Resistance of Pseudomonas aeruginosa mutants with altered control of chromosomal beta-lactamase to piperacillin, ceftazidime, and cefsulodin

Abstract

Examination of 3-lactam susceptibility of mutants altered in the control of chromosomal J3-lactaimase of Pseudomonas aeruginosa supports the view that a constitutive level of P-lactamiase is not an adequate explanation for resistance to cefsulodin and ceftazidime but could be for resistance to piperacillin which has an efficiency of hydrolysis ca. 10 times higher than does cefsulodin or ceftazidime.In initial studies of expanded&spectrum cephalosporins and penicillins, the rapid development of resistance to many of these agents has beeh reported among Pseudomonas, Enterobacter, and Serratia strains which possess inducible ,3-lactainases (10). Resistance is reported to, develop to most recent P-lactams, with the exception of those such as mecillinam and imijOikm (N-forminiidoyl thienamycin) that bind primarily to penicillin-binding protein 2 (10). The rapidity and extent of such resistance is of major concern and could lead to curtailment of the tise of second-and thirdgeneration cephalosporins and antipseudomonal penicillins.The basis of such resistance has been proposed to be due to a derepression or mutation to stable derepressed (cOnstitutive) production of the inducible -lactamase (3,4,6,10). Resistance is achieved by either hydrolysis of p-lactams or by a nonhydrolytic barrier for those not subject to hydrolysis (10, 13). In the latter case it has been proposed that 1-lactamase binds P-lactam molecules and prevents them from bindihg to target penicillin-binding proteins. Although it is clear that some of the resistant isolates are constitutive mutants, it has not yet been cohfirmed that constitutive production is the only mechanism operating to produce resistance, particularly to nonhydrolyzed -lactams in the various strains isolated to date. Recently, Seeberg et al. (11) showed by genetic transfer experiments to Escherichia coli that chromosomal 13-lactamases of Enterobacter cloacae are responsible for resistance to expanded-spectium cephalosporins. However, details of the transfer of the resistance gene(s) were not provided so it is not yet possible to conclude that only a single gene product is involved. To determine whether constitutive P-lactaniase is the sole explanatidh for this type of resistance in! Pseudomonas aeruginosa, we examined a set of isogenic mutants of a bacterium obtained from H. Matsumoto (7); these mutants vary in the control of chromosomal P-lactamase. The P.. aeruginosa strains used were PA04069 met-9020 pro-9024 (normally inducible), PA04082 met-9020 pro-9024 blaJ91ll (cohstitutive), and PA04098 met-9020 pro-9024 blaP-9208 (weaklactamfnase producer).We confirmed that this set of P. aeruginosa strains and strain PA01 have identical patterns of outer membrane proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2), penicillin binding (2), and lipopolysaccharide binding (5)

Decreased Baseline β-Lactamase Production and Inducibility associated with Increased Piperacillin Susceptibility of Pseudomonas cepacia Isolated from Children with Cystic Fibrosis

“…Mutated strains of P. aeruginosa unable to produce significant amounts of chromosomally mediated (3-lactamase are more susceptible to piperacillin and other P-lactamase-susceptible P-lactam agents than their respective parent strains with normal enzyme production (20,21). Conversely, mutated strains of P. aeruginosa capable of increased P-lactamase production without induction (baseline concentrations) are more resistant to piperacillin than nonhyperproducing strains (22).…”

Evidence for multiple forms of type I chromosomal beta-lactamase in Pseudomonas aeruginosa

“…aeriiginosa appears to undergo derepression of its beta-lactamase at several levels (1,2,5,8,12,16,20,25,27). Most isolates reported to date are only partially derepressed for beta-lactamase.…”

Role of beta-lactamase in in vivo development of ceftazidime resistance in experimental Pseudomonas aeruginosa endocarditis

“…One novel approach taken by pharmaceutical companies in the development of newer ,-lactam antibiotics has been to search for compounds that are refractory to ,-lactamase-mediated hydrolysis. Recently, however, it has been observed that, despite the extremely low rates at which these compounds are hydrolyzed, clinical isolates of P. aeruginosa and Enterobacter cloacae that are resistant to these so-called P-lactamase-stable P-lactams often have much-increased levels of the chromosomal P-lactamase (4,30,31,(34)(35)(36). The mechanism of resistance has been suggested to involve nonhydrolytic binding of the ,-lactam by molecules of ,-lactamase, thus reducing the periplasmic concentration (i.e., the concentration in the vicinity of the target PBPs) to subinhibitory levels (34).…”