Tazobactam, structure

Tautomer, 264, 842 Tautomerism, 842 Tazobactam, 836 Teflon, structure and uses of, 242 Template strand (DNA), 1108 Tercphthalic acid, synthesis of, 576-577... 

Figure 5.21 Structure of tazobactam. Reprinted from Biochim. Biophys. Acta, 1547, Bonomo, R. A., Liu, J., Chen, Y., Ng, L., Hujer, A. M. and Anderson, V. E., Inactivation of CMY-2 /3-lactamase by tazobactam initial mass spectroscopic characterization , 196-205, Copyright (2001), with permission from Elsevier Science.

After clavulanic acid, the penicillanic acid derivatives (particularly the corresponding sulfone analogs) have been the subject of intense research in the -lactamase inhibitor area. From this extensive investigation, two compounds (sulbactam and tazobactam) from this class have been successfully introduced into clinical use. The penicillanic acid sulfones are /3-laclamasc inhibitors that are quite homologous to clavulanate in both their mechanism of action and in the spectrum of -lactamases susceptible to their action. The first notable success in this field was the discovery of sulbactam 7 (Fig. 7), which was reported by Pfizer chemists in 1978 and shown to possess potent inhibitory activity, principally for class A //-lactamases. It had greater affinity for class C types than clavulanate. From careful comparison of its structure to clavulanate, a rational basis for the similarities between the two is apparent. Both lack a C-6 substituent. Since the absence (or presence) of this substituent is an important, but not exclusive, factor in //-lactamase recogni-... 

Beta-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. They are structurally related to the beta-lactam antibiotics however the antibacterial activity of these compounds is very weak or negligible. They are strong inhibitors of bacterial beta-lactamases and can protect beta-lactam antibiotics from hydrolysis by these enzymes. 

Enzymatic inactivation or modification of antibiotics has been discussed by many authors [179-182, 186-188], As described earlier, /(-lactams may be susceptible to /(-lactamases. During the past 30-odd years, several -lactams have been synthesized that are less susceptible to these enzymes. Such drugs include (i) newer types of /(-lactam structures, e.g. carbapenems (37), cephamycins (40) and carbacephems (53), and (ii) modifications of the side-chains of existing penams (38) or cephems (39) [317]. Nevertheless, the wide diversity of /(-lactamases [180,181,318] means that organisms producing enzymes with broad-spectrum activity may be able to resist some members of the /(-lactam group, /(-lactamase inhibitors such as clavulanic acid (36), and the penicillanic acid sulphone (54) derivatives, tazobactam (55) and sulbactam (56) have been combined with, and protect, appropriate /(-lactamase-susceptible penicillins, with useful clinical results. Most extended-spectrum /(-lactamases are susceptible to these inhibitors, but newer -lactamase inhibitors may still be needed. 

Imipenem caused positive dipstick tests for leukocytes in patients with agranulocytosis and normal urinary sediments. This phenomenon was reproducible in vitro with imipenem, meropenem, and clavulanic acid. Sulbactam, tazobactam, three penicillins, three cephalosporins, and the basic structures of penicillins, cephalosporins, and monobactams tested negative (50). 

Tazobactam, USP. Tazobactam is a penicillanic acid sulfone that is similar in structure to sulbactam. It is a nioK potent /3-lactamase inhibitor than sulbactam and ha.- 3 slightly broader spectrum of activity than clavulanic acid. Ii has very weak antibacterial activity. Tazobactam is available in fixed-dose, injectable combinations with piperacillin, a broad-spectrum penicillin consisting of an 8 I ratio of pipci- acillin sodium to tazobactam sodium by weight and ma-keted under the trade name Zosyn. The pharmacokineticsprotein bound, experience ven little metabolism, and are excreted in active forms in the urine in high concentrations. 

Sulbactam (Fig. 10.6G) is a semisynthetic 6-desaminopenicillin sulphone structurally related to tazobactam. Not only is it an effective inhibitor of many P-lactamases but it is also active alone against certain Gram-negative bacteria. It is used clinically in combination with ampicillin. 

Graham DR, Lucasti C, Malafaia O, et al. Ertapenem once daily versus piperacillin-tazobactam four times per day for treatment of complicated skin and skin-structure infections in adults Results of a prospec- 53. live, randomized, double-blind multicenter study. Clin Infect Dis 2002 34 1460-1468. 

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