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Development of sulphonamide-trimethoprim combinations for urinary tract infections

Entwicklung von Sulphonamid-Trimethoprim-Kombinationen für die Behandlung von Harnwegsinfektionen. Teil I: Vergleich der antibakteriellen Aktivität von Sulphonamiden allein und in Kombination mit Trimethoprim

Part I: Comparison of the antibacterial effect of sulphonamides alone and in combination with trimethoprim

  • Pharmacological Evaluation
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Summary

Plasma half life and in vitro activity were major criteria for selection of sulphonamides which are likely to give a strong synergistic action with trimethoprim in vivo. On the basis of literature data six sulphonamides, sulphadiazine, sulphachloropyridazine, sulphamethoxazole, sulphaisodimidine, sulphamerazine and sulphamethomidine appeared particularly suitable for combination with trimethoprim. An investigation of the activity in vitro of these compounds and their combinations with the latter against clinically isolated, sulphonamide-sensitiveKlebsiella-Enterobacter andEscherichia coli strains showed optimal synergy at trimethoprim-sulphonamide ratios between 1:10 and 1:40, but that appreciable mutual potentiation occurred within a rather broad range of concentration ratios. Limited experiments indicated that synergy occurs less frequently and is less pronounced against sulphonamide resistant bacteria. The different sulphonamides behaved rather similarly in their combinations with trimethoprim, and in order to find the best sulphonamide, detailed comparisons of the pharmacokinetic properties of the different combinations are necessary.

Zusammenfassung

Plasmahalbwertszeit und Aktivität in vitro waren Hauptkriterien bei der Auswahl von Sulphonamiden, die mit Trimethoprim eine starke synergistische Wirkung in vivo geben sollten. An Hand von Literatur-Daten erschienen sechs Sulphonamiden, Sulphadiazin, Sulphachlorpyridazin, Sulphamethoxazol, Sulphaisodimidin, Sulphamerazin und Sulphamethomidin, als besonders geeignet zur Kombination mit Trimethoprim. Eine Untersuchung der In-vitro-Aktivität dieser Verbindungen und deren Kombinationen mit Trimethoprim gegen klinisch isolierte sulphonamidempfindlicheKlebsiella-Enterobacter-undEscherichia coli-Stämme zeigte einen optimalen Synergismus bei einem Verhältnis Trimethoprim-Sulphonamid zwischen 1:10 und 1:40, jedoch wurde eine nachweisbare gegenzeitige Potenzierung der Aktivitäten beider Komponenten über einen ziemlich breiten Bereich von Konzentrationsverhältnissen gefunden. Begrenzte Untersuchungen zeigten, daß die synergistische Wirkung weniger oft und weniger ausgeprägt bei sulphonamidresistenten Keimen vorkommt. Die verschiedenen Sulphonamide verhielten sich in der Kombination mit Trimethoprim ziemlich ähnlich; um das geeignetste Sulphonamid herauszufinden sind eingehende Vergleiche der pharmakokinetischen Eigenschaften der verschiedenen Kombinationen notwendig.

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Authors and Affiliations

  1. Research and Development Laboratories, Astra Läkemedel AB, S-151 85, Södertälje, Sweden

    B. Ekström &  B. Örtengren

  2. Department of Clinical Microbiology, Gävle Hospital, S-803 54, Gävle, Sweden

    U. Forsgren

  3. Department of Microbiology, University of Oslo, Institute of Pharmacy, Postboks 1108, Blindern, Oslo 3, Norway

    T. Bergan

Authors
  1. B. Ekström
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  2. U. Forsgren
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  3. B. Örtengren
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  4. T. Bergan
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Ekström, B., Forsgren, U., Örtengren, B. et al. Development of sulphonamide-trimethoprim combinations for urinary tract infections. Infection 7 (Suppl 4), S359–S366 (1979). https://doi.org/10.1007/BF01639014

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