Inducible Type I βlactamases of Gram-negative bacteria and resistance to βlactam antibiotics

Journal of Medical Microbiology

Williams

1988

Summary. The activities of P-lactam antibiotics were compared against Enterobacter cloacae clinical isolates and mutants which had inducible, stably-derepressed, and basal expression of a PI 8.4 subtype of the Ia chromosomal P-lactamase. These activities were correlated with the results of studies of the P-lactamase-lability and /?-lactamase-inducer-power of the antibiotics. Cefoxitin and ampicillin were labile, and induced p-lactamase production strongly at concentrations below their MIC values. Consequently, /?-lactamase-inducible and p-lactamase-stably-derepressed organisms were highly resistant (MIC > 256 mg/L) to these antibiotics, whereas enzyme-basal strains and mutants were much more susceptible (MIC 1-16 mg/L). Imipenem also induced p-lactamase production strongly at concentrations below its MIC, but was more stable than ampicillin and cefoxitin. It was active against enzyme-inducible and stably-derepressed organisms at 0-25-0.5 mg/L and against P-lactamase-basal organisms at 0.06-0-25 mg/L. Thus the P-lactamase afforded only very low-level protection against imipenem ; this appeared to be by a non-hydrolytic mechanism, with the enzyme binding to the antibiotic in a relatively stable complex. This complex, which probably was an intermediate in a hydrolytic pathway, was isolated by gelfiltration chromatography and shown to have a breakdown half-life of 47 f 2 min. Cefotaxime, ceftriaxone and mezlocillin were labile to the PI 8.4 P-lactamase but induced p-lactamase production weakly at concentrations below their MIC values. Consequently, P-lactamase-inducible and P-lactamase-basal organisms remained equally susceptible (MIC 0.06-4 mg/L), but stably-derepressed organisms were considerably more resistant (MIC > 64 mg/L) to these antibiotics.

Section: Introductionsupporting

confidence: 78%

Chromosomal -lactamase expression and antibiotic resistance in Enterobacter cloacae

Yang

Journal of Medical Microbiology

Williams

1988

“…The levels of resistance to new penicillins and cephalosporins seen in stably derepressed Proteeae mutants were much lower than those observed in stably derepressed E. cloacae and Pseudomonas aeruginosa, for which MICs of cefotaxime and ceftriaxone often exceed 256 ,ug/ml (3,8,16 …”

Section: Methodsmentioning

confidence: 79%

“…Yet the M. morganii enzyme provided considerably less protection against cefoxitin than against cefotaxime and ceftriaxone and generally rather less than against carbenicillin. The failure of inducible and/or stably derepressed M. morganji P-lactamase to protect the organism against cefoxitin is evident also from the results of others (3,19) and is in contrast to the function of other class I enzymes, such as those of E. cloacae and Pseudomonas aeruginosa. The reason for cefoxitin susceptibility in P-lactamase-inducible or -derepressed M. morganii is unclear, but it may be that the drug is an unusually good permeant of this species, such that it readily overloads the P-lactamase.…”

Section: Methodsmentioning

confidence: 99%

“…Activity is lost against mutants (variously termed "constitutive," "macroconstitutive," or "stably derepressed") that produce ,-lactamase copiously without induction (8,9,16). Such mutants are segregated at high frequency by inducible populations (3,23) and may be selected during cephalosporin or ureidopenicillin therapy, sometimes resulting in clinical failure (8,15).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chromosomal beta-lactamase expression and resistance to beta-lactam antibiotics in Proteus vulgaris and Morganella morganii

Yang

Antimicrob Agents Chemother

1988

Indole-positive members of the Proteeae usually have inducible expression of chromosomal ,-lactamases.Mutants with stably derepressed P-lactamase expression occur in inducible populations at frequencies in the range of 10-6 to 10-8. The contribution of these P-lactamases to drug resistance was examined in Morganella morganii and Proteus vulgaris. The M. morganii enzyme was a high-molecular-weight (49,000) class I cephalosporinase with low Vm.x rates for ampicillin, carbenicillin, and broad-spectrum cephalosporins. The P.vulgaris enzyme had a lower molecular weight (32,000) and high Vmax rates for ampicillin, cephaloridine, cefotaxime, and ceftriaxone. Imipenem and cefoxitin inactivated the P. vulgaris enzyme but were low-Vmax, low-Km substrates for that of M. morganii. Despite these differences, the two I-lactamases caused similar resistance profiles. Ampicillin and cephaloridine were strong inducers for both species, and ,I-lactamaseinducible strains and their stably derepressed mutants were resistant, whereas basal mutants (those with low-level uninducible P-lactamase) were susceptible to these two compounds. Mezlocillin, cefotaxime, ceftriaxone, and (usually) carbenicillin were almost equally active against P-lactamase-inducible organisms and their basal mutants, but were less active against stably derepressed mutants. This behavior reflected the P-lactamase lability of these drugs, coupled with their weak inducer activity below the MIC. Carbenicillin was a labile strong inducer for a single P. vulgaris strain, and inducible enzyme was protective against the drug in this atypical organism. Cefoxitin and imipenem, both strong inducers below the MIC, were almost equally active against P-lactamase-inducible organisms and their basal and stably derepressed mutants.

“…Most antipseudomonal cephalosporins and penicillins are hydrolyzed more rapidly than imipenem by the 1-lactamase but do not induce its synthesis. Consequently, their MICs for ,-lactamase-inducible strains are as low as those for basal mutants, whereas derepressed mutants are more resistant (6,10). An important consequence of these observations is that the penicillins and cephalosporins tend to select derepressed mutants from inducible populations, whereas imipenem does not (3,10).…”

mentioning

confidence: 99%

Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa

Antimicrob Agents Chemother

1992

271

155

Mutational loss of the D2 porin causes imipenem resistance in Pseudomonas aeruginosa. It was found that this mechanism could function only when the chromosomal 13-lactamase was expressed. Mutants lacking both the 13-lactamase and the D2 porin were almost as susceptible as those that lacked the 13-lactamase but retained the porin. Thus, imipenem resistance reflected an interplay of the enzyme and impermeability, not either factor alone. These findings suggest that the activity of a carbapenem more 13-lactamase stable than imipenem should be less affected by the porin loss. Meropenem approached this behavior.