Nathaniel J Rhodes1, Bradley J Gardiner2, Michael N Neely3, M Lindsay Grayson4, Andrew G Ellis5, Nathan Lawrentschuk6, Albert G Frauman5, Kelly M Maxwell7, Teresa R Zembower8, Marc H Scheetz9. 1. Department of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA. 2. Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia. 3. Laboratory of Applied Pharmacokinetics and Bioinformatics, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 4. Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. 5. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia Department of Clinical Pharmacology, Austin Health, Heidelberg, Victoria, Australia. 6. Department of Surgery, Urology Unit, University of Melbourne, Melbourne, Victoria, Australia Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Victoria, Australia. 7. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 8. Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 9. Department of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA mscheetz@nm.org.
Abstract
OBJECTIVES: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS: Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS: Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS: Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L.
OBJECTIVES: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS: Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS: Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS: Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L.
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