Cephalothin activity

Oxadethiacephalosporins. The first compound in which the sulfur of a cephalosporin was replaced by oxygen was 1-oxa-dethiacephalothin [54214-83-4] (64), C gH N20yS, (199) which is approximately twice as active as cephalothin (27) taking into account that the synthetic material was... 

Acylation of 7-ACA with 2-thienylacetylchloride gives the amide cephalothin (43). Displacement of the allylic acetyl group by pyridine affords the corresponding pyridinium salt cephalori-dine (44). Both these compounds constitute useful injectable antibiotics with some activity against bacteria resistant to penicillin by reason of penicillinase production. 

Among the semisynthetic derivatives, cephalothin (9.47) is the most widely used since it is a broad-spectrum antibiotic resistant to lactamase. Its main drawback is that it must be injected. Cefazolin (9.48) and cephaloridine (9.49) are metabolized to a lesser extent cephalexin (9.50, analogs to ampicillin) is orally active and has a much higher acid stability than the penicillins. Cefotaxime (9.51) and moxalactam (9.52) are highly active against meningitis. 

These resemble the penicillins structurally, in mode of action and in general lack of toxicity. They are primarily excreted by the kidney by tubular secretion and some also by glomerular filtration (e.g. cephalothin) or only by glomerular filtration (e.g. cefazolin). Cefoperazone is excreted by the bile. Cefotaxime undergoes hepatic biotransformation to active metabolites. Hypersensitivity reactions are qualitatively similar to those of the penicillins, but the epileptogenic potential is less. 

The compound (which had a dihydrothiazine ring fused to the P-lactam core) showed resistance to P-lactamases and was less toxic than benzylpenicillin. The discovery that the basic building block, namely 7-aminocephalosporanic acid (7-ACA), could be synthesised, led to the preparation of numerous cephalosporin derivatives eg cephalothin, cephaloglycin (orally active), cefaclor and cefuroxime (Figure 7). 

The preferred route, which involves diazotization of the C-6(7) amino group is useful to functionalize C-6(7) by the introduction of methoxy and other groups [189]. The 7a-methoxycephalothin (R=T) (99) end-product exhibits cephalothin-like activity and an enhanced resistance against cephalosporinase. At the same time, it is curious that the inhibiting-ability of 6a-methoxypenicillin G (100) is 15% that of penicillin G [189], while the activity of 6/8-methoxypenicillin G (101) is at most only 1% of that of... 

Desacetylation of cephalosporins occurs in liver and kidney via the activity of acetylesterases. Desacetylated cephalosporins all maintain some antibacterial activity. Desacetylcefotaxime penetrates well extra vascular body sites, achieves high tissue concentrations and acts synergistically with cefotaxime [94,95]. Desacetylation of cephaloglycin, cephalothin and cephapiiin resulted in formation of less active desacetyl forms [94] and less toxicity [64]. About 50% of cephaloglycin is metabolized to desacetylcephloglycin, which is less nephrotoxic at... 

Cephalothin Sodium, USP. Cephalothin stxlium (Kc-flin) occurs us a white to off-white, cry.stallinc powder that is practically odorles.s. It i.s freely soluble in water and insoluble in most organic solvents. Although it has been described as a broad-.specirum antibacterial compound, it is not in the same ela.ss as the tetracyclines. Its spectmm of activity is broader than that of penicillin G and more similar to that of ampicillin. Unlike ampicillin. cephalothin is rc.si.stnnt to penicillinase produced by S. aureus and provides an alternative to the use of penicillina.se-resistant penicillins for the treatment of infections caused by such strains. 

Pharmacokinetic properties of the cephalosporins depend to a considerable extent on their chemical nature, e.g. the substituent R2. The 3-acetoxymethyl compounds such as cephalothin, cephapirin and cephacetrile are converted in vivo by esterases to the antibacterially less active 3-hydroxymethyl derivatives and are excreted partly as such. The rapid excretion means that such cephalosporins have a short half-life in the body. Replacement of the 3-acetoxymethyl group by a variety of groups has rendered other cephalosporins much less prone to esterase attack. For example, cephaloridine has an internally compensated betaine group at position 3 (R2) and is metabolically stable. 

Solid dry sodium cephalothin, stored in tightly closed glass containers and protected from moisture, is stable for at least three years at 25 C. Aqueous solutions held at 25 C for 2k hours lost approximately 8% activity, and rate of loss of activity was about the same in buffers between pH values of 3 0 and 7.0. Ampoules of cephalothin reconstituted in saline, U.S.P. water for injection, or 3% dextrose maintained label potency after 3 days storage at k C. Cephalothin in water solution only slowly hydrolyzed to produce deacetylcephalothin, and under mild acid conditions the deacetyl compound and cephalothin was converted into cephalothin lactone. 

Deacetylcephalothin is biologically active. In vitro studies demonstrated that the metabolite has an antimicrobial spectrum similar to cephalothin, but from 2 to 16 times more meta-... 

Deacetylcephalothin and cephalothin lactone are microbiologically active hydrolysis products of cephalothin. Since these hydrolysis products give dose-response curves with the same slope as cephalothin, their presence can interfere with potency determinations of the parent compound. In the presence of high levels of hydrolysis products, the plate method using B. subtilis is recommended35 for assaying cephalothin because the method is quite insensitive to these substances. The presence of 13, or less, of deacetylcephalothin does not interfere with the assay for cephalothin, when measured relative to a cephalothin standard curve, and the low activity of cephalothin lactone precludes its interference. 

The conventional plate assay using Sarcina lutea ATCC 9341 has application for assay of urine, serum, and tissue extracts because of its sensitivity, 5 The method can measure activities as low as 0,2 pg/ml of cephalothin and 0,4 p.g/ral of deacetylcephalothin. In this assay, deacetylcephalothin is one-half as active as cephalothin, and since the dose-response curve of the deacetyl compound parallels that of the parent compound the method measures total activity of mixtures of these substances in terms of one of the pure standards. 

Paper chromatographic methods have been devised to determine cephalothin and its micro-biologically active metabolite deacetylcephalothin in body fluids. Miller developed a method that is satisfactory for analysis of urine samples. Hoehn e t al. odescribed a method that affords quantitative disassocia-tion of cephalothin from plasma proteins, and developed a chromatographic technique to measure low levels of cephalothin and its metabolite in urine, plasma, synovial fluid, and cerebrospinal fluid. 

Several new compounds have been reported that affect the formation of a fibrin clot. Aromatic diamidines, such as, 21, were reported to inhibit several proteolytic enzymes including thrombin.74 Concanavalin A (a globulin protein from the jack bean) inhibits fibrin formation by inhibiting the lipoprotein cofactor in the production of thrombin and thus decreasing the rate of thrombin production.75 Several antibiotics (penicillins and cephalosporins) have been reported to affect fibrin clot formation as well as platelet function. Cephalothin (22) has been shown to delay fibrin polymerization and thus prolong the activated partial thromboplastin time (APTT) and thrombin time tests.78... 

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