Validation of a Dried Blood Spot Ceftriaxone Assay in Papua New Guinean Children with Severe Bacterial Infections

Abstract

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 with severe illness from Papua New Guinea (PNG), a setting in which health care resources are limited and anemia is common. Using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5 to 10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models. Ten children were recruited with an admission hematocrit of 0.22 to 0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman's rank correlation coefficient [] = 0.94 [95% confidence interval, 0.91 to 0.97], < 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, including clearance, volume of distribution, and residual variability. 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 severely unwell children hospitalized in a resource-limited setting. It highlights the importance of hematocrit bias in validation studies of DBS assays.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies

“…As in this study, using a DBS assay overcomes this challenge but does have some limitations. Some DBS assays are vulnerable to systematic bias when there are a wide range of haematocrits 32 . With this particular assay, and with a narrow range of haemoglobin measurements seen amongst the participants of this study, a significant haematocrit effect is unlikely.…”

Determination of ceftriaxone in human plasma using liquid chromatography–tandem mass spectrometry

“…Although the drug was discovered in the 1980s by Hoffmann-La Roche, some PK/PD properties, particularly in neonates, have not been well defined. Published pharmacokinetic studies were mostly performed in adults, excluding populations such as neonates with severe infections, infants, and malnourished young children [6][7][8][9][10] . To be able to perform PK/PD studies on these groups, a sensitive and selective bioanalytical method is needed.…”

Population Pharmacokinetic Study of Ceftriaxone in Elderly Patients, Using Cystatin C-Based Estimates of Renal Function To Account for Frailty

“…We then explored whether estimation of renal function through plasma CysC might have more utility in a PK model than Cr-based equations. Because ceftriaxone is typically initiated in an emergency department (ED) setting, we used validated measurement of ceftriaxone concentrations in capillary dried blood spots (DBS) that allowed repeated, nondisruptive, small-volume sampling (17,18).…”