61477-96-1

Therapeutic Function

Antibiotic

Antimicrobial activity

It displays good activity against non-β-lactamaseproducing strains of N. gonorrhoeae, ampicillin-susceptible H. influenzae and many Enterobacteriaceae. It is the most active of the antipseudomonal penicillins against Ps. aeruginosa and retains its activity in the absence of a β-lactamase inhibitor. Synergy with aminoglycosides has been demonstrated against many strains of Enterobacteriaceae and Ps. aeruginosa.

Acquired resistance

There is complete cross-resistance with other ureidopenicillins, but ticarcillin-resistant strains of Ps. aeruginosa may be susceptible. Piperacillin-resistant strains of B. fragilis and other Bacteroides spp. are common. Because piperacillin is hydrolyzed by most β-lactamases, many β-lactamaseproducing isolates are resistant unless it is protected by β-lactamase inhibitors.

Pharmacokinetics

Oral absorption: Negligible Cmax 2 g (2–3 min intravenous injection): 305 mg/L after 5 min Plasma half-life: 0.9 h Volume of distribution: 16–24 L/1.73 m2 Plasma protein binding: 16% In patients with meningitis, mean CSF penetration of 30% has been found. The urine is the principal route of excretion, 50–70% of the dose appearing over 12 h, most in the first 4 h. Most is excreted via the tubules, 75–90% in active form. The half-life is prolonged in renal failure but much less than is the case with carboxypenicillins. There is substantial biliary excretion, levels in the common duct bile after a 1 g intravenous dose commonly reaching 500 mg/L or more. During hemodialysis the plasma half-life remains elevated and only 10–15% of the dose is removed.

Side effects

Piperacillin is generally well tolerated, with mild to moderate pain on injection, thrombophlebitis and diarrhea in some patients. It otherwise exhibits side effects common to the group, including hypersensitivity, leukopenia and abnormalities of platelet aggregation without coagulation defect, except on prolonged treatment.

Synthesis

Piperacillin, (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2R)-2-[(4-ethyl-2,3-dioxo- 1-piperazinyl)formamido]-2-phenylacetamido]-4-thia-1-azabicyclo[3.2.0]-heptan-2-carboxylic acid (32.1.1.30), is also synthesized by acylating ampicillin (32.1.1.16), but with 1-chlorocarbonyl-4-ethylpiperazin-2,3-dione (32.1.1.29). The necessary 1-chlorocarbonyl-4- ethylpiperazin-2,3-dione (32.1.1.29) is synthesized by reacting N-ethylethylenediamine with diethyloxalate, forming 4-ethylpiperazin-2,3-dione (32.1.1.28), and then acylating this with phosgene after initial silylation of the product at the nitrogen atom with trimethylchlorosilane.

Mode of action

Piperacillin binds to penicillin binding proteins (PBP) located on the inner membrane of the bacterial cell wall, thereby interfering with the cross-linking of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. As a result, cell wall synthesis is interrupted leading to a weakened cell wall and eventually cell lysis.

Definition

ChEBI: Piperacillin is a penicillin in which the substituent at position 6 of the penam ring is a 2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carboxamido]-2-phenylacetamido group. It has a role as an antibacterial drug. It is a penicillin and a penicillin allergen. It is a conjugate acid of a piperacillin(1-).