Global antibiotic dosing strategies in hospitalised children: Characterising variation and implications for harmonisation of international guidelines

Abstract

Background: Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in antibiotic dosing using data from five global point prevalence surveys.

Methods & findings: Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed. For each antibiotic, we identified standard doses given as either weight-based doses (in mg/kg/day) or fixed daily doses (in mg/day), and investigated the pattern of dosing using each strategy. Factors underlying observed variation in weight-based doses were investigated using linear mixed effects models. Weight-based dosing (in mg/kg/day) clustered around a small number of peaks, and all antibiotics had 1-3 standard weight-based doses used in 5%-48% of doses. Dosing strategy was more often weight-based than fixed daily dosing for all antibiotics apart from teicoplanin, which had approximately equal proportions of dosing attributable to each strategy. No strong consistent patterns emerged to explain the historical variation in actual weight-based doses used apart from higher dosing seen in central nervous system infections, and lower in skin and soft tissue infections compared to lower respiratory tract infections. Higher dosing was noted in the Americas compared to the European region.

Conclusions: Antibiotic dosing in children clusters around a small number of doses, although variation remains. There is a clear opportunity for the clinical, scientific and public health communities to consolidate behind a consistent set of global antibiotic dosing guidelines to harmonise current practice and prioritise future research.

Fig 1. Frequency and dosing strategy by antibiotic.

A. Frequency of antibiotic dosing within 24h. Antibiotics are ordered by most common frequency–once per day at the top and 4 times per day at the bottom. Note that frequency once per day includes 5 doses given less than once per day (e.g. every 36h). B. Dosing strategy for each antibiotic. Each dose was assigned to being consistent with dosing by fixed daily dose (FDD), weight-based dose (WBD), both or neither. Antibiotics are sorted by the proportion assigned to a dosing strategy.

Fig 2. Antibiotics showed between one and three peaks (coloured bars) consistent with dosing by standard WBD.

Overlaid are guideline recommendations for IV dosing in children, generally and for priority syndromes (severe infection, pneumonia, sepsis, acute otitis media, pharyngitis, urinary tract infection) from five different guidelines: Blue Book (BlueBk), British National Formulary for children (BNFc), Indian National Centre for Disease Control (NCDC), WHO pocket book (PktBk) and Red book (RedBk). Multiple entries for a single guideline indicate different frequencies of daily dosing, indications (e.g. meningitis) or age/weight group of children. Lines denote recommended range, and dots denote recommended dose. Seven recommendations of fixed daily doses (mainly for larger children) have been converted to relative daily doses. Bars coloured both gray and ranked are due to rounding used to produce graph.

Fig 3. Antibiotics varied in their use of standard fixed doses (FDD).

Black dots show doses in mg shared by at least 5% of children. Grey dots show all other doses–the doses following diagonal lines are constant mg/kg/day.

Fig 4. Effect estimates and 95% confidence intervals of significant effects (p<0.05) from models of standardised WBD for the most common diagnoses.

Models were run separately for each antibiotic and contained the same fixed and random effects for each model. Reference levels for each factor were chosen as the level with the highest proportion of doses (region: Europe, PPS: most recent survey (4th), diagnosis: bacterial LRTI, empiric: empiric, sex: male). CNS: central nervous system infection; CRBSI: catheter related blood stream infection; FN: febrile neutropenia; GUTI: gastro-intestinal tract infections; SSTI: skin and soft tissue infections; Dis: disease; UTI: urinary tract infection; HAI: hospital acquired infection; Vent: ventilation; ab: antibiotic; PPS: point prevalence survey; SE: south-east; W: west.