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High dose treatment with antibiotics in cystic fibrosis — A reappraisal with special reference to the pharmacokinetics of betalactams and new fluoroquinolones in adult CF-patients

Antibiotika-Hochdosis-Therapie bei Patienten mit zystischer Fibrose — Kritische Revision unter besonderer Berücksichtigung der Pharmakokinetik derβ-Laktame und der neuen fluorierten Chinolone bei erwachsenen CF-Patienten

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Summary

In this review we analyzed the pharmacokinetic basis for high dose treatment with antibiotics of patients with cystic fibrosis. Both our results and those from other well designed pharmacokinetic studies do not support the view that low blood levels of antibacterials are a common feature of CF. We were unable to detect a decrease in absorption, nor could we find evidence for enhanced elimination of antibacterials in CF. Both these factors have been considered responsible for reducing the plasma (and tissue) levels of antibiotics. Most recent studies on kidney function are in agreement with these findings, since neither inulin nor creatinine clearance differ between CF-patients and healthy volunteers. In contrast to previous discussion, the volume of distribution (Vdss) was not elevated for any compound. The rational of weight correction of volume terms like Vdss or total clearance has never been clearly demonstrated and should therefore not be used without prior proof of relevance. Since the variability of pharmacokinetic parameters of antibiotics in CF-patients may be considerable, we suggest that a dose increase of 20–30% may be justified, but cannot agree with two to fourfold increases in dosage as previously proposed and applied in many CF-centers. Until more findings become available for non-adult CF-patients, these conclusions are only valid for adult CF-patients.

Zusammenfassung

In dieser Übersichtsarbeit wurde von uns die Grundlage der Hochdosierungstherapie von Antibiotika bei Mukoviszidose kritisch analysiert. Wir verwendeten sowohl Daten aus der Literatur als auch eigene Ergebnisse. Weder die Literaturdaten, die von uns geforderte Kriterien für Vergleichbarkeit erfüllen, noch unsere eigenen Daten haben Hinweise für generell niedrige Plasmaspiegel von Antibiotoka bei Mukoviszidose-Patienten ergeben. Wir haben außerdem nicht zeigen können, daß die Resorption verringert oder die Elimination beschleunigt ist. Beides würde die Plasma-(Gewebs-) Spiegel von Antibiotika erniedrigen. Neuere Untersuchungen zur Nierenfunktion bestätigen diese Ergebnisse, da sich weder die Inulin- noch die Kreatinin-Clearance von CF-Patienten und Gesunden unterschied. Auch die Verteilungsvolumina der Antibiotika waren nicht erhöht, wie das oft diskutiert worden war. Wir haben außerdem die Grundlagen für die oft praktizierte Gewichtskorrektur von Volumenparametern wie Cltot oder Vdss analysiert und sind zu dem Ergebnis gekommen, daß man nicht ungeprüft annehmen kann, daß eine Gewichtskorrektur dieser Volumenparameter für jede Substanz sinnvoll ist. Um die jedoch vorhandene beträchtliche Variabilität der pharmakokinetischen Parameter von Antibiotika bei Mukoviszidose-Patienten ausgleichen zu können, schlagen wir eine Dosiserhöhung um 20 bis 30% vor. Eine Dosiserhöhung um das Zwei- bis Vierfache, wie bisher vorgeschlagen und in vielen CF-Zentren durchgeführt, ist jedoch nach unserer Ansicht nicht gerechtfertigt. Bevor nicht ähnliche Untersuchungen auch bei nicht-erwachsenen CF-Patienten vorliegen, gelten die hier gemachten Dosierungsvorschläge nur für erwachsene Mukoviszidose-Patienten.

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Authors and Affiliations

  1. Department of Pediatrics, University of Essen, Hufelandstr. 55, 4300, Essen 1, FRG

    F. Sörgel

  2. Institute for Biomedical and Pharmaceutical Research, Harrichstr. 5, 8500, Nürnberg, FRG

    F. Sörgel

  3. Department of Pediatrics, University of Essen, Hufelandstr. 55, 4300, Essen, FRG

    U. Stephan,  H. -G. Wiesemann &  B. Gottschalk

  4. Department of Pediatrics, University of Erlangen, Loschgestr. 15, 8520, Erlangen, FRG

    C. Stehr,  M. Rey &  H. B. Böwing

  5. Department of Pediatrics, University of Münster, Albert-Schweitzer-Str. 33, 4400, Münster, FRG

    H. C. Dominick

  6. Institute for Forensic Toxicology, University of Erlangen-Nürnberg, Universitätsstr. 22, 8520, Erlangen, FRG

    M. Geldmacher von Mallinckrodt

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Sörgel, F., Stephan, U., Wiesemann, H.G. et al. High dose treatment with antibiotics in cystic fibrosis — A reappraisal with special reference to the pharmacokinetics of betalactams and new fluoroquinolones in adult CF-patients. Infection 15, 385–396 (1987). https://doi.org/10.1007/BF01647751

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