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The concentrations of these molecules that resulted in 50% inhibition of enzyme activity were 0.4 to 3.1 nM for the TEM-1 enzyme, 7.8 to 72 nM for Imi-1, 1.5 to 4.8 nM for AmpC, and 14 to 260 nM for a CcrA metalloenzyme. All the inhibitors were more stable than imipenem against hydrolysis by hog and human dehydropeptidases. Piperacillin was combined with a constant 4-\u03bcg\/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2- to 32-fold for extended-spectrum \u03b2-lactamase (ESBL)-producing<jats:italic>Escherichia coli<\/jats:italic>and<jats:italic>Klebsiella pneumoniae<\/jats:italic>strains. The MICs for piperacillin-resistant (MIC of piperacillin, &gt;64 \u03bcg\/ml) strains of<jats:italic>Enterobacter<\/jats:italic>spp.,<jats:italic>Citrobacter<\/jats:italic>spp., and<jats:italic>Serratia<\/jats:italic>spp. were reduced to the level of susceptibility (MIC of piperacillin, \u226416 \u03bcg\/ml) when the drug was combined with 4, 2, or 1 \u03bcg of these penem inhibitors\/ml. Protection against acute lethal bacterial infections with class A and C \u03b2-lactamase- and ESBL-producing organisms in mice was also demonstrated with piperacillin plus inhibitor. Median effective doses were reduced by approximately two- to eightfold compared to those of piperacillin alone when the drug was combined with the various inhibitors at a 4:1 ratio. Pharmacokinetic analysis after intravenous administration of the various inhibitors showed mean residence times of 0.1 to 0.5 h, clearance rates of 15 to 81 ml\/min\/kg, and volumes of distribution between 0.4 and 2.5 liters\/kg. The novel methylidene penem molecules inhibit both class A and class C enzymes and warrant further investigation for potential as therapeutic agents when used in combination with a \u03b2-lactam antibiotic.<\/jats:p>","DOI":"10.1128\/aac.48.12.4589-4596.2004","type":"journal-article","created":{"date-parts":[[2004,11,24]],"date-time":"2004-11-24T03:00:46Z","timestamp":1101265246000},"page":"4589-4596","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["In Vitro and In Vivo Activities of Novel 6-Methylidene Penems as \u03b2-Lactamase Inhibitors"],"prefix":"10.1128","volume":"48","author":[{"given":"William J.","family":"Weiss","sequence":"first","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LuAnna","family":"Tardio","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia A.","family":"Bradford","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aranapakam M.","family":"Venkatesan","sequence":"additional","affiliation":[{"name":"Chemical and Screening Sciences, Wyeth Research, Pearl River, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Abe","sequence":"additional","affiliation":[{"name":"Wyeth-Lederle Japan, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Isoda","sequence":"additional","affiliation":[{"name":"Wyeth-Lederle Japan, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ado","family":"Mihira","sequence":"additional","affiliation":[{"name":"Wyeth-Lederle Japan, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Ushirogochi","sequence":"additional","affiliation":[{"name":"Wyeth-Lederle Japan, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Takasake","sequence":"additional","affiliation":[{"name":"Wyeth-Lederle Japan, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Projan","sequence":"additional","affiliation":[{"name":"Protein Technologies, Wyeth Research, Cambridge, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"O'Connell","sequence":"additional","affiliation":[{"name":"Infectious Disease and Oncology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tarek S.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Chemical and Screening Sciences, Wyeth Research, Pearl River, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.1016\/S0021-9258(19)39692-9","volume":"265","year":"1990","unstructured":"Adachi, H., Y. 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