This report was reviewed for medical and scientific accuracy by Amisha Malhotra, MD, Assistant Professor of Pediatrics, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Perspective

Selection of antibiotic therapy for a child necessitates the consideration of several factors. First and foremost is the efficacy of the antibiotic in eliminating the offending pathogen. The propensity of an antibiotic to produce adverse or toxic effects is also crucial. After the antibiotic's efficacy and adverse event profile, clinicians must consider the likelihood of compliance. It is frustrating for physicians to learn that poor compliance has undermined the potential therapeutic benefit of a medication, thus it is an important factor in determining therapeutic choices.

Because children frequently experience difficulty swallowing tablets or capsules, bacterial infections are often treated with suspensions. From the child's perspective, compliance with a medication is largely determined by its palatability, and perhaps also by its smell or appearance. Medication palatability and patient acceptance are essential for compliance.^1-3 Parents are all too familiar with the challenge of cajoling a child into swallowing a bad-tasting medication. This influences physicians' and parents' preferences for therapy.^4,5 Several other factors can influence compliance in children. The nature of the illness, quality of rapport between physician and parent, and various social and cultural factors may positively or negatively affect compliance.

While the efficacy and safety of antibiotics are thoroughly tested before they are approved by the Food and Drug Administration, the palatability of these medications is less well studied. This Pediatric Press Newsletter reviews data relevant to the assessment of palatability and patient acceptance to a variety of antibiotic suspensions available to the physician.

Factors Associated with Poor Compliance in Children Prescribed Antibiotics

The identification of factors leading to poor compliance in taking medications by children is an important first step to improving clinical outcomes. Mattar and colleagues evaluated the compliance of 100 children who were prescribed antibiotic therapy for acute otitis media.⁶ The subjects were children aged 1 to 12 years, each prescribed a 10-day course of oral antibiotics and/or an oral decongestant. Parents of the children were asked to bring all bottles of medication to the follow-up visit, at which time the parents were interviewed with a standard questionnaire and the bottles of medication examined. Compliance was measured as the number of full days' worth of medication taken during the 10-day period.

The overall compliance rate was poor, with only 5 (5%) children completing the full course of medication in 10 days. Fifty-nine (59%) patients took less than half of the medication.

Several factors were identified as contributing to poor compliance. Most parents had incomplete knowledge of the medication, with only 4 of the 100 families able to correctly identify the medications and state their purposes. Only 20 families used calibrated medicine vials to measure the correct dose of medication. Thirty-six families found it challenging to administer a medication 4 times a day for 10 days. It was reported that parents of 40 (40%) children had difficulty giving the medications with 19 (19%) children spitting the doses back; several having problems with taste. In addition to identifying palatability of the medication as a contributing factor to compliance, the importance of detailed therapy instructions to patients and their caretakers was recognized.

Recognizing the significance of poor compliance contributing to poor clinical outcomes, two well-respected studies looked at factors that affect compliance.

Selection of Therapy: Issues Related to Compliance

A great deal of effort in developing antibiotic suspensions is expended by pharmaceutical companies on the palatability of these agents. In order to evaluate the taste of 11 commonly used antibiotic suspensions, Steele and colleagues assessed the opinions of 86 physicians and healthcare personnel regarding variables contributing to the selection of antibiotics for children.⁷ Specific variables evaluated were palatability, cost, duration of therapy, and dosing interval. Suspension characteristics that were evaluated included appearance, smell, texture, taste, and aftertaste.

Amoxicillin (Amoxil) served as the standard to which the other antibiotics were compared, chiefly due to its good taste, low cost, and widespread use for treating otitis media in the pediatric population. In addition to amoxicillin, evaluated antibiotic suspensions included cefdinir (Omnicef), trimethoprim-sulfamethoxazole (Bactrim, Septra), trimethoprim (Primsol), cefpodoxime (Vantin), azithromycin (Zithromax), cefuroxime (Ceftin), clarithromycin (Biaxin), cefixime (Suprax), loracarbef (Lorabid), amoxicillin/clavulanate (Augmentin), and ciprofloxacin (Cipro). Individuals with a history of allergy to any of the antibiotics, pregnant women and those with upper respiratory infections (altered smell or taste) were excluded from participation. Before evaluating the antibiotics, each participant spent time briefly discussing the implications of cost, duration of therapy and dosing intervals in the selection of antibiotics.

All of the antibiotic suspensions were reconstituted and randomly assigned numbers by the investigators to ensure blind evaluation with the exception of amoxicillin since it was used as the basis of comparison. The participants evaluated amoxicillin first and then one of the other suspensions until each participant had compared amoxicillin with all 11 of the other suspensions. Participants were encouraged to frequently re-evaluate amoxicillin to reinforce the taste and physical characteristics of the standard.

The participants first evaluated the palatability of the antibiotic suspensions. Following previous study designs and echoing the format of wine tasting,⁸ palatability was comprised of taste, aftertaste, appearance, smell, and texture. A scoring scale from 0 to 5 was used, in which 0 or 1 reflected the participant's opinion that compliance with the antibiotic might be very difficult due to the poor acceptability of the product. A score of 2 reflected moderate concern that compliance based on palatability might be poor. Amoxicillin was assigned a score of 3 for all variables as a basis for comparison. An overall palatability score was calculated by assigning extra weight to taste (multiplied by 3) and aftertaste (multiplied by 2) as suggested in an earlier study,⁹ with the other parameters having a weight of 1 each.

After evaluating the palatability of each antibiotic suspension, the participants were presented with the cost of the antibiotic. They then gave a new palatability score, adjusted for cost. In addition, the participants also gave scores for each antibiotic adjusted for treatment duration (5 vs 10 days) and dosing interval (once or twice daily vs 3 or 4 times daily; once vs twice daily). Loracarbef, cefdinir, and cefixime suspensions had the highest overall palatability scores (average of 3.25, 3.00, and 2.77, respectively) (Table 1). Thus, loracarbef and cefdinir were the only suspensions rated as palatable as or more palatable than amoxicillin (P = NS).

Seven of the antibiotics were significantly less palatable than amoxicillin. For the taste component of the overall palatability score, only loracarbef (3.19) and cefdinir (3.12) scored higher than amoxicillin (P = NS) (Table 2).

In terms of the cost-adjusted overall palatability score, loracarbef, cefdinir, and cefixime scored the highest (average of 3.12, 2.87, and 2.64, respectively).

When cost-adjusted overall palatability was adjusted for duration of therapy (5 vs 10 days), the highest rated antibiotics were cefdinir, azithromycin, and loracarbef (average scores of 3.53, 3.16, and 3.12, respectively). With these scores further adjusted for dosing interval (once or twice daily vs 3 or 4 times daily), the same 3 antibiotics prevailed. The average score for cefdinir was 3.88, azithromycin 3.51, and loracarbef 3.47. Adjustment for dosing interval comparing once vs twice daily antibiotics revealed that azithromycin scored the highest at 4.25, with cefdinir second at 3.88, and loracarbef third at 3.47 (P = NS).

The palatability of an antibiotic suspension for children is an important factor to consider when physicians select a therapeutic agent. Consideration of cost, duration of therapy, and dosing interval also influences the selection of antibiotic treatment. But, the successful treatment of pediatric infections is determined primarily by the efficacy of the antibiotic. Previously published studies evaluating azithromycin and loracarbef in otitis media infections with sensitive and resistant organisms has suggested a suboptimal response,^10,11 which may partially negate the favorable profile characterized in this study. Of the antibiotic suspensions that were judged favorably to amoxicillin, cefdinir represents an effective, palatable antibiotic choice for children. Its palatability may improve compliance in children when taste is an issue.

Consistency in Palatability Evaluations

Six randomized, single-blind, crossover trials compared the taste and smell of cefdinir oral suspension with suspensions of amoxicillin/clavulanate, cefprozil (Cefzil), and azithromycin.¹² Each medication comparison was conducted in a single, as well as multiple centers.

A total of 715 healthy volunteer boys and girls, aged 4 to 8 years, participated in the trials. Subjects indicated their perception of taste and smell by pointing to a corresponding "smile-face" on a gender-specific visual scale (Figure 1). A score of 5 indicated the antibiotic tasted or smelled "really good," while 4 indicated good. The worst score of 1 indicated "really bad".

Cefdinir was rated superior to amoxicillin/clavulanate in taste. In the single-center trial (N = 90), the taste rating for cefdinir was 4.47 compared to 3.82 for amoxicillin/clavulanate (P = .0222). More subjects rated the taste of cefdinir as "good" or "really good" compared to amoxicillin/clavulanate (91% vs 65%). In the multicenter trial (N = 148), the taste of cefdinir was rated as 4.39 compared to 2.99 for amoxicillin/clavulanate (P = .0001) and more subjects rated the taste of cefdinir as "good" or "really good" (84% vs 45%) (Table 3).

Cefdinir was also rated superior to amoxicillin/clavulanate with regard to smell. In the single-center trial, the smell rating for cefdinir was 4.12 compared to 3.61 for amoxicillin/clavulanate (P = .0041). More subjects rated the smell of cefdinir as "good" or "really good" (72% vs 62%). In the multicenter trial, the smell of cefdinir was rated as 3.92 compared to 3.37 for amoxicillin/clavulanate (P = .0001) and more subjects rated the smell of cefdinir as "good" or "really good" (70% vs 52%).

Cefdinir scored higher than cefprozil in terms of taste. In the single-center trial (N = 95), cefdinir scored 4.55 for taste compared to 3.72 for cefprozil (P = .0001), with more subjects rating cefdinir as "good" or "really good" (91% vs 68%). The multicenter trial (N = 126) yielded similar results. Cefdinir scored 4.25 for taste compared to 3.65 for cefprozil (P = .0010), with more subjects rating cefdinir as "good" or "really good" (81% vs 64%). In terms of smell, there was no statistically significant difference between cefdinir and cefprozil.

In the single-center trial (N = 124) comparing cefdinir and azithromycin, cefdinir was rated superior to azithromycin for taste (4.59 vs 3.86, P = .0001) (Table 4) and smell (4.06 vs 3.79, P = .0188). More subjects rated cefdinir as tasting "good" or "really good" (93% vs 70%) and smelling "good" or "really good" (71% vs 61%) compared with azithromycin. In the multicenter trial (N = 132), there was no statistical difference between cefdinir and azithromycin in ratings for taste or smell.

These data demonstrate that cefdinir suspension was judged to taste better than amoxicillin/clavulanate, cefprozil, and azithromycin, and smells better than amoxicillin/clavulanate and azithromycin.

Conclusion

The palatability of a medication, mostly determined by its taste, is one of many important factors to consider when prescribing antibiotic therapy for children. A good tasting efficacious antibiotic such as cefdinir may enhance compliance thus allowing the full course of therapy to be completed in patients for whom taste and palatability are significant issues. Improving compliance with an efficacious antibiotic is important in facilitating eradication of the bacteria and may help reduce the incidence of antibiotic resistance.

References

1. Boccazzi A, Careddu P. Acute otitis media in pediatrics: are there rational issues for empiric therapy? Pediatr Infect Dis J. 1997;16:S65-S69.
2. Pichichero ME. Empiric antibiotic selection criteria for respiratory infections in pediatric practice. Pediatr Infect Dis J. 1997; 16:S60-S64.
3. Matsui D, Barron A, Rieder MJ. Assessment of the palatability of antistaphylococcal antibiotics in pediatric volunteers. Ann Pharmacother. 1996;30:586-588.
4. Bauchner H, Klein JO. Parental issues in selection of antimicrobial agents for infants and children. Clin Pediatr. 1997; 36:201-205.
5. Bauchner H, Adams W, Barnett E, et al. Therapy for acute otitis media: preference of parents for oral or parenteral antibiotics. Arch Pediatr Adolesc Med. 1996;150:396-399.
6. Mattar ME, Markello J, Yaffe SJ. Pharmaceutic factors affecting pediatric compliance. Pediatrics. 1975;55:101-108.
7. Steele RW, Thomas MP, Begue RE. Compliance issues related to the selection of antibiotic suspensions for children. Pediatr Infect Dis J. 2001;20:1-5.
8. Ruff ME, Schotik DA, Bass JW. Antimicrobial drug suspensions: a blind comparison of taste of fourteen common pediatric drugs. Pediatr Infect Dis J. 1991;10:30-33.
9. Steele RW, Thomas MP, Begue RE, et al. Selection of pediatric antibiotic suspensions: taste and cost factors. Infect Med. 1999; 16:197-200.
10. Dagan R, Leibovitz E, Fliss DM, et al. Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute otitis media in infants and young children. Antimicrob Agents Chemother. 2000;44:43-50.
11. Thorburn CE, Knott SJ, Edwards DI. In vitro activities of oral β-lactams at concentrations achieved in humans against penicillin-susceptible and -resistant pneumococci and potential to select resistance. Antimicrob Agents Chemother. 1998;42:1973-1979.
12. Powers JL, Gooch WM, Oddo LP. Comparison of the palatability of the oral suspension of cefdinir vs amoxicillin/ clavulanate potassium, cefprozil and azithromycin in pediatric patients. Pediatr Infect Dis J. 2000;19:S174-S180.

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Disclosure
Amisha Malhotra, MD
No significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Abbott Laboratories.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Pediatric Press Newsletter does not include discussion of treatment and indications outside of current approved labeling. This Pediatric Press Newsletter was made possible through an educational grant from Abbott Laboratories.

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