Clavulanic acid
Clavulanic acid has relatively weak antibacterial activity,
but has been shown to be a potent inhibitor of the blactamases produced by staphylococci and plasmidmediated b-lactamases of Escherichia coli, Klebsiella,
Proteus, Shigella, Pseudomonas and Hemophilus (Brown
et al. 1976). The molecule is a naturally produced
compound consisting of a b-lactam ring fused to an
oxazolidine ring (Howarth et al. 1976). The antibiotic is
produced by strains of S. clavuligerus (Reading and Cole
1977).
Clavulanic acid shows broad affinity for a number of
penicillin-binding proteins and is currently used in
combination with amoxicillin and is marketed under the
trade name Augumentin for the treatment of infections
caused by b-lactamase producing pathogenic bacteria.
Strains of S. clavuligerus are propagated on a fermentation medium containing soy bean meal, soluble starch,
glycerol and potassium phosphate at a pH of 6.5 at 26C
for 100 h (Lawrence and Lilly 1980). There is no recently
reported production data for the clavulanic acid fermentation.
The bulk of the clavulanic acid is found in culture
filtrates. Adsorption of the antibiotic on active carbon
followed by elution with aqueous acetone or solvent
extraction at pH 2.0 using butanol with back-extraction
into water at pH 7.0 proved to be effective primary
purification protocols. Secondary purification has been
achieved by conversion of the purified clavulanate to the
benzyl ester, which was then dissolved in ethyl acetate
and subjected to two chromatographic steps using
Sephadex LH20 and silica gel. The purified benzyl ester
was then hydrogenated over 10% Pd/C in the presence of
sodium bicarbonate to yield sodium clavulanate tetrahydrate.
Clavulanic acid possesses only weak antibiotic activity
against a variety of Gram-positive and Gram-negative
bacteria, but is an excellent inhibitor of a variety of blactamases. The molecule has been coformulated with a
variety of broad-spectrum semi-synthetic penicillins with
amoxicillin being one of the best known formulations.
Augmentin had a world sales value of ~$1.3 billion in
1995 and was the second largest selling antibacterial that
year.