Validation of a dried blood spot ceftriaxone assay in Papua New Guinean children with severe bacterial infections [PublishAheadOfPrint]

Background: Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children from Papua New Guinea (PNG) with severe illness, a setting in which healthcare resources are limited and anemia is common.

Methods: Using a previously validated liquid chromatography-mass spectroscopy (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5-10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models.

Results: Ten children were recruited with an admission hematocrit of 0.22-0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman r_s =0.94 [95% confidence interval 0.91-0.97], P<0.0001). A marked systematic hematocrit bias was observed, with lower hematocrits resulting in underestimation of DBS-predicted plasma concentration. After adjustment for red-cell partitioning and hematocrit bias, a population PK model comparing plasma and DBS-predicted plasma concentrations did not differ in terms of key PK parameters in including clearance, volume of distribution or residual variability.

Conclusion: The performance of the ceftriaxone DBS assay is robust and provides reassurance that this platform can be used as a surrogate for plasma concentrations to provide valid PK and PK/pharmacodynamic studies of severe unwell children hospitalised in a resource limited setting. It highlights the importance of hematocrit bias in validation studies of DBS assays.

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