for fosfomycin, especially in P. aeruginosa.[166–168] It has been suggested that the combination of fosfomycin with other active drugs might protect against this effect.[88,169] However, development of resistance to fosfomycin in three cases of KPC-producing K. pneumoniae bacteremia, where this drug was used as a part of combination schemes, raised concerns on the ability of such a combination to prevent the emergence of fosfomycin resistance, at least in severe infections by KPC-producing K. pneumoniae.[169] Further studies on prevention of resistance strategies for fosfomycin are warranted.