Importance of beta-lactamase stability in treating today's respiratory tract infections.
In respiratory tract infections Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae and Klebsiella spp. are the most frequently encountered bacterial pathogens. Resistance of clinical S. pneumoniae isolates is known to be independent of beta-lactamase production, whereas resistance of the other species mentioned is due to beta-lactamase production. With respect to M. catarrhalis the first beta-lactamase-producing (bla+) isolate was detected in clinical specimens in 1976 and now, 70-90% of all clinical isolates are bla+. The enzymes BRO-1 and BRO-2 are transposon-mediated thus explaining their rapid spread; they hydrolyze penicillin compounds very rapidly and, to a lesser extent, the older cephalosporins. Resistance in clinical H. influenzae isolates is mainly due to the prevalence of the most widespread transposon-mediated beta-lactamase, TEM-1, which has a substrate profile resembling that of the BRO enzymes. Bla+ H. influenzae isolates make up to 6% of the total in Northern Europe, in Southern Europe up to 55% and in many African countries more than 80%. More than 95% of Klebsiella spp. isolates possess a chromosomally encoded penicillinase and to a varying extent a plasmid-mediated enzyme in addition. Recently, reports from several countries have pointed to the clinical relevance of 'extended-spectrum enzymes' derived by point mutation from the 'classical' TEM-1 or TEM-2 enzymes. These new enzymes (TEM-3 to TEM-21) exhibit a broadened substrate profile, inactivating even the oxyiminocephalosporins. The most stable compounds are ceftibuten and cefetamet. With respect to the future, these enzymes may spread between species due to their location on transposons.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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Cullmann
D001419:Bacteria / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D002511:Cephalosporins / Q000494:pharmacology / Q000627:therapeutic use*; D004251:DNA Transposable Elements; D004352:Drug Resistance, Microbial; D004795:Enzyme Stability; D006801:Humans; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
D002511:Cephalosporins; D004251:DNA Transposable Elements; D001618:beta-Lactamases