Summary
Bacterial resistance to β-lactam antibiotics is becoming increasingly important. This resistance is often mediated by the production of β-lactamase enzymes which destroy the antibiotics. Such resistance might be overcome firstly by developing antibiotics which are resistant to destruction by β-lactamase; secondly, by developing antibiotics of very high potency; thirdly, antibiotics could be developed which release antibacterially active moities on hydrolysis by β-lactamase. The fourth and perhaps one of the most promising approaches is to develop molecules which inactivate β-lactamases. Combinations of broadspectrum penicillins with isoxazole penicillins have been investigated but for various reasons were not successful in therapy. Recently clavulanic acid, a naturally occurring β-lactam molecule, has been investigated by the authors and other workers. Unlike isoxazole penicillins, clavulanic acid inhibits β-lactamase activity at low concentrations. The activity of ampicillin, cephaloridine or carbenicillin in combination with clavulanic acid against 215 bacterial isolates has been investigated. Concentrations as low as 1 mg/l of clavulanic acid regularly rendered ampicillin-resistant strains ofBacteroides fragilis, Haemophilus influenzae andStaphylococcus aureus sensitive to attainable blood concentrations of amoxycillin. 5 mg/l of clavulanic acid brought the majority of strains ofProteus mirabilis, all strains ofProteus vulgaris, most strains ofKlebsiella pneumoniae and a small proportion of ampicillin-resistant strains ofEscherichia coli into the therapeutic range of amoxycillin. Increasing the concentration of clavulanic acid to 10 mg/l rendered the majority of strains ofE. coli sensitive to amoxycillin. The combination did not show enhanced activity againstEnterobacter species,Serratia marcescens, and most strains ofProteus rettgeri andProteus morganii. There was no enhanced activity between carbenicillin and clavulanic acid against either carbenicillin-sensitive or carbenicillin-resistant strains ofPseudomonas aeruginosa. As would be expected the activity of amoxycillin was not enhanced against ampicillin-sensitive strains of various species or against inherently sensitive species. In a single, simple preliminary experimental mouse infection using intra-peritoneal inoculation ofKlebsiella pneumoniae, protection was suggested by a combination of amoxycillin with clavulanic acid given as two doses where as the individual drugs did not protect. It was concluded that the combined use of clavulanic acid with a broad-spectrum β-lactum antibiotic showed therapeutic potential and was deserving of further evaluation.
Zusammenfassung
Eine Bakterienresistenz gegen β-Laktam-Antibiotika wird immer bedeutsamer. Diese Resistenz beruht oft auf der Erzeugung von β-Laktamase-Enzymen, die die Antibiotika zerstören. Sie ließe sich überwinden erstens durch Entwicklung von gegenüber dieser Zerstörung resistenten Antibiotika; zweitens durch die Entwicklung hochpotenter Antibiotika; drittens durch die Entwicklung von Antibiotika, die bei der Hydrolyse durch β-Laktamase antibakteriell aktive Gruppen freisetzen. Das vierte und vielleicht eines der zukunftsreichsten Verfahren ist die Entwicklung von Molekülen, die β-Laktamasen inaktivieren. Erprobt wurden Kombinationen von Breitband-Penicillinen mit Isoxazol-Penicillinen, die sich aber aus verschiedenen Gründen therapeutisch nicht bewährt haben. Neuerdings wurde die Klavulansäure, ein natürlich vorkommendes β-Laktammolekül, vom Verfasser und anderen Autoren untersucht. Im Gegensatz zu Isoxazol-Penicillinen hemmt die Klavulansäure die β-Laktamase-Aktivität in niedrigen Konzentrationen. Untersucht wurde die Aktivität von Ampicillin, Cephaloridin und Carbenicillin in Kombination mit Klavulansäure gegen 215 Bakterienisolate. Konzentrationen von nicht mehr als 1 mg/l Klavulansäure machten Ampicillin-resistente Stämme vonBacteroides fragilis, Haemophilus influenzae undStaphylococcus aureus empfindlich gegen übliche Blutkonzentrationen von Amoxicillin. 5 mg/l Klavulansäure brachten die Mehrzahl von Stämmen vonProteus mirabilis, alle Stämme vonProteus vulgaris, die meisten Stämme vonKlebsiella pneumoniae und einen kleinen Anteil Ampicillin resistenter Stämme vonEscherichia coli in den therapeutischen Bereich des Amoxicillins. Steigerung der Konzentration auf 10 mg/l machte die meisten Colistämme Amoxicillinempfindlich. Die Kombination ergab keine gesteigerte Aktivität gegenEnterobacter-Arten,Serratia marcescens und die meisten Stämme vonProteus rettgeri undProteus morganii. Die Kombination Carbenicillin-Klavulansäure erhöhte die Aktivität gegen Carbenicillin-empfindliche oder -resistente Stämme vonPseudomonas aeruginosa nicht. Wie zu erwarten, ließ sich die Aktivität von Amoxicillin gegen Ampicillin-empfindliche Stämme verschiedener Spezies oder gegen vorgegeben empfindliche Spezies nicht erhöhen. Bei einer experimentellen Mäuse-Infektion mittels intraperitonealer Inokulation mitKlebsiella pneumoniae erbrachte eine Kombination von Amoxicillin mit Klavulansäure (als 2malige Einzelgabe) eine stark erhöhte Schutzwirkung, im Gegensatz zum Versagen dieser Substanzen bei ihrer isolierten Verabreichung. Bei Steigerung der Infektionsdosis war eine gewisse Schutzwirkung zu beobachten, die aber nicht anhielt. Es wurde gefolgert, daß die Kombination von Klavulansäure mit einem Breitband-β-Laktam-Antibiotikum ein therapeutisches Potential darstellt und weitere Prüfung verdient.
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Reeves, D.S., Bywater, M.J. & Holt, H.A. Antibacterial synergism between beta-lactam antibiotics: Results using clavulanic acid (BRL. 14151) with amoxycillin, carbenicillin or cephaloridine. Infection 6 (Suppl 1), S9–S16 (1978). https://doi.org/10.1007/BF01646057
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DOI: https://doi.org/10.1007/BF01646057