Feiyan Liu (1), Calie Dyer (2), Katy Thomson (2), Kirsty Sands (2), Timothy Walsh (2), J.G. Coen van Hasselt (1)
(1) Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; (2) Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
Objectives: Neonatal sepsis in low- and middle-income countries (LMICs) represents a global health concern due to high mortality rates and the rise of antimicrobial resistance. The BARNARDS project is an international collaborative of research into the Burden of Antibiotic Resistance in Neonates in Developing Societies. Recently, BARNARDS has completed an international multi-center study investigating treatment of neonatal sepsis in LMICs.
In this analysis we study the expected efficacy for four of the most commonly used antibiotic combination dosing schedules for treatment of sepsis in neonates enrolled in the BARNARS study. Efficacy was inferred by deriving the model-based probability of pharmacokinetic-pharmacodynamic (PKPD) target attainment (PTA) values in individual patients. Specifically we aimed to (i) evaluate the relationship between PTA and observed clinical outcomes (i.e. mortality); (ii) determine the effect of site-specific differences of antibiotic dose regimens on PTA; and (iii) compare expected PTA of the four most commonly used combinations against meropenem, fosfomycin or colistin.
Methods:
We included 476 neonates in our analysis who received the four most commonly used antibiotic combinations: ampicillin-gentamicin (AMP-GEN), amoxicillin-amikacin (AMX-AMK), ceftazidime-amikacin (CAZ-AMK), and piperacillin/tazobactam-amikacin (TAP-AMK). The dataset contained information on patient age (including gestational age and post-natal age), sex, antibiotic therapies used, dose regimens by countries and MIC values for pathogens isolated from each patient. We derived individual patient characteristics including birth weight, current body weight, serum creatinine (SCR) and albumin (ALB) using global global growth chart reference values for weight-by-age and renal-function-by age after adjusting by a ratio between global and local values in LMICs[1-6]. These additional characteristics were included as covariates in population PK models used for the PK/PD simulations. In case of missing values for individual patients we imputed these values with population means.
We simulated expected concentration-time profiles for each antibiotic combination used in individual patients, taking into account known inter-individual variation in PK parameters and patient-specific predictors for such variations (e.g. age, renal function). Simulations which performed 1000 times were based on previously published population PK models in neonates [7-12] and were conducted using the R package RxODE.
The PTA for each combination was computed when at least one of the antibiotics reaches their target value. The resulting PTA values were compared to observed survival outcome. Additional simulations for meropenem, fosfomycin and colistin with recommended maximum dose regimens (10mg/kg every 8h for meropenem, 200mg/kg every 12h for fosfmycin and 5mg/kg per day for colistin, respectively) [13-21] were tested to compare with the final PTAs for four common used combination therapies.
Results: Mean PTA values for the combinations AMP-GEN, AMX-AMK, CAZ-AMK, TAP-AMK were 67.5%, 56.5%, 96.4% and 87.5%, respectively. A reasonable association between mean PTA values and observed survival rates was found except for AMP-GEN. The distributions of PTA values across all individuals showed a large spread, in particular for AMP-GEN and AMX-AMK. This spread was related to high rates of resistance against these antibiotics and major differences in dosing schedules used across study sites.
Meropenem, fosfomycin and colistin have been proposed as potential alternatives to currently recommended combinations, In our simulations, all three antibiotics show high expected mean PTA values of 100% (range 98.3 – 100%) for meropenem, 96.6% (range 66.6 – 98.3%) for fosfomycin, and 97.0% (range 95.1 – 98.5%) for colistin.
Sensitivity analyses showed that a number of necessary assumptions made regarding patient characteristics did not result in statistically significant differences in simulated PTA values.
Conclusions: We performed PK/PD simulations to compute PTA values for individual neonates in LMICs who received four of the most commonly used antibiotic combinations, and compared expected PTA of these four combinations against three potential alternatives. This model-based simulation may guide the optimization of antibiotic treatment regimens for neonatal sepsis.
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Reference: PAGE () Abstr 9306 [www.page-meeting.org/?abstract=9306]
Poster: Drug/Disease Modelling - Infection