Cefaloridine

Cephaloridine (or cefaloridine) is a first generation semisynthetic derivative of cephalosporin C. It is unique among cephalosporins in that it exists as a zwitterion. Cephaloridine (or cefaloridine) is a first generation semisynthetic derivative of cephalosporin C. It is unique among cephalosporins in that it exists as a zwitterion. Since the discovery of cephalosporins P, N and C in 1948 there have been many studies describing the antibiotic action of cephalosporins and the possibility to synthesize derivatives. Hydrolysis of cephalosporin C, isolation of 7-aminocephalosporanic acid and the addition of side chains opened the possibility to produce various semi-synthetic cephalosporins. In 1962, cephalothin and cephaloridine were introduced. Cephaloridine was temporarily popular because it was better tolerated intramuscularly and attained in higher and more sustained levels in blood than cephalothin. However, it binds to proteins to a much lesser extent than cephalothin. Because it is also poorly absorbed after oral administration the use of this drug for humans declined rapidly, especially since the second generation of cephalosporins was introduced in the 1970s. Today it is more commonly used in veterinary practice to treat mild to severe bacterial infections caused by penicillin resistant and penicillin sensitive Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, Streptococcus pneumoniae, Bacillus sutbtilis, Klebsiella, Clostridium diptheriae, Salmonella and Shigella. Interest in studying cephalosporins was brought about by some unusual properties of cephaloridine. This antibiotic stands in sharp contrast to various other cephalosporins and to the structurally related penicillins in undergoing little or no net secretion by the mammalian kidney. Cephaloridine is, however, highly cytotoxic to the proximal renal tubule, the segment of the nephron responsible for the secretion of organic anions, including para-am-minohippurate (PAH), as well as the various penicillin and cephalosporin antibiotics. The cytotoxicity of cephaloridine is completely prevented by probenecid and several other inhibitors of organic anion transport, including the nearly nontoxic cephalothin. Cephaloridine is a cephalosporin compound with pyridinium-1-ylmethyl and 2-thienylacetamido side groups. The molecular nucleus, of which all cephalosporins are derivatives, is A3-7-aminocephalosporanic acid. Conformations around the β-lactam rings are quite similar to the molecular nucleus of penicillin, while those at the carboxyl group exocyclic to the dihydrothiazine and thiazolidine rings respectively are different. Cephaloridine can be synthesised from Cephalotin and pyridine by deacetylation. This can be done by heating an aquous mixture of cephalotin, thiocyanate, pyridine and phosphoric acid for several hours. After cooling, diluting with water, and adjusting the pH with mineral acid, cephaloridine thiocyanate salt precipitates. This can be purified and converted to cephaloridine by pH adjustment or by interaction with ion-exchange resin. Before the 1970s, cephaloridine was used to treat patients with urinary tract infections. Besides the drugs has been used successfully in the treatment of various lower respiratory tract infections. Cephaloridine was very effective to cure pneumococcal pneumonia. It has a high clinical and bacteriological rate of success in staphylococcal and streptococcal infections. Cephaloridine is easy absorbed after intramuscular injection and poorly absorbed from the gastrointestinal tract. The minor pathway of elimination is biliary excretion. When the blood serum concentration is 24 µg/ml, the corresponding biliary concentration is 10 µg/ml. In the spinal fluid the concentration of cephaloridine is 6-12% of the concentration in the blood and serum.Cephaloridine is distributed well into the liver, stomach wall, lung and spleen and is also found in fresh wounds one hour after injection. The concentration in the wound will decrease as the wound age increases. However, the drug is poorly penetrated into the cerebrospinal fluid and is found in a much smaller amount in the cerebral cortex. When cephaloridine is administered to pregnant women, the drug crosses the placenta. Cephaloridine concentrations can be measured in the serum of the newborn up to 22 hours after labor, and can reach a level of 54% of the concentration in the maternal serum. When given an intramuscular dose of 1 g, a peak occurs in the cord blood after 4 hours. In amniotic fluid, the concentration takes about 3 hours to reach its antibacterial effect.