cefoxitin and temocillin

While carbapenem resistance in Gram-negative bacteria is mainly due to the production of efficient carbapenemases, β-lactamases with a narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10-type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study, two novel OXA-10 variants were identified as the sole carbapenem-hydrolyzing enzymes in meropenem-resistant enterobacteria isolated from hospital wastewater and found by next-generation sequencing to express additional β-lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host-range plasmids. Compared to the sequence of OXA-10, they both harbored a Thr26Met substitution, with OXA-655 also bearing a leucine instead of a valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Base Sequence; beta-Lactam Resistance; beta-Lactamases; Catalytic Domain; Cefoxitin; Cloning, Molecular; Enterobacteriaceae; Gene Expression; Hospitals; Humans; Hydrolysis; Isoenzymes; Kinetics; Meropenem; Microbial Sensitivity Tests; Models, Molecular; Oxacillin; Penicillins; Plasmids; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Recombinant Proteins; Substrate Specificity; Wastewater

Hamsters given the new penicillin temocillin, either orally or by injection, did not develop antibiotic-associated colitis, whereas animals given the control antibiotics cefoxitin or clindamycin developed the disease, which is characterized by marked hemorrhagic cecitis and high cecal levels of Clostridium difficile cytotoxin.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cefoxitin; Clindamycin; Clostridium; Colitis; Cricetinae; Feces; Gastrointestinal Hemorrhage; Injections, Subcutaneous; Mesocricetus; Penicillins

The studies reported here were designed to ascertain whether or not the new beta-lactam antibiotic, temocillin, would produce antibiotic-associated colitis in the hamster. The experiments were controlled with clindamycin and cefoxitin, which are known to induce antibiotic-associated colitis experimentally and clinically. All three antibiotics were administered to groups of animals both parenterally and orally. Clindamycin, at 1 mg/hamster, caused a slow onset of antibiotic-associated colitis by both routes, with death occurring at between 4 and 8 days. 80 to 100% of the animals had diarrhoea and showed signs of haemorrhage and caecal distension, with the caecal contents being Clostridium difficile toxin-positive. The onset of antibiotic-associated colitis after administration of cefoxitin was less marked at the 1 mg parenteral dose, with only 40% of the hamsters showing signs of colitis. At the higher doses of cefoxitin, colitis was more severe and the animals exhibited dramatic weight loss, with death occurring at between 3 and 5 days. The majority of animals had diarrhoea and were C. difficile toxin-positive; 60 to 80% also showed signs of haemorrhage and caecal distension. In contrast, the hamsters receiving temocillin remained healthy with no signs of diarrhoea, and showed consistent weight gain. No pathological abnormalities were observed and the caecal contents were toxin-negative. These results suggest that temocillin therapy in humans is unlikely to cause significant disturbance of the gastrointestinal flora.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cecum; Cefoxitin; Clindamycin; Colitis; Cricetinae; Injections, Subcutaneous; Male; Penicillins

The interaction of 6 alpha-(temocillin) and 7 alpha-methoxy substituted (cefoxitin) beta-lactam compounds with various beta-lactamases was studied employing enzyme kinetics and compared to that of unsubstituted compounds. Both chromosomally mediated enzymes from Enterobacter cloacae and Citrobacter freundii were competitively inhibited by the methoxy-substituted compounds. Higher concentrations of cefoxitin caused a competitive inhibition of the plasmid-mediated Tem-1 enzyme, whereas temocillin led to a non-competitive inhibition of the Tem-1 enzyme. These results indicate that the discrepancies in the interaction on the above mentioned compounds have to be attributed to the different molecular structure of the beta-lactam nucleus. Moreover, no predictions can be made on the basis of an analogy between 6 alpha-methoxy-penams and 7 alpha-methoxy cephems.

Topics: beta-Lactamases; Binding, Competitive; Cefoxitin; Cephalosporinase; Cephalosporins; Cephalothin; Chromosomes, Bacterial; Citrobacter; Enterobacter; Escherichia coli; Kinetics; Penicillinase; Penicillins; Plasmids; Ticarcillin