Sulbactam, lactamase inhibitor

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

Although a broad range of P-lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid (12, R = CH2OH, R = H), manufactured by SmithKlinp Beecham, is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin [34787-01-4], C25H2gN20 S, has the trade name, Timentin. In 1990 worldwide sales of clavulanic acid containing products were about 725 million. 

Treatment for septic patients with hospital-acquired, ventilator-acquired, and health care-associated pneumonia is dependent on risk factors for multi-drug resistant (MDR) organisms (Fig. 79-2). Recommended treatment for patients with no MDR risk factors are third-generation cephalosporins, fluoroquinolones, ampicillin-sulbactam, or ertapenem (see Table 79-3).35 Recommended treatment for patients with MDR risk factors are P-lactam/p-lactamase inhibitors (piperacillin-tazobactam), antipseudomonal cephalosporin, or carbapenem, plus an aminoglycoside, plus vancomycin or linezolid (see Table 79-3).35 If an aminoglycoside is undesirable, a antipseudomonal fluoroquinolone may be utilized with a P-lactam/p-lactamase inhibitor. 

GS-Lactamase inhibitor combination-IV ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanate po amoxicillin-clavulanate. Cefoxitin. 

Treatment options for patients requiring intravenous therapy include /J-lactam-/3-lactamase inhibitors (ampicillin-sulbactam or piperacillin-tazobactam), second-generation cephalosporins with antianaerobic activity (cefoxitin), and carbapenems. 

Beginning in the late 1980s, three -lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) have been used against serine enzymes, usually in combination with penicillins more susceptible to /1-lactamase hydrolysis. This therapeutic strategy has been effective over two decades. The following section provides a brief overview on various classes of -lactam-based inhibitors. 

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-... 

Clavulanic acid and sulbactam An addition of beta-lactamase inhibitors, such as clavu-lanic acid (32.1.1.35) and sulbactam (32.1.1.36) to penicillins or to aminopenicillins of a broad spectrum of action significantly expands their antimicrobial spectrum. 

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. 

Efforts to overcome the actions of the p-lactamases have led to the development of such p-lactamase inhibitors as clavulanic acid, sulbactam, and tazobactam. They are called suicide inhibitors because they permanently bind when they inactivate p-lactamases. Among the p-lactamase inhibitors, only clavulanic acid is available for oral use. Chemical inhibition of p-lactamases, however, is not a permanent solution to antibiotic resistance, since some p-lactamases are resistant to clavulanic acid, tazobactam, or sulbactam. Enzymes resistant to clavulanic acid include the cephalosporinases produced by Citrobacter spp., Enterobacter spp., and Pseudomonas aeruginosa. 

Rx amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G benzathine, penicillin G potassium, penicillin Vpotassium, piperacillin, pivampicillin, pivme-cillinam, ticarcillin Penicillin and beta-lactamase inhibitors amoxicillin/ clavulanate potassium, ampicillin/sulbactam sodium, piperacillin sodium/ tazobactam sodium, ticarcillin disodium/clavulanate potassium Chemical Class Penicillin, natural... 

Ampicillin, amoxicillin, ticarcillin, and piperacillin are also available in combination with one of several 3-lactamase inhibitors davulanic acid, sulbactam, or tazobactam. The addition of a 3-lactamase inhibitor extends the activity of these penicillins to include 3-lactamase-producing strains of S aureus as well as some 3-lactamase-producing gram-negative bacteria (see Beta-Lactamase Inhibitors). 

BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM, TAZOBACTAM)... 

Inhibition of enzymatic inactivation Enzymatic inactivation of 3-lactam antibiotics is a major mechanism of antibiotic resistance. Inhibition of 3-lactamase by 3-lactamase inhibitor drugs (eg, sulbactam) results in synergism. 

Bycroft et al. [83] have reported a series of semisynthetic penicillin derivatives such as, 6-spiro-epoxypenicillins F, G (Fig. 8) possessing both (3-lactamase inhibitory and antibacterial activity (Fig. 8). It has been found that novel chlorinated 6-spiro-epoxypenicillins F are potent in vitro inhibitors of a range of chemically important (3-lactamases [84], whereas, 6-spirocyclopropylpenems, G, show a reduced level of (3-lactamase inhibitory activity. The significance of the five fold difference between the turnover numbers for F(a) and G(b) (differ only in their stereochemistry at one center) was found to be in close comparison with the turnover number of 20,000, reported for the established (3-lactamase inhibitor, sulbactam [140]. Thus, the notable (3-lactamase inhibitory and antibacterial properties of these spiro-(3-1 actams depend upon the substituents and the stereochemistry of the epoxide. 

Beta-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, Tazobactam)... 

Oxidation reactions on the sulfur atom of penicillins remain the most important reactivity of S-1 encountered in the literature. Penam sulfoxides and sulfones are indeed important compounds as they confer to the skeleton an ease of thiazolidine ring opening by weakening the C(5)-S(l) and S(l)-C(2) bonds (see Section 2.03.5.9) <2004CHE816>. In particular, the former constitute key intermediates in ring-expansion transformations from penams to cephems (see Section 2.03.5.9), while the latter have a special biological interest as /3-lactamase inhibitors (e.g., sulbactam, tazobactam see Sections 2.03.1, 2.03.5.2, and 2.03.12.4). Since CHEC-II(1996) covers all the aspects of these oxidation reactions on the S-1 atom of penicillins, this section focuses on the most relevant recent papers. As there is no particular change in the subject, only a few articles have been released since 1995. 

The synthetic penicillin sulfone [sulbactam, (42) has been shown to act as a p-lactamase inhibitor. The inhibition is based on a similar mechanism as proposed above 62). A prodrug, sultamicillin 43), which combines sulbactam and amoxacillin by labile... 

Beta-Lactamase Inhibitors (clavulanic acid, sulbactam, tazobactam)... 

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. 

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