A Reappraisal of Current Dosing Strategies for Intravenous Fosfomycin in Children and Neonates
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The rising incidence of multi-drug resistant bacterial pathogens has renewed interest in the long-known antibacterial fosfomycin. Not least because of its low toxicological potential, there is good clinical experience with intravenous fosfomycin for various Gram-positive and Gram-negative infections in the treatment of children and neonates. However, the current dosing recommendations for intravenous fosfomycin vary widely in paediatric patients.
In the present review, we summarized available plasma pharmacokinetic data derived from neonates or children following intravenous administration of fosfomycin. Subsequently, we used this information for recalculation of different dosing strategies and simulated a variety of clinically applied dosing regimens. The percentage of time above the minimal inhibitory concentration (T>MIC) was calculated for each dosing strategy, as this pharmacokinetic-pharmacodynamic parameter was shown to be most predictive of antimicrobial and clinical success of fosfomycin treatment.
Our data corroborate the current practice of selecting the dosage of intravenous fosfomycin primarily on the basis of bodyweight and age in paediatric patients. As with other ‘time-dependent’ antibacterials, a dosing interval of 6–8 hours should be preferred over 12 hours except for immature neonates. Given a T>MIC target of 40–70%, currently recommended dosing strategies appear to be insufficient in children aged 1–12 years, if pathogens with MICs of ±32mg/L are suspected and subjects are presenting with normal renal function. Likewise, the lowest recommended daily dose for neonates and infants (aged up to 12 months) of 100 mg/kg body weight of fosfomycin should be considered only for pre-term neonates with a postmenstrual age below 40 weeks.
KeywordsFosfomycin Plasma Concentration Data Interstitial Space Fluid Effective Target Site Concentration Apparent Terminal Elimination Rate Constant
We very much appreciate Dieter Steinort’s personal input and significant dedication to make this interdisciplinary article possible. He is a consultant for J&P Medical Research Ltd (Vienna, Austria).
Transparency declarations: J&P Medical Research Ltd is an international independent life-science research institute, basically operating according to the public-private-partnership concept. C. Joukhadar is the managing director of J&P Medical Research Ltd, owns 100% options, and is also a consultant for pharmaceutical companies, including Sandoz and InfectoPharm, two manufacturers of fosfomycin. F. Traunmüller is an employee of J&P Medical Research Ltd. All other authors declare that they have no relationship with companies that make products relevant to the manuscript, and that they have no conflicts of interest with the present work. No funding was received for the present article.
List of authors and contributions: Friederike Traunmüller — primary author of the manuscript; Martin Popovic — pharmacokinetic modelling of data; Karl-Heinz Konz — substantive suggestions for revision; Patrick Vavken — co-author of the manuscript and figures; Andreas Leithner — proofreading and substantial revision of the manuscript; Christian Joukhadar — planning of the article, interpretation of data, approval of the final version of the manuscript and corresponding author.
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