Lactams moxalactam

Later in his career, Nagata s group made notable and useful synthetic contributions to the beta lactam field. This included developing an economically feasible synthetic method for the industrial manufacture of 1-oxacephems from penicillin G. These efforts led to the worldwide introduction in the 1980s of several clinically prominent and effective beta lactam antibiotics of the 1-oxacephem class including moxalactam. 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

Colonies were grown in presence of Moxalactam, so activity enhancement also served as a selection criterion successful cephalosporinase mutants would cleave the /3-lactam antibiotic and allow the cells of the respective colony to grow. The procedure was tested over four generations, and about 50 000 colonies per cycle were tested. 

The iodometric assay for moxalactam involves the hydrolysis of moxalactam in aqueous base which results in the cleavage of the 3-lactam ring. This is followed by oxidation of the hydrolysis products with iodine, and the titrimetric determination of the iodine consumed. Since the unhydrolyzed drug does not react with iodine, an unreacted sample is used as a blank to compensate for iodine consuming impurities. 

This procedure therefore may not be a stability indicating assay for the drug. This is a very real problem for moxalactam for one of the major degradation products is the decarboxyl ated product of moxalactam which retains the 3-lactam moiety and is itself a compound with considerable antibiotic activity (61-63). 

Moxalactam is also amenable to the popular hydroxyl amine assay for g-lactam antibiotics. In this procedure the -lactam is reacted with hydroxyl amine to cleave the e-lactam moiety and form a hydroxamic acid. The hydroxamic acid will in turn react with acidified ferric ion to form a colored complex which is measured at 480 nm. A blank correction for non-e-lactam impurities which react with hydroxyl amine is incorporated by adding hydroxylamine to an acidified sample where the acid is used to destroy all e-lactam species. 

Again, this test is not specific for moxalactam and will react with all e-lactam moieties. This test would therefore include the decarboxylated product of moxalactam which may be present in the sample, and is not a good stability indicating assay for moxalactam (59,60). 

Figure 6 shows a typical chromatogram obtained from such a procedure. In this chromatogram, the elution of the thio-tetrazole, the R and S isomers of moxalactam, and the moxa-lactam decarboxylated product are shown. In this test for other related substances, only those substances which are not dealt with by specific tests are considered. Quantitative information is obtained by summing the response for all the extraneous peaks and comparing them to the sum of the response for the R and S isomers of a diluted moxalactam reference standard. The assumption is made that all of these materials have similar spectral response characteristics at 254 nm. 

Altered platelet numbers and function Platelet dysfunction occurs dose-dependently with carbenicillin, ticarcillin, and, infrequently, other broad-spectrum penicillins (105), but the NMTT cephalosporin moxalactam has also been associated with altered platelet function in both healthy subjects and in patients treated with standard regimens (106-110). In contrast, clinical studies including cefotaxime, ceftizoxime, cefoperazone, and ceftracone did not show platelet dysfunction attributable to these compounds (109-111). There is evidence that beta-lactam-antibiotic-induced platelet dysfunction is at least partially irreversible (112). 

Cephamycins include p-lactam such as cefoxitin, cefotetan, cefmetazole and latamoxef (moxalactam). Cephamycins are active against anaerobic bacteria, are less active against gram-positive cocci and, have no activity against methicillin-resistant staphylococci and enterococci. Cephamycin antibiotics such as cefotetan and latamoxef have a side chain called the... 

Kelly, J.W. Stewart, J.T. Separation of selected beta lactam antibiotic epimers on gamma cyclodextrin, ion exchange ethylvinylbenzene/divinylbenzene/copolymer and polyCstyrene- divinylbenzene) copolymer stationary phases. J.Liq.Chromatogr, 1991, 14, 2235-2250 [also carbemicillin, moxalactam, ticarcillin]... 

---