Carbapenems 3-lactamase inhibitors

First (3-lactamase inhibitor combination. First monobactam and a synthetic product. First carbapenem. 

Carbapenems and penems, Cephalo sp orins, P-Lactamase inhibitors, Monobactams,... 

The sulfated compounds MM 13902 (3, n = (5) and MM 17880 (4) are also broad-spectmm agents, but not as potent as thienamycia and all lack any significant activity against Pseudomonas (73). Many carbapenems are excellent inhibitors of isolated P-lactamases, particularly the olivanic acid sulfoxide MM 4550 (3, n = 1) (3). The possible mechanism of action of the carbapenems as inhibitors of P-lactamases has been discussed in some detail (74). Other carbapenems such as PS-5 (5) (75), the carpetimycins (76), asparenomycins (77), and pluracidomycins (8) are all highly active as antibiotics or P-lactamase inhibitors. The parent nucleus itself (1, X = CH2) is intrinsically active, but chemically unstable (9). 

Garbapenem P-Lactamase Inhibitors. Carbapenems are another class of natural product P-lactamase inhibitors discovered about the same time as clavulanic acid. Over forty naturally occurring carbapenems have been identified many are potent P-lactamase inhibitors. Garbapenem is the trivial name for the l-a2abicyclo[3.2.0]hept-2-ene ring system (21) shown in Table 3. The synthesis (74), biosynthesis (75), and P-lactamase inhibitory properties (13,14,66) of carbapenems have been reviewed. Carbapenems are often more potent than clavulanic acid and include type I Cephases in the spectmm of inhibition. Table 3 Hsts the available P-lactamase inhibition data. Synergy is frequendy difficult to demonstrate because the compounds are often potent antibacterials. 

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),... 

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. 

Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and clavams (/8-lactamase inhibitors). The metabolic engineering of penicillin and cephalosporins production has been summarized by several good reviews [71,72], so the focus here is clavulanic acid, which has attracted interest in recent years. 

Skin/soft tissue Catheter-related Vancomycin or linezolid or daptomycin /J-Lactamase inhibitor combo or clindamycin plus ciprofloxacin or carbapenem Vancomycin ... 

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. 

Broad spectrum therapy is started on an empirical basis. Intra-abdominal infections can be treated by ampicillin (or amoxycillin) or clindamycin combined with aminoglycosides, penicillin-beta-lacta-mase inhibitors such as amoxycillin-clavulanic acid or a second or third generation cephalosporin combined with metronidazole are good alternatives. In patients with impaired immunity and/or prior use of antibiotics, i.e. when it is reasonable to expect resistant pathogens, a broad spectrum penicillin plus beta-lactamase inhibitor or a carbapenem can be used empirically in monotherapy. In septic patients, the rapidly bactericidal action of aminoglycosides is useful. Aminoglycosides should preferentially not be given for more than 3-5 days. 

The penicillins share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and -lactamase inhibitors. All are 3-lactam compounds, so named because of their unique four-membered lactam ring. 

Bacteroides fragiiis Metronidazole Chloramphenicol, carbapenem,6 3-lactam-3-lactamase-inhibitor combinations, clindamycin... 

ANTIBIOTICS - BETA-LACTAMS - CARBAPENEMS AND PENEMS] (Vol 3) [ANTIBIOTICS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] (Vol 3)... 

Semisynthetic products, b First oral cephalosporins. c First commercial cephamycin. dFirst -lactamase inhibitor combination, e First monobaclam and a synthetic product. f First carbapenem. 

Carbapenem-fi-Lactamase Inhibitors. Carbapenems are another class of natural product /8-lactamase inhibitors discovered about the same time as clavulanic acid... 

Penem ff-Lactamase Inhibitors. The synthesis and antibacterial properties of penems have been reviewed. Like die 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. 

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. 

The /8-lactam antibiotics are a broad class of antibiotics which include penicfllin derivatives, cephalosporins, monobactams, carbapenems and /8-lactamase inhibitors that is, any antibiotic agent that contains a /3-lactam nucleus in its molecular structure (Figure 20.1). They are the most widely-used group of antibiotics. 

Methylethylidene)azetidinones. CSI reacts with the allenyl acetate 2 to give, after reduction, the unsaturated azetidinone 3, which was converted into the stable sulfide 4 in 44% overall yield. This product was converted in several steps into a carbapenem (5). Compounds of this type are potent p-lactamase inhibitors. 

Application of the above screen led to the detection of a number of /8-lactamase inhibitors from a number of strains of Streptomyces olivaceus. They were identified as the carbapenem derivatives, MM 13902 (12), MM 4550 (13) and MM 17880 (14), known collectively as the olivanic acids [27, 28]. Not only are they potent -lactamase inhibitors, but are also powerful antibacterial agents. Subsequently, a whole series of carbapenem derivatives... 

Degradation prodncts spontaneously formed in aqueous solutions, for example cnltnre media, rather than the parent molecnles themselves, may be responsible for the observed effects (4). Antiproliferative activities were generally more prononnced with cephalosporins than with penicillins, while monobactams appear to be practically free from snch effects. Carbapenems have not been thoronghly stndied in this respect, and some data on clavnlanic acid and two other beta-lactamase inhibitors do not clearly reflect the same kind of toxicity as observed with penicillins and cephalosporins (20). 

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