Clavulanic acid sulbactam tazobactam

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

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

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

Extended-activity spectrum The amino-penicillin amoxicillin is active against many Gram-negative organisms, e.g., colibacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam). 

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). 

Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity. The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms is thus a major mechanism of bacterial resistance. Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) are sometimes used in combination with peni-... 

However, there are three important P-lactamase inhibitors duly recognized, namely clauvulanic acid, sulbactam, and tazobactam as given under Clavulanic acid Sulbactam Tazobactam... 

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. 

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. 

The -lactamase inhibitory activity of BRL 42715, in comparison with clavulanic acid, sulbactam and tazobactam is shown in Table 6.14. It can be seen that BRL 42715 displays potent and progressive broad spectrum yff-lactamase inhibitory activity which represents a significant improvement over that of clavulanic acid, sulbactam and tazobactam. This was most noticeable with the chromosomal class I cephalosporinases, against which clavulanic acid is poorly active and sulbactam and tazobactam show only moderate activity. 

Because they cause prolonged inactivation of certain fi-lactamases. class I inhibitors ate particularly useful in combination with extended-spectrum, lactamase-sen.sitive penicillins to treat infections caused by lactamase-producing bacteria. Three such inhibitors, clavulanic acid, sulbactam, and tazobactam. are currently marketed in the United States for this purpose. A class II inhibitor, the carbapenem derivative imipenem. has potent antibacterial activity in addition to its ability to cause transient inhibition of some /3-lactamases. Certain antibacterial cephalosporins with a leaving group at the C-3 position can cause transient inhibition of lactamases by forming stabilized acylenzyme intermiediates. These are discu.ssed more fiilly below in this chapter. 

P-Lactamase inhibitors — clavulanic acid, sulbactam and tazobactam... 

Imipenem or meropenem amoxicillin/clavulanic acid ticarcillin/clavulanic acid piperacillin/tazobactam ampicillin/sulbactam cefoxitin cefotetan chloramphenicol cefmetazole penicillin G gatifloxacin or moxifloxacin Gentamicin... 

A fluoroquinolone a tetracycline gentamicin A fluoroquinolone amikacin a tetracycline trimethoprim-sulfamethoxazole cefotaxime, ceftizoxime, ceftriaxone, cefepime, or ceftazidime Gentamicin, tobramycin or amikacin trimethoprim-sulfamethoxazole ciprofloxacin, ticarcillin, mezlocillin, or piperacillin aztreonam cefotaxime ceftizoxime ceftriaxone cefepime or ceftazidime Ampicillin gentamicin, tobramycin, or amikacin carbenicillin, ticarcillin, mezlocillin, or piperacillin gentamicin, tobramycin, or amikacin amoxicillin/clavulanic acid ticarcillin/clavulanic acid piperacillin/tazobactam ampicillin/sulbactam trimethoprim-sulfamethoxazole imipenem or meropenem aztreonam a fluoroquinolone another cephalosporin... 

Ampicillin, amoxicillin, ticarcillin, and others in this group can be protected from destruction by beta-lactamases if they are administered together with beta-lactamase inhibitors such as clavulanic acid, sulbactam, or tazobactam. Such mixtures have been employed against lactamase-producing H. influenzae or coliform organisms. 

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-... 

Current commercial inhibitors of /3-lactamases include clavulanic acid (an oxapenam see Table 1), sulbactam, and tazobactam (two penam sulfones see Table 1). They are effective only against the class A serine /3-lactamases and they are administrated in the form of antibiotic/inhibitor combinations <2006BP930> Augmentin (amoxicillin/clavulanic acid), Timentin (ticarcillin/clavulanic acid), Unasyn (ampicillin/Sulbactam), Zosyn (piperacillin/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. 

Table 6.15. COMPARATIVE SYN ERGISTIC ACTIVITIES OF BRL 42715 (31), TAZOBACTAM (30), CLAVULANIC ACID (17) AND SULBACTAM (23) WITH A RANGE OF y9-LACTAMASE PRODUCING BACTERIA [92, 93]...

The discovery of clavulanic acid in 1976 heralded a new era in antibacterial chemotherapy. The enormous success of Augmentin (amoxycillin in combination with clavulanic acid) for the treatment of infections caused by /5-lactamase producing bacteria has established that /5-lactamase inhibitors have an important role to play in solving the problem of bacterial resistance. The widespread interest and enthusiasm created by the discovery of clavulanic acid has culminated in the development of two additional /5-lactamase inhibitors, namely, sulbactam and tazobactam. 

Clavulanic acid has a very low immunogenic and allergenic potential in animals. The possible impact of its co-administration with other beta-lactam antibiotics is unknown (53). Two patients with IgE-mediated hypersensitivity to oral co-amoxiclav and positive skin tests for clavulanic acid, but not for penicillins, both tolerated oral amoxicillin. One patient was also challenged with clavulanic acid and developed urticaria, conjunctivitis, and bronchial obstruction (54). Since co-amoxiclav has been widely used since its introduction in 1981, the frequency of hypersensitivity reactions is low. The clinical data available on sulbactam and tazobactam are stiU hm-ited and do not allow an assessment of the frequency and pattern of associated hypersensitivity reactions (55). 

Clavulanic acid caused false-positive dipstick tests for leukocytes sulbactam and tazobactam did not (57). 

Clavulanic acid was discovered in 1976 and is a P-lactam antibiotic with low antibiotic activity, but does protect p-lactamase-sensitive compounds of high intrinsic activity such as benzylpenicillin, ampicilhn, and amoxicillin from p-lactamase destruction. Subsequently other p-lactamase inhibitors such as sulbactam and tazobactam were developed [4]. 

Piperacillin/tazobactam (PT) Ticarcillin/clavulanic acid (TQ Ampicillin/sulbactam (AS) Amoxicillin/clavulanic acid (AQ... 

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. 

Clavulanic acid, which may be used orally or intravenously, and the intravenous agents sulbactam and tazobactam. 

Tazobactam often is coadministered with piperacillin because of tazobactam s ability to inhibit (3-lactamases. Tazobactam, like other (3-lactamase inhibitors, has little or no antibacterial activity. This effect is analogous to that of clavulanic acid and sulbactam (discussed above). 

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