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Height-Based Azithromycin Treatment for Pediatric Trachoma
Author Response: Height-Based Azithromycin Treatment for Pediatric Trachoma
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Eva V. Basilion International Trachoma Initiative, Jeffrey W. Mecaskey, Charles Knirsch
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ebasilion{at}aol.com Eva V. Basilion, et al.
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In their recent article, Muñoz et al.1 present a single height-based dosage schedule for the treatment of pediatric trachoma with azithromycin based on tolerance limits of 15-30 mg/kg and a half-tablet increment of delivery. While a standardized height schedule that can be applied to several populations represents a significant step forward in the treatment of children with trachoma, this analysis does raise two concerns. Since the time this work was conducted, new data have demonstrated that azithromycin is safe at higher single dosages (30 mg/kg) than previously documented and make possible further treatment schedule improvements.2 Increasing the treatment range with higher dosages decreases the proportion of children receiving dosages less than the target dosage of 20 mg/kg, reducing the possibility of sub-therapeutic dosage regimens. Currently, no published data exists to support the efficacy of dosages as low as 15 mg/kg. The wider treatment range afforded would also obviate the need to split tablets in half, a practice that is inaccurate, time-consuming, and one that may significantly alter the pharmacokinetic properties of the whole tablet preparation. Zithromax® tablets, an improved dosage form relative to capsules, do not exhibit a pharmacokinetic food effect and are the formulation used in the International Trachoma Initiative donation program. Data from food effect studies from the capsule formulation raise concern about altering the integrity of capsule or tablet formulations.3 In vitro, azithromycin degrades relatively quickly to des-cladinose azithromycin (DCA) in low pH human gastric fluid (half-life 27 minutes at 37 °C). Exposing azithromycin to gastric acid by splitting tablets may result in sub-therapeutic dosing regimens. While lauding the work of Muñoz et al. toward the development of a standard treatment schedule, we felt it important to present this information. A treatment schedule that avoids the risks associated with both sub-clinical dosages and half-tablet delivery increments will be a significant improvement over the schedule presented in this paper. Eva V. Basilion
Jeffrey W. Mecaskey
Charles Knirsch
References 1. Muñoz B, Solomon AW, Zingeser J, et al. Antibiotic dosage in trachoma control programs: height as a surrogate for weight in children. Invest Ophthalmol Vis Sci. 2003;44:1464-1469. 2. Pfizer, Inc. Zithromax® Product Insert. 2002. 3. Foulds G, Luke D, Willavize S, et al. Effect of food and formulation on bioavailability of azithromycin. In: SH Zinner, ed. Expanding Indications for the New Macrolides, Azalides, and Streptogramins. Marcel Dekker Press; 1997:469-473. |
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Sheila K. West Johns Hopkins Hospital, Wilmer Eye Institute, Beatriz Muñoz
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shwest{at}jhmi.edu Sheila K. West, et al.
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We thank Basilion et al. for pointing out the potential problems of splitting the tablets into 125 mg doses, which improves dosing within the tolerance limits. The trade-off is the imprecision in dosing children at the lower weights if 250 mg tablets are used. For example, a 13 kg child will need 260 mg to stay above 20 mg/kg; one 250 mg tablet will be an underdose at 19 mg/kg, and two tablets will be an overdose at 38 mg/kg. Basilion et al.1 recognized the problem as well, as their article used 125 mg tablets assumptions, but did not describe splitting the tablets to achieve that level of precision. As Basilion et al. know, the side effects of azithromycin such as diarrhea are dose related, increasing in frequency as the dose increases. We chose (as they did in their article) the upper bound of 30 mg/kg to be conservative, and presented an alternative using an upper bound of 35 mg/kg. Interestingly, the lower bound we chose, 15 mg/kg, was supplied to us by representatives of Pfizer and International Trachoma Initiative. These concerns do not affect our basic modeling approach for constructing the best fit of height to weight for multiple country settings, which can be used to construct dosing tables using any set of tolerance limits and tablet/half tablet constraints. If we use the suggestion of 20-35 mg/kg and 125 mg increments (allowing ½ tablets), as Basilion et al. did, the dosing schedule in Table 1 is easily generated, with slight overdosing of 1.6% of children and underdosing of 1.8% in our data. Table 1. Recommended Azithromycin Dose According to Height Allowing ½ Tablets (125 mg increments).
However, if splitting tablets is not appropriate, 250 mg increments are needed when using tablets. With this approach we will underdose 5.4% of the children and overdose 7.1%. The corresponding dosing schedule is shown in Table 2. Table 2. Recommended Azithromycin Dose According to Height (increments of 250 mg).
This is an area that needs further discussion, as it is not clear that use of 250 mg tablets in smaller children, based on height, is warranted. Sheila K. West
Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD References 1. Basilion EV, Kilima PM, Turner VM, Mecaskey JW. Height as a proxy for weight in determining azithromycin treatment for paediatric trachoma. Trans R Soc Trop Med Hyg. 2002;96:691-694. |
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