Fosfomycin

Published 17.7.21

• Small (Mol weight – 138) phosphoenolpyruvate analogue, manufactured synthetically but originally obtained from Streptomyces fradiae and some Pseudomonas sp.

• A broad-spectrum, a bactericidal antibiotic.

• Fosfomycin inhibits bacterial cell wall formation at an early stage by inactivating enol pyruvate transferase (MurA).
  MurA catalyses the transfer of enolpyruvate from phosphoenolphyruvate to uridine diphospho-N-acetylglucosamine (UNAG); this is the first step of bacterial cell wall synthesis. [Jin 2009].

• It also has immunomodulatory action.

• Synergy: It shows the synergistic/additive effect with many antibiotics against St. aureus, E coli, Pseudomonas aeruginosa, Proteus, Providencia, etc

• Reduced permeability – mutation in chromosomal GlpT, UhpT genes alters the transporter proteins responsible for uptake of fosfomycin – Glycerol 3-phosphate transporter and glucose 6-phosphate transporter. This mechanism is seen in gram positives (e.g. Staph aureus) and gram-negative bacteria.

• Target modification – change in the fosfomycin target, the enzyme enolpyruvate transferase (MurA) can confer resistance – seen in gram-negative bacteria like E coli. It is mediated by a mutation in the chromosomal gene murA, which encodes for enolpyruvate transferase.

• Enzymatic inactivation of Fosfomycin –
  fosA gene-mediated glutathione transferase (this mechanism is seen in E coli and Pseudomonas).
  fosB is a transferase (Senn in Staphylococcus and Bacillus).
  fosX are hydrolase (Seen in Listeria ).
  
  These 3 are metalloenzymes, and the genes (fosA, fosB, fosX) could be located on chromosome or plasmid.

FomA or FomB are kinases that also inactivates fosfomycin (seen in some Pseudomonas sp).
The location of these two genes (fomA, fomB) is chromosomal.

Gram-positive

• Staph aureus, including MRSA (GISA may be resistant), Enterococcus – Susceptible.

• Staph saprophyticus could be resistant.

• Streptococcus (including GAS/GBS) – variable. Many alpha haemolytic Streptococcus are resistant.

Gram-negative

• E coli, Citrobacter, Proteus mirabilis (including ESBL, MBL)- sensitive.

• Enterobacter, Proteus vulgaris, Providencia, Serratia may be resistant.

• Pseudomonas, Acinetobacter, Morganella – Resistant.

Anaerobes

• Not active.

• Metabolism: Excreted unchanged in urine and faeces.

• Excretion: Mainly renal.

• Bioavailability or oral preparation: approx. 40% (for tromethamine preparation), food reduces absorption.

• Route: IV, PO.

• PK/PD index – Optimum PK/PD index is not clear (Time>MIC or AUC/MIC; however, it is most likely AUC/MIC and Cmax/MIC).

Gastrointestinal adverse effects, vaginitis, headache.

UTI

Often used in combination with another antibiotic for various indications.

Surgical prophylaxis.

Fosfomycin – Short answer.

Mechanism of fosfomycin resistance.

Which bacteria are intrinsically resistant to fosfomycin? (Leave your answer below)