Analysis of histamine and sisomicin in gentamicin: Search for the causative agents of adverse effects.

Jonas Wohlfart, Ulrike Holzgrabe

Archiv der Pharmazie 2021 Dec

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In 1998, the aminoglycoside antibiotic gentamicin sulfate caused several cases of deaths in the United States, after the switch from twice- to once-daily application. Endotoxins were discussed as the cause for the adverse effects and sisomicin was identified as the lead impurity; batches containing sisomicin were contaminated with more impurities and were responsible for the fatalities. In 2016, anaphylactic reactions in horses, and later in humans with one fatality, were observed after application of gentamicin sulfate contaminated with histamine. To determine whether histamine was responsible for the 1990s death cases as well, histamine was quantified by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 samples of gentamicin sulfate analyzed in previous studies. Furthermore, a relative quantification of sisomicin was performed to check for a correlation between histamine and the lead impurity. A maximum amount of 11.52 ppm histamine was detected, which is below the limit for anaphylactic reactions of 16 ppm, and no correlation of the two impurities was observed. However, the European Medicines Agency recommends a stricter limit with regard to the maximum single dose of gentamicin sulfate to reach a greater gap between the maximum histamine exposition of 4.3 µg and the quantity known to cause hypotension of 7 µg. The low amounts of histamine and the fact that there is no connection with the contamination with sisomicin showed that histamine was not the cause for the death cases in the United States in 1998, and endotoxins remain the most probable explanation. © 2021 The Authors. Archiv der Pharmazie published by Wiley-VCH Verlag GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.

Citation

Jonas Wohlfart, Ulrike Holzgrabe. Analysis of histamine and sisomicin in gentamicin: Search for the causative agents of adverse effects. Archiv der Pharmazie. 2021 Dec;354(12):e2100260