Cefoperazone

Toxicity

Symptoms of overdose include blood in the urine, diarrhea, nausea, upper abdominal pain, and vomiting.

Description

Cefoperazone has a C-7 side chain reminiscent of piperacillin's and also possesses the C-3 side chain (MTT ) that often is associated with the bleeding and alcohol intolerance problems among patients taking cephalosporins. Its useful activity against pseudomonads partly compensates for this, although it is not potent enough to be used as a single agent against this difficult pathogen. The C-7 side chain does not convey sufficient resistance to many β-lactamases, although the addition of clavulanic acid or sulbactam would presumably help.

Chemical properties

white crystals

Originator

Cefobid,Pfizer,W. Germany,1981

The Uses of Cefoperazone

Cefoperazone also has a broad spectrum of antimicrobial action, including most clinically significant microorganisms: Gram-positive, Gram-negative, aerobic, and anaerobic. It is stable with respect to most beta-lactamases of Gram-positive and Gram-negative bacteria.
Cefoperazone is used for bacterial infections of the lower respiratory tract, urinary and sexual tracts, bones, joints, skin, soft tissues, abdominal, and gynecological infections. Synonyms of this drug are cefazon, cefobid, cefobis, and many others.

The Uses of Cefoperazone

Antibacterial.

The Uses of Cefoperazone

Cefoperazone acid is an antimicrobial β-lactamase inhibitor.

Background

Cefoperazone is a semisynthetic broad-spectrum cephalosporin proposed to be effective against Pseudomonas infections. It is a third-generation antiobiotic agent and it is used in the treatment of various bacterial infections caused by susceptible organisms in the body, including respiratory tract infections, peritonitis, skin infections, endometritis, and bacterial septicemia. While its clinical use has been discontinued in the U.S., cefoperazone is available in several European countries most commonly under the product name, Sulperazon.

What are the applications of Application

Cefoperazone acid is an antimicrobial β-lactamase inhibitor

Indications

Indicated for the treatment of following infections caused by susceptible bacteria:
1) Respiratory tract infections caused by S. pneumoniae, H. influenzae, S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes (Group A beta-hemolytic streptococci), P. aeruginosa, Klebsiella pneumoniae, E. coli, Proteus mirabilis, and Enterobacter species.
2) Peritonitis and other intra-abdominal infections caused by E. coli, P. aeruginosa, and anaerobic gram-negative bacilli (including Bacteroides fragilis).
3) Bacterial septicemia caused by S. pneumoniae, S. agalactiae, S. aureus, Pseudomonas aeruginosa, E. coli, Klebsiella spp., Klebsiella pneumoniae, Proteus species (indole-positive and indole-negative), Clostridium spp. and anaerobic gram-positive cocci.
4) Infections of the skin and skin structures caused by S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes, and P. aeruginosa.
5) Pelvic Inflammatory Disease, Endometritis, and Other Infections of the Female Genital Tract caused by N. gonorrhoeae, S. epidermidis, S. agalactiae, E. coli, Clostridium spp., Bacteroides species (including Bacteroides fragilis), and anaerobic gram-positive cocci.
6) Urinary tract infections caused by Escherichia coli and Pseudomonas aeruginosa.
7) Enterococcal Infections. Although cefoperazone has been shown to be clinically effective in the treatment of infections caused by enterococci in cases of peritonitis and other intra-abdominal infections, infections of the skin and skin structures, pelvic inflammatory disease, endometritis and other infections of the female genital tract, and urinary tract infections, the majority of clinical isolates of enterococci tested are not susceptible to cefoperazone but fall just at or in the intermediate zone of susceptibility, and are moderately resistant to cefoperazone. However, in vitro susceptibility testing may not correlate directly with in vivo results. Despite this, cefoperazone therapy has resulted in clinical cures of enterococcal infections, chiefly in polymicrobial infections. Cefoperazone should be used in enterococcal infections with care and at doses that achieve satisfactory serum levels of cefoperazone.

Definition

ChEBI: A semi-synthetic parenteral cephalosporin with a tetrazolyl moiety that confers beta-lactamase resistance.

Manufacturing Process

To a suspension of 3.0 g of 7-[D-(-)-α-amino-p-hydroxyphenylacetamido]-3- [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-?3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone were added to the aqueous layer, and then the resulting solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid. Thereafter, an organic layer was separated off, the organic layer was washed two times with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of acetone, and 60 ml of 2-propanol was added to the solution to deposit crystals. The deposited crystals were collected by filtration, washed with 2- propanol, and then dried to obtain 3.27 g of 7-[D-(-)-α-(4-ethyl-2,3-dioxo)-1- piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl- 1,2,3,4-tetrazolyl)thiomethyl]-?3-cephem-4-carboxylicacid, yield 80.7%. The product forms crystals, MP 188°C to 190°C (with decomposition).

brand name

Cefobid (Pfizer).

Therapeutic Function

Antibiotic

Antimicrobial activity

A semisynthetic parenteral cephalosporin. It is unstable, losing activity on storage even at –20°C. A formulation with sulbactam is available in some countries.
It exhibits moderate activity against carbenicillin-sensitive strains of Ps. aeruginosa. Activity against Burk. cepacia and Sten. maltophilia is unreliable. It is much less stable to enterobacterial β-lactamases than most other cephalosporins of groups 4–6 and consequently has unreliable activity against many species, including β-lactamase-producing strains of H. influenzae and N. gonorrhoeae. It is active against Achromobacter, Flavobacterium, Aeromonas and associated non-fermenters. Past. multocida is extremely susceptible (MIC <0.01–0.02 mg/L). It exhibits modest activity against most Gram-negative anaerobes, but not B. fragilis. Sulbactam increases activity against many, but not all, enterobacteria and non-fermenters, and almost all B. fragilis.
A 2 g intravenous infusion achieves a peak plasma concentration of 250 mg/L. The plasma half-life is 1.5–2 h. Over 85% is bound to plasma proteins. It achieves therapeutic concentrations in tissue and inflammatory exudates. Variable low levels are found in the sputum up to 1.5% of simultaneous serum levels. Penetration into CSF is unreliable even in the presence of meningeal inflammation.
The bile is a major route of excretion, accounting for almost 20% of the dose. About 20–30% is eliminated in urine, almost entirely by glomerular filtration. Clearance is effectively unchanged by renal failure or dialysis.
Side effects associated with the methylthiotetrazole side chain have been reported. Diarrhea has been notable in some studies. Marked suppression of fecal flora, with the appearance of C. difficile, has occasionally been found. There is a 5–10% incidence of mild transient increases in liver function tests. Its potential toxicity and the availability of compounds with better β-lactamase stability and more reliable antipseudomonal activity have undermined its popularity.

Pharmacokinetics

Cefoperazone is a third generation cephalosporin antibiotic. Cefoperazone exerts its bactericidal effect by inhibiting the bacterial cell wall synthesis

Synthesis

Cefoperazone, (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazincarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.84), is synthesized by acylating 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-3-cefem-4-carboxylic acid (32.1.2.24) with a mixed anhydride synthesized from ethyl chloroformate and |á-(4-ethylpiperazin-2, 3-dion-1-carbonylamino)-4-hydroxyphenylacetic acid (32.1.2.83), which in turn is synthesized from 4-ethylpiperazin-2,3-dion-1-carboxylic acid (32.1.1.29) and the sodium salt of 4-hydroxyphenylglycine.

Metabolism

No significant quanitity of metabolites have been identified in urine.

References

[1]. kato y1,takahara s,kato s,kubo y,sai y,tamai i,yabuuchi h,tsuji a. involvement of multidrug resistance-associated protein 2 (abcc2) in molecular weight-dependent biliary excretion of beta-lactam antibiotics.drug metab dispos.2008 jun;36(6):1088-96. doi: 10.1124/dmd.107.019125. epub 2008 mar 13.
[2]. craig wa,gerber au. pharmacokinetics of cefoperazone: a review. drugs.1981;22suppl 1:35-45.