Cefoxitin

Description

Cefoxitin contains the same C-7 side chain as cephalothin and the same C-3 side chain as cefuroxime. The most novel chemical feature of cefoxitin is the possession of an α-oriented methoxyl group in place of the normal H-atom at C-7. This increased steric bulk conveys very significant stability against β-lactamases. The inspiration for these functional groups was provided by the discovery of the naturally occurring antibiotic cephamycin C derived from fermentation of Streptomyces lactamdurans. Cephamycin C itself has not seen clinical use but, rather, has provided the structural clue that led to useful agents such as cefoxitin. Agents that contain this 7α methoxy group are commonly referred to as cephamycins. Ingenious chemical transformations now enable synthetic introduction of such a methoxy group into cephalosporins lacking this feature.

Originator

Mefoxin,Merck Sharp and Dohme,US,1978

Uses

Antibacterial.

Uses

Cefoxitin?is a semisynthetic, broad-spectrum second-generation cephalosporin with antibacterial activity. The activity of cefoxitin results in the weakening of the bacterial cell wall and causes cell lysis. Cefoxitin acts by interfering with cell wall synthesis. Its activity spectrum includes a broad range of gram-negative and gram-positive bacteria including anaerobes.

Definition

ChEBI: Cefoxitin is a semisynthetic cephamycin antibiotic which, in addition to the methoxy group at the 7alpha position, has 2-thienylacetamido and carbamoyloxymethyl side-groups. It is resistant to beta-lactamase. It has a role as an antibacterial drug. It is a cephalosporin, a semisynthetic derivative, a beta-lactam antibiotic allergen and a cephamycin. It is a conjugate acid of a cefoxitin(1-).

Manufacturing Process

Benzhydryl 3-carbamoyloxymethyl-7α-hydroxy-7β-(2-thienylacetamido) decephalosporanate, 543 mg, is stirred in 15 ml dry DMSO. Sodium hydride, 24 mg (48 mg of a 50% suspension of NaH in mineral oi1, which has been washed with hexane to remove the oil), is added. When hydrogen evolution has ceased, 126 mg dimethyl sulfate is added. The solution is stirred for one hour at room temperature, diluted with 100 ml benzene and washed six times with water; the last wash is made to pH 8, if necessary, by adding sodium bicarbonate. The solution is dried over MgSO4, filtered and evaporated, leaving benzhydryl 3-carbamoyloxymethyl-7β-(2-thienylacetamido)-7α- methoxydecephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 25:1 chloroformethyl acetate.
Other methylating agents may be used in place of methyl sulfate, e.g., an equimolar amount of methyl iodide, bromide or chloride, using the same conditions, or methyl trifluoromethylsulfonate or trimethyloxonium trinitrobenzenesulfonate. The solvent in the latter two reagents is dimethyl ether-HMPA 1:1, using a reaction temperature of -20°C warming later to 25°C. In each instance, the benzhydryl 3-carbamoyloxymethyl-7β-(2- thienylacetamido)-7α-methoxydecephalosporanate is obtained.
Benzhydryl 3-carbamoyloxymethyl-7β-(2-thienylacetamido)-7α- methoxydecephalosporanate (300 mg) in 0.5 ml in anisole and 2.5 ml of trifluoroacetic acid is reacted for 15 minutes at 10°C. The resulting mixture is evaporated at reduced pressure and flushed twice with anisole. The residue is dissolved in methylene chloride and extracted with 5% sodium bicarbonate solution. The aqueous solution is adjusted to pH 1.8 with 5% phosphoric acid and extracted with ethyl acetate. The organic solution is dried and evaporated to yield the pure 3-carbamoyloxymethyl-7α-methoxy-7β-(2- thienylacetamido)decephalosporanic acid, MP 165°C to 167°C. This may then be converted to the sodium salt.

brand name

Mefoxin (Merck).

Therapeutic Function

Antibiotic

Antimicrobial activity

Most Gram-positive bacilli are susceptible, but L. monocytogenes is resistant. It is resistant to many Gramnegative β-lactamases and is active against organisms elaborating them, including some Citrobacter, Providencia, Serratia and Acinetobacter spp. Enterobacter spp. are resistant. It is moderately active against Bacteroides spp., but considerable strain variation in susceptibility occurs.

Acquired resistance

Resistant strains of Bacteroides, some of which produce β-lactamases that hydrolyze cefoxitin, have been described. Resistance may be transferable to other Bacteroides spp. It is a potent inducer of chromosomal cephalosporinases of certain Gram-negative bacilli and can antagonize the effect of cefotaxime and other β-lactam agents.

Pharmacokinetics

C_max 500 mg intramuscular: 11 mg/L after 20 min
1 g intravenous: c. 150 mg/L end injection
Plasma half-life: 0.7–1 h
Volume of distribution: c. 10 L
Plasma protein binding: 65–80%
Absorption
It is not absorbed when given orally, but is very rapidly absorbed from intramuscular sites. Doubling the dose approximately doubles the plasma level. It is absorbed from suppositories to varying degrees depending on the adjuvants: peak serum levels around 9.8 mg/L have been obtained after a dose of 1 g, giving a bioavailability of around 20%. In infants and children treated with 150 mg/kg per day, mean serum concentrations 15 min after intravenous and intramuscular administration were 81.9 and 68.5 mg/L, with elimination half-lives of 0.70 and 0.67 h, respectively.
Distribution
About 20% of the corresponding serum levels are found in sputum. In patients given 1 g by intravenous bolus preoperatively, concentrations in lung tissue at 1 h were around 13 mg/g. Penetration into normal CSF is very poor; even in patients with purulent meningitis CSF concentrations seldom exceed 6 mg/L. In children with meningitis receiving 75 mg/kg every 6 h, peak concentrations of 5–6 mg/L were found around 1 h after the dose. In patients receiving 2 g intravenously before surgery, the mean penetrance into peritoneal fluid was 86%. In patients receiving 2 g intramuscularly before hysterectomy, mean concentrations in pelvic tissue were 7.8 mg/g. Breast milk contained 5–6 mg/L after a 1 g intravenous dose. Concentrations up to 230 mg/L have been found in bile after 2 g intravenously.
Metabolism and excretion
Less than 5% of the drug is desacetylated and in a few subjects deacylation of 1 or 2% of the dose to the antibacterially inactive descarbamyl form also occurs.
It is almost entirely excreted in the urine by both glomerular filtration and tubular secretion, 80–90% being found in the first 12 h after a parenteral dose, producing concentrations in excess of 1 g/L. Furosemide, in doses of 40–160 mg, had no effect on the elimination half-life of doses of 1 or 2 g. Probenecid delays the plasma peak and decreases the renal clearance and urine concentration. The renal clearance has been calculated variously to lie between 225 and 330 mL/ min. The plasma half-life increases inversely with creatinine clearance to reach 24 h in oliguric patients, with corresponding reduction in total body clearance. In patients on peritoneal dialysis, peritoneal clearance accounted for only 7.5% of mean plasma clearance and the mean plasma half-life during 6 h dialysis was 7.8h.

Clinical Use

As for other group 3 cephalosporins, with particular emphasis on mixed infections including anaerobes, notably abdominal and pelvic sepsis. In considering its use, its low activity against aerobic Gram-positive cocci should be noted.

Side effects

Reactions are those common to cephalosporins. Pain on intramuscular, and thrombophlebitis on intravenous, injection occur. Substantial changes can occur in the fecal flora, with virtual eradication of susceptible enterobacteria and non- fragilis Bacteroides, and appearance of, or increase in, yeasts, enterococci and other resistant bacteria including C. difficile. Development of meningitis due to H. influenzae and Str. pneumoniae in patients treated for other infections has been observed.

Synthesis

Cefoxitin, 3-(hydroxymethyl)-8-oxo-7-methoxy-7-[(2-thienylacetyl)amino]- 5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid carbamate (32.1.2.30), is synthesized in various ways starting from cefamicin C-7β-(D-5-amino-5-carboxyvaleramido)- 3-aminocarbonylhydroxymethyl-7-methoxy-3-cefem-4-carboxylic acid, in which a methoxy group is initially present at C7, and the task of making the desired drug essentially consists of a transamidation reaction.
The other way is to start synthesis from 7-aminocephalosporanic acid, to which it is necessary to insert a methoxy group at C7. In one of the examples of the synthesis of cefoxitin starting from cefamicin C, the free amino group is initially protected via tosylation, and the product in the form of a well-crystallizing dicyclohexylamine salt is isolated (32.1.2.28). Next, the carbonyl group at position 2 of the cephalosporanic system is esterified using methylchloromethyl ether. The resulting compound (32.1.2.29) is reacted with 2-(2-thienyl)acetylchloride, then the ester protection is removed from the carboxylic group with hydrogen chloride in methanol, producing the desired cefoxitin (32.1.2.30).

Another way for the synthesis of cefoxitin is started from 7-aminocephalosporanic acid, more correct, from its benzhydryl ester (32.1.2.31), which is synthesized by previous tosylation of the amino group of the initial 7-aminocephalosporanic acid, esterification of the carboxyl group by diphenyldiazomethane, and subsequent removal of the tosyl protection.
When reacted with nitrous acid, the product is diazotized, giving the diphenyl methyl ester of 7-diazocephalosporanic acid (32.1.2.32). A subsequent reaction of the resulting compound with triethylammonium azide in dichloromethane and then with bromine azide gives the diphenyl methyl ester of 7-bromo-7-azidocephalosporanic acid (32.1.2.33). Treating this with methanol in the presence of silver borofluoride results in the replacement of the bromine atom, giving the diphenylmethyl ester of 7-methoxy-7-azidocephalosporanic acid (32.1.2.34). The resulting azide is reduced by hydrogen in the presence of a platinum oxide catalyst, forming the diphenyl methyl ester of 7-methoxy-7-aminocephalosporanic acid (32.1.2.35). Acylation of this compound with 2-(2-thienyl)acetylchloride gives the benzhydryl ester of 7-methoxy-7-[2-(2-thienyl)-acetamido]cephalosporanic acid (32.1.2.36), the ester protecting group of which is hydrolyzed using trifluoroacetic acid and then upon reacting the resulting acid with sodium bicarbonate, it is transformed to the potassium salt (32.1.2.37). The resulting product is then hydrolyzed by the enzyme Citrusi acetylesterase to the potassium salt of 3-hydroxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cefem- 4-carboxylic acid (32.1.2.38). Using the method described above, i.e. the initial reaction with chlorosulfonyl isocyanate followed by hydrolysis with water, the resulting compound, (32.1.2.38), is transformed to the desired cefoxitin (32.1.2.20).