Methodology Used to Assess Acceptability of Oral Pediatric Medicines: A Systematic Literature Search and Narrative Review
Regulatory guidelines require that any new medicine designed for a pediatric population must be demonstrated as being acceptable to that population. There is currently no guidance on how to conduct or report on acceptability testing.
Our objective was to undertake a review of the methods used to assess the acceptability of medicines within a pediatric population and use this review to propose the most appropriate methodology.
We used a defined search strategy to identify literature reports of acceptability assessments of medicines conducted within pediatric populations and extracted information about the tools used in these studies for comparison across studies.
In total, 61 articles were included in the analysis. Palatability was the most common (54/61) attribute measured when evaluating acceptability. Simple scale methods were most commonly used, with visual analog scales (VAS) and hedonic scales used both separately and in combination in 34 of the 61 studies. Hedonic scales alone were used in 14 studies and VAS alone in just five studies. Other tools included Likert scales; forced choice or preference; surveys or questionnaires; observations of facial expressions during administration, ease of swallowing, or ability to swallow the dosage; prevalence of complaints or refusal to take the medicine; and time taken for a nurse to administer the medicine.
The best scale in terms of validity, reliability, feasibility, and preference to use when assessing acceptability remains unclear. Further work is required to select the most appropriate method to justify whether a medicine is acceptable to a pediatric population.
Many different methods to assess the acceptability of pediatric medicines have been described in the literature; however, this lack of standardization in approach and methodology makes comparisons between products complex.
Few studies have defined criteria that define acceptability of a product to a pediatric population.
Simple 5-point hedonic scales or visual analog scales are appropriate to evaluate acceptability provided the anchor phrases are meaningful to participants.
Further work is required to define the most appropriate methodology to use when ensuring medicines are acceptable to pediatric populations.
Pediatric formulation development is currently a “hot” topic within the pharmaceutical industry, and substantial efforts are being invested into developing medicines that are acceptable to children. Making medicines acceptable to children is a challenge but is critical in ensuring adherence to treatment. The palatability of pediatric medicines is one of the most important formulation factors with the potential to influence adherence to therapeutic regimens and outcomes . It has been demonstrated that making medications more pleasing to the child can have a positive effect on compliance . Acceptability has previously been defined as “an overall ability of the patient and caregiver (defined as “user”) to use a medicinal product as intended (or authorized),” which often encompasses taste and palatability . The European Medicines Agency (EMA) has issued guidance that requires acceptability to be assessed (preferably in children), yet guidance on the methodology that should be used for this evaluation is lacking . Palatability is defined as acceptable to the mouth and incorporates textural and olfactory attributes as well as taste. EMA guidance on the palatability of veterinary products proposed that voluntary acceptance rates should be >80% in dogs and >70% for all other species . The lack of a standardized method to assess acceptability of pediatric medicines has been highlighted previously [3, 6].
A key barrier in the development of acceptable age-appropriate medicines is the lack of knowledge about what is currently considered to be acceptable to pediatric patients and how the acceptability of a new product should be assessed. In support of the development of guidance on appropriate methodology to use when assessing acceptability, this paper provides a systematic review of peer-reviewed literature on acceptability and preference testing of medicines in children.
Information on methodology to assess acceptability of medicines in pediatric populations was sought from a literature search. Overall, the methods for the search protocol were informed by the Cochrane Handbook for Systematic Reviews of Interventions . This review was limited to acceptability testing of oral dosage forms in pediatric populations.
The literature search identified indexed publications by searching Scopus, PubMed, Embase, and MEDLINE databases up until May 2016. Search keywords included acceptability OR preference AND medicine AND (child OR infant OR pediatric OR pediatric) AND palatability OR taste OR smell OR size OR shape OR appearance OR swallowability. The search profile is provided in the Electronic Supplementary Material (ESM) 1.
The process used to identify the most relevant research included screening titles and abstracts, selecting studies based on inclusion criteria with checks from a second reviewer, searching reference lists of included studies, contacting experts for the details of any unpublished or ongoing studies (European Paediatric Formulation Initiative [EuPFI] network (http://www.eupfi.org) and consortium members within Smart Paediatric Drug Development-UK, accelerating paediatric formulation development (SPaeDD-UK; http://www.paediatricscienceuk.com), and, finally, data extraction using a bespoke data extraction table.
Only papers including information specifically related to methodology when assessing the acceptability of medicines in pediatric populations were extracted and included in the results; many papers described the acceptability of dosage forms but did not contain sufficient details on the methodology and therefore were not included.
The SPaeDD-UK project is guided by a steering committee with pharmaceutical scientists from academia and UK industry; this committee provided valuable input throughout the development of this review.
3 Results and Discussion
3.1 Study Characteristics
A total of 61 unique papers were included in this review; this compares with 31 papers in a previous review on palatability only  (17 related to acceptability not limited to palatability and 14 on palatability). All papers included measured the acceptability of medicines in a pediatric population; one paper included data pooled from adults and children as the authors found the results to be similar across these groups . The age of participants ranged from 0 to 18 years across all studies, with more than two-thirds of studies involving only those aged ≤12 years (full details are available in ESM 2). A total of 15 studies included participants whose ages spanned at least 10 years; this may lead to variability in data capture because of the different cognitive functions of younger versus older participants within these studies. Only one study reported using age-based scales to assess acceptability: a simple scale was used for those aged 3–5 years and an alternative was used for those aged 6–15 years .
In total, 147 products were evaluated, although some duplications were found. A table of all studies included is available in ESM 2. Brand names were rarely reported within the literature, which limited direct comparison between studies; it is already known that therapeutic equivalents can have very different organoleptic properties [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22].
The number of products evaluated by each individual within a study varied from one to five (mean 2.6, median 2) products tasted by each participant. Only two of the studies included a placebo [23, 24].
Palatability with an emphasis on taste was the most common acceptability parameter (54 of 61 studies). Where taste was not assessed, common measures of acceptability included the swallowability of dosage forms [25, 26, 27, 28] or the ease of use of a product [19, 29, 30], with just one study evaluating the volume of liquid swallowed .
3.2 Methodology Used to Assess Acceptability
Scale methods were the most commonly used in assessing the acceptability of medicines in children; this includes direct pediatric reports and reports made by parents/carers or healthcare professionals on behalf of children. Visual analog scales (VAS) and hedonic scales were used separately as well as in combination in 32 studies: hedonic scales without VAS in 16 studies and VAS alone in five studies. Eight studies used a Likert scale alone or based on a question (e.g. 5-point scale from 0 = disliked the taste a lot to 4 = liked the taste a lot ). Five studies used a forced-choice or preference between multiple products to rank their order in terms of acceptability. Surveys or questionnaires were used in eight studies. A range of other methods were reported, including observation of facial expressions during administration; ease of swallowing or ability to swallow the dosage form [26, 27]; prevalence of complaints or refusal to take the medicine ; and time taken for a nurse to administer the medicine, where 60 s was taken as the average administration time .
Using observations to assess swallowing seems to be a recent addition to the battery of tests available to assess acceptability, whereas Likert scales have become less popular with time.
3.2.1 Hedonic Scales
Although adult sensory studies typically use a 9-point hedonic scale, it has been suggested that fewer points are more appropriate for children, with 5-point hedonic scales being suitable for children aged ≥4 years . The number of faces within hedonic scales used to assess acceptability of medicines varied from two  up to seven . Sex-specific scales were identified [35, 36, 37], but in most cases were gender neutral. The 5-face hedonic scale was most popular and used in 12 studies, four faces were used in two studies, and two and seven faces were used in one study each. The 2-face scale was used specifically in a young population aged 3–5 years as a subset of a larger study that used four faces in children aged 6–15 years . It has been suggested that the inclusion of a middle response in scale-based questions can often be selected as an “easy way out” and prevents thought being put into the question being asked . However, a neutral face seems appropriate in determining what is acceptable (and not necessarily liked).
Hedonic scales are used with verbal descriptors for children in the sensory evaluation of food. Chen et al.  showed that three faces with verbal descriptors could be used with children aged 3–4 years, five faces in those aged 4–5 years, and a 7-point version with children aged >5 years .
Hedonic scales provide categorical data, which can limit the number of statistical tests that can be applied, although the more points on the scale the better the tool will be. Chi-squared statistical analysis is used to determine whether differences are observed between two products assessed. They have proven useful for young children, although it is critical that the facial expressions be meaningful to the participants. These tests rely on a comparison of two products to determine whether the score for one product differs from that for the control.
Hedonic scales have been demonstrated to be appropriate for use in sensory testing with children aged >4 years . There are also reports of parents interpreting the behavior of a toddler as he/she tasted the food and reporting the child’s acceptance on a hedonic scale . Several acceptability studies used hedonic scales with children as young as 3 years [10, 13, 18, 41, 42, 43].
Age-appropriate VAS and hedonic scales are widely used in the assessment of pain in pediatric populations, and these are often used as the basis for other scales of this type. The Wong–Baker FACES Pain Rating Scale has been extensively used in children to rate pain severity and has been validated outside the emergency department, mostly for chronic pain . This validated scale includes six faces and reads from “no pain” (positive happy face) at the left to “most painful” (negative sad face) at the right. The 9-point hedonic scale is the most commonly used scale in adult consumer preference and acceptability of food tests; studies investigating whether structural differences (e.g. whether scales read from positive to negative or vice versa) showed no differences . In this review, taste scales in 22 studies were structured from negative (sad face) to positive (happy face), whereas scales in five studies were structured from positive (happy face) to negative (sad face).
Overview of hedonic scales used in acceptability studies in children
Two sex-specific 5-face hedonic scales used in children aged 4–8 years to assess palatability of antibiotic suspensions
Male faces were shown to male subjects and female faces to female subjects
The expression change was demonstrated by changes in the eyes, eyebrows, and mouth
The age of the child images reflected the age of the participants
The scale direction was positive at the left and negative at the right
A 5-face hedonic scale used to assess palatability of a range of medicines in children aged 3–16 years
The faces were gender neutral with no hair; the only expression change was the mouth
The scale direction was negative at the left and positive at the right
A 5-face hedonic scale used to assess the palatability of a modified-release granule formulation of valproate
The faces were gender neutral with no hair; the expression change was demonstrated by changes in the eyes, eyebrows, and mouth. The negative face showed tears, and the most positive face was winking
The scale direction was negative at the left and positive at the right
A 5-face hedonic scale proposed as the best practice scale for assessing palatability of pediatric medicines by the Global Alliance for Pediatric Therapeutics, a public–private consortium under the guidance of the Institute for Pediatric Innovation
The faces were gender neutral with no hair; the expression change was demonstrated by changes in the eyes, eyebrows, and mouth
The scale direction was negative at the left and positive at the right
Two hedonic scales used to assess the acceptability of a micro-granule formulation of sodium valproate
Children aged 3–5 years used a 2-face scale and those aged 5–14 years used a 4-face scale
The faces were gender neutral with short hair; the expression change was demonstrated by changes in the eyes and mouth. The negative face showed tears
The scale direction was negative at the left and positive at the right
3.2.2 Visual Analog Scales (VAS)
VAS require respondents to select a point on a straight line (usually 100 mm) to represent the dimension of agreement with statements written beneath the line (“anchor phrases”). They have been extensively researched in the assessment of pain and show good sensitivity and validity for most children aged ≥7 years [54, 55]. They have been used to assess the acceptability of a medicine in children as young as 5 years .
List of phrases used in visual analog scales to assess acceptability of medicines in children
From “I did not like it” to “I liked it very much”
From “Did not like at all” to “Liked very much”
From “I find it very easy to use this medicine” to “I find it very difficult to use this medicine”
From “Nice taste” to “Foul taste”
From “Really good” to “Really bad”
From “Bad” to “Good”
From “Very poor taste” to “Very good taste”
From “Very much unpleasant, bothersomea” to “Not at all unpleasant, bothersomea”
3.2.3 Combined VAS and Hedonic Scales
Combining VAS with hedonic scales uses facial expressions in place of or as well as anchor phrases to generate a tool that is meaningful to participants. In the studies that reported using a combination of VAS and hedonic scales, five faces were most popular, with ten studies using this combination. One study used ten faces  and another used two faces in combination with a VAS . One study used a VAS and a hedonic scale, but provided no further details .
Combining a VAS with hedonic images means that both categorical and continuous scales are used, which complicates statistical analysis and makes it complex. A participant is likely to select a point on the line that correlates to a face rather than considering the line a continuous scale; therefore, data interpretation is flawed. It is acknowledged that, despite these methodological flaws, this has become common practice in acceptability testing.
The results of an industry survey on tools used to assess palatability and swallowability also reported that 5-face hedonic scales and VAS were most popular; however the survey only received six responses and the data are unclear as to whether the scales were used in combination .
3.2.4 Observations of Acceptability
Observations of facial reactions have been used in acceptability testing of medicines [53, 60, 63]. Moniot-Ville et al.  used simple researcher observation of a child: if the child smiled whilst taking the medicine, it was rated as good or fairly good; if the child accepted the medicine without making faces, it was rated as acceptable; and if the child made faces or complained about the taste, it was rated as poor. Verrotti et al.  queried parents about their child’s reaction or facial expression as a surrogate for palatability, asking “On the basis of reaction/facial expression of your child, do you think that the medication is: pleasant, not sure or unpleasant?”
Three studies that investigated the use of mini-tablets in children used observations to assess acceptability, where swallowing of the dosage form, even with chewing, was reported as an acceptable formulation [26, 27, 28].
Other studies used parent-reported outcomes of acceptability; observations of behavior and facial expressions were likely to form the basis for this but was not explicitly stated [14, 17, 19, 57, 61, 64, 65, 66].
Very badly accepted/unacceptable: child showed great displeasure compromising use of formulation.
Badly but accepted: child showed displeasure with dosing but could be coaxed to take complete dose.
Neither good nor bad: child showed no apparent displeasure and with little effort was coaxed to take complete dose.
Well accepted: child appeared to enjoy the formulation and with little coaxing ingested most of dose.
Very well accepted: child appeared eager and ingested most of dose without special coaxing.
3.2.5 Other Tools Used to Assess Acceptability
Likert scales (verbal or written categorical response scales) have also been used in the evaluation of acceptability of pediatric medicines. In many cases, Likert scales were combined with facial expressions or used within a questionnaire with responses such as “1 = very tasty” to “5 = very bitter”  or “0 = disliked the taste a lot” to “4 = liked the taste a lot” .
Some studies also captured spontaneous verbal reactions [12, 18, 21]. These are of value because palatability or acceptability is a subjective measure, and the reasons for non-acceptance are critical in adapting the medicine for that individual. The prevalence of complaints or refusals has also been recorded , and these data are of value because they record the longer-term acceptability or compliance with the medication, which can be essential for therapeutic success. Some studies [23, 48] also recorded the child’s willingness to take the medicine again.
One study recorded the time taken by a nurse to administer the medicine as a surrogate for acceptability .
3.3 Criteria to Define Acceptability
Literature reports of criteria to define acceptability of medicines
Limit of acceptance/palatability
Products deemed to be acceptable
In a 2-face scale, the positive face was considered acceptable = score >1/2
In the 4-face scale, the two positive faces were considered acceptable = score >2/4
33–43% of children found the sodium valproate syrup acceptable
77–88% of children found the sodium valproate sustained-release granule acceptable
In a 5-point scale, neutral to positive was recorded as acceptable = score >2/5
17/22 (77%) participants reported that the taste was neutral to positive, which was considered to be acceptable
Excellent palatability = mean score of 4.21/5
The amoxicillin reference product was stated to have excellent palatability
Acceptable taste = mean score of 3.4/5
Unacceptable taste = mean score of 2.1/5
Two products were included that were stated to be acceptable and unacceptable in terms of taste. The acceptable taste was brand W penicillin; the unacceptable taste was brand U penicillin
Primary endpoint was percentage of participants with a score >4/7
85.3 and 49.0% of subjects found the strawberry-flavor and the orange-flavor lozenge to be acceptable, respectively
50-mm point on a 100-mm VAS considered ambivalent taste, scores >50 mm are palatable
Paracare double-strength paracetamol was considered palatable and acceptable vs. Parapaed
A child accepting the drug without making faces or smiling whilst observed taking the medicine
70.5% of children accepted roxithromycin tablet for suspension
Observations were used to assess swallowing of the dosage form. Swallowing the dose, even with chewing, was considered an acceptable formulation
Mini-tablets 2–3 mm in diameter were acceptable to children ≥6 months. When suspended in jelly, up to ten mini-tablets were acceptable as a single dose
Carers needed to state that the product was equally or more acceptable to their child than other medicines (70% of population agreeing was used as basis for statistical powering)
93.1% of the treated children thought that zinc tablets were equally or even more acceptable than other medicines; 83.5% of caregivers stated they would use these tablets again
A more detailed definition of acceptability used descriptors aligned to a hedonic scale to classify medicines as unacceptable to very well accepted ; these descriptors of acceptability ensured that participants, in this case parents, were aware of the parameter under evaluation. A simple report based on caregivers’ reports of their child and their perception of the taste being better than, the same, or worse than other medicines has also been reported . Proxy reports by parents or carers on the acceptability of a medicine may be a useful method to triangulate patient responses from VAS or hedonic scales to assess the validity of such scales.
In veterinary medicine, non-acceptance is characterized as delayed uptake, partial uptake, regurgitation, spitting out the product, or direct refusal . Other reports of rejection behaviors in sensory testing include a child closing their mouth firmly, pushing the food/drink away, crying, or spitting out the tastant [69, 70].
3.4 Statistical Methodology in Acceptability Assessment
The evaluation of acceptability needs to be underpinned by robust statistical methodology. However, reports of the application of statistics to acceptability testing or of an up-front definition of the hypothesis or criteria for acceptance have been very limited, as reported in Table 3. Existing criteria for acceptance are somewhat limited. A value of 80% of the sample population in agreement that the product is acceptable is generally considered to be the current standard requirement. This 80% threshold value was used in proposed regulatory guidelines on the demonstration of palatability of veterinary medicinal products, which may be similar to considerations given to the palatability of medicines for human use . The choice of sample size is complex in this type of analysis, as previously highlighted in the literature on consumer rejection threshold values in sensory assessment .
The size of the study population in this review varied from 10 to 769 participants evaluating each product (average 112.6, median 46). EMA veterinary guidance on palatability proposed a sample size of 50 animals if the product is only observed once or 25 if the product is administered at least twice; the statistical justification for this is not recorded, but the sample sizes are similar to those used in sensory analysis for acceptance . Use of the total number that accept a product is more robust than providing a mean VAS or hedonic score; a mean value may not accurately reflect the extremes within the population. The sample size used in sensory testing is also widely debated and depends upon the methodology used and the ultimate endpoint. A sample size adequate enough to allow the documentation of clear sensory differences in foods when performing discrimination tests is 25–40 participants . Nevertheless, some discrimination tests can be performed with as few as six participants if differences between samples are large and panelists are trained .
In sensory testing conducted in adults, assessment of differences in two products using either hedonic scales or VAS will depend upon the size of difference considered significant as well as the competence of the assessors . Statistical analysis is typically via a t test for two items and an analysis of variance (ANOVA) for more than two. A significant ANOVA result may be compared using an appropriate post hoc test depending upon the distribution of data. In cases where different groups of participants are trying different products, a simple chi-squared test can be performed.
Studies have reported the statistical parameters used when comparing the tastes of more than one sample. For example, when assessing acceptability of zinc dispersible tablets, Nasrin et al.  proposed a sample size of 140 children per group to identify a ±7.5% difference in acceptability when acceptability was set at 70% with a level of confidence of 95%; this study required parents to report whether the medicine was better than, the same as, or worse than other medicines, with responses indicating “the same” or “better than” being recorded as acceptable. Thompson et al. , proposed using a non-inferiority test to a reference product where, to achieve a significance level of 0.05, a sample size of 50 subjects was required based on a VAS scale, although the basis for this methodology is missing from the original report. The most important aspect is the clinical significance of a change, which needs to be considered as it is feasible that both the reference and the sample product are either acceptable or unacceptable depending on the values of the scale. This has previously been observed using pain scales: does a reduction in the level of a child’s pain from eight to seven following an intervention necessarily represent treatment success?
Many different measurements have been used to assess the acceptability of medicines designed for children; however, no standardized methodology has been identified, and the wide range of ages and products requiring evaluation may mean it is not possible to do so. It is important that a scale to assess acceptability is suitable for that intended purpose.
Developmentally and culturally appropriate to participants (i.e., within the child’s cognitive and language skills).
Easily and quickly understood by participants who have minimal formal education.
Well-liked by participants and clinicians.
Places low burden on clinician and participant.
Inexpensive and easy to obtain, reproduce, and distribute to clinicians, participants, and their families.
Existing VAS and hedonic scales are likely to be preferred by those administering and undertaking the evaluation because they meet the criteria outlined above. The use of space, graphics, underlining, bold type, color, shading, and other design qualities can affect how participants react to and engage with a questionnaire . It is important that the images used are meaningful to participants. It has been reported that children prefer hedonic scales to VAS when given a choice .
A definition of the meaning of “acceptable” in a clinical setting as well as that provided is required to drive the development of the most appropriate scale such that the sample size, statistical analysis, and endpoints allow classification of the medicines being tested as either acceptable or not. This may be linked to the use of a standardized control, for example, in taste evaluation, whether the medicine under test is better or worse than the control. A standardized methodology would allow better comparisons of acceptability across studies, enable comparisons of products to define which are better accepted within a given population, and would provide a better link to clinical relevance. Such methodology would be beneficial both to those working in the development of pediatric medicines and to regulators involved in the approval of pediatric medicines. The tool to assess acceptability may influence the overall results; therefore, the definition needs to be related to the tool under use. Using the existing definition of acceptability, “an overall ability of the patient and caregiver (defined as “user”) to use a medicinal product as intended (or authorized)” , observations are a useful part of the overall toolkit that should be used to assess acceptability.
The best scale in terms of validity, reliability, feasibility, and preference remains unclear. Current practice demonstrates that hedonic scales and VAS are most commonly used and seem appropriate at this stage. Further work required in this area includes an evaluation of an appropriate standardized scale within the relevant population to ensure descriptors are meaningful and that the resulting data are reliable rather than developing new scales, as so many already exist.
Compliance with Ethical Standards
This project was supported by Innovate UK Formulated Products Collaborative R&D project (Ref: 101709). SPaeDD-UK (Accelerating Paediatric Formulation Development through Smart Design and Predictive Science), which is co-funded by Innovate UK and the contributing companies of AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Juniper Pharmaceuticals, and Pfizer.
Conflict of interest
PM and HB have no conflicts of interest.
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