High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

• Main Authors: Ezra B Ketema (Author), Nigus Z Gishen (Author), Abraha Hailu (Author), Abadi Leul (Author), Abera Hadgu (Author), Kiflom Hagos (Author), Samual Berhane (Author), Temesgen Tsega (Author), Madhu Page-Sharp (Author), Timothy Me Davis (Author), Brioni Moore (Author), Kevin T Batty (Author), Jonathan Carapetis (Author), Sam Salman (Author), Laurens Manning (Author)
• Format: Book
• Published: Public Library of Science (PLoS), 2021-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<h4>Introduction</h4>Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control.<h4>Methods</h4>To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM.<h4>Results</h4>A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively.<h4>Conclusions</h4>The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

Item Description

1935-2727
1935-2735
10.1371/journal.pntd.0009399