Pseudomonas lactamase

Enzyme inhibitors such as cloxacillin and methicillin have been shown to potentiate the action of certain penicillins and cephalosporins against Ps. aeruginosa Figure 7.7). Thus, the presence of cloxacillin, which is a strong inhibitor of the inducible enzyme, potentiates the effect of cephaloridine which alone is susceptible to hydrolysis by the pseudomonas lactamase. Cloxacillin shows no antibacterial activity against... 

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). 

Widespread clinical acceptance continues to be accorded to the cephalosporins, and the field is extremely active as firms search for the ultimate contender. Among the characteristics desired is retention of the useful features of the older members (relatively broad spectrum, less antigenicity than the penicillins, relative insensitivity toward 3-lactamases, and convenience of administration) while adding better oral activity and broader antimicrobial activity (particularly potency against Pseudomonas, anaerobes, meningococci, cephalosporinase-carrying organisms, and the like). To a considerable extent these objectives have been met, but the price to the patient has been dramatically increased. 

Livermore DM, Woodford N (2006) The (3-lactamase threat in Enterobacteriaceae, Pseudomonas and Acine-tobacter. Trends Microbiol 14(9) 413—420... 

In complicated exacerbations with risk of Pseudomonas aeruginosa, recommended therapy includes a fluoroquinolone with enhanced pneumococcal and P. aeruginosa activity (levofloxacin). If IV therapy is required, a /f lactamase resistant penicillin with antipseudomonal activity or a third- or fourth-generation cephalosporin with antipseudomonal activity should be used. 

Cefotaxime can be used in infections due to beta-lactamase producing strains of H. influenzae and N. gonorrhoeae. Ceftriaxone has an antibacterial spectrum similar to that of cefotaxime but its longer half-life allows for less frequent dosing. Ceftazidime is especially effective against Pseudomonas aeruginosa. Cetixime and cefpodoxime are third-generation cephalosporins that can be administered orally. 

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. 

It is formed by acylases that cleave off the side chain of the penicillins, and can also be obtained by the selective chemical cleavage of the amide, leaving the lactam intact. After this, 6-APA can be easily acylated by any carboxylic acid, and this has yielded literally thousands of semisynthetic penicillins in the past 30 years, many showing improved stability and activity. Some of them are lactamase resistant (methicillin (9.41), oxacillin (9.42) and its halogenated derivatives), whereas others are broad-spectrum antibiotics, like the orally active ampicillin (9.43), which also inhibits Gramnegative bacteria but is sensitive to lactamase. Carbenicillin (9.44) is particularly active against Pseudomonas and Proteus infections, which are unaffected by natural penicillins. Piperacillin (9.45), a broad-spectrum compound, is spectacularly active against Pseudomonas. 

These substances resemble 3-lactam molecules (Figure 43-7) but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial 3 lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase inhibitors are most active against Ambler class A lactamases (plasmid-encoded transposable element [ ] lactamases in particular), such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and pneumoniae. They are not good inhibitors of class lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal 3 lactamases of bacteroides and moraxella. 

The effect of replacement of the APA nucleus with an ACA nucleus on the susceptibility of the substrate to enzymic hydrolysis depends on the nature of the /3-lactamase 2). It has been richly illustrated in the case of the /3-lactamase of Pseudomonas pyocyanea (31) and analyzed in terms of conformative response (see Section IV,B) in a study of a B. cereus /3-lactamase (75). In that study the role of the nucleus was examined in both catalytic and noncatalytic enzyme-substrate interactions. Little has been published on the effect of modifications within each nucleus, presumably because such modifications lead, as a rule, to the loss of antibiotic activity. 

Conversion of the carboxyl groups in penicillins confers partial resistance to /3-lactamase (85-87). In cephalosporins, replacement of the acetyl group in position 3 of the dihydrothiazine ring [R in Fig. 1, (III)] by pyridine causes increased susceptibility to hydrolysis by /3-lactamases of Pseudomonas pyocyanea (31, 88), Enterobacter cloacae (45), E. coli (42, 88), and both the extracellular and cell-bound enzymes of B. cereus (38). 

B. Carbenicillin Urinary tract infection caused by Pseudomonas aeruginosa (p-lactamase negative)... 

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