Latamoxef

Originator

Moxam,Lilly,US,1981

Uses

Latamoxef is an oxacephem antibiotic usually grouped with the cephalosporins. An anti-bacterial agent.

Uses

Anti-infective.

Definition

ChEBI: A broad-spectrum oxacephem antibiotic in which the oxazine ring is substituted with a tetrazolylthiomethyl group and the azetidinone ring carries methoxy and 2-carboxy-2-(4-hydroxyphenyl)acetamido substituents.

Manufacturing Process

To a stirred suspension of p-(p-methoxybenzyloxy)-phenylmalonic acid (125 mg) in methylene chloride (3 ml) are added triethylamine (55 l) and oxalyl chloride (26 l) at -15°C, and the suspension is stirred for 40 minutes at 0°C. The mixture is added to a solution of diphenylmethyl 7β-amino-7α-methoxy-3- (1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate (100 mg) in methylene chloride (3 ml) and pyridine (63 l), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N-hydrochloric acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99:1) to give diphenylmethyl-7β-[α-p-(pmethoxybenzyloxy)phenyl-α-carboxyacetamido]-7α-methoxy-3-(1- methyltetrazol-5yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate as foam (71 mg). Yield: 45%.
To a solution of diphenylmethyl-7β-[α-p-(p-methoxybenzyl)-oxy-phenyl-α-pmethoxybenzyl-oxycarbonil-acetamido]-7α-methoxy-3-(1-methyltetrazol-5- yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate (1.20 g) in methylene chloride (24 ml) are added anisole (2.4 ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0°C under nitrogen. After stirring for 15 minutes at 0°C, the mixture is poured into cold 5% sodium hydrogen carbonate aqueous solution (100 ml) and filtered to remove the formed precipitate. The filtate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N-hydrochloric acid to pH 2.60, and poured in a column of high porous polymer HP-20 (60 ml) sold by Mitsubishi Chemical Industries Ltd. The column is washed with water (300 ml) and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methanol, treated with active carbon, and concentrated under reduced pressure to give 7β(α-p-hydroxyphenyl-α-carboxyacetamido)-7β- methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl1-oxadethia-3-cephem-4- carboxylic acid as powder (595 mg) decomposing at 125°C to 132°C. Yield: 88.5%.
To a solution of 7β(α-p-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1- methyl-tetrazol-5-yl)thiomethyl1-oxadethia-3-cephem-4-carboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mols/liter; 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7β(α-p-hydroxyphenyl-α- carboxyacetamido)-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl1- oxadethia-3-cephem-4-carboxylic acid (342 mg). Yield: 888%. Colorless powder. MP decomposition from 170°C.

brand name

Moxam (Lilly);Baxal;Betalactam;Festamoxin;Latoxacet;Mactam;Moxacef;Moxatres;Priollat;Sectam;Shiomalin;Shiomarin.

Therapeutic Function

Antiinfective

World Health Organization (WHO)

Latamoxef, a cefamycin antibiotic, was introduced in 1982 for the treatment of serious infections. Its use has subsequently been associated with reports of clinically important haemorrhage, sometimes fatal, and in some countries routine co-administration of vitamin K is advised to minimize this risk.

Antimicrobial activity

Moxalactam. A semisynthetic 7-methoxyoxacephem, supplied as the disodium salt.It is generally slightly less active than cefotaxime, especially against Staph. aureus, but unlike other group 4 cephalosporins it exhibits fairly good activity against B. fragilis. Other Bacteroides spp. are generally less susceptible. The 7-methoxy substitution, also found in cephamycins such as cefoxitin, confers resistance to hydrolysis by a wide range of β-lactamases including those of Staph. aureus, various enterobacteria and B. fragilis. Resistance, predominantly in Enterobacter spp., Ps. aeruginosa and Ser. marcescens due to induction of chromosomal enzymes, has been found in vitro and in some patients.
A 500 mg intramuscular injection achieves a serum concentration of 12–22 mg/L after 1.2 h. Infusion of 1 g over 30 min results in a concentration of 60 mg/L. The plasma half-life is c. 2 h and plasma protein binding 40–50%. There is reasonably good penetration into serous fluids, the concentration in ascitic fluid reaching 75% and in pleural fluid 50% of the concentration simultaneously present in the serum. Levels of 5–35 mg/L have been obtained in inflamed meninges. Sputum levels are of the order of 2 mg/L following 1 g of the drug intravenously.
Renal elimination accounts for 90% of the clearance, but significant concentrations are found in the feces. Excretion is depressed in renal failure. Hemodialysis removes 48–51% of the drug in 4 h; peritoneal dialysis has little or no effect.
Increased bleeding and decreases in platelet function associated with the methylthiotetrazole side chain are sufficiently common to have been cited as reasons for restricting use of the agent. Use is contraindicated in patients on anticoagulant therapy. Uses are similar to those of group 4 cephalosporins. It is generally less successful in the treatment of infections due to Gram-positive organisms.