Abstract
IntroductionIntramuscular 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.MethodsTo 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.ResultsA 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.ConclusionsThe 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.
Highlights
Accepted: April 21, 2021Published: June 11, 2021
Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD)
[1] The administration of benzathine penicillin G (BPG) injections remains the cornerstone of secondary prophylaxis to prevent recurrent acute rheumatic fever (ARF) and Rheumatic heart disease (RHD). [2,3,4] BPG is superior to oral penicillin and non-penicillin antibiotics in preventing skin or throat infections caused by Streptococcus pyogenes (Group A Streptococcus; Strep A) which precede episodes of ARF. [5,6] Based on efficacy and pharmacokinetic (PK) data from studies conducted in the 1950s, most guidelines still recommend a 900 mg dose (1.2 million international units [MU]) of BPG every 3–4 weeks administered by deep intramuscular (IM) injection for a minimum of 10 years. [3,4,7] After injection, the benzylpenicillin G dissociates from the benzathine moiety and is absorbed from the injection site into the blood stream
Summary
Data Availability Statement: All data are in the manuscript and its supporting information files. The laboratory analysis was supported by Curtin University and University of Western Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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
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