32887-01-7

White Solid

Selexidin,Leo,UK,1979

ChEBI: Mecillinam is a penicillin in which the 6beta substituent is [(azepan-1-yl)methylidene]amino; an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 (PBP2), and is only considered to be active against Gram-negative bacteria. It has a role as an antibacterial drug and an antiinfective agent.

The starting material N-formylhexamethyleneimine was prepared from hexamethyleneimine and chloral.
12.7 g of N-formylhexamethyleneimine were dissolved in 250 ml of dry ether. While stirring and cooling, 8.5 ml of oxalyl chloride in 50 ml of dry ether were added dropwise, whereafter the mixture was stirred overnight at room temperature. The precipitated amide chloride was filtered off and washed with dry ether, and was placed in an exsiccator.
A solution of the amide chloride (4.6 g) in dry, alcohol-free chloroform (20 ml) was added slowly to a solution of trimethylsilyl 6-amino-penicillanate (7.2 g) and triethylamine (3.5 ml) in dry, alcohol-free chloroform (50 ml) with stirring and cooling to -70°C. The temperature was raised to 0°C during 1.5 hours. The solution was evaporated to dryness in vacuo and the residue was triturated with dry ether (200 ml). The precipitate was filtered off and washed with dry ether. The filtrate was diluted with ether (200 ml). 2-Butanol (2.8 ml) was added dropwise with stirring and cooling to 0°C. The stirring was continued for 1/4 hour at 0°C, whereupon the precipitate was filtered off, washed with ether and dried. It was a white, amorphous powder, soluble in water.

Coactin (Roche).

Antibacterial

The antibacterial spectrum differs greatly from that of the aminopenicillins in that the compound displays high activity against many Gram-negative bacteria but limited activity against Gram-positive organisms. Mecillinam is active against many Enterobacteriaceae due to its selective binding to PBP 2, although the susceptibility of Proteus and Providencia spp. is variable. H. influenzae is less susceptible than enteric bacilli, and Acinetobacter spp., B. fragilis and Ps. aeruginosa are resistant.
It is readily inactivated by many β-lactamases, although it is more stable than ampicillin.

Intrinsic resistance in susceptible species of enterobacteria is uncommon and many ampicillin-resistant strains are susceptible. Bacteria that are resistant to both ampicillin and mecillinam are usually those producing large amounts of β-lactamase, most commonly plasmid-mediated enzymes.

Oral absorption (pivmecillinam): c. 75%
C_max 200 mg intravenous infusion: 12 mg/L end infusion
200 mg intramuscular: c. 6 mg/L after 45 min
400 mg oral (pivmecillinam): 2–5 mg/L after c. 1 h
Plasma half-life: 50 min
Volume of distribution: 0.2–0.4 L/kg
Plasma protein binding: 5–10%
Absorption
Oral absorption is very poor, with conventional doses producing plasma levels of <1 mg/L and recovery of only about 5% in the urine. A 400 mg dose of the pivaloyl ester is equivalent to 273 mg mecillinam. It is relatively well absorbed and rapidly liberates the parent compound. Metabolism and excretion
The amidino side chain undergoes spontaneous aqueous hydrolysis to the N-formyl derivative, which retains some antibacterial activity. Hydrolysis of the β-lactam ring also occurs.
Approximately 60% is excreted unchanged in the urine in the first 6 h, achieving concentrations exceeding 1 g/L. The concentration in bile can reach 40 or 50 mg/L in patients with normally functioning gallbladders treated with 800 mg intramuscularly.

Urinary tract infection (pivmecillinam)
Other infections with susceptible Gram-negative bacilli (usually in combination with other agents)

It is generally well tolerated, and serious anaphylactic responses are said to be rare. Nausea and vomiting, which may be persistent, occur with diarrhea in some patients treated with pivmecillinam.