Clavulanate and beta-lactamase induction.

Concern has been expressed that clavulanate can antagonize ticarcillin against enterobacteria and pseudomonads that have inducible expression of chromosomal 'Class I' beta-lactamases. It is suggested that clavulanate-induced enzyme inactivates ticarcillin, which itself is a feeble inducer. We confirmed that this mechanism applied, showing that antagonism was abolished in beta-lactamase-basal mutants of inducible strains.

Interactions of meropenem with class I chromosomal beta-lactamases.

Most newer penicillins and cephalosporins are labile to the Class I beta-lactamases that are inducible in Pseudomonas aeruginosa. Enterobacter spp., Citrobacter spp.

Comparative activity of meropenem against Pseudomonas aeruginosa strains with well-characterized resistance mechanisms.

Four major mechanisms cause resistance to beta-lactams in Pseudomonas aeruginosa: (i) cell wall impermeability gives broad-spectrum intrinsic resistance to all beta-lactams except imipenem, (i) loss of D-group outer membrane proteins correlates with narrow spectrum imipenem resistance, (iii) plasmid mediated beta-lactamases compromise antipseudomonal penicillins, cefoperazone and cefsulodin, and (iv) chromosomal beta-lactamase hyper-production compromises most beta-lactams except carbenicillin and imipenem. Meropenem was tested in vitro against P. aeruginosa isolates, mutants and transconjugants with these mechanisms.

Interactions of FCE 22101 with class I beta-lactamases.

Hyperproduction of chromosomal Class I beta-lactamase causes resistance to newer cephalosporins in Enterobacter cloacae, Citrobacter freundii, Serratia spp. and indole-positive Proteeae. We examined the interactions of FCE 22101 with these enzymes, measuring (i) antibiotic lability to pure enzyme, (ii) inducing power and (iii) activity against beta-lactamase-inducible strains and their -depressed and -basal mutants.

In-vitro interactions of FCE 22101 with aminoglycosides against gram-negative rods.

Agar dilution MICs of FCE 22101 were measured for 894 consecutively-isolated Gram-negative rods from clinical specimens (413 Escherichia coli, 104 Klebsiella spp., 54 Enterobacter spp., 19 Citrobacter spp.

In-vitro activity of tigemonam, an oral monobactam, against gram-negative rods, including variants in beta-lactamase-production.

Tigemonam was compared in vitro with other orally active beta-lactams, aztreonam and ciprofloxacin against a selection of Gram-negative clinical isolates and laboratory-derived beta-lactamase-producing variants. Of the orally active beta-lactams, tigemonam was the most potent, with a spectrum of activity similar to that of aztreonam. This included stability to plasmid-mediated beta-lactamases and poor induction of chromosomal beta-lactamases.

Activity of cefpirome (HR810) against Pseudomonas aeruginosa strains with characterised resistance mechanisms to beta-lactam antibiotics.

The activities of cefpirome, cefotaxime, ceftazidime and ceftriaxone were compared against laboratory and clinical strains of Pseudomonas aeruginosa. Isolates with well characterised resistance mechanisms were included. Against carbenicillin-susceptible isolates cefpirome was more active than cefotaxime and ceftriaxone, but less active than ceftazidime.

Mechanisms of chloramphenicol resistance in Haemophilus influenzae in the United Kingdom.

Of 2458 isolates of Haemophilus influenzae examined in a recent British survey, 42 were resistant to chloramphenicol. Two resistant isolates were of type b and 40 were non-capsulate. Spectrophotometric assay showed that all the resistant isolates produced chloramphenicol acetyltransferase (CAT).

Activity of temocillin and other penicillins against beta-lactamase-inducible and -stably derepressed enterobacteria.

MICs of temocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin and ampicillin were determined for mutant series of Enterobacter cloacae, Citrobacter freundii, Proteus vulgaris, Morganella morganii and Serratia marcescens with inducible, stably derepressed or basal expression of chromosomal Class I beta-lactamases. Ampicillin was inactive (MIC greater than 256 mg/l) both against beta-lactamase-inducible organisms (except C. freundii) and their stably derepressed mutants, whereas basal mutants were sensitive (MIC 2-8 mg/l).

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

Indole-positive members of the Proteeae usually have inducible expression of chromosomal beta-lactamases. Mutants with stably derepressed beta-lactamase expression occur in inducible populations at frequencies in the range of 10(-6) to 10(-8). The contribution of these beta-lactamases to drug resistance was examined in Morganella morganii and Proteus vulgaris.

Permeation of beta-lactam antibiotics into Escherichia coli, Pseudomonas aeruginosa, and other gram-negative bacteria.

Cell wall impermeability is a major determinant of the susceptibility of gram-negative bacilli to beta-lactam antibiotics. The outer membrane, which beta-lactam agents cross via pores composed of porin proteins, is the major individual barrier in the wall structure but does not of itself exclude these antibiotics. Rather, it slows their influx to a level that the periplasmic clearance mechanisms may manage to contain.

Chromosomal beta-lactamase expression and antibiotic resistance in Enterobacter cloacae.

The activities of beta-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 beta-lactamase. These activities were correlated with the results of studies of the beta-lactamase-lability and beta-lactamase-inducer-power of the antibiotics.

Expression of H1 outer-membrane protein of Pseudomonas aeruginosa in relation to sensitivity to EDTA and polymyxin B.

During growth in magnesium (Mg++)-deficient mineral media, Pseudomonas aeruginosa cells synthesise large amounts of H1 outer-membrane protein and are resistant to polymyxins and EDTA. It has been suggested that H1 protein replaces Mg++ as an outer-membrane-stabilising component in Mg++-deprived cells, thereby removing the EDTA target and blocking an adsorption site for polymyxins. Induction of H1 protein synthesis also occurred in P.

beta-Lactamase of Pseudomonas pseudomallei and its contribution to antibiotic resistance.

beta-Lactamase production was examined in nine strains of Pseudomonas pseudomallei isolated from human, animal and environmental sources in Thailand and Hong Kong. All produced the same weakly inducible, membrane associated chromosomal cephalosporinase, which had a molecular weight of 29,500 and an isoelectric point of 7.4-7.

Clinical significance of beta-lactamase induction and stable derepression in gram-negative rods.

Most strains of enterobacteria and Pseudomonas aeruginosa produce chromosomally-determined Class I beta-lactamases. When synthesized copiously these enzymes cause resistance to almost all beta-lactams, except imipenem and, sometimes, carbenicillin and tenocillin. Elevated beta-lactamase production arises transiently, via induction, in Pseudomonas aeruginosa and Enterobacter, Citrobacter, Morganella, indole-positive Proteus and Serratia spp.

'Covalent trapping' and latamoxef resistance in beta-lactamase-derepressed Pseudomonas aeruginosa.

Three Pseudomonas aeruginosa strains which constitutively produced chromosomal (Id, or Sabath and Abraham) beta-lactamase in large amounts were resistant to latamoxef (moxalactam) MICs, 128-256 mg/l). Their beta-lactamase-basal mutants, which produced 1200-18,000-fold less enzyme, were latamoxef-sensitive (MICs, 4-16 mg/l), suggesting that the enzyme caused the resistance of the parent organisms. Latamoxef was a feeble substrate of the enzyme (kcat less than 0.

Radiolabelling of penicillin-binding proteins (PBPs) in intact Pseudomonas aeruginosa cells: consequences of beta-lactamase activity by PBP-5.

The time-course of labelling of penicillin-binding proteins (PBPs) was compared for intact and sonicated cell preparations of nine Pseudomonas aeruginosa strains, all of which gave identical PBP profiles. Saturation of all the PBPs in cell-sonicates occurred within 2 min of exposure to 35 mg/l 14[C] benzylpenicillin. PBP-5 formed an unstable penicilloyl-complex: the other PBPs formed highly stable complexes.

Beta-lactamase lability and inducer power of newer beta-lactam antibiotics in relation to their activity against beta-lactamase-inducibility mutants of Pseudomonas aeruginosa.

The interactions of imipenem, carbenicillin, cefotaxime, ceftriaxone, and azlocillin with the chromosomal beta-lactamase of Pseudomonas aeruginosa were compared. Imipenem was hydrolyzed very slowly (kcat, 1/min) and induced beta-lactamase synthesis strongly. Its minimal inhibitory concentrations (MICs) reflected this behavior, being equal (1-2 micrograms/ml) for enzyme-inducible strains and their stably derepressed mutants.

Mechanisms of resistance to cephalosporin antibiotics.

Cephalosporins, like other beta-lactams, bind to the bacterial penicillin-binding proteins (PBPs). These correspond to the D-ala-D-ala trans-, carboxy- and endo-peptidases responsible for catalysing the cross-linking of newly formed peptidoglycan. Resistance arises when the PBPs-and particularly the transpeptidases-are modified, or when they are protected by beta-lactamases or 'permeability barriers'.

Mechanisms by which imipenem may overcome resistance in gram-negative bacilli.

Imipenem is one of the carbapenem class of new beta-lactam antibiotics. It is a potent antibacterial with a broad spectrum of activity. Against Gram-negative rods, it appears to be able to circumvent the classical resistance mechanisms by way of its high affinity for PBP 2 and its good penetration of the cell wall.

Dissociation of surface properties and "intrinsic" resistance to beta lactams in Pseudomonas aeruginosa.

Carbenicillin resistance in strains of Pseudomonas aeruginosa isolated in Britain is mediated more frequently by "intrinsic factors" than by beta-lactamase production. Intrinsically carbenicillin-resistant isolates almost invariably were more resistant to azlocillin, cefoperazone, cefotaxime, ceftazidime, chloramphenicol, tetracycline and nalidixic acid than were carbenicillin-susceptible strains. This cross-resistance to different classes of antimicrobials suggested an impermeability-based mechanism of resistance, perhaps involving the outer membrane.

Behaviour of TEM-1 beta-lactamase as a resistance mechanism to ampicillin, mezlocillin and azlocillin in Escherichia coli.

Escherichia coli isolates which synthesised the extremely common 'TEM-1' plasmid mediated beta-lactamase were more resistant to the alpha-aminopenicillins, ampicillin, mezlocillin and azlocillin, than were strains which lacked this enzyme. However, many TEM-1+ isolates remained sensitive to therapeutic concentrations of mezlocillin (less than 64 mg/l), whereas virtually none was susceptible to such levels of ampicillin or azlocillin. Transconjugants of E.