B-Lactamase inhibitors

Penem B-Lactamase Inhibitors. The synthesis and antibacterial properties of penems, the trivial name for the 4-thia-l-azabicyclo[3.2.0]hept-2-ene ring system (24), have been reviewed (107,108). Like the closely related carbapenems, many of the penems are potent antibacterials. Additionally, penems are also susceptible to degradation by renal dipeptidase, but to a lesser extent. The limited -lactamase inhibitory data available for penems are presented in Table 4. SCH-29,482 [77646-83-4] (24, R = H, R = CH(OH)CH2, R = SCH2H ), C2qH23NO S2, is reported to be an inhibitor of type I Cephases and the OXA-2 enzyme (109). Compounds [101803-54-7] and [101914-68-5] (24, R = H, R = CH2CH(OH),... 

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),... 

Table 5. Activity of Penam Sulfone B-Lactamase Inhibitors ...

B-Lactamase inhibitors, 31 (1994) 297 Leprosy, chemotherapy, 20 (1983) 1 Leukocyte elastase inhibition, 31 (1994) 59 Leukotriene D4 antagonists, 38 (2001) 249 Ligand-receptor binding, 23 (1986) 41 Linear free energy, 10 (1974) 205... 

Other Imipenem/cilistatin, meropenem, ertapenem, or extended-spectrum penicillins with B-lactamase inhibitor 1. Ciprofloxacin with metronidazole 2. Aztreonam with clindamycin or metronidazole 3. Antianaerobic cephalosporins.3... 

Penems -as b-lactamase inhibitors [ANTIBIOTICS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] (Vol 3)... 

Penicillins - [ANTIBIOTICS - BETA-LACTAMS - PENICILLINS AND OTHERS] (Vol 3) - [ANTIBIOTICS - SURVEY] (Vol 2) -as b-lactamase inhibitors [ANTIBIOTICS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] (Vol 3) -silylation m synthesis of [SILICON COMPOUNDS - SILYLATING AGENTS] (Vol 22)... 

These substances resemble 13-lactam molecules (Figure 43-7) but themselves have very weak antibacterial action. They are potent inhibitors of many but not all bacterial Blactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. B-Lactamase inhibitors are most active against Ambler class A Blactamases (plasmid-encoded transposable element [TEM] 13-lactamases in particular) such as those produced by staphylococci, H influenzae, Ngonorrhoeae, salmonella, shigella, E coli, and Kpneumoniae. They are not good inhibitors of class C 13-lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal Blactamases of legionella, bacteroides, and branhamella. 

The three inhibitors differ slightly with respect to pharmacology, stability, potency, and activity, but these differences are of little therapeutic significance. B-Lactamase inhibitors are available only in fixed combinations with specific penicillins. The antibacterial spectrum of the combination is determined by the companion penicillin, not the B-lactamase inhibitor. (The fixed combinations available in the USA are listed in the Preparations Available section.) An inhibitor will extend the spectrum of a penicillin provided that the inactivity of the penicillin is due to destruction by B... 

The indications for penicillin-B-lactamase inhibitor combinations are empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intraabdominal infections. Doses are the same as those used for the single agents except that the recommended dosage of piperacillin in the piperacillin-tazobactam combination is 3 g every 6 hours. This is less than the recommended 3-4 g every 4-6 hours for piperacillin alone, raising concerns about the use of the combination for treatment of suspected pseudomonal infection. Adjustments for renal insufficiency are made based on the penicillin component. 

SN Maiti, OA Phillips, RG Micetich, DM Livermore. B-Lactamase inhibitors agents to overcome bacterial resistance. Curr Med Chem 56 441-456, 1998. 

Page MG. B-Lactamase inhibitors. Drug Resist Updat 2000 3(2) 109-125. 

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