High dose oral amoxicillin attains pharmacokinetic efficacy endpoints in young infants (0-59 days) with suspected sepsis - a population pharmacokinetic pilot study Open Access

Abstract

Background: WHO recommends hospital admission and parenteral antibiotics for young infants (aged 0-59 days) with serious bacterial illness in developing countries. Oral antibiotics however are an important, though understudied alternative in settings where these recommendations are poorly accepted or implemented. This pharmacokinetic (PK) pilot study assesses efficacy of oral amoxicillin in young infants in Karachi receiving high dose oral amoxicillin and intramuscular gentamicin for sepsis, heretofore unknown in this population.

Objective: To observe serum levels of amoxicillin and assess PK efficacy targets (Time above MIC) in 0-2 month infants with suspected sepsis receiving 75-100mg/kg/dose of oral amoxicillin

Methods: A pilot study using population pharmacokinetic approach with a minimum of three blood samples per subject was considered optimal to determine serum levels of amoxicillin in sick young infants in Karachi. Timepoints for sparse sampling were 0 (before index dose), 2-3 and 6-8 hours (after index dose). Samples were shipped to Department of Clinical Pharmacology, Childrens Mercy Hospital, Kansas, MO for amoxicillin concentrations by HPLC with mass spectrometry.

Results: Amoxicillin levels were determined in 129 sera samples from 60 young infants. Forty-four infants contributing blood at ≥2 of 3 specified timepoints were included in analysis. Mean amoxicillin levels at 2-3 hours (11.6±9.5 mg/L, n=44) and 6-8 hours (16.4±9.3 mg/L, n=20) following the index dose exceeded the susceptibility breakpoint for amoxicillin (2.0mg/L) against resistant S.pneumoniae strains. Of 20 infants with 3 serum levels, 7 showed a classic dose-exposure profile, 13 showed delayed excretion. Two of 7 infants with classic time-exposure curves had atypically prolonged half life unexplained by gestation and weight. In remaining children, patient-specific pharmacokinetics could not be determined. Two of 24 had clinical treatment failure. Six of 44 infants had a positive blood culture with predominance of gram positive organisms.

Conclusion: This pilot study generated observational data showing that oral amoxicillin concentrations in newborns following oral administration exceed the susceptibility breakpoint for >50% of a 12-hour dosing interval. A powered study to look into reasons for delayed excretion of oral amoxicillin in our young infants should follow.

Table of Contents

Table of Contents
INTRODUCTION 1
BACKGROUND 6
Etiology of neonatal sepsis in developing countries 6
The case for oral antibiotics for neonatal sepsis 7
Standard of care for neonatal sepsis 7
Clinical Studies where oral antibiotics were used for Neonatal Sepsis 8
Clinical Studies where oral antibiotics were used for Pneumonia 9
Clinical Studies where oral antibiotics were used for Meningitis 10
Population PK versus Classic PK approach 11
Public Health Implications 12
Single dose versus multiple dose pharmacokinetics 12
Pharmacodynamic Surrogate 12
Mechanism of Action 15
Pharmacokinetics of Amoxicillin 15
Systemic bioavailability 15
Absorption 16
Excretion 17
Volume of distribution (VD) 17
Clearance (CL) 18
Elimination half life (t1/2) 18
Indications 18
Resistance 19
Dosing 20
Dosage Forms 20
Safety and adverse effects 20
Pharmacokinetic Studies of Parenteral amoxicillin in newborns and young infants 20
Pharmacokinetic Studies of Oral amoxicillin in newborns and young infants 21
Pharmacokinetic Studies on aminoglycosides co-administered with oral β-lactams in young infants 22
METHODOLOGY 23
Objectives 23
Null Hypothesis: 23
Study Design 23
Study Subjects 24
Selection Criteria for oral amoxicillin population-pharmacokinetic study: 24
Inclusion Criteria 24
Exclusion Criteria 25
Variables of Interest 26
Predictor Variables 26
Outcome Variables 27
Sample size 27
Study Antibiotic 28
Amoxicillin Assay Method Development and Validation 28
Reagents 28
QC samples and standard solutions 28
Sample Preparation 29
HPLC/MS conditions 29
Data analysis 30
Validation 30
Quality Assurance 32
Data Analysis 32
RESULTS 35
DISCUSSION 38
REFERENCES 44
FIGURES 52
Figure 1 Time-concentration curve for Patient 101 52
Figure 2 Time-concentration curve for Patient 216 53
Figure 3 Time-concentration curve for Patient 225 54
Figure 4 Standard Curve showing linearity of Amoxicillin Kinetics 55
Figure 5a Composite dose concentration-time plot showing > 80% of amoxicillin concentrations at second and third sampling were above MIC2.0 56
Figure 5b Minimal improvement in goodness of fit (composite dose concentration-time curve) of 20 young infants with >2 amoxicillin levels by removing outliers 56
Figure 6 Distribution of time-concentration values in 44 infants with ≥2 and 20 infants with 3 amoxicillin serum levels (on 75-100mg/kg/dose oral amoxicillin) 57
Figure 7 Range of Sampling Time and amoxicillin concentration achieved based on elimination kinetics status 58
Figure 8a Serum Amoxicillin Levels in 7 young infants at 0, 2, 6 and 12 hours of index dose 59
Figure 8b Serum Amoxicillin Levels in 13 young infants at 0, 2 and 6 hours of index dose 59
TABLES 60
Table 1 Social demographic, clinical and laboratory profile of young infants with sepsis undergoing oral amoxicillin pharmacokinetic assessment (n=44) 60
Table 2 Distribution of socio-demographic, clinical and pharmacokinetic covariates by achievement of amoxicillin excretion kinetics (appropriate for age n=7) (delayed excretion n=13) 61
Table 3 One-way ANOVA to show comparability between three outcome groups 62
Table 4 PK/PD Parameters for patients achieving appropriate dose concentration curves (n=7) 63
Table 5 Predictors of delayed excretion among 7 achieving dose-concentration - time curves 64
ANNEXURES 65
Annex 1 Flowchart showing sequence of venepuncture for determining amoxicillin kinetics in young infants with sepsis 65
Annex 2 Flowchart showing progress of Amoxicillin PK study participants from enrolment to end of study 66
Annex 3 Antibiotic Dosage for Neonatal Sepsis Trials 67
Annex 4 Amoxicillin pharmacokinetic parameter estimates derived from the medical literature 68
Annex 5 Clinical Studies with amoxicillin use in children derived from the medical literature 77

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Medicine and Surgery Health Sciences, Epidemiology
Keyword	population pharmacokinetics pakistan primary health care settings oral amoxicillin young infant sepsis
Committee Chair / Thesis Advisor	Keyserling, Harry L, Emory University
Committee Members	Boring, John R, Emory University McGowan Jr., John E, Emory University Klein, Mitchel, Emory University

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